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RJ Reynolds

Gloria Scott and Deania Jackson, on Behalf of Themselves and All Other Persons Similarly Attended, Plaintiffs, Vs. The American Tobacco Company, Inc, Et Al, Defendants. Videotape Deposition of: Kenneth Marc Ludmerer, M.D.

Date: 18 Oct 2000
Length: 805 pages
523243351-523244155
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A Williams Roberts Jr & Assoc
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Ludmerer, K.M.
Berzon, A.D.
Hartman, T.
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DEPOSITION
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US Comprehensive Request 215
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1 A P P E A R A N C E S (Continued) : 2 ATTORNEYS FOR DEFENDANT IN THE SCOTT CASE 3 LORILLARD 4 THOMPSON COBURN, LLP One Firstar Plaza 5 St. Louis, Missouri 63101 BY: J. WILLIAM NEWBOLD, ESQ. • • 6 ATTORNEYS FOR THE DEFENDANTS 7 IN THE SCOTT CASE R.J. REYNOLDS AND SELLER 8 BOWLES, RICE & MCDAVID, 9 ORAFFE & LOVE 600 Quarrier Street 10 Charleston, West Virginia 25325-1386 BY: FAZAL SHERE, ESQ. 11 (Via telephone) 12 ATTORNEYS FOR PLAINTIFF BLANKENSHIP 13 SEaAL LAW FIRM 810 Kanawha Boulevard East 14 Charleston, West Virginia 25031 BY: DEBORAH L. MCHENRY, ESQ. 15 (Via telephone) 16 ATTORNEYS FOR DEFENDANT LORILLARD 17 FARRELL, FARRELL & FARRELL 914 Fifth Avenue 18 Huntington, West Virginia 25701 BY: SUSAN MORTON, ESQ. 19 (Via telephone) 20 21 22 23 24 25 A. William Roberts, Jr. & Associates (600) 743-DEPO w
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• . 6 1 My name is Thomas Hartman. I'm the 2 videographer. The court reporter is Abner 3 Berzon. we are associated with the firm of 4 Veritext Court Reporting with offices located at 4 5 Becker Farm Road Roseland, New Jersey. 6 The time is 10:20 a.m. Counsel is 7 going to introduce themselves, after which the 8 court reporter will swear in the witness. 9 MR. EVANS: I'm Jerry Evans with 10 Ness, Motley for the plaintiff in the West 11 Virginia case. 12 MR. MAISTROS: Jack Maistros with 13 the Climaco law firm in Cleveland for the 14 plaintiffs in the Louisiana case. 15 MR. DODDS: My name is William 16 Dodds with Dechert and I represent Philip Morris. 17 MR. NEWBOLD: My name is Bill 18 Newbold with Thompson Coburn in St. Louis 19 representing Lorillard in the Blankenship West . 20 Virginia case. 21 MR. CONOROVE: Tim Congrove of, 22 Shook, Hardy & Bacon, Kansas City, Missouri. 23 We're representing the defendants Philip Morris 24 and Lorillard. 25 MS. COKER: Tammie Coker of Shook, t W1iWsUWWd7 A. William Roberts, Jr. & Associates (800) 743•DEPO W ~ ~I
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1 CIVIL DISTRICT COURT FOR THE PARISH OF ORLEANS STATE OF LOUISIANA 2 1 NUMBER 96-8461 DIVISION "K" DOCKET NO. 4 3 GLORIA SCOTT AND DEANIA JACKSON, 4 on behalf of themselves and all other persons similarly attended, 5 Plaintiffs, 6 vs. 7 THE AMERICAN TOBACCO COMPANY, INC., et al, Defendants., 8 9 IN THE CIRCUIT COURT OF OHIO COUNTY, WEST VIRGINIA IN RE: TOBACCO LITIGATION 10 Civil Action No. 00-C-6000 11 12 VIDEOTAPE 13 DEPOSITION 0F: 14 DATE : 15 TIME: 16 LOCATION: 17 18 REPORTED BY: 19 20 21 22 23 24 II I KENNETH MARC LUDMERER, M.D. Wednesday, October 18, 2000 10:24 a.m. Dechert, Price & Rhoads 30 Rockefeller Plaza New York, New York ABNER D. BERZON, Registered Professional Reporter A. WILLIAM ROBERTS, JR., & ASSOCIATES Charleston, SC Columbia, SC (843) 722-8414 (B03) 731'-5224 Greenville, SC Charlotte, NC ~ 25 (864) 234-7030 (704) 573-3919 A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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• 1 A. Agreeable to me. 2 Q. Good. Dr. Ludmerer, I have been 3 provided with a Cv which bears a date of November 4 1999 and let me ask you: To your knowledge, is 5 this your most current, up-to-date CV? 6 A. That's correct. I simply have not updated 7 it since then. 8 Q. Okay. Well, I am going to ask the 9 court reporter to mark'this as Exhibit No. 1, 10 please. 11 (Plaintiff's Ludmerer 1, Cv, marked ].2 for identification, this date.) ].3 Q. Dr. Ludmerer, can you confirm that ].4 this is your CV? ].5 A. It is. 36 Q. Let me ask you a couple of 17 questions about your education. You''re listed as 18 having an AB degree from Harvard College in 19 History and Science. And I just wanted to 20 clarify. Was that a double degree or is History 21 and Science a particular degree field? 22 A. That was a particular degree field and 23 still is at Harvard College. 24 Q. And also your master's degree from 25 John Hopkins is in History of Medicine? L9W A. William Roberts, Jr. & Associates (800) 743-DEPO
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12 1 Q. And approximately what time period 2 did that cover, the rise and fall of the Eugenics 3 Movement? 4 A. 1870 to the 1930's. 5 Q. And you listed a number of visiting 6 professorships and invited lecturers on your CV as 7 well. And let me just ask you: Did any of those 8 visiting professorships or invited lecturers 9 involve the topic of smoking and health? 10 A. No. ].1 Q. And lastly, I notice a number of 12 publications are listed here. Let me ask you if 13 any of your publications deal with the subject of 14 smoking and health? 15 A. No. 16 Q. Have you brought any documents with 17 you today, doctor? 18 A. No. 19 Q. Do you keep any file of your work 20 on this particular case, the west Virginia medical 21 monitoring case? 22 A. No, I donI t. 23 Q. Any correspondence at all that 24 relates to this case that you have? 25 A. Therets been no correspondence. A. William Roberts, Jr. & Associates (800) 743-DEPO
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2 1 APPEARANCES OF COUNSEL: 2 ATTORNEYS FOR THE PLAINTIFFS IN THE BLANKENSHIP CASE 3 NESS, MOTLEY, LOADHOLT, 4 RICHARDSON & POOLE, ESQS. BY; JERRY HUDSON EVANS, ESQ. 5 28 Bridgeside Boulevard P.O. BOX 1792 6 Mount Pleasant, SC 29465 (843) 216-9000 ATTORNEYS FOR THE PLAINTIFFS 8 IN THE SCOTT CASE 9 CLIMACO, LEFKOWITZ, PECA, WILCOX & GAROFOLI CO., L.P.A. 10 1228 Euclid Avenue, Suite 900 Cleveland, Ohio 44115-1891 11 BY: JACK D. MAISTROS, ESQ. 12 ATTORNEYS FOR THE DEFENDANT IN THE SCOTT CASE 13 PHILIP MORRIS 14 DECHERT, PRICE & RHOADS 30 Rockefeller Plaza 15 New York, New York 10112-2200 BY: WILLIAM K. DODDS, ESQ. 16 (212) 698-3500 17 ATTORNEYS FOR THE DEFENDANT IN THE SCOTT CASE ].8 PHILIP MORRIS AND LORILLARD 3.9 SHOOK, HARDY & BACON L.L.P. 20 21 22 23 24 25 One Kansas City Place 1200 Main Street Kansas City, Missouri 64105-2118 BY: TIMOTHY E. CONGROVE, ESQ. TAMMY B. COKER, ESQ. (816) 474-6550 I A. Willfam Roberts, Jr. & Assoolates (800) 743-DEPO
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1 STIPULATION 2 3 It is stipulated by and among Counsel that this 4 deposition is being taken in accordance with the 5 Federal Rules of Civil Procedure; that all 6 objections as to Notice of this deposition are 7 hereby waived; that all objections except as to . 8 form are reserved until the time of trial; and 9 that this witness has reserved the right to read 10 and sign the deposition after review by counsel. 11 +++** 12 13 THE VXDEOGRAPHER: This is the 14 videotape deposition of Kenneth Ludmerer, M.D. 15 taken by the plaintiff. This is a double 16 litigation case. The first case is "In Re: 17 Tobacco Litigation," In The Circuit Court of Ohio 18 County, West Virginia, No. 00-6000. 19 The second case is entitled, 20 "Gloria Scott and Deania Jackson vs. American 21 Tobacco, Inc., et al," Civil District Court for 22 the Parish of Orleans. This is No. 96-8461. 23 Today's deposition is being'held at 24 30 Rockefeller Plaza New York, New York on October 25 18th, 2000. A. William Roberts, Jr. & Associates (800) 743-DEPO . .........:._.__~ W W N 0
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1 A P P E A R A N C E S (Continued): 2 ATTORNEYS FOR DEFENDANT PHILIP. MORRIS 3 ALLEN, OUTHRIE & McHUGH 707 Virginia street East 4 Charleston, West Virginia 25301 BY: JOHN MCHU(3H, ESQ. 5 (Via telephone) 6 ATTORNEYS FOR DEFENDANTS BROWN & WILLIAMSON 7 JACKSON & KELLY P0 Box 5533 8 Charleston, West Virginia 25322 BY: ROGER WOLFE, ESQ. 9 (V5a telephone) 10 11 12 13 14 A L 6 0 P R E S E N T: THOMAS HARTMAN, Videographer 15 (INDEX AT REAR OF TRANSCRIPT) 16 17 18 19 20 21 22 23 24 25 A. William Roberts, Jr. & Associates (800) 743-DEPO
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1 of Washington. • 2 Q. And let me back up just a bit. we 3 were talking about a number of hours you would 4 spend, and we talked about the Year 2000. Last 5 year, 1999, have you compiled records or can you 6 give me an estimation of the total number of hours 7 you spent in 1999 on tobacco litigation related 8 work? 9 A. I don't recall precisely, but the number of 10 hours involved for the Portland case was 70 or so. 11 Q. Were there any other cases other 12 than the Williams case in Portland? 13 A. That was it. 14 Q. When were you first approached with 15 the idea of doing research for a tobacco related 16 case? 17 A. August of 1988. 18 Q. And by whom? 19 A. Murray Garnick. 20 Q. And he is with what law firm? 21 A. Arnold & Poxter. 22 Q. And that was in connection with 23 what case? 24 A. That was not in connection with any case. 25 Q. Okay. Can you describe for me what A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • • 1 describe his 2 his research 5 mid 1960's." 6 Do the same principles apply to 7 knowledge and belief or do you treat those.two 8 areas somewhat differently? 9 A. No, I'm saying that these are general 10 principles that an historian in medicine or an 23 application of these principles to on the state of scientific knowledge 3 and belief regarding the relationship between ` 4 smoking and health from the early 1900's to the 11 historian of science would take into account into F 12 doing any project in a responsible, scholarly way, 23 whether you're studying the history of an idea, a.` ~ 14 biographical study, the history of an institution, 15 such as a medical school or hospital. My own t 16 particular interest were two recent books, the 17 History of Medical Education in America. But 18 these are general principles that you would apply 19 in any project that you might undertake in the 20 history of medicine. 21 22 23 24 25 qWW I understand that. And I okay Q . . ; take it you have applied those five principles to ; ~ your research in this -- A. Correct. Q. -- matter? E A. William Roberts, Jr. & Assocfates (800) 743-DEPO N to N d' I w W ~ .P
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i . 24 1 A. Those were principles that guided me as I 2 did my day-by-day work, and as I planned the 3 project and as I executed it in 1988 when Murray 4 Garnick contacted me. 5 Q. Since you did use the phrase "the 6 state of scientific knowledge and belief,° I do 7 want to clarify. Are you using that phrase as 8 sort of one unit of information, or have you made 9 a distinction between scientific knowledge and, on 10 the other hand, belief? 11 A. I'm not drawing a strong distinction 12 between knowledge and understanding. You know, 13 certain aspects of science are very factual and 14 other aspects are more conceptual and theoretical 15 and explanatory, but I am not really drawing a 16 strong distinction between those two. 17 Q. Tell me about avoiding hindsight. 18 Can you give me an example of how you applied this 19 principle to some of your research and how you 20 went about specifically attempting to avoid 21 hindsight. 22 A. Well, hindsight is the conceit that we in 23 the present have as we think about the past. And 24 we typically think of -- we tend to believe that 25 the past knew everything we did. You know, we N I A. William Roberts, Jr. & Assoolates (800) 748-DEPO
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• 21 Q. Do you teach any courses in history 22 that do not deal with the history of medicine? 23 A. No. 24 Q. Have you ever? 25 A. No. 10 1 A. Correct. 2 Q. ip that also a separate degree unto 3 itself that would be different from a history 4 degree? 5 A. It's a graduate degree. It's a separate 6 degree. 7 Q. You are currently listed as a 8 professor of medicine and of history at Washington 9 University. Do you currently teach courses in the 10 history of medicine? 11 A. Yes, I do. 12 Q. what's the exact title of your most 13 current courses? 14 A. The most current course in the arts and 15 science campus is a seminar on the History of the 16 American Medical Profession and I'm also teaching 17 a course at the medical school this spring, and, 18 to tell you the truth, I don't remember what we 19 decided to call it, but it has to do with the 20 past, present and future of American medicine. A. William Roberts, Jr. & Associates (800) 743-DEPO Ln N W N H
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• 8 1 K E N N E T H M A R C L U D M E R E R, having 2 first been duly sworn by Abner D. Berzon, a Notary . t 24 feel is appropriate. i 16 understand my question, please let me know. if i 17 you answer, I will assume that you have understood ~ 18 my question. If you need to take a break at any 19 time please let me know and I'll be happy to 20 accommodate you. 21 If I ask a yes or no question, I 22 would appreciate you to begin your answer with a 23 yes or no and then follow with any explanation you 12 Carolina representing the plaintiffs in the West 13 Virginia medical monitoring action. 14 I'm going to be asking you 15 questions today. If at any time you don't 3 Public of the 8tate of New York, was examined and 4 testified as follows: 5 DIRECT EXAMINATION BY MR. EVANS: 6 Q. Good morning, Dr. Ludmerer. Thank 7 you for your patience this morning. It takes a 8 while to get a lot of people on the record and I 9 appreciate your patience. 10 I introduced myself on the record. 11 I am Jerry Evans. I'm from Charleston, South i N 25 Is that agreeable to you, sir? A. William Roberts, Jr. & Associates (800) 743-DEPO 11
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i 41 * * * A. William Roberts, Jr. & Assoaiates (800) 743-DEPO .P 1 Hardy & Bacon, Kansas City, Missouri, for 2 defendants Philip Morris and Lorillard in the 3 Scott case. 4 MR. DODDS: on the phone, could you 5 please enter your appearance. 6 MS. McHENRY: Debora L. McHenry, 7 the Segal Law Firm, representing the plaintiffs in 8 the Blankenship matter in West Virginia. 9 MR. SHERE: Fazai Shere from the 10 law firm of Bowles, Rice & McDavid representing R. 11 J. Reynolds and the Seller defendants. 12 MR. McHUaH: John McHugh from Allen 13 Guthrie & McHugh in Charleston representing Philip 14 Morris in the West Virginia case. 15 MR. WOLFE: Roger Wolfe with 16 Jackson Kelly in Charleston, West Virginia, 17 representing Brown & Williamson. 18 MS. MORTON: Susan Morton with 19 Farrell, Farrell & Farrell in Huntington, 20 representing Lorillard. 21 THE VIDE0f3RAPHER: Swear in the 22 witness. 23 24 25 W " W Ln 00
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• 29 1 cancer. So it is important to point out that 2 cigarette smoking was among those two dozen causes 3 that was listed as a possible cause of lung 4 cancer. But it was not the only one. It was one 5 of twenty or twenty-five causes. 6 It's also important to point out 7 that there was no evidence linking any of these 8 causes with lung cancer. So if you were to ask a 9 bottom line conclusion, what is the cause of lung 10 cancer, even in 1939, it would have to be, the 17 consensus in the scientific community, was that it 12 was unknown, even though there were a few people 13 who speculated without evidence, hum, maybe it's 14 cigarettes, but they didn't know and they didn't 15 have any evidence, and the consensus view was that 16 the cause is unknown, that it's unknowable because 17 of the difficulties of studying this mystery of 18 scien-- of cancer at that time, and the consensus 19 was that there was no evidence linking cigarette 20 smoking with lung cancer. 21 Q. Why was cigarette smoking one of 22 the suspects, if there was no evidence to link 23 It? Why did some people include it in their list 24 of suspected dauses? 25 A. Well, people start to speculate. I want to A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • • 1 health from the early 1900's to the mid 1960's, 2 and I just want to clarify: Have you expanded 3 backward your time-frame to approximately 1900? 4 A. I noticed that now as we speak. More 5 27 properly that should be 1930, and mid 1960's more 6 properly would be January of 1964. So I have not 7 gone back in time. 8 Q. So there's nothing in particular 9 about the period from 1900 to 1930? 10 A. Correct. That's correct. 11 Q. Okay. Thank you for that 12 clarification. I just got three decades out of my 13 questions. 14 What -- again, this is perhaps a 15 broad question, but we can narrow it down, but -- 16 from there -- but what was the state of scientific ].7 knowledge regarding the relationship between 18 smoking and health in the period of the 1930's? 19 MR. DODDS: I object to the form of 20 that question. Go ahead. 21 A. well, in specific, as I said, I was 22 focusing on the possible relationship to lung 23 cancer and what was understood about the cause of 24 lung cancer. •And you can look at that in two 25 ways: If you are looking at lung cancer itself in A. William Roberts, Jr. & Assoolates (800) 743-DEPO Ni I 0 N W N A OD
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31 1 though, as you said, there's no evidence linking? 2 A. Well, even "suspected" is a stronger term 3 than I would use because even if you say you 4 suspect it, that suggests some evidence, even 5 circumstantial. I think it would be more accurate 6 to say that in the 1930's there was a list of 20 7 to 25 causes that would be hypothesized as 8 possible considerations, and it was on that list 9 along with, as I say, other items as well. But 10 the important point is to recognize that there was 13. no evidence linking'the two. It was just merely, 0 come 15 A. I came across that list from my review of 16 the world's literature. 17 Q. From scientific articles? 18 A. Scientific articles. 19 Q. Okay. When it was mentioned as -- 2o when cigarette smoking was mentioned as a suspect, 12 hey, maybe it's smoking. 13 Q. I understand. Aihere did you 14 across that list of suspects? 21 was there any suggestion of how one might go about 22 furthering the knowledge on that link? 23 A. Not at that time. 24 Q. • That's because, as you described 25 it, as unknowable? N A. William Roberts, Jr. & Associates (800) 743-DEPO W. w Co N
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• • 10 you spent? And, again, I'm talking about 11 preparation for the West Virginia medical 12 monitoring case. 13 A. I haven't added it up yet, but several 14 dozen. 4 Q. Are you charging for the time that 5 you're spending in your work for this case? 6 A. Yes, I am. 7 Q. What is your rate for that? 8 A. $300 an hour. 9 Q. Approximately how many hours have 13 1 Q. Do you keep billing records or 2 invoices pertaining to your work on this case? 3 A. No. 15 Q. Several dozen. Three dozen, four 16 dozen? Could you be any more specific. 17 A. You know, call it five dozen. I have not 18 added these hours up yet. 19 Q. can you estimate for me how many 20 hours you've spent in preparation for any tobacco 21 litigation related work in the Year 2000? 22 A. I had a trial appearance in May or June in 123 Brooklyn and I don't recall precisely, but for 24 order of magnitude, call it a hundred. 125 Q. And the approximately one hundred A. William Roberts, Jr. & Associates (800) 'iA3-DEPO I ~ N W N ~ i I W W ~
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• MR. CONC3ROVE: Tim. Tim and Ned. And then there were a couple A. William Roberts, Jr. & Associates (800) 743-DEPO 1 your assignment at that time or what you were 3 A. He approached me in the aftermath of the 4 first Chipellone case. The trial had been 5 completed and he inquired about my undertaking a 6 project on the scientific knowledge from the 7 scientific community about the health hazards of B cigarettes and particularly in reference to lung 9 cancer from the 1930 period to January of 1964, 10 which, as you know, was the data of the first 11 Surgeon C3eneral's report. 12 Q. And, Dr. Ludmerer, have you met 13 with any attorneys in preparation for your 14 testimony here today? 15 16 17 18 19 A. in preparation for this deposition? A. Q. Yes, Yes. I have. Q. Who did you meet with? A. I met with three of the four individuals on 20 the left side of the table yesterday. 21 Q. Can you designate which three of 22 those four. 23 A. With Tammie -- I'm sorry.
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• 1 than the Brooklyn incident you just described 2 me? 3 A. No, I have not. 4 Q. What about last year, the year 5 1999; did you give any deposition or trial 6 testimony? 15 for 7 A. I gave no deposition testimony. I did give 8 one trial testimony. 9 Q. And what was that case? 10 A. That was the Williams case in Portland. 11 Q. And that was also an individual 12 smoker case; is that correct? 13 A. That's correct. 14 Q. I know you were deposed in the 15 Mississippi Attorney General action. 16 A. That's correct. 17 Q. Were there any other Attorney 18 General state cases that you gave testimony in? 19 A. You mean deposition? 20 Q. Yes. 21 A. Or testimony? 22 Q. Deposition. 23 A. No court testimony. There was one 24 additional deposition with in relation to the 25 Attorneys General cases. That was for the state A. William Roberts, Jr. & Associates (800) 748-DEPO 0
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0 1 Q. Were you shown any documents at 19 2 all? 3 A. No. 4 Q. So it wouldn't clarify things if I 5 were to break down what types of documents? 6 A. I guess you're right. We did not go for " 7 any documents. 8 Q. What is your understanding of the 9 nature of the West Virginia case? or let me be a 20 little more specific. What is your understanding 11 of what the plaintiffs are seeking in this West 12 Virginia case? 13 A. I actually know very little about the case 14 itself. 15 Q. Okay. 16 A. It's my understanding that this has to do 17 with medical monitoring of smokers, and that's the 18 extent of my knowledge.. 19 Q. You said you weren't shown any 20 documents yesterday. But have you ever seen the 21 complaint that the plaintiffs filed in this case? 22 A. No, I have not. 23 Q. Have you at any time seen any 24 pleadings or documents filed in connection with 25 this case? A. William Roberts, Jr. & Associates (800) 743-DEPO
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22 1 And I realize this is going to be a 2 broad question, but let's start out and then we 3 can narrow it down. 4 Can you, based on this paragraph, 5 can you explain the principles of historical 6 analysis as they relate to developments in 7 scientific and medical knowledge? 8 A. Yes, I could. 9 Q. Could you do that for me. 10 A. I would particularly identify five. 17. Q. Okay. 12 A. The first, being context, the importance of 13 having a full intellectual, social, cultural 14 context of the subject you're studying so you can 15 put it in the appropriate framework and context; 16 secondly, comprehensiveness; third, accuracy; 17 fourth, an understanding -- and this is something 18 that historians in medicine and historians of 19 science study very hard to develop through years 20 of training, and I did have additional historical 21 training besides my master's degree at Johns 22 Hopkins, but to develop an understanding of how 23 24 25 i~ ~ I scientific knowledge and medical knowledge' I evolves. And'then lastly, avoiding hindsight. ~ 1 Q. This paragraph says, °He will ! , A. Wllliam Roberts, Jr. & Assoolates (800) 743•DEPO
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• 1 Q. Have you ever done any teaching on 11 I 2 the subject of tobacco in relationship to the 1 subject 8 Q. Yes. Any type of lecturing or 3 history of medicine? 4 A. No. 5 Q. Any teaching at all on the 6 of smoking and health? 7 A. You mean lecture-type teaching? 9 teaching. 30 A. Courses and that type of thing? 11 Q. Yes. 12 A. No, I have not. 14 Awards and Honors, and I just notice that you 15 received a research prize on the history of 13 Q. Looking on page 3 of your CV, this 16 17 18 19 22 subject matter of that topic on, that paper on the 23 Eugenics Movement? 24 A. well, it was a study of its rise and fall 25 in the United States. science department for an outstanding senior ~ 1 honors thesis, and I was just wondering what was , the topic of that senior honors thesis? i A. The topic was the American Eugenics. ~ i 20 Movement. 21 Q. And-very briefly, what was the A. William Roberts, Jr. & Associates (800) 748•DEP0 W W N
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hours, that was all devoted to the case in Brooklyn that you were talking about? 14 3 A. That was the preparation and the review of materials, the several days, you know, in court, and then it got postponed and had to come back. You know that type of thing. I'm speaking from memory, but order of magnitude. Q. I know that type of thing all too well. What was the name of that case, if you recall? 12 A. I believe it was the Anderson case. Is 13 that correct? I'm not certain, but I believe it 14 was the Anderson case. 01 Q. Are you involved in any tobacco litigation related work currently, other than the two cases that you're appearing in connection with ~ on this day? A. There is one additional case that is active ~ right now, in addition to these two cases here. And I can't tell you the name of the case; I don't know. But it's an individual smoker case in Brooklyn. Q. . Iiave you given any other trial testimony or deposition testimony this year other t A. William Roberts, Jr. & Associates (800) 743-DEPO I
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36 1 with individuals who are not smokers, so that made 2 it impossible to draw any conclusion from those 3 suggestions. The investigators at the time 4 properly viewed this as a hypothesis, but not as 5 data. 6 Q. Did you also see at that time 7 criticisms of those studies? 8 A. Oh, yes. 9 Q. And on the basis -- was the 10 criticism on the basis of what you were just 11 describing, there being no -- 12 A. The criticism was on two principal bases. 13 Q. What were those bases? 14 A. Number one, lack of any experimental i5 evidence linking cigarette smoking with lung 1.6 cancer, and B) the uncontrolled natures of these 17 clinical reports. Yes, Dr. Smith had -- 7ot of 18 Dr. Smith's patients had lung -- excuse me, 70t of 19 Dr. Smith's patients with lung cancer smoke, but 20 70% of the population were smoking, so that's not 21 really evidence. so those two criticisms were 22 made at the time. 23 Q. would you describe this as a -- let 24 me rephrase this. Was there a great deal of 25 discussion in the literature at this time, back A. William Roberts, Jr. & Associates (800) 743-DEPO I V
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• M • 2S 1 ascribe our values and our attitudes to the past, 2 and if they didn't know as much as we did, ; 3 sometimes we say, well, they're silly, they're ! 4 stupid. It's an important -- the issue is, for ; 5 historians, is to understand that the past is in 6 its own time. So, no, it's easy today to say, 7 well, the stock market crash of '87 or 1929, every 8 -- it was -- everyone should have sold; the signs 9 were clearly there that there would be a crash. 10 Well except in the times it wasn't so clear , , . 11 It's easy today to say, well, if Los Angeles -- 12 St. Louis Rams were going to be the football 13 champion last year. Well, at the time it wasn't 14 so clear who would win. ]5 So we have to recognize that the 7.6 past existed on its own terms, it didn't have the 17 knowledge and understanding that we have today. ~ 18 We have to put it in the context of its times. So 19 avoiding hindsight is closely related to this ~ 20 other principle of putting the subject you study j 21 in the appropriate context of the time and not to 22 give the past the values and the knowledge and the 23 understanding of the present. 24 Q. Give me an example of a study 25 relating to tobacco and held from the time period MVM A. William Roberts, Jr. & Associates (800) 743-DEPO n I
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. • . 1 A. I don't know for certain. I would hazard a 7 A. Quite frankly, I don't remember. I.did seel 2 -- if I were to hazard a guess, I would say Ned 3 Dodds, but actually I don't know for certain. 4 Q. Were you ever shown a draft to 5 which you made any sort of edits of this 6 statement? 8 a draft of this at the time. But, as you know, a 9 few cases have been going on at the same time and 10 I don't remember if I did any editing of this 11 before the final approval or if I approved this 12 without asking for any editing. I simply don't 0 13 remember. 14 Q. But does this statement in fact 15 accurately reflect the matters you expect to 16 testify to in this case? 17 A. Yes, it does. 18 Q. Let me ask you some specific things 19 about it. 20 If you look at the second 21 paragraph, it says, "Dr. Ludmerer is expected to 22 explain principles of historical analysis. 23 Specifically, he is expected to testify about 24 historical analysis of developments in scientific, 25 and medical knowledge.,, A. William Roberts, Jr. & Associates (800) 743-DEPO 0
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18 1 of other attorneys yesterday. Charles -- 2 MR. DODDS: Cox. 3 A. -- Cox. There was one other attorney 4 yesterday that I remember who was not here today. 5 MR. NEWBOLD: Jim Cox. 6 A. Excuse me 3im Cox. And Charles. Was he 7 not an attorney? ! 0 22 today? 23 A. Yes. 8 MR. DODDS: Correct. 9 A. Correct. So there were two individuals 10 yesterday who are not here today. 11 Q. So the total number of people 12 you -- the total number of attorneys you met with 13 was five? Have I counted correctly? 14 A. Correct. They were not all present at the 15 same time. Some were in and out. 16 Q. Okay. About how long did the 17 meeting go on? 18 A. well, we began around 9:30, we finished 19 around 4:30. Seven hours. 20 Q. And was that the only meeting 21 you've had in connection with your testimony here 24 Q• Were you shown any documents? 25 A. What type of documents? A. William Roberts, Jr. & Assoolates (800) 743-DEPO t t P i ip W W O W
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• • 4 than your own? 5 A. No, I have not. 6 Q. And have you 7 expert reports of any other 8 experts? 9 A. No, I have not. 20 1 A. No, I have not. 2 Q. Have you.reviewed the expert 3 reports of any of the defendants, experts other reviewed any of the of the plaintiffs, 10 MR. EVANS: will you mark this, 11 please, as No. 2. 12 (Plaintiff's Exhibit 2, expert 13 disclosure, marked for identification, this 14 date.) 15 Q. Doctor, I've asked the court 16 reporter to mark as Exhibit No. 2 a two-page 17 statement that was provided to us as your expert 18 disclosure in this case. I'd like you to look at, 19 it and ask you a couple of questions. 20 Have you seen this document before? 21 A. Yes, I have. 22 Q. Did you in fact draft this 23 statement? 24 A. I did not draft it. . 1 25 Q. Did you -- do you know who did? I &V A. William Roberts, Jr. & Associates (800) 743-DEPO
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• . 26 1 you were researching that you had to guard against 2 avoiding hindsight on? Does that question make 3 sense? 4 A. Well, it's not the studies per say. My 5 task is to interpret the past on its own terms, so 6 that that question really doesn't make sense. The 7 studies are there. My task as a scholar, as an 8 historian, is to avoid hindsight and to put the 9 studies in the context of the time, as opposed to 10 pretending that they had information that later 171 became available or that they existed in the 12 environment of the present. So the onus is on 13 me. The studies are there. The studies are'raw 14 data. Avoiding hindsight is the responsibility of 15 the scholar, of the historian doing the work. 16 Q. You mentioned when you were first 17 approached by Mr. Garnick to do this study, and I 18 believe you said you were asked to study the 19 time-frame from approximately the 1930's to the 20 mid 60's; is that correct? 21 A. That's correct. 22 Q. And I have read other testimony 23 you've given where you do talk about that 'same 1 6 s I 24 time period. 'I notice here you say you will be ~ 25 discussing the relationship between smoking and j A. William Roberts, Jr. & Associates (800) 743-DEPO )
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1 the 40's. • 2 Q. All right. This is the third 3 paragraph of your disclosure. 4 A. Okay. 5 Q. And the last sentence says: 6"specifically, he is expected to testify that 7 prior to the early 1950's there was no reliable 8 scientific or medical evidence that cigarette 9 smoking -- 10 A. If I may interject. Just looking at 11 this -- 12 Q. Sure. 13 A. -- more carefully, as we are now, I would 14 change that as earlier, "to 1950." 1950 is the 15' turning point. 16 Q. so you want to change, instead of 17 saying "the early 1950's --" 18 A. I would just say "prior to 1950.° 19 Q. "To 1950." Okay. 20 when you say there was no reliable 21 scientific or medical evidence that cigarette 22 smoking posed a serious threat to the public 23 health, was there some evidence? Are you 24 distinguishing between reliable evidence and 25 nonreliable evidence? A. William Roberts, Jr. & Associates (800) 743-DEPO
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28 , 1 the 19301s, you find a perceived increase in the 2 incidence of that disease. It was not certain to 3 investigators at the time whether this increase • 11 cancer. 12 If you look at things from the 10 did not have the tools to understand the cause of 9 but unknowable, because it was felt that science B That's a very important point: Not only unknown, 6 of the disease. The cause of lung cancer was 7 considered unknown and unknowable at the time. 4 was a real increase or a perceived increase, 5 better diagnosis as opposed to,an actual increase of cigarettes, smoking, there was 14 evidence to suggest a relationship between 15 cigarette smoking and lung 18 the scientific community believe there was a 4 no Ili cancer at that time. I 16 Q. Did anyone in the scientific ~ 3.7 community, based on your research, did anyone in ~ 19 relationship between smoking and lung cancer sn G 21 A. If you -- what years are you looking at? 20 the period of 193018? 22 Q. Period of 1930's. 23 A. Okay. If you are examining that decade, 24 there were approximately two dozen causes that 25 were hypothesized as the causes leading to lung A. William Roberts, Jr. & Associates (800) 748-DEPO
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• I I • 42 3. Q. The first sentence is describing 2 medical and scientific articles that began to 3 appear in the 1950's; correct? 4 A. Correct. !s Q. And the second sentence says: "He 6 in further expected to testify that these articles 7 primarily concern statistical studies which were 8 not considered sufficient under then prevailing 9 medical and scientific standards to prove that 10 cigarette smoking caused lung cancer or any other 11 disease.^ 12 First, doctor, are statistical 13 studies considered sufficient under currently 14 prevailing medical and scientific standards to 15 prove that cigarette smoking causes lung cancer? 16 A. This was the great contribution of the 17 Surgeon General's report of 1964 which showed that 28 under certain circumstances epidemiological and ]9 statistical evidence could be used to draw 20 conclusions about causality in chronic diseases. 21 1 want to emphasize that it wasn't epidemiological 22 evidence alone; it was in conjunction with 23 coherence, which is biological plausibility. 80 24 it wasn't statistics alone. But if you had the 25 right circumstance and biologic coherence, if A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • 33 1 came much later. So there really was very little 2 that a scientist could do methodologically to 3 understand cancer. And this is reflected in the 4 literature, and I reviewed the world's literature, 5 article by article, every one, and what you see, 6 if you look, there was a literature on lung 7 cancer, but there is virtually no mention of 8 cause, because they didn't have the tools to 9 investigate cause. The papers on lung cancer 10 looked at -- well, were saying more cancers, what 11 is the true incidence of this? Is it real or 12 perceived? How do you diagnose cancer? What are 13 the various cell types? How does cancer behave? 14 Where does it go? How does it metastasize? How 15 does one diagnosis it? How does one treat it? 16 These were the issues in lung cancer that were 17 actively studied in the 1930's; not cause. 18 Q. You talk in the next paragraph, you 19 begin, "A period of time in the early 1950's..." 20 So let me ask you: The status of scientific 21 knowledge that we've been talking about in the 22 1930's, is there any change in the 1940's, any 23 significant change? 24 A. No. Sa the description that I have 25 provided for the 30's, in general, also applies to 0 A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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• 17 hindsight. We today are the beneficiaries of the 18 Surgeon General's report. We have used 19 epidemiological techniques successfully with a 20 variety of important chronic conditions, 21 hypertension, cholesterol, and many other things. 22 We're accustomed to using this today. The 1950's, 23 that had never been done before„ and the criteria 24 to do it properly hadn't even been invented or 25 developed. It would be classic conceit for 11 completion. 12 Q. Okay. 13 A. And by the way, if I may interject with 14 other point. 15 Q. Certainly. 16 A. This is a wonderful example of avoiding 43 1 certain specific conditions were met which were 2 outlined by the first Surgeon General's report, 3 one can draw conclusions, and, of course -- about 4 the causality in chronic diseases from the 5 epidemiological evidence. We have developed, 6 inherited and developed that tradition today. So, 7 yes, we're using that widely today. But it was 8 done sometime in the history of medicine for the 9 first time, and that was the Surgeon General's 10 report of 1950 -- of '64 that brought this work to A. William Roberts, Jr. & Assooiates (800) 743•DEPO
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0 • 35 1 A. There was no credible evidence. The most 2 that could be said was that there were a handful 3 of studies where investigators had assembled cases 4 of patients who had lung cancer and they saw that, 5 you know, maybe 704 of their patients had lung 6 cancer and they would hypothesize, hum -- excuse 7 me, maybe 70t of the patients had -- were smokers, 8 so they would hypothesize that perhaps cigarette 9 smoking contributed to lung cancer. The problem 10 was that there were no controls. $o you have the 1]. suggestion in the literature from these 12 uncontrolled case studies; but without controls it 13 was impossible to draw any conclusions. 14 Q. What were the studies you were just 15 referring to? 16 A. Oh, there were a handful. I'd have to 17 actually get out, you know, the papers and see 18 them. There were -- I don't want to speculate on 19 the names of the writers. I've looked at maybe 20 1400 studies altogether, but there were very few 21 of these, but there were a handful of 22 investigators who assembled their own patients who 23 bad lung cancer and, you know, some of them smoked 24 and they said,that, you know, maybe smoking is the 25 cause, but there was no comparison, no control A. William Roberts, Jr. & Associates (800) 743-DEPO I .
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• 30 1 emphasize that speculation is ideas and 2 brainstorming. it doesn't mean data. Most 3 speculations are wrong. But this lung cancer is 4 starting to be seen more frequently. Before 1930, 5 it was a very rare disease. Now it is appearing 6 in clinical practice more frequently, and this led 7 people to wonder: what might have changed in 8 western Civilization to lead to this rise in lung 9 cancer? One of the changes in culture, of course, 10 and in society, was the increased spread of 11 smoking during that time. So was automobiles, 12 tarring of roads. There was a major influenza 13 epidemic -- pandemic of 1918 and 119 that led to 14 scarred lungs. There were many other factors as 15 well, but one of them was cigarette smoking and it 16 was -- you know, it's possible, maybe it is linked 17 to cigarette smoking. On the other hand, there 18 were literally tens of millions of cases of 19 smokers and three thousand deaths from lung cancer 20 around 19301s. So people also said, you know, 21 if -- it's not very many cases; maybe it's 22 something else. 23 Q. Does smoking as a suspect, does 24 that show up in scientific literature? Does that 25 show up among the list of suspected causes even A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • 32 1 A. Right. If you do what historians should do 2 and put a subject into the context of the time, 3 one has to recognize how undecipherable cancer was 4 relative to the state of scientific methods of the 5 1930's. It was considered such a mystery that 6 scientists were advised to avoid cancer research 7 because if you want to progress in your career, 8 you want to ask questions that are potentially 9 answerable. And cancer was such a mystery, and 10 the methods and tools weren't there, that it was 1]. considered unknowable. You go into cancer 12 research, you're going to have a dead-end career, 13 Dr. Jones; you better to pick another subject. 14 you're looking at the experimental side, 15 biochemistry is primitive, molecular biology has 16 not begun, genetics as we know it today hasn't 17 been there, immunology has not been developed. 18 So the laboratory tools to 19 understand cancer on an experimental basis were 20 not existent. And then, similarly, the 21 epidemiological tools that later proved so useful 22 and important in establishing the relationship 23 between smoking and lung cancer and then later 24 were used for•other diseases as well, those ri I 25 techniques had not been invented yet either. That ~ A. William Roberts, Jr. & Associates (800) 743-DEPO Ln N W N A W W I W W
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• 40 1 of the scientific knowledge and what was 2 established in the scientific literature, in the 3 biomedical community. If a smoker were to look at 4 that literature, you would find no evidence 5 linking cigarette smoking with coronary arteries 6 disease or lung cancer. So I'm speaking the 7 scientific literature. I'm not talking about 8 popular perceptions. 9 Q. So regardless of what a smoker 10 might have believed, a smoker could have pointed 11 to no reliable scientific evidence that cigarette 12 smoking caused lung cancer prior to 1950? 13 A. I'm not even sure if I would agree with 14 that wording, simply because I'm not in the 15 popular area and I don't know how many smokers -- 16 how many nonscientific nonmedical smokers studied 17 the scientific literature and understood it. So I 18 would feel more comfortable with the wording that 19 there was no scientific or medical evidence 20 linking cigarette smoking with lung cancer or 21 coronary artery disease prior to 1950. This is a 22 literature that is clearly accessible to the 23 medical and scientific community and I really 24 don't feel it would be appropriate for me to 25 speculate what the nonsmoker might have been able 9 b I s~+rwaMj A. William Roberts, Jr. & Associates (800) 743-DEPO W W t0 N
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37 1 and forth between these studies and the criticism 9 11 corpus of papers on lung cancer at that time, the 2 of them? Is this something that you came across 3 many times in your search of the literature? 4 A. Well, actually, I'm glad you asked that 5 question, because it's another example of putting 6 things in context, of being comprehensive. In 7 fact, there's very little discussion of cause, B because the cause of cancer -- of lung cancer in 9 particular. Cancer in general at the time was 10 considered unknowable. If you were to take the 25 eVidence priox to 1950 that cigarette smoking 24 your answers.' Was there any scientific or medical 23 talking somewhat specifically about lung cancer in 21 "a serious threat to the public health" in this 22 paragraph we're talking about, but we've been 20 Q. Thank you. You've used the phrase 12 proportion of time spent on cause was very, very 13 little. Most of the energy, most of the words, 14 most of the publications, most of the discussion, 15 as I already said, was on other aspects of lung 16 cancer. The discussion, the buzz, was on 7.7 diagnosis, on treatment, natural history of 18 disease, those sorts of issues. The overriding 19 point was how little discussion there was. A. William Roberts, Jr. & Associates (800) 743-DEPO
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47 1 to us today appear silly were in vogue. Sometimes 2 we find important discoveries and important ideas 3 in which there was resistance to those ideas. it 4 took 20 years for doctors to accept germ-free 5 antiseptic surgery. It took 30 years to accept 6 general anesthesia, ether anesthesia. 7 So things don't just turn around 8 overnight. So that is just as true in the 9 circumstances regarding the interpretation of 10 epidemiological evidence as it is throughout the 11 history of medicine and the history of science. 12 I would say the beginning of the 13 wave thought occurred with the first prospective • 14 epidemiological studies, which, as you know, 15 appeared in 1954. 16 Q. And whose studies were those? 17 A. There were two important studies. There is 18 the Doll and Hill study. These were English 19 scientists who studied British doctors, and then 20 there was a second important study, the Hammond 21 and Horn study sponsored by the American Cancer 22 Society here in the United States, and that had 23 even more patients, as I recall, that had 24 ultimately in'the range of a couple of hundred 25 thousand. The,Doll and Hill study had had tens of A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 0 • 49 there were also some epidemiologists who did not yet believe that. There were some statisticians who didn't believe those studies. So there was quite a bit of disagreement at that time. Q. Can you name someone -- can you recall someone who stated in the literature they found these studies unpersuasive? A. There were statisticians, and there was Berkson from the Mayo Clinic. There was R. A. Fisher from England who was the single greatest scientific figure. There was the -- all the scientists at the National Cancer Institute, the director of the National Cancer Institute, the director, Dr. Horsefald, the director of the rtemorial Sloan-Kettering institute. There were -- you know, these would be some examples. There was Dr. Green, who was chairman of pathology. There were a lot of cardiac surgeon -- excuse me, chest surgeons. These would be some examples. Q. Let's take, for example, the National Cancer institute that you had mentioned. What was their basis of criticism of the studies in finding them insufficient? A. Well, there were -- now, the National Cancer Institute is a large organization, lots of A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 41 7. to -- excuse me, the nonscientist might have been 2 able to know about it. 3 Q. Would the nonscientist have had 4 access to scientific literature that a scientist 5 would not have? 6 A. No. No. 7 Q. You may have just answered this 8 question, but let me ask it directly. Has any of 9 your research been directed to what the average 10 consumer of cigarettes would have known about the 11 dangers of smoking? 12 A. I think you're correct, that was really -- 13 pardon my last answer. No, I haven't. My 14 investigation twelve years ago, and my testimony 15 today, has to do with the state of scientific 16 knowledge and medical knowledge, not with consumer 17 awareness or popular perceptions. 18 Q. Let me just go to the next 19 paragraph of your disclosure. In the second 20 sentence of that disclosure, says: "He is further 21 expected to testify that these articles --" and 22 you're talking about the scientific articles? 23 A. I'm sorry, which paragraph are you In? 24 Q. I'm in the fourth full paragraph. 25 A. Uh-hum. A. William Roberts, Jr. & Associates (800) 743-DEPO
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. 0 39 ]. talk about vascular disease, I'm talking about 2 peripheral arteries and veins and not coronary. 3 But I don't know precisely when that linkage was 4 first made. 5 Q. So is it your testimony that prior 6 to 1950 there was also no reliable scientific or 7 medical evidence that cigarette smoking caused 8 coronary vascular disease? 9 A. I believe that's a fair statement. 10 Q. Would a smoker, not a scientist, 11 would a smoker have had any basis for believing 12 that cigarettes posed a risk of lung cancer or 13 coronary vascular disease in 1950? n 14 MR. DODDS: I'll object to the form 15 and the lack of foundation. It's outside the 16 scope. 17 A. Well, please remember, as I'm sure you do, 18 that the issue of public awareness of science is a 19 different entity from the scientific knowledge and 20 scientific understanding, and there is lots of 21 common wisdom, lots of folklore about health and 22 medicine. That's not my area. So I'm not really 23 in the position to discuss what popular 24 perceptions might have been. 25 I'm speaking from the perspective A. William Roberts, Jr. & Associates (800) 743-QEPO 1 W W ~ m
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0 • 38 1 played -- posed any other serious threat to 2 health? 3 A. It was recognized that cigarette smoking 4 was not good if you have vascular disease, if you 5 have Berger's Disease, vascular insufficiency to 6 the extremities, as one example. So it was not 7 suggested that cigarette smoking was benign. But e in terms of this very important issue of lung 9 cancer, there was no evidence linking cigarette 10 smoking with lung cancer at that time, and the 11 consensus in the scientific community was that 12 cigarette smoking is not the cause and is not 13 related to lung cancer, if we're looking at the 14 1930's and 1940's. 15 Q. Can you give me a time period when 16 there was reliable evidence regarding the effect 17 of cigarette smoking on vascular diseases? 18 A. I didn't investigate that in detail, so I 19 know that the concern with peripheral vascular 20 disease goes back a while. Quite frankly, I'm not 21 certain how far it goes back or when it begun -- 22 when it began. I do wish to distinguish between 23 peripheral vascular disease and coronary artery 24 disease. That•linkage which was later established 25 had not been established before,1950. So when I A. William Roberts, Jr. &Assooiates (800) 743-DEPO
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44 1 • . 1 someone in 2000 to look at the 1950's and say, 2 hey, the evidence was there, why didn't they just 3 listen to the epidemiological studies? That is a 4 classic example of hindsight, assuming the past 5 had the same knowledge and understanding that we 6 do today. The techniques were being developed and 7 development had not yet matured and had not yet 8 gained general acceptance. 9 Q. So we're talking about a time 10 period when statistical studies, according to your 11 statement, were not considered sufficient under 12 then prevailing medical and scientific standards 13 to prove that cigarette smoking caused lung 14 cancer? 15 A. Correct. 16 Q. Were there some scientists in the 17 1950's who had concluded that cigarette smoking 18 caused lung cancer? 19 A. Which -- the 1950's was a rapidly moving 20 decade. 22 22 A. Yes. 23 24 '52. 25 A. Then let's take it apart. f 13 , Let's say the early 1950's, '50 to '50 to '52, in general, this was the era, A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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50 i scientists, and there were two grounds of doubt 2 from the National Cancer Institute. One was 3 represented by Hubner. You're asking for names. 4 Dr. Hubner was himself an epidemiologist working 5 at National Cancer Institute who did not believe 6 that cigarette smoking was the major cause of lung 7 cancer. He thought that environmental,factors 8 were much more important than cigarette smoking, 9 looking at epidemiological data. 10 More to the point for the National 11 Cancer Institute was the fact that the scientists 12 at the National Cancer Institute were adherents of 13 the 500-year old gold standard of needing 14 experimental verification. They felt that 15 statistical evidence was, though worrisome, was 16 simply insufficient to allow conclusions about 17 causality to be made, and without experimental 18 evidence any hypothesis must be considered 19 unproved. 8o, it was this question of what is the 20 gold standard, what type of evidence do you need. 21 They were not willing at that time to accept 22 epidemiological data. 23 Q. You've described criticisms, of the 24 epidemiological data and -- as establishing 125 causation; correct? Can you -- were there any A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 14 ultimately there are going to be people at the end 15 who -- and there's nothing morally wrong with 16 them; they just have different standards or needed 17 more persuasion. So it occurs in this 18 evolutionary fashion before you can say a 19 consensus has been reached. 20 It's also important to remember 21 that consensuses are often wrong in science. This 22 is another aspect of science that the historian in. 23 medicine and science learns from years of serious 24 inquiry and study of the subject: That lots of 25 times that the consensus is wrong and ideas that 46 1 scientist stating his conclusion that there is a 2 causal link between smoking and lung cancer. 3 A. I think the -- now, remember, things go in 4 waves, and to answer your question fully I have to 5 resort to one of the principles of historical 6 analysis, namely, an understanding of how science 7 evolves. And if you have a paradigm shift, a 8 revolution, one viewpoint or world view replacing 9 another, which is what happened, there is always 10 going to be someone at the beginning who's the 11 first. it doesn't mean there's a consensus. 12 There's -- then you'll have most people here in 13 the broad middle to accept the new view. Then A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 45 1 as you know, of the retrospective studies. Those 2 were shocking in terms of providing for the first 3 time -- and I want to emphasize "the first 4 time" -- good evidence showing a statistical 5 relationship between cigarette smoke and lung 6 cancer. The question was, what did it mean? And 7 I hesitate to speak in absolute terms. I'm sure 8 you could find a 90-year old scientist today who 9 said, well, I believed it in 1950.. It might be 10 memory shaking. In general, the scientific 11 community did not accept cause and effect 12 relationship. They were worried about that. They ~ 13 felt this is a subject needing further 14 investigation. I won't say that absolutely no ~ 15 scientist believed it, but I will certainly say 4 16 that very, very few believed it, if you're looking , ; 17 1950 to 1952. 18 Q. And let's try and avoid hindsight, 19 as you've cautioned. 20 A. I can assure you one thing. I will not let 21 hindsight, I will not permit it, to enter into our 22 conversation today. Q. Okay. Can you point to me a 24 scientific article -- can you point to me where 23 25 the scientific literature you first encountered A. William Roberts, Jr. & Associates (800) 743-DEPO I
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• • 21 research. so, many -- so, many scientists who ~ 20 been the 500-year gold standard of medical 19 They weren't experimental in design. And this had 17 epidemiological and statistical. They were not 18 experimental. They were not laboratory based. 16 of discussion and a lot of debate. But they were 48 1 thousand of patients; the Hammond and Horn 2 studies, the American Cancer Society study 3 ultimately had hundreds of thousands of patients. 4 So it was even larger in terms of numbers. And 5 these studies were continued over time, but the 6 first reports appeared in 1954. 7 Q. Who was criticizing those studies 8 in the medical literature at the period of '54 or 9 'S5? 10 A. well, there was widespread discussion of 11 what those studies meant. Certainly because they 12 were prospective studies and had all the.design 13 advantages that prospective studies can bring to 14 bear on the subject that retrospective studies 15 cannot, they were powerful. They stimulated a lot 22 came from experimental tradition, whether they be 23 pathologists or pharmacologists or cardiac' 24 surgeons or others who were looking for 25 experimental evidence, were unpersuaded. And A. William Roberts, Jr. & Assoolates (800) 743-DEPO
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51 1 studies using the same sort of epidemiological 2 techniques that came to contrary results? Were 3 there any studies at this time period which were 4 refuting the results using the same methods? 5 A. Actually, there were not, which ultimately 6 was one of the factors that helped lead to the 7 Surgeon General's conclusion, because you were 8 referring to the criterion of consistency. And 9 the -- in general, both the retrospective studies ]o and prospective studies were consistent. There 11 was some differences. Relative risk in the early 12 years ran all over the map, but later that evened I* 13 out with time. But in the early years some people 24 were suspicious that the relative risks calculated 15 from the different studies were so different that 36 maybe there is something wrong with these 17 studies. That's a minor point. The larger point 18 is that, in general, the studies were consistent. 19 That's a point that the Surgeon General's report 20 considered very important. 21 But the question was you're doing 22 the same thing, you're getting the same result. 23 And if you do it twenty times, you'll get the same 24 result twenty•times. To those who looked for 25 experimental verification, it didn't matter if you A. William Roberts, Jr. & Associates (800) 743-DEPO to
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• i 52 1 did it 2,000 times. The question was, what 2 conclusions can you draw from epidemiological and 3 statistical data? And if you did not accept that 4 paradigm, as many scientists did not, then it 5 didn't matter how many times you did it. But, 6 yes, consistency, there was consistency in 7 results. 8 Q. Okay. You've said a bona -- you 9 called it a bona fide scientific controversy 10 continued at least up to the publication of the 11 report of the Surgeon General's report in 1964. 12 A. i7h-hum. 13 Q. Have you formed any opinion 14 regarding when or if that bona fide controversy 15 ended? 16 A. Yes, I have. 17 Q. And when would that be? ].e A. As a spirited public debate within the 19 scientific community, it ended in the aftermath of 20 the first Surgeon General's report. As I 21 mentioned, the Surgeon General's report made a new 22 intellectual contribution as it formulated its 23 five criteria, and of course it assembled and. 24 reviewed the world's literature in a way no one ' 25 had done before, and it also had new evidence that A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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• • 54 i draw judgments. It's not about one whether 2 there's controversy or not. But some things that 3 will help us do so: when you see papers 4 challenging the cigarette hypothesis, when those 5 stop to -- when those stop occurring in any 6 significant numbers; when you see attention moved 7 too other subjects; when you see people who once 1 8 posed the cigarette hypothesis changed their mind; 9 when ou see the clinical e idemiolo acce ted y gy p p as , t 14 when professional organizations of clinical , 15 epidemiology and training programs begin; when you 16 see the text books talk -- draw conclusions about 17 causation; these are all various types of evidence 18 that we as historians can use to draw conclusions. ~ 19 Q. can you cite to an example of some 20 scientist who had publicly announced their ~ 21 opposition to the Causation theory who then ~ 22 changed their mind? , , 23 A. Well, it's -- you know, people don't write i 24 articles about this, but certainly surgeon General ~ 10 a new discipline; when departments of clinical 11 epidemiology are created, which is the mid and 12 late 196o's; when journals of clinical 13 epidemiology begin in the mid and late 196o'sr 25 Bernie in the late 'SO's discusses the growing A. William Roberts, Jr. & Associates (800) 743-DEPO i ~
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01 • 58 1 people. But two places in particular -- well, the 2 place in particular I was thinking, I believe, was 3 the American Public Health Association for the 4 first time used that term, and I was specifically 5 referring to that organization. 6 MR. EVANS: Can we take a 7 five-minute break. B THE VIDEOaRAPHER: Off the 9 videotape. 10 (Discussion held off the record.) i]. (Time noted: 11:38 a.m.) 12 (Brief recess.). 13 (Time noted: 11:52 a.m.) 14 THE VIDEOC3RAPHER: we're back on 15 the videotape 11:52. 16 Q. Dr. Ludmerer are you familiar with 17 the Tobacco Industry Research Committee, sometimes 18 known by its initials TIRC? 19 A. I've heard the name. I really do not know 20 much about it. 21 Q. In your study of, scientific 22 studies about smoking and disease, did you come 23 across studies that were response stored by or 0 0 0 24 connected in any way to the TIRC? 25 A. Occasionally. A. William Roberts, Jr. & Associates (800) 743-DEPO
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0 • 1 sentiment. nrow, he's speaking at a population 2 level. 3 You know, you have to put some 4 reality in it. You know, people don't write 5 articles saying, well, you know, I -- you know, 6 last year I wrote an editorial against it, but 7 I've accepted it today. They just stop -- they 8 just stop the denial. They just start teaching 9 it. They start accepting it. It would be 10 unrealistic to expect there to be article after 11 article saying, well, I've changed my mind. You 12 just accept it and move on to something else and 13 start teaching it. And it's done in that type of 14 an informative fashion so. It's more the 7.5 disappearance of resistance and seeing the ideas 16 disseminate into the review articles, into the 17 text books, into the.medical teachings, as opposed 18 to articles saying, well, I changed my mind. 19 Q. You had listed that as one example 20 of the things -- 21 A. Right. 22 Q. -- you would look at -- 23 A. Right. 24 Q. -- in the consensus and 25 development, as people who had opposed it and A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • 53 1 no one had seen before and it was able to take 2 into account. So it's a new contribution. And in 3 the aftermath of that you see a conspicuous, you 4 know, dying down of the controversy in the 5 scientific community. That's not to say that 6 everyone agreed to accept epidemiological 7 evidence. You know, if you were a bona fide 20 have died down given that there were still who did 19 your conclusions about when the controversy would 14 you're looking for a general quieting down and 15 acceptance among -- what a historian can call a 16 consensus, it would be in the aftermath of the 17 report. 18 4. what criteria do you use to form 13 irresponsible to disagree with the report. But if 8 toxicologist or pharmacologist who -- independent 9 thinker, as most scientists are -- who required 10 experimental evidence to prove causation, that 11 doesn't mean that everyone was persuaded by the 12 report, and it doesn't mean that it was 21 not accept? 22 A. It's a judgment. All scholarship is 23 judgments. Science is a judgment. Conclusions 24 about causation are a judgment, as the Surgeon 25 General pointe.out. And, similarly, historians A. William Roberts, Jr. & Assoaiates (800) 743-DEPO
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2 recall specific studies that are linked in any 3 to the TIRC? 4 A. Not at this time. 5 Q. No? 6 A. I'd have to look at the papers again in • 7 terms of which study was funded by TIRC or which 8 9 10 were by National Cancer Institute, which by U.S. Public Health Service and so forth. Q. So there's nothing about the link 11 with TIRC that makes any particular study stand 12 out in your mind; is that correct? 13 A. That's correct. 14 15 16 Q. We were talking about the bona fide scientific controversy on the link between cigarette smoking and lung cancer. Did your 17 research include how that controversy was 18 addressed by cigarette manufacturers? 19 A. No. 20 Q. Did you in your research consider 21 any internal documents produced or generated from 22 cigarette manufacturers? 23 A. No. 24 Q. if there were documents from 25 cigarette manufacturers regarding the state of ..v.~.,.,~ A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 62 1 Medicine or 1958 in the Journal of'the American 2 Medical Association or the surgeon cieneral,s :; report. Secondary sources would be examinations 4 of the topic and of the primary data and of 5 related subjects by other historians or other 6 writers. 7 Q. In other historical context, you've 8 described primary sources as things such as 9 researchers on notes, notebooks, and 1o correspondence, and published literature as being 11 a secondary source. Now, is your research on this 12 topic somewhat different in that regard? 13 MR. DODDS: Objection to form. 14 A. The primary sources can be unpublished, but 15 they can be published, and this is consistent. If 16 1 were writing a biography of Abraham Lincoln, 17 primary sources would include his published 18 writings and published speeches. A secondary 19 source would be another biography by someone in 20 1985 about Lincoln that I might read for 21 background or maybe a history of the Civil War by 22 someone else or maybe a history of the economy at 23 that time, something of that sort. But I 24 think -- a publication in some -- depending on 25 the circumstances, is, in some cases, is a A. William Roberts, Jr. & Associates (800) 743-DEPO 41 ' W W
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• M 67 1 unknown. 2 Q. And regarding possible causes other 3 than cigarette smoking, was there any change in 4 the period from 1950 to 1954? 5 A. No. 6 Q. Okay. Going back to the frank 7 statement, under that No. 2, it says: "Again, 8 distinguished authorities point out that there is 9 no agreement among the authorities regarding what 10 the cause is.,, And we're talking about lung 17. cancer. Is that a true statement, based on your 12 research? 13 A. Yes, it is. 14 Q. And if you look down toward the 15 bottom of that first column, the statement, which 16 is identified as being from the Tobacco Industry 17 Research committee, it says: "we believe the 18 products we make are not injurious to health." 19 Now, again, based on your review of the scientific 20 literature of this time period, would you describe 21 that as being an agreement with the consensus of 22 the time? 23 MR. DODDS: Objection. No 24 foundation. 25 A. The consensus at the time was that there A. William Roberts, Jr. & Assooiates (800) 748-DEPO
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• 56 1 changed their mind? 2 A. Right. 3 Q. Okay. 4 A. What you do see in the 50's and even in the 5 early 60's is a significant discussion in the 6 scientific literature with lots of articles, even 7 in the 60's, indicating the author's unwillingness 8 to accept epidemiological evidence, holding out 9 for experimental evidence, even in the 1960's, 10 saying that epidemiological evidence is 11 insufficient. What you find is that for the most 12 part that type of thing stops. 13 Q. The last thing I want to talk about 14 in your expert statement, it says "Dr. Ludmerer is 15 also expected to testify how this controversy was 16 addressed by public health officials." 17 what are you going to talk about in 18 terms of how public health officials address the 19 controversy? 20 A. Well, I don't know precisely what i'm going 21 to say because I have no idea what the direct 22 examination will be. 23 Q. I understand that.. How was the 24 smoking and health controversy addressed by public 0 1 25 health officials in, say, the early 1960's? A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 9 61 1 Q. Okay. Now, well, let me then 2 narrow my question to documents. Nonpublic -- in 3 what I call internal documents of cigarette 4 manufacturers, if they're on the topic of smoking 5 and health, would you have considered those 6 documents to be helpful to your research? 7 MR. DODDS: Objection to form. 8 A. First it's a hypothetical because I don't 9 know what documents there were, but -- or what 10 quality they were, so there are a lot of 11 hypotheticals in the question. But also the -- my 12 assignment was the world scientific literature, 13 which by definition is published literature. it 14 doesn't include unpublished work anywhere. So, 15 from that perspective, I was able to have total 16 access to what I needed to look at. 17 Q. In the context of your research, 18 have you used both primary and secondary sources? 19 You've used the terms primary and secondary 20 sources in talking about historical research. In 21 the context of this research, how would you define 22 primary sources and secondary sources? 23 A. Primary sources would be publications by 24 people at the time. The publication on lung 25 cancer from 1936 in the New England Journal of I 0 A. William Roberts, Jr. & Associates (800) 743•DEPO
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• • • 66 1 medical literature of the period 1954 or earlier 2 which would establish any of those things as a 3 cause of lung cancer? 4 A. Nothing was -- 5 MR. DODDS: Objection to form. 6 A. Nothing, including cigarette smoking, was 7 established as a cause of lung cancer at that 8 time. The list that you asked for were the 9 factors that were receiving the most attention in 10 terms of further investigation and studies as 11 possible causes. 12 Q. We talked about earlier in the 13 context of your expert disclosure -- pardon me 14 just a second -- that prior to the early 1950's, 15 there was no reliable scientific or medical 16 evidence that cigarette smoking posed a serious 17 threat to public health. 18 A. Uh-hum. 19 Q. was there reliable scientific or 20 medical evidence at that time period that any 21 other exposure was a cause of lung cancer? 22 A. Prior to 1950? 23 Q. Yes. 24 A. No, there was not. As i stated before, the 25 cause of lung cancer before 1950 was considered A. William Roberts, Jr. & Assoolates (800) 743-DEPO iP . ~ V
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63 1 secondary source and in some cases it can be a 2 primary source. It's topic dependent. 3 Q. Have you considered anything in 4 what I would call the popular press, newspapers 5 and that sort of thing, other than scientific 6 journals? Did you consider any newspaper articles 7 in your research? 8 A. As I may have said before, I have not. I 9 studied the scientific literature, but not how 10 this science was represented to the public. 11 Q. Doctor, are you familiar with the 12 frank statement? Does that phrase mean anything 13 to you? 14 A. Yes, it does. 15 Q. What is your understanding of the 16 frank statement? 17 A. could you clarify that question. l8 Q. Well, you -- I asked you if you ].9 were familiar with that phrase and you did say 20 yes, so I want to know, just based on your 21 familiarity, what you believe the frank statement 22 to be. 23 A. Well, the frank statement, as I recall, was 24 a statement that appeared widely in the popular - w 25 media in early 1954 in response the skin painting A. William Roberts, Jr. & Assooiates (600) 743-DEPO
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• 0 1 was no agreement. 2 we don't know or that there are multiple competing 3 -- if you're describing the state of knowledge, 4 sometimes the characteristic is disagreement 5 rather than agreement, competing views. I think 6 it would be more accurate to say that that 7 statement was consistent with the views of many 8 respectable members of the scientific community at 9 that time. 10 Q. Can you give me examples from the 11 literature of respected members of the scientific 12 community who are opining at this time that 13 cigarettes were not injurious to health? 14 A. well, there were papers, as I indicated, at 15 that time, that editorials in major journals that 16 would discuss the cigarette controversy and 17 conclude that in their view the evidence was not 18 sufficient to warrant a conclusion that cigarette 19 smoking caused lung cancer. So there were 20 editorials, there were.essays, there were, you 23. know, things of that sort. 22 Q. I understand that. And we talked 23 at length about that link between cigarette 24 smoking and lung cancer. Can you point to 25 anything in the scientific literature at this time A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • • 57 1 A. Well, again, you see this evolution. The 2 first time the term "primary prevention of lung 3 cancer," that is prevent lung cancer by not 4 smoking, as opposed to prevention, see your doctor 5 early if you're coughing up blood, the first time 6 that was used in the public health community ever 7 was 1954. And you see an evolution as of view 8 over the time. I think another notable date would 9 be 1957. Surgeon General Bernie issued a 10 statement that said that excessive cigarette 11 smoking -- and I want to underline "excessive" -- 12 excessive cigarette smoking is one of the factors 13 leading to lung cancer. In the United States that 14 was replaced by a more strongly worded statement 15 by Surgeon General Bernie in 1959. And then this 16 continues to evolve in this country. The 17 culmination of this movement is the first Surgeon 18 General's report of January 164, which you know of 19 course draws the causal linkage between cigarette 20, smoking and lung cancer in men at that time. 21 Q. You mentioned 1954 as the first 22 date when you saw the statement that one should 23 stop smoking to avoid lung cancer. Who made that 24 statement? 25 A. I suspect it was made by a number of ' A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • 60 1 scientific knowledge on smoking and health, do you 2 consider that they would have been helpful sources 3 to you? 4 A. No. 5 MR. DODDS: Objection. 6 A. Could you repeat that question. 7 Q. If there were documents from 8 cigarette manufacturers regarding the state of 9 scientific knowledge regarding smoking and health, 10 would you have considered those important to your 11 research? 12 A. Are you talking about published papers from 13 cigarette companies? Are you talking about 14 internal company records? Are you -- 15 Q. Well, let me clarify. Have you, in 16 your research, looked at any published papers by 17 cigarette manufacturers? 18 A. I examined the world's scientific ]9 literature. Sometimes papers indicated that they 20 were either funded by TIRC or that they were 21 scientists at a tobacco company. But I have not 22 systematically studied the scientific research 23 from the standpoint of the company and everything 24 that one company did or another. No, I have not 25 studied that. A. William Roberts, Jr. & Associates (800) 743-DEPO
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0 64 1 experiments of Dr. Winder and Dr. Graham and 2 putting that in context for the public. I believe 3 it was published in early 1954. 4 Q. We are talking about the same frank 5 statement. 6 MR. EVANS: I'd like the court 7 reporter to mark this. They're stapled to go for 8 some reason. 9 (Plaintiff's Exhibit 3, article 10 entitled, "A frank statement to cigarette 11 smokers," marked for identification, this date.) 12 (Discussion held off the record.) 13 Q. Doctor, I've had the court reporter 14 mark what I apologize is a rather hard to read 15 copy of "a frank statement to cigarette smokers," 16 which, as you accurately described, was a 17 statement appearing in early 1954. And based on 18 your research of the scientific literature, I just 19 want to ask you a couple of questions on what was 20 stated in this frank statement. 21 if you want to take just a moment 22 to read through it, that will be fine. 23 A. Okay. 24 Q. Okay. Doctor, keeping in mind 25 we're talking about the time period of 1954, about A. William Roberts, Jr. & Assoclates (800) 743•DEPO
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76 1 high level until that report? 2 MR. DODDS: Objection to form. You 3 can answer. 4 A. Well, as indicated, as a new idea is is 0 5 developed, succeeds an old idea, things 6 happen instantaneously. 7 Q. Correct. do not 8 A. It's a process. What you find beginning in 9 the early 50's -- and I think you chose probably 10 the two best examples at the very beginning -- is 11 people accepting the hypothesis, but others 12 refusing to do so. And it's difficult to assess 13 -- I think it would be more accurate to say that 14 a very strong controversy continued through the 15 report. You have to look both at numbers -- are 16 you talking 50/50, 60/40, 70/30, things of that 17 sort? You also have to look at the.scientific 1B stature of the people. so if we're playing 19 basketball and Michael Jordon is on my team, I'll 20 let you have four or five guys, maybe even six or 21 seven. So I think it's accurate to say that there 22 was a controversy that continued through the 23 Surgeon General's report. 24 Q. Thank you, doctor. Let me ask you 25 a few questions about the state of West Virginia. A. William Roberts, Jr. & Associates (800) 74$•DEPO ~ N J
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r 01 84 1 questions asked. It's not doing new work. 2 Q. And you did that for Blankenship as 3 well? 4 A. Correct. 5 Q. But you've testified I think 6 approximately -- although you don't have records 7 for it, that you spent approximately 60 hours on B Blankenship. Is it an additional 60 hours on 9 Scott? 10 A. No. I was lumping the two together. 11 Q. So you've spent 60 on Scott and 12 Blankenship? 13 A. Right. 14 15 your deposition today? 16 A. When did I come in? 17 Q. To New York. 18 A. What day is today, Wednesday? 19 Q. Today is Wednesday the 18th. 20 A. I came in Monday night. 21 Q. When did you start billing for the 22 Scott or Blankenship cases? 23 A. I haven't done any billing yet for either. Q- When did you come in to prepare for Is that yesterday? 24 Q. For this week, when did your time 25 start? When did you start keeping track of hours? A. William Roberts, Jr. & Assoalates (800) 743-DEPO I t LA
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72 1 constituents of tobacco and of tobacco smoke is 2 now needed and it is surely incumbent upon the 3 tobacco manufacturers to do this." 4 Let me ask you if based on this 5 research have you seen other examples in the 6 literature of references to what tobacco 7 manufacturers should or should not do. 8 MR. DODDS: Objection to form. 9 A. That is at most a minor theme. so I would 10 say that there is not a lot of discussion of that 11 point as opposed to, you know, study -- there was 12 lots of discussion about the importance of 13 studying cigarette smoking, but there was not much 14 discussion of the responsibilities of different 15 organizations and different companies, and I'm not 16 really an expert on the company behavior or 17 responsibility and -- at the time that.this is 18 also being studied very.widely by the scientific 19 community. 20 Q. Okay. Do you have any opinion on 271 whether it was incumbent upon tobacco 22 manufacturers at that time to study the chemical 23 constituents of tobacco and tobacco smoke? 24 MR. DODDS: Objection. outside the 25 scope. A. William Roberts, Jr. & Assoclates (800) 743-DEPO
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• . 20 causation, but it is far from representative of 21 the literature. It is one type of article, but. 22 there are many other types as well. 23 Q. Okay. A couple of more sentences 24 down, we're at about the middle of this column, it 71 1 preventive action we can, accepting the theory as 2 though the proof were absolute until further 3 research leads,to some modification." 4 Now, based upon your research, , 5 would you describe that statement as reflecting a° 6 consensus of the time, 1952? ; i 7 A. I think it has always been recognized that ~ 8 any conclusion about causality in science is an 9 act of judgment. This is a point that the Surgeon 10 General reiterated as part of the 1964 report. 1]. The question in the early 50's was 12 what is the meaning of the statistical informatioa ~ i 13 that has been assembled, what conclusions can we j 14 draw from it? As I indicated, some people at that , ; 15 time began to accept a causal relationship, but ~ 16 many were unwilling to take the same step. So, 17 this is an example of -- so -- of an editorial ~ 18 that -- one of the early ones to take the position ; 19 that statistical evidence can be used to draw from i ! ~ 25 says, "Intensive research on the chemical I A. William Roberts, Jr. & Associates (800) 743-DEPO
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0 1 A. Yesterday morning. 2 Q. So Tuesday morning? 3 A. Right. 4 Q. Where are you staying? 5 A. Where am I staying? 6 Q. What hotel? I'm staying at the Waldorf. Q. And who's paying for the Waldorf I presume.the law firm Dechert Price. 11 Q. Do you have a regular room, a 12 suite? 13 A. A regular room. 14 Q. What's the nightly rate? 15 A. I don't know. 16 Q. who pays for your dinners when 17 you're in New York? 18 A. My expenses are paid for by the firm. 19 Q. Do you get 1099s.from the firms? 20 A. Yes, I do. 21 Q. What was your 1099 approximately 22 for last year, 1999? 23 A. I don't remember. 25 were paid by the tobacco companies or the law A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 70 1 a Q. And do you in fact recognize this 9 article? 10 A. Uh-hum. 11 Q. Okay. I'd like you to look on the 12 second page and the second column, the right-hand 1 article from the British Medical Journal, dated 2 December of 1952. 3 A. Okay. 4 Q. And I believe this is an article 5 that you have in prior testimony indicated.that 6 you are familiar with? 7 A. Correct. F 13 column. In this article.is discussing statistical ~ 21 Q. -- about two or three sentences 22 down in that paragraph it says, * 'All that these 23 things can do is to show that the probability of a 24 causative connection between an agent and a 25 disease is sogreat that we are bound to take what 14 studies, such as the Doll & Hill studies that 15 you've mentioned earlier today. 16 A. Uh-hum. Are you referring to the 17 paragraph, "Where do we go from here?" 18 Q. Yes. And this paragraph is 19 discussing the statistics and -- 20 A. Uh-hum. A. William Roberts, Jr. & Associates (800) 743-DEPO W N A W A N H
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I 69 1 that was making -- that was stating the conclusion • 2 that cigarettes are not injurious to health? 3 A. There were statements throughout the 4 medical literature, including editorials in New 5 England Journal of Medicine, editorials in the y 6 Journal of Medical Education, in the 501s, but 7 they phrased it differently. They weren't saying e that cigarette smoking is safe. They were saying ' 9 that there is no evidence at this time to believe 10 that it causes lung cancer. They were saying 11 something different from -- related but different. 12 Q. Different than cigarettes are not 13 injurious to health? 14 A. Right. They were saying that there's no 15 evidence that it causes lung cancer and there's no 16 evidence at this point to fear it. 17 18 Q. All right.. MR. EVANS: I'd like you to mark 19 that as the next exhibit, please. 20 (Plaintiff's Exhibit 4, article 21 from British Medical Journal, London, Saturday 22 December 13, 1952, marked for identification, this 23 date.) 24 Q. Now, doctor, I've asked the court 25 reporter to mark as the next exhibit a copy of an A. William Roberts, Jr. & Associates (800) 743-DEPO
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73 1 A. I don't have any expertise to address the 0 2 issue of company responsibility, you know, what a 3 company should do, what an appropriate research 4 program for them is, versus funding research by 5 others, which of course they did. That's really 6 outside my scope. 7 Q. And at trial of this case, is it 8 true that you don't plan to offer any opinion on 9 what tobacco manufacturers should or should not 10 have done regarding research into cigarette 11 smoking? 12 A. That's correct. z 1 may n ac e e y 22 in an earlier answer, but can you confirm for me 23 that this is a document that you have seen and are 24 familiar with? 25 A. It looks very familiar, but there is no ~ A. William Roberts, Jr. & Associates (800) 743-DEPO w N W A I N ~ 13 MR. EVANS: One more article I want 14 to show you. 15 (Plaintiff's Exhibit 5, editorial 16 from the New England Journal of Medicine, marked 17 for identification, this date.) 18 MR. EVANS: And, doctor, I'm having ].9 the court reporter mark a copy of an editorial 20 from the New England Journal of Medicine, and this 9 i f t b the ditorial that ou referenced
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0 75 1 extensively, if you agree with the conclusion that 2 they're stating in this editorial, that if similar 3 statistical data had incriminated a food 4 contaminant, effective countermeasures would have 5 followed quickly. 6 MR. DODDS: Objection. 7 A. I'm not an expert -- even though I'm an 8 historian, I'm not an expert on the history of 9 food and drug regulation, so I really don't know 10 what their requirements at that time would have 11 been, so I'm unable to say if that statement is 12 true or not, that a food additive would have been 13 prohibited. But, as I said, before the break, in 14 the early 5o's people began to accept the 15 causation hypothesis, and this is part of the 16 early wave. 17 Q. So you're not going to offer any 18 opinion in this case on research into things other 19 than tobacco and its impact on the public health; 20 is that correct? 21 A. Correct. 22 Q. Did the bona fide controversy on 23 the link between smoking and lung cancer begin to 24 abate or die down at some period prior to the 1964 25 surgeon General's report or did it continue at a A. William Roberts, Jr. & Associates (800) 743•DEPO
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f r . i halfway down the first column of this frank 65 i 2 statement, it states: "Distinguished authorities 18 A. As alternative suggestions.as to the cause, ~ 19 you mean? Besides tobacco? 20 Q. Yes. ' 21 A. Examples would include radiation, air ~ 22 pollution, tarring of the roads, atmospheric 23 pollution, genetic factors, occupational 3 point out..." and then it says: "No. 1. That 4 medical research of recent years indicates many 5 possible causes of lung cancer." Noa, based on 6 your research; is that true? Is that a true 7 statement? 8 A. Yes, it is. 9 Q. What were the many -- what were 10 some of the many possible causes of lung cancer 11 that were in -- that medical research had pointed 12 out at this time period, 1954? 13 A. I'm sorry, I couldn't hear you. What were 14 the? 15 Q. At this time period in 1954, what 16 were some of the many possible causes of lung 17 cancer that were appearing in medical research? Q• 24 exposures. 25 t Now, had -- were there -- was there ! A. William Roberts, Jr. & Associates (800) 743-DEPO W' N W .P r O~ i
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• • 0 77 1 Have you ever lived in West Virginia? 2 A. No. 3 Q. Ever traveled there with any 4 regularity? 5 A. No. 6 Q. Do you have any knowledge at all of 7 the class representatives in this case? And I'll 8 tell you their names, Christa Blankenship and Mae 9 Sivo. 10 A. What do you mean by any knowledge of them? 11 Q. Do you have any knowledge 12 whatsoever about those two individuals, other than 13 that they are named plaintiffs in this case? 14 A. No, I don't. 15 Q. Do you have any experience at all 16 with the healthcare system in West Virginia? 17 A. No, I don't. 18 Q. And do you plan to give any 19 testimony at all regarding in any way the delivery 20 of healthcare services in West Virginia? 21 A. No. 22 Q. Are you familiar with the medical 23 monitoring proposals offered by the plaintiffs, 24 experts in this case? 25 A. No. 0 I A. William Roberts, Jr. & Associates (800) 743-DEPO
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. ! 78 1 MR. EVANS: Could we go off record 2 for a second. 3 THE VIDEOGRAPHER: we're going off 4 the videotape at 12:24. 5 (Discussion held off the record.) 6 THE VIDEOCdRAPHER: Back on the 8 MR. EVANSs Doctox' I thank you forW 7 videotape. We're back on the videotape, 12:26. 9 your time. I don't have any further questions for 10 you, but the attorney representing the Louisiana 11 case may have some questions. 12 THE VIDEOGRAPHER: Off the 13 videotape. 14 (Time noted: 12:27 pm.) 15 (Recess.) 18 19 20 21 22 23 24 25 A. William Roberts, Jr. & Assoolates (800) 743-DEPO (A i A ~0
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• 0 86 1 firms to testify in 1099? 2 A. I only testified one time in 1999. 3 Q. Pardon me? 4 A. I only testified one time in 1999. 5 Q. So it should be pretty easy to tell 6 me how much you were paid in 1999? 7 A. I testified in the Portland case, the 8 Williams case, and my bill for that was, oh, I 9 don't remember exactly, but it was probably around 10 70 hours worth of work. 11 Q. So you think in addition to 12 expenses you got a 1099 reflecting approximately 13 $21,000? 14 A. That's what I recall, as we sit here right 15 now. 16 Q. How about for 1998? 17 A. I don't remember. 18 Q. is it more than $21,000? 19 A. It probably was, but I don't remember 20 exactly. 21 Q. More than 100,000? 22 A. No. Not that -- not as I remember. 23 Q. Do you have copies of your 1099's 24 for 1998 and 1999? 25 A. With me? A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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• 74[ 18 paragraph I've just pointed out to you, says, "If 19 similar data had incriminated a food contaminant 20 that was not habit forming and was not supported 21 by the advertising of a financial empire, there is 22 little doubt that effective countermeasures would 23 have followed quickly." 24 Now, I want to ask you as a medical 25 historian, who has studied this time period 7 this and confirm if this is an article that you 8 have seen. 9 A. I've seen this. 10 Q. Okay. Thank you. If you would 11 look at page 2, doctor, the first full paragraph 12 that begins, "If such figures...." And, again, 13 this article -- this editorial is discussing the 14 same statistical Doll & Hill studies that we 25 discussed earlier? 1.6 A. Uh-hum. Correct. 17 Q. The second sentence of this 1 date on my copy. 2 Q. You're correct. That's my 3 understanding this is a date -- an editorial from 4 1953? 5 A. Uh-hum. 6 Q. But please take a moment to look a A. William Roberts, Jr. & Associates (800) 743-DEPO
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9 • . 4 A. I don't know what you mean by work product. 5 Q. Have you drafted any reports in 6 Scott case? 7 A. No, I have not. 8 Q. Have you taken any notes in the 9 Scott case? 10 A. Not beyond original notes from -- upon 2 to -- from the five dozen or so 3 spent on the Scott case? 11 which I base my opinions, and 12 those. you already have 13 Q. And other than yesterday, have you 14 met with any attorneys in preparation for your 15 deposition in the Scott case? 16 A. No, I have not. 17 Q. So tell me what you've done for the 18 60-odd hours in the Scott case. 19 A. Well, it's the same as I've done for the 20 Blankenship case. I've reviewed my own 21 testimony. I've reviewed previous depositions, 22 I've reviewed previous trial testimony, I reread 23 many of the key articles and key documents which 24 you have, and it's, in essence, reviewing my own 25 work so I can give the most accurate answers to a we A. William Roberts, Jr. & Associates (800) 743-DEPO
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R 92. 1 with the tobacco companies ever been raised by the 2 university? 3 A. The university hasn't raised it, but I 9 raised it with them. 5 Q. How did you raise it? 6 A. When Murray Garnick contacted me in 1988, 7 and initially invited me to become involved, I had 8 conversations with high ranking university 9 officials including my department chairman and 10 dean and some wise members of the faculty at that 11 time and they all thought it was appropriate to d 12 so and they have been in the loop in terms of 13 involvement in the two or three cases in the last 14 few years. 15 Q. Have you ever looked to see if the 16 university has received any grant monies from 17 tobacco related entities? 18 A. No, I haven't. 19 Q. Would you consider the fact that if 20 the university received grant money from tobacco 21 related entities that that might raise a potential 22 conflict of interest in testifying on behalf of 23 tobacco entities? 24 A. I haven't considered that. I would find 25 that an extraordinary stretch. A. William Roberts, Jr. & Associates (800) 743•DEPO N' w N ~
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M . 79 1 A F T E R N 0 O N S E S S I O N 2 1:32 p.m. 3 THE VIDEOC4RAPHER: We're back on 4 the record videotape. We're starting tape 2 of 5 today's deposition. The time is 1332. 6 K E N N E T H M. L U D M E R E R, 7 having been previously duly sworn, testified 8 further as follows: 9 CROSS EXAMINATION 10 BY MR. MAISTROS: 11 Q. Doctor, my name is Jack Maistros. 12 I represent the plaintiffs Scott in Jackson, in 13 the Louisiana action. Are you basically familiar 14 with that action or unfamiliar? 15 A. Only an outline. 16 Q. Have you seen the complaint? 17 A. No, I have not. 18 Q. In the petition, I think they call 19 it in Louisiana. Have you read any of the 20 pleadings in that case? 21 A. No, I have not. 22 Q. Have you read any depositions from 23 that case? 24 A. No, I have not. 25 (Plaintiff Ludmerer Exhibit 6, A. William Roberts, Jr. & Associates (800) 743-DEPO I
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0 93 1 Q. Do you study ethics as part of your 2 work as an historian? I 3 A. Do I study ethics? 4 Q. Do you know what °ethics" means? 5 A. Do I study the field of ethics? 6 Q. Yes. 7 A. I'm not an ethicist. 8 Q. You have written on ethics, haven't 9 you? 10 A. I'm -- 11 Q. Narrow issues? 12 A. On what issues? 13 Q. Some narrow issues on ethics in 14 medical research. 15 A. Not that I recall. You know, I've written 16 in widely in medical history and medical education 17 and healthcare delivery, and certainly there are 18 enormous number of ethical issue that pervade both 19 the practice of medicine and of the delivery of 20 healthcare in the healthcare system, but I have 21 not written as an ethicist. 22 Q. You began your work, as I 23 understand it, in August of 088? 24 A. That's correct. ~ N 25 Q. Was your first trial Chipellone? A. William Roberts, Jr. & Assooiates (800) 743-DEPO W P,
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0 • 81 1 week, you did ask last week for billing records as 2 well. So that's noted in -- 3 MR. MAISTROS: Just keeps getting 4 noted and sometime I'11 file a motion and we'll S have a hearing on it. 6 MR. CONGROVE: I don't think you'll 7 have to file a motion on that. 8 Q. You do have billing records for the 9 Scott case, particularly the Scott case? 10 A. No, I don't. 1]. Q. Have you billed any time for the 12 Scott case? 13 A. No, I haven't. 14 Q. Your preparation that you testified 15 about earlier, was it just for the West Virginia 16 case yesterday? 17 A. The preparation yesterday? 18 Q. Yes. 19 A. Is what you're asking about? It's my 20 understanding that was to be for both depositions 21 since they were both going to be at the same time. 22 Q. How many hours have you devoted I 23 thus far to the Scott case? 24 A. Oh, approximately the same number of hours 25 that I've devoted to the Blankenship case. A. William Roberts, Jr. & Associates (800) 743-DEPO W ~F+ W N
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87 ~ 1 Q. No. 2 A. No. 3 Q. Somewhere. 4 A. Somewhere. My accountant probably does. ~ 5 Q. Do you have any objection to ; 6 providing those? 7 A. If my attorney asks me to. I would like to 8 discuss it. But quite frankly I don't feel that's 9 appropriate to my testimony here today, and it's a 10 private matter, and quite frankly I would prefer , 13 not to. 12 Q. vrho's your attorney? ~ 13 A. Well, I presume the attorney in this case, 14 Dechert, Price. Actually, it might be -- in your 3 0 15 case, it would probably be Shooke, Hardy. 16 Q. Are the 1099's issued by the law 21 Q. Do you know which tobacco companies 22 you're being paid money to testify in behalf of? 23 A. I'm being paid money for my time. i'm not 17 firms or the tobacco companies? 18 A. I don't pay a lot of attention to these 19 details, but my recollection is that they come 20 from the law firms. 24 being paid money for any, you know -- the 25 testimony is mine, I'm being paid for my time. A. William Roberts, Jr. & Associates (800) 743-DEPO f i OD
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• . 90 1 Q. Have any of the grants that you've 2 listed on your CV been funded by tobacco related 3 entities? 4 A. None. 5 Q. The money that you receive in your 6 tobacco consultations, do you have to report that 7 to the university? 8 A. We are not required to do so. 9 Q. Are there any guidelines 10 established by the university in terms of your 12 consulting work, any limitations placed on it? 12 A. The greatest concern with the university is 13 on the subject of conflict of interests. Their 14 great concern is with a-- oh, I'm speaking in the 15 hypothetical, you know -- a clinical investigator 16 is studying a new drug involved with the clinical 17 trial who owns stock in the drug company or who 18 has some financial ties with the drug company. So 19 conflict of interest in the sense that I'm 20 describing it now I would describe as the great 21 concern of the university. 22 Q. Does the university have written 23 guidelines on conflict of interest? 24 A. Yes, there are. 25 Q. Where could I find those if I was A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • 88 1 Q, which companies are paying for your 2 time? 3 A. Frankly, I don't know. 4 Q. Does it matter to you? 5 A. In terms of whether the defendant is Philip 6 Morris or Lorillard? Not really. Not as far as I 7 know. 8 Q. Other than your work with the 9 tobacco companies, do you do outside consulting 10 work with any other entities? 11 A. I'm asked to be a consultant at various 12 healthcare things from time to time. 13 Q. what type of issues are -- are they 14 cases? 15 A. Are you talking legal cases or consulting 16 that is not related to a legal issue? 17 Q. ].B A. Yes. ].9 Q . 20 A. Yes. 21 Q. 22 today? 23 A. Right. 24 You teach; correct? And you get paid to teach? And you consult, like you're doing Is this consulting? • 1 25 A. Yes. But Ism asking you -- I don't A. William Roberts, Jr. & Associates (800) 743-DEPO { H
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89 1 understand your question. 2 Q. I'm getting to that. 3 A. I'm seeking a clarification. 4 Q. You teach? 5 A. Are you talking about legal consulting or 6 are you talking about other organizations. 7 Q. We'll get to that. You teach and 8 you get paid; right? 9 A. Correct. 10 Q. And you consult and you get paid? 13. A. Correct. 12 Q. And part of your consultation is in 13 the tobacco area; correct? 14 A. That's correct. These cases here. 15 Q. What other type of cases do you 16 receive monies for consulting? 17 A. I have been involved with no other legal 18 cases. 19 Q. How about nonlegal cases? 20 A. Well, occasionally I get asked to speak or 21 give a talk and usually there's an honorarium 22 associated with that. 23 Q. Have you received any honorariums 24 from tobacco related entities? r N 25 A. None. A. William Roberts, Jr. & Associates (800) 743•DEPO
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• • i 91 ] interested in looking at them? 2 A. if you're interested in looking at them, 3 they're probably in the medical school business 4 office somewhere. They send them out 5 periodically. Most of us just kind of toss them 6 when we see them. I don't know offhand which 7 individual to direct you to, but if you were to 8 call the dean of the Washington University Medical 9 School they probably could help. 10 Q. Who is that? 11 A. Who's the dean? 12 Q. Yes. 13 A. The dean is -- well, we've got quite a few 14 deans. 15 Q. Is there a dean for academic 16 affairs? 17 A. We don't have one right now. You could 18 call Ken Polansky's office. Ken is the chairman 19 of the department of medicine and he circulates 20 those. 21 Q. Has anyone at the university ever 22 made inquiry of you as to your activities in 23 consulting with the tobacco companies? 24 A. I don't understand that question. 25 Q. Has the issue of your consultation 0 A. William Roberts, Jr. & Associates (800) 743-DEPO i 0 W d* .P ' to
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• • • 102 1 was written in 1963 by a tobacco scientist that 2 traced the history of literature in terms of 3 smoking'and health and disease, would that be of 4 interest to you as an historian? 5 MR. CONGROVE: Objection. Asked and 6 answered. 7 MR. DODDB: Object to the form as 8 well. 9 A. Well, as an historian of medicine, I was 10 interested in all the literature that I could 11 obtain pertinent to my subject. And also you have 12 to understand what the borders are, and in my_case 13 the borders of this project was to publish 0 5 14 scientific literature, so I would be especially 15 interested in that if that had been a published 16 study. 17 Q. Did you ever ask the tobacco 18 companies if they had a research library of 19 medical articles concerning smoking and health and 20 disease? 21 A. I had no -- no, I had no reason to do 22 that. I had complete access to the world's 23 literature myself, as an independent investigator. 24 Q. And so we're clear on this, when 25 you refer to the world's literature, you're not A. William Roberts, Jr. & Assoc(ates (800) 743-DEPO 0 ~ 0
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95 I the tobacco company since '88? 2 A. well, as I mentioned I have kept senior 3 officials in the loop, so they are cognizant of my 4 involvement. 5 Q. Are you aware of allegations 6 leveled at the tobacco industry since 1994 7 concerning destruction of documents, suppression 8 of research, bribing of medical practitioners? 9 MR. DODDS: Objection to form. 10 Q. Allegations. Are you aware of 11 those allegations? 12 13 14 15 A. During what time period? Q. From 1994, '5 to the present? A. No, I'm not aware of those. Q. Do you read any of the JAMA 16 articles on the BSO documents? 17 A. I have -- I know that JAMA did have 18 articles on the BW documents. I have not read 19 those articles. 2o Q. Just as a general proposition, in 21 your work as an historian, was it easier, harder. 22 or it makes no difference to look at the history 23 of a subject such as tobacco smoking and health 24 from, let's say, the period you took was 1930 to 25 1964 -- A. William Roberts, Jr. & Assoolates (800) 743-DEPO
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• • • 98 1 most of those were published after 1964. So, from 2 that sense, there would have been fewer things.to 3 look at and it would have been easier. 4 Q. Did you, as part of your study, S look at any historical analysis that was done by 6 researchers at the tobacco companies as to the 7 state of the science from that 1900 to 1964? 8 A. Any published studies? 9 Q. Yes. 10 A. As we sit here today, I do not remember any 1]1 histories of the subject or accounts of the 12 subject written by individuals who were employed 13 by the tobacco companies. 14 Q. Do you think -- 15 A. There were histories of cancer and 16 histories of public health and things of that sort 1'7 that were part of my understanding of the subject, 18 but I do not recall any history written by, you 19 know, someone who was a tobacco company scientist. 20 Q. would it interest you as an 21 historian, as an expert in this case, to review a 22 survey of the literature that was done by somebody 23 that was employed by a tobacco company in 1963 to 24 determine what they thought the status was of the 25 state of the medical science concerning smoking A. William Roberts, Jr. & Associates (800) 743-DEPO 4 A %D
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. . 1 A. 94 I never appeared at Chipellone trial. j ~ 2 Q. Did you testify in deposition at i 3 Chipellone? i 4 A. Not for the Chipellone trial. + 5 Q. For the retrial? ; 6 A. For the retrial. There was a deposition i 7 for the retrial. As you know, that case was never ; 8 -- that -- never tried. 9 Q. Was that your first experience 10 testifying in behalf of the tobacco companies? 11 A. That was my first experience with the ' 17 was in the Chipellone matter? 18 A. The first time in terms of a formal legal 19 proceeding, that was my first deposition. 20 Q. Did you raise the issue of your 21 participation in that matter with the university 22 before or after you participated in that matter? 23 A. Before. 12 deposition. As I've said before, I am testifying 13 in behalf of my ideas, not on behalf of tobacco 14 companies. 15 Q. The first time you expressed your 16 ideas as it related to smoking and health issues 24 Q. Has the university revisited the 0 1 25 issue of your participation as a consultant for A. William Roberts, Jr. & Associates (800) 743-DEPO I U
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• • 104 1 schools, universities, the tobacco companies? 2 A. I didn't keep such a sheet. 3 Q. Do you know -- 4 A. If you're interested you can look at the 5 articles and identify as to what institutions 6 people came from. 7 Q. Is there a list that is not in your 8 handwriting that Is worse than my handwriting that 9 i could actually read? Is there a typed list? 10 A. Everything is in -- you have the best 11 available. I did everything by hand. And if you 12 don't have better copies, you can ask r7ark Edell 13 for the originals. 14 Q. He still has the originals? 15 A. He still has the originals. He took them 16 to have copies and to have his staff type them up, 17 and despite multiple requests he never returned 18 them. 19 Q. He has original handwritten notes? 20 A. He has original handwritten notes. He was 21 going to have his staff type them up, because, as 22 you point out, i've got one of the world's bad 23 handwriting -- 24 Q. And mine is worse. 25 A. -- and T was going to help him with any A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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0 • 96 1 A. Correct. 2 Q. Is that true in Scott as well? 3 A. Yes. 4 Q. I assume it is. That period, is it 5 easier to look at that historical period today or 6 if you were back in 1964 looking at that period or 7 doesn't it matter? 8 A. As an historian? Are you talking about the 9 issue of the stated knowledge? My subject, the -- 10 Q. Let's just -- 11 A. The state of scientific knowledge and 12 understanding? 13 Q. Assume for me you were hired to do 14 what you were hired to do in this case, but you 15 were hired in 1964, do you think your task would 16 have been easier in 1964 than today or the same 17 or -- 18 A. if I were hired in 1964? I think I would 19 have a hard time doing that. I was a school boy. 20 Q. Well, you were 17; right? 21 A. High school. I mean, if I were hired to 22 begin a study today that had 1964 as the beginning 23 point? Is that what you're asking? 0 24 25 Q. No. Let's put yourself as a historian -- let's assume that you could put 0 0 A. William Roberts, Jr. & Associates (800) 743-DEPO
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• ! 97 1 yourself back in time in January of 1964 and you 2 have all the credentials and education that you 3 have now sitting here today? 4 A. I see. 5 Q. You're not 17 in high school. 6 A. So I'm an historian working in January 7 164? 8 Q. Yes. Would your task have been 9 easier? 10 A. My task would have been about the same. 11 Q. And back in 1964 if you had 12 undertaken this task, do you think it would have 13 been relevant to look at some of the historical 14 reviews that predated 1964; in other words, to 15 look at what other people had done in terms of 16 looking at the history of health, smoking, 17 tobacco? 18 A. Well, actually I did that. 19 Q. Do you think that your task would 20 have been the same in 164 as it was today? 21 A. it would have been a little easier in that 22 regard, because the secondary literature was much 23 thinner in 1964. Most of the secondary literature r ; t 24 about tobacco and the history of cancer research 25 and the whole panoply of subjects that I studied, 1 ~ A. William Roberts, Jr. & Associates (800) 748-DEPO W I N ~ ~ . ~ ~
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• • 99 1 and health and disease? 2 A. Well, first of all, there are two -- your 3 question is compound. Number one, I thoroughly 4 examined the existing world's literature myself. 5 So, from that perspective, I did as thorough an 6 examination of the published literature as was 7 humanly possible. I literally read every article, 8 every article, that was published in the world's 9 literature 1930 to January 1964. So.I did a very 10 systematic review of the subject. if an article 11 had been published on the subject written by 12 anyone, I don't care if it's someone who was 13 employed as a tobacco company scientist or someone 14 at the National Institutes of Health, if it was 15 published, it was of interest to me because that 16 was part of the marketplace of ideas. It was not 17 my project or concern to look at unpublished 18 materials and, you know, interim reports and, you 19 know, the huge amount of internal conversation 20 that goes on in any company or any organization. 21 You'll have the same thing in a medical school, in 22 Memorial Sloan-Kettering, National Institutes of 23 Health. So I didn't even attempt unpublished 24 material, but-it wasn't necessary because, for my 25 purposes, the marketplace of scientific ideas is 'i I I A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 0 103 1 suggesting, are you, that the literature that's in 2 the archives, libraries, law offices of the 3 tobacco companies attorneys are part of the 4 world's literature? 5 A. I'm talking about the published scientific 6 literature pertaining to lung cancer and health 7 hazards of cigarette smoking, and these are e obtainable from the Index Medicus, which is the 9 guide to the word's scientific.literature, and 10 that's how I generated my bibliography of sources 171 to be looked at. 12 Q. And in one of your depositions, I 13 think you testified you spent 2,000 hours reading 14 these articles? 15 A. About a 1,000 hours. This is 19 -- this 16 is 1988 and 1989 and that was a summation that 17 included -- most of the time was actually spent on 18 the articles themselves, but it also included the 19 work that I did in the secondary literature, and 20 things of that sort. So that was the total, not 21 just articles, but all the work that I did. There 22 was work beyond the primary published literature. 23 Q. And can you tell as you were 24 reading those -- you didn't keep a cheat sheet as 25 to whether these scientists were from medical A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • 105 i words he had difficulty deciphering, but he never 2 returned those to us. So I am now without my 3 originals and have been for the last ten, eleven 4 years. 5 Q. Let me -- well, what did I mark? 6 6 was the notice? Is 7 the accurate version of your 7 report in the Scott case? 8 (Plaintiff's Exhibit 7, report in 9 Scott case, marked for identification, this date.) 10 Q. Is No. 7 an accurate version of 1]. your report in the Scott case? 12 A. Looking at it quickly, it seems to be. 13 Q. Did you prepare that report? 14 A. No, I did not. 15 Q. Do you know who prepared it? 16 A. I'm not certain. It was someone at the 17 Shooke Hardy firm. And whether it was David 18 Woods, whether it was Billy Randalls, whether it 19 was someone else, I don't know precisely who did 20 it. 21 Q. Shooke, Hardy is the law firm for 22 which defendant in this case? 23 A. I don't know. 24 Q. Tn any event, you did not prepare 25 that report? A. William Roberts, Jr. & Associates (800) 743-DEPO
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. . 106 1 A. That's correct. 1 2 Q. This will be number 8. 3 (Plaintiff's Exhibit 8, Defendants' 4 Joint Expert Reports Index Volume 4, marked for 5 identification, this date.) 6 Q. Now, Exhibit 8, I'll represent to 7 you, is provided by your counsel, somebody 8 associated with your counsel, and I'd like you to ~ 9 take a look at it and can you tell me what 10 Exhibit 8 is made up of. 1 11 A. The first article is by Dr. Churchill, I S 12 1948, which is a very important special article he i 13 wrote reviewing the state of understanding of 14 cancer of the lung as of 1948, and that's, I 15 thought, an important and useful article. 1 16 There is an article by Luvin, I 37 Hullstein and Gerhart, from Journal of American ~ ].8 Medical Association in 1950, which is an important f 19 study. It was one of the early retrospective 20 studies -- there were several of,them published ~ 21 that year, as I mentioned this morning -- but one ~ 22 of the earlier retrospective studies linking i ~ 23 cigarette smoking with primary carcinoma of the i 24 lung. 25 There is Tobacco Smoking as an A. William Roberts, Jr. & Associates (800) 7a3-QEPO N w . N ~ . I '7J A J
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0 • 101 1 see what the scientists of 1930 to 164 had to say 2 about tobacco and cancer or tobacco and health? 3 What was it? 4 A. Tobacco and lung cancer. 5 Q. Tobacco and lung cancer. Did you 6 look at any other specific diseases? 7 A. I looked -- no, I did not. I looked at 8 lung cancer 9 Q. 12 A. I am -- part of the review of tobacco, 13 including the Surgeon General's course -- report, 14 does discuss the consequences of tobacco on other 15 organs. so insofar as I read the Surgeon 16 General's report and some of those studies, that 17 would be included. But I did not specifically go 18 out to study bladder cancer or to study peptic at and tobacco. And you're not prepared to offer an least an historical opinion, on 11 diseases other than lung cancer in the Scott case? 10 opinion, I 19 ulcer or anything of that sort. 20 Q. Or emphysema? 21 A. No. The focus was lung cancer. 22 Q. Was that by choice or were you 23 instructed to focus on lung cancer? 24 A. That was the mutual agreement. 25 Q. If I could give you an article A. William Roberts, Jr. & Assoolates (800) 743-DEPO that A Ln N
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• • . 100 1 the published medical literature and that's what I 2 reviewed. 3 Q. What is the source of the material 4 for the public medical literature? 5 A. what is the source? 6 Q. From where does that information 7 come? e A. Do you mean who does medical research or 9 where did I find articles? 10 Q. You read 1400 articles. 11 A. Correct. 12 Q. Did you categorize them into 13 different areas as to where they originated from, 14 those articles? 15 A. I'm not sure I follow that. what do you 16 mean characterize -- 17 Q. Are they written by sports writers, 18 are they written by actors? 19 A. Scientists. Physicians and biomedical 20 scientists. This is scientific literature; it's 21 not Reader's Digest. It's not an actor talking 22 about his views of tobacco smoking for U.S.A. 23 Today. No, this is the scientific literature. 24 Q. . So you -- the 1400 articles you 25 read, you went to the library and said I want to A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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• 109 1 had, but the actual composition of the report was 2 done from the law office. 3 Q. Did you provide editorial comment 4 on the report? 5 A. When reports would be sent to me, I would 6 read them, and in some cases -- as you yourself 1 7 are pointing out, there are a lot of cases and 8 it's easy to get them confused with each other and 3 9 you're doing this all the time. I'm just involved ~ , 10 with an occasional case, and it's even more ~ 11 confusing for me. So if you're looking at the i i 12 cases that you mentioned, Scott, Blankenship, and ~ 13 then Anderson from this year, in some instances I 14 would read the report and approve it and in other 15 instances I do remember having minor changes to 16 suggest. I cannot tell you which report i 17 approved without suggesting changes and which ones 7.8 I did have the changes to. ].9 Q. So, Exhibit 7, the report in this 20 particular case that has been submitted on behalf 21 of the tobacco defendants, you couldn't tell us, 22 as you sit here today, whether or not you provided 23 editorial input into that report? 24 A. Well, I approved it and that itself is 25 editorial input. Whether I suggested any changes G A. William Roberts, Jr. & Associates (800) 74S•DEPO
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• 107 ~ 1 Etiological Factor in Disease, Cancer, published 2 in -- it's hard to read these -- from Cancer ; ~ 3 Research. I'd actually have to reread the article 4 to explain why it is listed in here, but it's -- ; 5 it looks as, you know, one of the studies from the : 6 early 5o's that helped provide evidence linking 7 the two, but I'd have to read that article.. 8 There is an important paper from 9 winder, Graham and Korniger, Experimental 10 Production of Carcinoma and Cigarette Tar that ~ 11 reviews the evidence to date in terms of the skin 12 painting experiments. 13 Let's see, what's next? There is 14 another article by Dr. Barr, Carcinogenic Activity ( C 16 and Remote Radiation. I 15 of Cigarette Smoke Condensate, Effective Trauma 23 Q. You're welcome to go through them 24 all, but you'll see as get further in, as then 25 your handwritten copies of notes, the original of 20 that I have used. Some of them I am extremely 21 familiar with; others that I am -- others I 22 haven't reread quite as recently. 19 A. These are all articles that I have read andp; 18 these out to be provided? 17 Q. These articles, did you select A. William Roberts, Jr. & Assoolates (800) 743-DEPO
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• 110 1 to the draft, I don't remember. As I said, I did 2 not compose it, but I approved it. 3 Q. Did you do anything unique to the 4 State of Louisiana with respect to your report in 5 the Scott case? 6 A. No, I did not. 7 Q. Are your opinions, if they ever are 8 offered in the Scott case, are they going to be 9 similar to the opinions you've offered in other 10 cases or is there anything in particular you're 11 going to say with respect to Louisiana? 12 A. Well, as you undoubtedly know, I don't know 13 precisely what I'm going to be asked or what I'm 14 going to speak on in the Scott case, but the 15 general subject matter that I'm speaking on is 16 identical to the two cases and I do not have any 17 unique view of the material applicable to Scott 18 case that is not equally applicable to the 19 Blankenship case. 20 21 22 23 24 25 I A Q. If I could just quickly run through the cases you have testified in to make sure I have it straight. Okay? A. Certainly. Q• You testified in the Chipellone in i ! a deposition format in Chipellone? ® A. William Roberts, Jr. & Associates (800) 743-DEPO W O N
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! 108 1 which Mr. Edell has kept, and you've got some 2 other articles back towards the back, and my 3 question is, did you select these for any 4 particular reason, the articles, at least? 5 A. I did not select the articles. I presented 6 the concept and ideas. I mentioned the articles 7 and I think that the articles themselves were 8 selected as examples illustrating the points that 9 I was making. 10 Q. Do you know if the attorneys 13 selected those articles to include with your 12 report, or did you have input into it? 13 A. Well, I had input into it, because I saw 14 the reports and I saw the citations and I saw -- 15 if they report -- if they reported something to 16 you, it came from work that I did and they would. 17 send it to me and I would review it, but I did not 18 physically prepare the reports. Or when it came 19 to decide which of these skin painting articles or 20 retrospective studies or prospective studies, or 21 whatever it may be should be included, if they 22 were acceptable to me I approved the statement, 23 but I did not say you study A or study B. They 24 had some idea of the sense that I considered 25 things important just from conversations that we A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 0 9 the Mississippi AG action? 8 Q. And you testified in deposition in F 6 the Chipellone case. And that's all I know about 7 it. i11 1 A. Correct. 2 Q. And the retrial or hearing on 3 retrial? 4 A. I don't know anything about that. I gave 5 one deposition. That was part of the retrial of 10 A. Correct. I believe that's correct. 11 Q. And you testified in the Oregon 12 action. Was that a private case or AO case? 13 A. The Oregon was a private smoker case and 24 that was not a deposition. That was a court 3.5 testimony. Mississippi, as you know, was a 16 deposition. Those cases were settled. 17 Q. Did you have input into the 18 settlement of the AG cases? 19 A. Did I have input? 20 Q. Yes.. Were you consulted? 21 A. No, not at all. 22 Q. The Washington case was an AG 23 action? 24 A. Correct. 25 Q. That was a deposition or did A. William Roberts, Jr. & Assoofates (800) 743-DEPO t W ~ ~ N
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0 • 114 1 A. Oh, I don't know precisely. No. 2 Q. In excess of a half a million 3 dollars? 4 A. If you are looking at the total payment 5 from 1988 through the present, you know, over 6 twelve years, I'd say half a million dollars would 7 be a reasonable approximation. 8 Q. You testified in the case Kotler 9 vs. The American Tobacco Company? 10 A. That's correct. 11 Q. That was a trial? 12 A. That was a trial. 13 Q. Do you remember testifying in that 14 case that at least through 1964 the A.M.A. did not 15 take a position on smoking and health? 16 A. Yes. 17 Q. Is that still your opinion today? 18 A. Yes, the historical record hasn't.changed 19 and I would agree with all of my testimony from 20 the Kotler case today. I do not view anything 21 differently today from what I did at the time, 22 and, you know, as I point out -- you asked -- 23 either you or the other gentleman -- what type of 24 preparation do I do? We11, I want to give you the 25 fairest, most accurate answers, and I want to be A. William Roberts, Jr. & Assoalates (800) 743-DEPO W ~ ~ .
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• • • 1 this issue of 2 working -- if 3 instrument or 4 treatment and 5 outcome, that 113 investigator bias. If you are you are testing a drug or a new piece of apparatus or equipment or you have a financial stake in the clearly has the potential to create 6 bias and influence your collection of data and 7 your interpretation of data. I am not funded by 8 the tobacco company, I've had no relationship with 9 either the law firms or the tobacco industry 10 except for these specific cases. There is no 11 connection at all between these cases and my main 12 work as a physician and medical educator and 13 writer. So there is no conflict of interest as we 14 at the university would use the term. 15 Q. When you say you're not funded by 16 tobacco companies, you are paid by the tobacco 17 companies, aren't you? 18 A. I have been compensated for my time. I was 19 referring you to the grants that you pointed out 20 before. The tobacco companies do not support my 21 research, my writing that I've done in the history 22 of medicine and in medical education. 23 Q. Do you know how much money they 24 have paid you over the years since August of 1988 25 to testify in their behalf? A. William Roberts, Jr. & Associates (800) 743-DEPO
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120 1 biographies on any of the 1400 articles of people 0 2 who spoke. 3 Q. Would you agree that the position 4 the A.M.A. on a correlation or a relationship 5 between a smoking and any particular disease is 6 more significant than the opinion of a particular 7 scientist? 8 A. Well, the A.M.A. opinion is certainly 9 important. They certainly were one of many 10 important organizations that was speaking, 11 including National institutes of Health, National 12 Cancer Institute, Memorial Sloan-Kettering, U.S. 13 Public Health Service, American Public Health 14 Association, American Cancer Society, American 15 Heart Association. one could go on with the list 16 of important organizations that spoke 17 constructively on these issues. And scientists 18 also spoke on the issue, and the importance of 19 that often depended on the individual. Some 20 scientists were more notable than others. 21 Q. The period, though, that you were 22 studying from 1930 to 1954 in particular, don't 23 you think it was important to figure out the 24 potential biases of a group such as the A.M.A.? 25 A. Well, your question is based upon some A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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• • 119 i i remember one article on the A.M.A. that I read, ; 2 and that isn't part of my bibliography, and it 3 explains that they were on the tail end to accept 4 the clinical epidemiology as a legitimate way to 5 draw conclusions about the causation of chronic 6 disease. Some people at the beginning, some 7 people are at the broad middle, some people are at 8 the tail end. And I take that at least for the 9 moment as face value. This has to be taken in 10 context of the entire world's literature, which is 11 what I studied. 12 So when I study what the scientific 13 consensus is or what scientific attitudes are, 4 14 there is a period of time. You know, you will always have people with different opinions. 16 A.M.A. had one opinion. others shared that 15 The 17 opinion. But I didn't -- it was not necessary for 18 my description of the state of knowledge about the 19 causes of lung cancer to start going into personal 20 histories and biases of anyone who may have spoken 21 on it. You know, couldn't some of those who 22 thought there might have been a relationship been. 23 biased in some way? I did not go into the subject 24 of bias on anyone. They had their data, they 25 spoke, they gave their opinions, but I didn't do A. William Roberts, Jr. & Assoaiates (800) 743-DEPO
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tion is to reread 2 my earlier depositions and court testimonies, the ! . 1 consistent. part of my prepara 3 three testimonies that there have been, and I 4 would concur with everything I said in Kotler. 5 Q. So you have read Engle, Anderson, and as 9 part of my preparation for this deposition today, 6 Kotler? Any other case you've testified in? 7 A. There have been three court testimonies 8 three or four depositions prior to today. And 10 I did reread both the depositions and 11 testimony. 12 Q. And there's 13 today that jumps out that ~ 15 differently? my courtroom i nothing as you sit here you -- that says, I wish i 14 I hadn't said that, or I wish I said that 16 MR. DODDS: Object to the form. 17 A. As I sit here today, I would agree with cases 20 Q. Did you ever look from a 18 testimony both in the previous court 19 the depositions. and 21 perspective as to why the A.M.A. didn't take a 22 position on smoking and health before 1964? 23 A. I did not study the history of the A.M.A. 24 or its attitudes or views. 25 Q. Are you a member much? A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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. • 1 that -- 2 A. That was a deposition, and as all the AG 3 cases, as you know, with I guess the exception of 4 Minnesota, that was settled. 5 Q. Were you consulted for Minnesota? 6 A. I did not testify in the Minnesota case. 7 Q. Were you consulted on that case? 8 A. I was approached about it. There was talk 9 at one point that I might be asked to testify, 10 and, in fact, I was not asked to testify. 11 Q. Have you ever turned down a request 12 by the tobacco companies to be a consultant? 13 A. Yes, I have. 14 Q. What case? 15 A. Well, I don0t know the names of the cases, 16 but I have turned down, if I have been too busy to 17 work at that time. 18 Q. Have you ever refused to consult 19 for the tobacco companies because of what you 20 perceived as a conflict of interest? 21 A. You mean as I defined it before, 22 university? 23 Q. In any definition. 24 A. No. A conflict of interest in medical 25 skills and medical science today has focused on A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 122 1 any statement before then. On the other hand, the 5 because of the viewpoint that the cause was 4 issue before then, it was a broad spread silence 3 the 1950's either. So if there was silence of the 2 medical community was not making statements until 6 unknown -- and I'm speaking before 1950 -- the 7 cause of lung cancer was considered unknown, 8 unknowable, and there was no evidence before 1950 9 to link cigarette smoking with lung cancer. After 10 1950, earlier reports start coming in, this 11 becomes an area of very active inquiry worldwide, 12 and the frank statement is the first statement I'm 13 aware of from the tobacco industry. And, as I 14 said, it's very consistent in the context of when 15 it was written. 16 Q. At what point in time, if you can 17 offer an opinion, if you believe it to be the 18 case, at what point in time would it have been 19 inappropriate to publish the frank statement as an 20 accurate statement on the state of knowledge in 21 that area? 22 A. Could I see the frank statement? 23 Q. Did you say it? 24 A. Could Y see the frank statement? 25 Q. I'm sorry. Was it marked, sort 1 i 0 I A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 116 1 A. No, I'm not. 2 Q. Have you ever been? 3 A. I was a member for one year when they gave 4 me a grant. with the exception of that 5 twelve-month period, I have not been a member. 6 0. Have you read any documents, seen 7 any news articles that would suggest that for a 8 certain period of time that tobacco had devised a 9 strategy to fund the A.M.A. in order to buy their 10 silence in the smoking and health controversy? 11 MR. DODDS: ObjeCtion to form. 12 MR. CONGROVE: Objection to form. 13 A. Could you please repeat the question. 14 (Question read.) 15 A. To answer your question, honestly, I have 16 heard that allegation before, mainly through 17 plaintiff lawyers in some of these other cases who 18 have raised that question, but I have not studied 19 that and I have not seen any documents that would 20 allow me to draw any conclusions about that one 21 way or the other. 22 Q. If you saw a document that was 23 drafted by an attorney for the tobacco companies, 24 would that interest you? 25 MR. DODDS: Objection to the form. A. William Roberts, Jr. & Associates (800) 743-DEPO i W I A O1 , -J
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118 1 history of the scientific understanding of the 2 health hazards of cigarette smoking, in a precise 3 period, 1930 to January 1964, and that's what I 4 did. And I read secondary literature that helped 5 me understand that topic better. But I did not 6 feel it was necessary for me to do a history of 7 the American Medical Association, a history of the 8 tobacco industry, a history of the NIH, a history 9 of Memorial Sloan-ICettering, etcetera, etcetera, 10 as part of this project. 11 Q. Is it not relevant to your 12 historical analysis the position the A.M.A. 13 throughout the period from '30 to '64 -- ]4 MR. CONOROVE: object to form. ].5 Q. -- on smoking and health? 16 A. The position of the A.M.A. is relevant and 17 that actually is part of my testimony, and as you 18 pointed out a few minutes ago, the A.M.A., prior 19 to 1964, had not taken a position on the issue. 20 Q. And if the A.M.A.'s position on 21 smoking and health is relevant to your historical 22 analysis, wouldn't it also be relevant to 23 determine whether or not they were biased In their 24 presentation of their views? 25 A. Their -- actually, as we speak, I do A. William Roberts, Jr. &.Assooiates (800) 743•DEPO l
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121 1 inaccurate and incorrect premises, because 2 opinions are subject to the scientific 3 marketplace. it's not that any organization had 4 an opinion and could influence policy. Everyone 5 was speaking up. Their ideas were assessed by 6 others. Some agreed, some didn't agree. And I Is 17 not here to testify on history of tobacco company, 8 nature of scientific work and scientific 9 communication than is suggested by the way you're 10 phrasing your questions. i] Q. what position did the tobacco 12 industry espouse between '30 and 154 on the 13 smoking -- '30 and '64 on the smoking and health 14 issue? 15 A. Well, the first statement that I'm 16 personally aware of -- and as I said earlier I am 7 think that one has to understand more properly the 18 their attitudes, their behavior, their responses. 19 It's not what I'm testifying on. But ineofar as 20 they did issue the frank statement and I've seen 21 that as part of my work, I'm aware of that, that 22 is the first statement that I've seen, it's very 23 reasonable in my view. As I said before, it's a 24 very reasonable statement, in the context of the 25 scientific knowledge of the day. i'm unaware of A. William Roberts, Jr. & Assoaiates (800) 743-DEPO
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0 0 117 1 A. What do you mean by would it interest me? 2 Q. As an historian, would it interest 3 you to read a document drafted by an attorney for 4 the tobacco companies that suggested there is 5 evidence within the tobacco industry that they 6 paid off the A.M.A. for a certain period of time? 7 A. That's a question that is based upon some 8 false premises. You know, as a historian would 9 you be interested in a document? As a historian 10 would you be interested in a document on -- for 11 biography of Abraham Lincoln? In a general sense, 12 as an historian, you're interested in history, you 13 are interested in documents. That's what we do. 14 But we also have to place -- we have to walk the 15 balance. On the one hand, we need to be 16 comprehensive in the work that we do, the study 17 that we do, and this was illustrated in my work by 18 reading the entirety of the world's published 19 literature. But, at the same time, you have to 20 know how to put borders around your work, 21 otherwise you're spending your whole life reading 22 and writing and not making any progress, in terms 23 of conceptualizing and writing things. So, for my 24 purposes, I was studying the history of the 25 scientific understanding of lung cancer, the A. WilHam Roberts, Jr. & Assooiates (800) 743-DEPO 3 t ~ a ~ ~ 00
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123 i 1 of? Do you have a copy? 2 MR. DODDS: Please note my 3 objection to the form and the foundation for that 4 question. 5 A. I'm not certain it is possible to answer 6 that question directly because it's a question 7 based on inaccurate and incorrect premises. 8 Historians deal with what happened, not with what 9 didn't happen or what might have happened. You 10 could equally have asked me what would have 11 happened if Napoleon had the B-52 Bomber. The 12 fact of the matter is that this statement was 13 published in 1953 -- or, excuse me, in early 1954, 14 and in my judgment it accurately reflects the 15 scientific context of the period. And I think 16 that's about all I'm able to say about it or that 17 any respectable and responsible historian could 16 say about it. 19 Q. You've already offered the opinion, 20 have you not, that at least by 1964, in the 21 aftermath of the Surgeon General's report, a 22 controversy was over at least in the scientific 23 community; is that a fair characterization? 24 A. Right. Yes, it is. 25 Q. So if you're offering the opinion ~ W A. William Roberts, Jr. & Assooiates (800) 743-DEPO N A W J A
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• • 125 1 the cause is," something of that sort, would not 2 be as accurate if you're looking post 1964. 3 Q. And that's -- and in fairness to 4 you, you didn't look post '64, did you? 5 A. That's correct. As i've stated all along 6 here today and in the previous depositions and 7 testimony, my work goes through 1964, but not '64 8 onward. 9 Q. And you could not offer an opinion 10 in this case on the state of medical knowledge at 11 any point subsequent to '64, or you've not been 12 asked to at least? 13 A. I've not been asked to. 14 Q. Could you? 15 A. what do you mean could I? 16 Q. Could you offer an opinion post 17 '64? 18 A. in terms of -- 19 Q. same issues you look at from '30 to 20 '64. 21 A. No. I have not, in the same systematic way 22 traced things forward, you know, looking at all 23 the studies that came out. Certainly my research 24 included '64 and the response to the immediate 25 response to the report, but if you're talking '68, 1 A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 0 126 3. '72, '80, '95, 2000, no the answer to that is, 2 quite correctly that I am not -- I couldn't -- I 3 could do it in the sense of if I had the time and 4 interest, which I don't, I could do such a study, 5 but in fact I haven't done such a study and I'm 6 not prepared to speak on that. 7 Q. If you were asked in 1964 by the B tobacco defendants whether it would be appropriate 9 to publish the frank statement, is it fair to say 10 that not -- that you would not recommend they do 11 so without certain revisions? 1964. 12 MR. DODDS: Objection to form. 13 A. You know, this question goes outside of my 14 expertise. I'm a medical historian and I deal 15 with the scientific ideas and their evolution in 16 the social context and I deal with what I've 17 studied. Even in 1953 or '54 when this did come 18 out, I would not be in a position to tell a 19 tobacco company what is proper to say, what is 20 improper to say, and I really have no claim to 21 speaking on company behavior, company responses or 22 public relations or what to publish. So you're 23 really going into areas that I am not qualified to 24 speak on and T-- 25 Q. You've already testified that you A. William Roberts, Jr. & Assooiates (600) 743-DEPO W J
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• 134 1 intensely debated medical issues of all times and 2 we have intense, and intensive scientific efforts 3 throughout this country and throughout other 4 countries investigating this. This is not just 5 the tobacco companies that are determining the 6 knowledge. 7 So, number one, if I am to get an 8 assignment done as a historian, I have to have my 9 borders, and if the topic is the existing state of 10 knowledge, then that's what I have to look at. 11 And I'm not interested, from that perspective, in 12 unpublished results from any laboratory, 13 Dr. Graham's laboratory, Dr. Winder's laboratory, 14 Hammond & Horn's laboratory. There's an enormous 15 amount of unpublished data that is a part of the 16 work of all science and none of that was of 17 concern to me from any laboratory. To understand 18 the medical marketplace I needed to know the 3.9 medical marketplace, and that was the published 20 literature and that's what I did and that's what I 21 did comprehensively. 22 And there is assumptions, if they 23 had suppressed research and so forth. I'm not 24 advocating supressing research. Please don't let 25 me misstate myself. But I would say two things ir A. William Roberts, Jr. & Associates (800) 743-DEPO
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r • 136 1 have to remember that there are lots of legitimate 2 reasons that people don't publish information they 3 have. And it would have made a difference only if 4 the scientific community had come up with 5 something totally -- excuse me, only if the 6 tobacco scientists had come up with something 7 totally extraordinary that the rest of the world's 8 scientific community did not have: If they had 9 produced.cancer human beings in their own 10 laboratories and didn't release that data. so, it 11 would -- even if suppressed, it wouldn't have 12 changed the understanding, unless it was huge and 13 different. 14 Q. And your answer would be the same 15 if the material was published research, that is, 16 it was in the world community of published 17 research, if it was edited by lawyers? 18 MR. DODDB: Objection to form and 19 foundation. 20 A. I did not follow that question. Could you 21 please repeat that. 22 Q. Your answer was based upon the 23 assumption that my question assumed that we were 24 talking about'unpublished literature. I want to 25 take it a step further -- A. William Roberts, Jr. & Assoaiates .(800) 743-DEPO
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• 128 1 the causes; that statistics purporting to link 2 cigarette smoking with the disease could apply 3 with equal force to any one of many other aspect 4 of modern life." 5 Indeed, the validity of the 6 statistics themselves is questioned by numerous 7 scientists. The scientific reports, you know, I B think is very accurate for January of 1954. if 9 you are going mid 60's forward, then we have a 10 decade's worth of new work, we have the Surgeon 11 General's report, and there would be modification 12 necessary. 13 Q. Including the conclusions that 14 there was no evidence linking cigarette smoking tc 15 cancer? 16 MR. DODDS: Same objeotion. 17 A. what year are you talking about? 18 Q. '66. 19 A. Well, I think that it's been my testimony 20 that during the 50's and 60's -- well, there are 21 really two parts to that, two answers, two parts 22 to that question. It all along has been part of 23 my testimony that new scientific evidence 24 continued to be generated in the mid 50's, the 25 late 50's, the,early 60's, the mid 60's, so the A. William Roberts, Jr. & Associates (800) 743-DEPO W N ~ 1i .o
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129 1 1964 Surgeon General's Committee has the advantage 2 of evaluating new work that did not exist in 1954; 3 new epidemiological and statistical techniques are 4 being created at that time, including in the 1959, 5 late 50's, early 60's. So there's more to draw 6 upon and we have the Surgeon General's report that 7 drew conclusions about causality. But it's also B important to recognize that science has a value 9 judgment, and what change was not so much the 3.0 evidence per se as attitude towards epidemiology 11 and statistics; the issue of statistical proof 12 versus experimental proof. Experimental proof had 13 been the gold standard accounting for essentially 14 every advance in medicine for the previous 500 15 years, and there were responsible medical 16 scientists who even after the Surgeon General's 17 report did continue to feel the case was not 18 proven because of the lack of the experimental 19 evidence. So that qualification has to be put in 20 there as well: That there could be disagreement 21 with the Surgeon General's report and that this 22 could be found among responsible scientists for 23 the reasons that I give. 24 Q. As part of your testimony in this 25 case, you're testifying as to the state of the A. William Roberts, Jr. & Associates (800) 743-DEPO ~ tJ W N ~ ...(a ' A CD 0
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• • 17 Q. Do you recall reviewing the Surgeon 18 General's report when you were a youth? 19 A. I did not read it at that time. 20 Q. Were you aware that it came out? 130 1 medical scientific knowledge on smoking now; 2 correct? 3 A. Correct. 4 Q. You're not prepared to and are not 5 offering an opinion on the public awareness of 6 that issue? 7 A. That is correct. 8 Q. or the awareness of a particular 9 percentage of the population, whether it be women, 10 children? 11 A. That is correct. 12 Q. You never did any analysis to 13 determine, for example, what percentage of the 14 population was aware of the Surgeon General's 15 report? 16 A. That is correct. 21 A. I was aware it came out. I told my old man 22 not to smoke. 23 Q. Pardon me? 24 A. I was telling my old man not to smoke. I 25 said, if you choose to smoke, you know, it's at A. William Roberts, Jr. & Associates (800) 743•DEPO W CO N -
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01 • 131 1 your own risk. 2 Q. And do you know if the scientific 3 community -- the scientific community would 4 include the tobacco defendants, would it not, 5 their scientists? 6 A. Sure. The tobacco scientists were 7 responsible members of the overall scientific 8 community, of course. 9 Q. Did you read any articles that 10 would suggest that the tobacco scientists came out 11 in support of the theory that there was a].ink 12 between smoking and certain diseases? 13 A. Well, we know that they did. 14 Q. When? 15 A. All you have to do is read the published 16 literature. 37 Q. When? 7.8 A. Even in the 50's, some of articles that 19 provided evidence that tightened the link between 20 cigarette smoking and lung cancer were performed 21 either by scientists employed by tobacco companies 22 or by scientists who had received research grants 23 from tobacco companies. 24 Q. . Any in particular that stick out in 25 your mind? A. William Roberts, Jr. & Associates (800) 743-DEPO
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i 132 1 A. There are, and this is where I reviewed 2 these things always before depositions and it 3 still filters out of my mind, but I believe that, 4 for example, that one of the important studies 5 showing that chemical smoke contained benzpyrene, 6 a known carcinogen was performed by Bentley who 7 was a scientist at the American Tobacco Company. 8 That report, as I recall, was published in 1958. 9 There was at least one skin painting experiment 10 that was performed either by a tobacco scientist 1]. or someone who was -- whose research was funded by 12 the TIRC. I believe that was a study by Bock, but 13 I would not swear to that right now. 14 Q. By who? 15 A. B-o-c-k. There were studies pointing out 16 -- these are just samples, but there were a 17 number of studies that had results that were 18 harmful to the tobacco industry that were 19 performed and published either by tobacco company 20 scientists or by scientists who received funding 21 support from the tobacco industry. 22 Q. Did you ever read any published 23 articles by Alan Rochman of Reynolds TobaCco? 24 A. It's pdssible that I did. I read, you 25 know, over a thousand articles. I am not A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 0 I 0 142 1 Reynolds, Brown & Williamson, American Tobacco, 2 Ligette, any of the companies, had that same 3 information? 4 A. Well, that information is immediately 5 available when it's published. 8o they had it at 6 the same time that the rest of the world's 7 scientific community had it. 8 Q. As a historian, would interest you 9 to know if they knew it before 1954, 1953? 10 MR. DODDS: Objection to form. 11 A. As a historian speaking to the state of 12 scientific medical knowledge, the fact is that the 13 first successful identification occurred in 1953, 14 and that's what's mattered. And it would not have 15 mattered if anyone.in any laboratory that had 16 circumstantial evidence or partial evidence or 17 even more detailed evidence proving this and for 3.8 whatever reason hadn't published. it wouldn't -- 19 it wouldn't have affected the opinions that I'm 20 presenting, in terms of the stated knowledge. 21 Q. So as a historian, if 22 hypothetically you assume that all of the tobacco 23 companies knew five years previous to 1953'that 24 there were certain carcinogens in tobacco smoke 25 but didn't disclose that to the public, that won't A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • 127 1 thought that the letter was accurate or that the 2 announcement was accurate in January of 1954; 3 correct? 4 A. I believe it was an accurate reflection of 5 the conditions of the scientific knowledge at that 6 time. 7 Q. Do you believe it's an accurate 8 reflection of the condition of the scientific 9 knowledge in 1964? 10 A. Let me see it again. 11 MR. DODDB: I think that question 12 has been asked and answered and I object to the 13 form. 14 A. I think if you're looking after the Surgeon 15 General's report, this would -- and I'm looking 16 specifically at the scientific part of this, 17 "Distinguished authorities point out that --" 18 Q. Sorry. Could you please just -- I 19 don't know if they can pick you up. 20 A. I'm looking at the part, "Distinguished 21 authorities points out that medical research of 22 recent years indicates many possible causes of 23 lung cancer; that there is no agreement among the 24 authorities regarding what the cause is; that 25 there is no proof that cigarette smoking is one of A. William Roberts, Jr. & Assoolates (800) 743-DEPO w 41 a W
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. • 133 1 remembering that name as we speak. it's not a 2 name that has come up in conversation in any of 3 the handful of depositions or cases I've been 4 involved with. 5 Q. As a historian reviewing the status 6 of the scientific or medical knowledge of smoking 7 and health and disease from 130 to '64, would it 8 interest you to review internal company documents 9 that would suggest that published papers by their 10 scientists were being edited by lawyers? 11 MR. DODDS: objection to form. 12 A. Well, that's a compound question with many 13 parts to it, and also some erroneous assumptions 14 as well. i5 Q. First tell me the erroneous 16 assumptions. 17 A. Well, first of all, would I be interested? 1s You know, as I said before -- 19 Q. That's a question. 20 A. -- in a general way, you know, you're 21 interested in everything, but if we are talking 22 unpublished research, it's not something that 23 is -- you know, affects the world's scientific 24 understanding,' and of course we have to keep in 25 mind the context, that this is one of the most A. William Roberts, Jr. & Associates (800) 743-DEPO W OD A
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• • • 138 1 different and it's a different set of issues and 2 I'm not going to speak on issues that I didn't 3 study or that I'm not prepared to comment on. 4 Q. I'm talking now about a published, 5 in the mainstream, you can go down to the Library 6 of Congress and you look in 1962 and see an 7 article that Rochman wrote on carcinogens and 8 tobacco smoke. 9 A. Uh-hum. 10 Q. And he writes in internal documents 11 and says, of course we didn't mention the three 12 carcinogens because of their cancer promoting 13 activity. That was removed from the final 14 manuscript. It wasn't mentioned in the article. 15 Would that interest you as a historian? 16 MR. DODDS: Objection to form. 17 A. well, you know your question is, again, 1e misleading, and I'm going to point this out every 19 time you do this. First of all, I read -- 20 Q. As you have in seven depositions 21 and three trials. 22 A. No, there have not been seven depositions. 23 This is -- there have been four deposition's. 24 There have been a total of seven episodes over 25 thirteen years now. So we should keep our facts A. William Roberts, Jr. & Associates (800) 743-DEPO I N N N W . ~ oD (D
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2 Q. -- and say that scientists within a 3 tobacco company published literature that's out 4 there in the medical journals, scientific 5 journals, and it's edited by lawyers to review -- 6 who review it and say we don't want this in her, 7 let's take that out, would that interest you at 8 all as a historian in reviewing the material ' 9 you've reviewed and arrived at the conclusions 10 you've arrived at? 11 MR. DODDB: Objection to form. 12 A. well, as I said before, for purposes of my 13 testimony I'm interested in the published 14 material. I'm not interested in all the steps. 15 You're asking questions that don't pertain to what 16 my testimony is about; that the various internal 17 steps and how scientists derive ideas and all the 18 internal to and forth, and is this idea right, is 19 this idea wrong? 20 You know, if one wishes to 21 understand the medical marketplace of ideas, your 22 starting point is the published literature and not 23 the various steps that it took to get to that 24 point. And II m not saying that that's.an 25 uninteresting question, but I'm saying it's A. William Roberts, Jr. & Associates (800) 743•DEPO
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139 1 straight. 2 But first of all, the marketplace 3 of ideas begins with what is out there. Now I 4 don't know what happened at the company. As I've 5 said, I've had no -- no exposure or scrutiny of 6 internal company documents at all. So I don't 7 know if that happened or not. But it's also not 8 clear that it would have made a difference even if 9 it did happen, because other people were 10 identifying the same results. And if it did 11 happen, i, as an historian, would need more than 12 one snippet after document. You can't make 13 accurate statements in history without 14 verification and validation. Now I just published 15 a book last November. I looked literally at 16 millions of documents, and documents were helpful, ].7 but they -- but sometimes you see something in 18 one case that was contradicted in another, and you 19 have to put this in the context and get 20 verification. To draw large conclusions from one 21 snippet of one internal company document is not a 22 justifiable approach to any responsible historian. 23 So, if they -- if they did,'I'm not 24 saying that I'approved that, but before we say 25 they did, I'd like to see a lot of evidence that A. William Roberts, Jr. & Assoclates (800) 743-DEPO ~ b
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135 1 response to your question: If there was research 2 suppressed, number one, you have to have evidence 3 to support that. And I am personally unaware -- I 9 haven't examined company behavior, company 5 documents. I have no personal evidence of 6 suppression of research. 7 Secondly, in the context of that 8 question, one must remember that.there are lots of 9 legitimate scientific reasons not to publish 10 work. It is an inaccurate view of science. And 11 part of my task as a teacher and a medical 12 historian is to point out how science works. To 13 think that every piece of data gets published is 14 incorrect and it would be wrong. All the time you 15 have preliminary results that don't pan out. 16 Sometimes you do experiments because you want to 17 duplicate someone else, just to make sure you 18 believe it, but not to publish again because it's 19 been published fifteen times, and it would have 20 not have changed the status of knowledge at all. 21 There are many legitimate reasons not to publish 22 your unpublished effort. 23 so I have no information A) that 24 they suppressed information. I cannot comment -- 25 speak with you on company behavior. As I say, we A. William Roberts, Jr. & Associates (800) 743-DEPO H 1 i W iP OD T
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• 0 146 1 company behavior. Number two, we know what did 2 happen in the published scientific community, and 3 that's what I've reported on. Number three, one 4 can assume anything one wishes: well, they had 5 evidence that it was suppressed. I think if one 6 is going to make charged allegations of that sort, 7 then the burden -- in any historical subject, 8 lots of historical fields are charged, and you 9 need evidence to support that, and good, hard, 10 reliable evidence, not one snippet of one letter. 11 For all one knows, there could be another letter 12 saying, you wanted to suppress it, terrible idea, 13 forget it, forget you even suggested it. 14 So you need rigorous critical 15 assessment and then you also have to ask the issue 16 of it have made a difference at a time that many 17 other people were publishing the same results even 18 if a another scientist had information. And, as I 39 said before, there are legitimate reasons not to 20 publish. 21 So there are a lot of 22 qualifications to this answer and the whole 23 subject does go beyond what I'm testifying', but 24 there are a lot of qualifications that come out 25 from the way you phrased that question. A. William Roberts, Jr. & Associates (800) 743-DEPO t0 , v
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141 1 report. 2 If you're asking what has changed • 5 cigarette smoke of a number of carcinogens, the 4 changed is the successful identification in 3 from 1954 to 1964, one of the things that has 23 done by Dr..Cooper, who published in 1953.' That's 22 identification of benzpyrene in tobacco smoke was 21 A. My recollection that the first 20 benzopyrene was identified in tobacco smoke? 19 Q. Did you say the mid 5o's, 17 identified in tobacco smoke? 18 A. I'm sorry? 16 think you put a year on it, mid 5o's, that it was 15 Q. How many years before -- I don't 14 concentrations, that wasn't clear either. 13 exceedingly low levels, exceedingly low 12 benzpyrene or other chemical carcinogens in 11 concentrations. so what it meant to have 10 was -- these were also present in very low 9 plausibility of this tobacco hypothesis, though it 8 Surgeon General called it, the biological 7 did change and it added to the coherence, as the 6 most important of which was benzpyrene. So that 24 my recollection. 25 Q. Do you know when Philip Morris, A. William Roberts, Jr. & Associates (800) 748•DEPO 0 kD N
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0 i 140 1 it indeed happened, more than one snippet of a one 22 first carcinogen was identified in 19-- I would 23 have to check the year, but mid 50's, the 24 benzpyrene, and later others were identified an 10 you don't have to publish this because this is 11 already known. 12 Q. As part of your review, did you 13 look at what was known at any particular time in 14 terms of the carcinogens in tobacco smoke? 15 A. That was part of the study, yes, the 16 chemical constituents. 17 Q. so would you be prepared to offer 18 an opinion that in 1953, there were 39 known 19 carcinogens in tobacco smoke, in 1956 there were 20 58 -- I'm just throwing the numbers out. 21 A. You are just throwing the numbers out. T 2 communication in a company that has millions and 3 millions of documents. And also if you're trying 4 to assess did this make a difference? It may not 5 have made a difference even, if you didn't like 6 the act. You would have to know what was 7 suppressed, if it was suppressed at all. And if 8 that's already known to the scientific community, 9 you know -- you know it's very possible they said, 25 these are part and parcel of the Surgeon Gener A. William Roberts, Jr. & Associates (800) 743-DEPO
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• • 152 1 between smoking and lung cancer? 2 A. I would phrase it a little bit differently, 3 but we're, I think, on the same wavelength here 4 that there was an enormous amount of scientific 5 literature that was assembled by the Surgeon 6 General's report, a new intellectual contribution 7 was made, and in the minds of most scientists, B this was sufficient to establish not only the link 9 between cigarette smoking and lung cancer, but 10 actually, more important, the validity and 1]. reliability of clinical epidemiology as a science 12 and as something offering methods that could be 13 applied to other conditions besides lung cancer, 14 and this happens afterwards. 15 And I think that's an accurate 16 description, but, as I also stated, and as you 17 were good enough to mention now, scientists are le bright people, they're independent people, and the 19 consensus is often wrong, historians know this, 20 and there was room for responsible disagreement 21 even though the majority viewpoint had switched. 22 If someone didn't accept the majority view point, 23 they -- you can find that contrary view among 24 respectable scientists. 25 Q. And I want to make sure I A. William Roberts, Jr. & Assoolates (800) 743-DEPO
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• 1 that fine detail going forward. We do know 2 that -- and I did learn this from my secondary 3 reading, A) that the Surgeon General's report did 4 lead to the warnings on cigarette packages; number 5 two, we know -- and I know tbis.from my secondary 6 reading -- that the clinical epidemiology gained 7 maturity with this report, and you find the first 8 departments of clinical epidemiology being -- and 9 teachings in the mid 50's. 10 we do know that, from secondary 11 reading that I've done, that the controversy 12 quieted down, but I also know, we also know, that 13 some responsible scientists who insisted upon 14 experimental verification after -- you know, 15 before 19 -- before January of '64 -- continued 16 to insist on that afterwards in their own 17 intellectual deliberations, so that it would be 18 important to state that there was room for 19 responsible scientists.to disagree even though the 20 controversy as we've talked about quieted down 21 fairly quickly after the report. 22 Q. Another way of phraeing it, would 23 it be fair to say that at.least in the aftermath 24 of the '64 report the majority of reliable 25 scientific evidence established a,relationship A. William Roberts, Jr. & Associates (800) 743-DEPO N
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• • 144 1 issue because scientists had been trying for a 2 while to do that. And there was.a major negative 3 studies in 1952, only a year before, and Cooper 4 succeeded mainly because he.had new techniques and 5 new apparatus that he used. 8o this was a 6 breakthrough. This is available to anyone. 7 Now, one has to understand how 8 science works. And part of the process of 9 science, in all fields, not just smoking and 10 health, but all fields, is confirmation and 11 replication. And particularly when someone for 12 the first time has positive results, as Cooper 13 did, when a number of noted scientists in the 14 preceding few years had tried to identify 15 benzpyrene and had been unsuccessful, the first 16 question the scientific community will ask and did 17 ask is is this real or is there something fluky 18 about how Dr. Cooper did his work, which means 19 that you repeat and confirm the results, and that 20 is precisely what was done. There were 21 approximately, oh, I don't remember the exact 22 number, but, you know, maybe ten or fifteen 23 confirmations of that work in the next few years, 24 one of which ivas done by a tobacco company 25 scientist. And by confirming that this indeed was A. William Roberts, Jr. & Assoolates (800) 743-DEPO ~
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• 143 1 matter to you? 2 MR. DODDS: Objection to form. 3 A. You know, there is so many incorrect 4 assumptions in your question. 5 Q. You haven't look at any internal 6 document, so you don't know they're incorrect; 7 correct? 8 A. Even -- 9 Q. Are they incorrect because -- N MR. DODDS: Could he answer? 0 • 11 Q. Tell me why they're incorrect, one 12 at a time, the assumptions. 13 MR. DODDS: I object. You're 14 refusing to allow the witness to answer your prior 15 question. If you are withdrawing that question -- 16 MR. MAISTROS: I'm not withdrawing 17 it. ].8 Q. Tell me the incorrect assumptions. 19 MR. DODDS: Be polite and allow him 20 to answer your question. 21 A. First of all, the knowledge was available 22 in 1953 to everyone. So the world's scientific 23 community was aware of that benzpyrene had been 24 demonstrated 'in cigarette smoke with Dr. Cooper's 25 publication in 1953. This was a very important A. William Roberts, Jr. & Assoolates (800) 743-DEPO
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0 155 1 mathematical tools. But putting all of this 2 together: The prospective study and the new 3 mathematical tools that were invented to analyze 4 the data, make sense of the data, that was much 5 more important than the retrospective studies. 6 Q. As you sit here today, do you know 7 what carcinogens are in tobacco smoke? 8 A. No, I don't. 9 Q. As part of your review of the 12 to 10 14 hundred articles, did you read articles that 11 discussed carcinogens? 12 A. Well, certainly that -- yes, and that 13 became a topic of interest, particularly after 14 benzpyrene was identified. And then the most 15 Important document, in my judgment, is the Surgeon 16 General's report itself, which reviews this 17 literature, and points out, you know, the various 18 known carcinogens that had been identified in 19 cigarette smoke. 20 Q. in the course of reviewing the 21 literature from 1930 to 1964, did you see 22 literature which pointed out, separate and apart 23 from tobacco smoke, there were certain knoian 24 carcinogens out there in the world? 25 A. I'm not sure I understand that question. A. William Roberts, Jr. & Associates (800) 743-DEPO O
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• • 145 1 real and you could do it, that was an important 2 contribution that was made by these others. They 3 weren't original discoverers, but they showed that 4 this was real, and this particular tobacco company 5 scientist a few years later was one of those who 6 helped demonstrate it was real. But this 7 knowledge is out there for everyone to see. 8 There's no suppression, it's out there for 9 everyone to see. And confirmation and 10 replication, as I say, is an important part of 11 good science. 12 Q. And I go back to my question. And 13 I'll rephrase it. You can forget my last 14 question, if you would like. would it be relevant 15 to you as a historian in arriving at your 16 conclusions in this case if you could be presented 17 with documents showing that three to five years 18 prior to 1953 the tobacco companies had knowledge 19 of the existence of those very chemicals in 20 tobacco smoke? 21 MR. DODDS; Object to the form and 22 to the lack of foundation. 23 A. You're asking questions that are compound, 24 and, again, go beyond my area. Number one, as 25 1've said before, I don't have any information on A. William Roberts, Jr. & Assooiates (800) 743-DEPO 0
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rr~ . • ~ 150 1 A. Internal medicine, that's correct. 20 the aftermath of that. 21 Q. And could you put a time-frame, a 22 border on the aftermath. 23 A. I have not studied that in a significant 18 year, and that the large-scale scientific 19 controversy that we've been discussing resolved i 14 A. My conclusion is that the controversy over 15 the relationship between cigarette smoking and 16 health continued through the appearance of the 17 first Surgeon General's report of January of that 2 Q. Is that still true today? 3 A. That's correct. I'm an internist. 4 Q. I want to make sure I'm clear on 5 the conclusion you arrived at, at least with 6 respect to the state of the -- and there's been 7 different words used, so maybe you should tell me 8 your conclusion. if I'm the defendant and I'm 9 asking you to express an opinion on the state of 10 whether it be medical or scientific knowledge in 11 1964 concerning the association between smoking 12 and health, put it in your own words as to what 13 your conclusion would be in this case. 24 way, in the thorough way that I did before, as we 25 talked about before. I didn't, you know, study in A. William Roberts, Jr. & Associates (800) 748-DEPO
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. • 147 ]. Q. Why was it significant that 2 scientists discover the existence of benzopyrene 3 in tobacco smoke in 1953? 4 A. Why was it significant? In terms of 5 developing the argument that cigarette smoking 6 causes lung cancer. 7 Q. When did the scientific and medical 8 community know there was a link between 9 benzopyrene and any cancer? 10 A. The link between benzpyrene and cancer was 11 an established link, and I don't know offhand when 12 that was first described, but, suffice it to say, 13 if we're examining the state of knowledge in the 14 mid 50's, benzpyrene was a, not only a known 15 carcinogen, but a known potent carcinogen. So -- 16 Q. An animal or human carcinogen? 17 A. Both, as I recall. 18 Q. Could you put an earliest time 19 period on it when you were -- 20 A. I'm sorry, I don't know, and I don't want 21 to guess in proceedings that are as important as 22 these. But it was a known carcinogen. 23 8o, discovering benzpyrene in 24 cigarette smoke was notable in terms of developing 25 experimental and laboratory evidence to give some A. William Roberts, Jr. & Associates (800) 743-DEPO 00
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0 157 1 the cause/effect relationship between carcinogens 2 and certain cancers or tumors? 3 A. This was an area of interest, but it is not 4 something that I studied as part of my work. I 5 looked at tobacco lung cancer link. I did not 6 look at the related but still separate subject of 7 chemical carcinogenesis, chemical carcinogens and 8 look into that. so I'm not able to give an 9 informed answer on that. So it's just not 10 something that I looked at. 11 Q. Did your review include 12 nitrosamines? 13 A. I'm not a chemist and I don't remember 14 precisely. I'd have to go through that 15 bibliography that you have a copy of and see the 16 articles. To answer your question, I could also 17 look at the Surgeon General's report, because he 18 lists -- the Surgeon General Committee lists a 19 number of known carcinogens in cigarette smoking. 20 T do not remember if nitrosamines were one of that 21 group or not. If they were, it falls into my 22 testimony, but I don't know that without looking 23 it up and checking. 24 Q. In terms of arriving at the 25 conclusions you arrived at, was the focus upon the A. William Roberts, Jr. & Assootates (800) 743-DEPO W N ( W L" Q CO
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• 0 148 1 biological plausibility to the statistics. So 2 that was an important observation. The fact that 3 good scientists had unsuccessfully tried made the 4 1953 publication even more notable. And, of 5 course, the next step was to confirm this and 6 replicate it and make sure that was a real finding 7 and not a fallacious finding in any way, and that 8 was done over the next several years by many 9 scientists, as I said, including one who is at 10 a -- who was a tobacco scientist, but many others 171 did it as well. And that was an important link, 12 though, as I have also stated, low concentrations, 13 so that significance of benzpyrene -- they were 14 expecting it in high concentrations and in fact it 15 was in low concentrations. So there was not 16 agreement as to what that finding meant; there was 17 still debate about it. 18 Q. Is it fair to say that at least ten 19 years prior to 1953 that it was fairly well 20 established there was a link between benzopyrene 21 and cancer? 22 A. There was a link between benzpyrene and 23 cancer that predated 1953, but, as I said before, 24 z have not studied the history of benzpyrene and I 25 do not believe.it would be appropriate for me to MV A. William Roberts, Jr. & Associates (800) 743-DEPO
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r 14 separate studies on chemical constituents of smoke 15 and other carcinogens and something that might 16 cause cancer of another organ and that sort of 17 thing. That got outside my scope. 10 because if you can find carcinogens in the smoke, 11 that adds to the biological credibility of your 12 hypothesis. So, from that perspective, it came 13 into what I looked at, but I did not start doing 4 cancer? 5 MR. DODDS: Objection to form. 6 A. The specific issue was the cause of lung 7 cancer and the effects of cigarette smoke, and 8 that's what.1 looked at. issues of chemical 9 carcinogens in cigarette smoke are important, 158 i 1 cause, association, link between smoking and lung j 2' cancer, or did you look at the specific issue of ! 3 carcinogens in tobacco smoke in a link with Q. 19 fair to refer to you as a medical historian? Do 1a 20 you consider yourself a medical historian? 21 A. Yes. 22 Q. Could somebody such as you go back, 23 If you were -- had the time and expertise and 24 money and look at the issue and arrive at a 25 conclusion as to what specific carcinogens were A. William Roberts, Jr. & Associates (800) 743-DEPO
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0 149 1 guess or to speculate in proceedings such as this 2 that are as important and significant as they are. 3 Q. in reviewing the literature from 4 1930 to 1964, are you comfortable or prepared to 5 offer an opinion on what specific chemicals were 6 known carcinogens at any given time? 7 A. At any given time? No, I'm not. e Q. Can we take a break. 9 A. If you wish. 10 THE VIDEOGRAPHER: Off the 11 videotape. 12 (Time noted: 2:59 p.m.) 13 (Brief recess.). 14 THE VIDEOORAPHER: We're back on at 15 videotape 1511. 16 Q. Doctor, do you presently treat 17 patients in the course of your practice? 18 A. Yes, I do. 19 Q. Do you treat cancer patients? 20 A. Occasionally. 21 Q. Do you consider yourself a cancer 22 specialist? 23 A. No, I don't. 24 Q. . And you're board certified in. 25 interna7l medicine? A. William Roberts, Jr. & Associates (800) 748-OEPO
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• • i concern a out cara nogens came from various I 156 1 Q. I want to get away from tobacco 2 smoke for a moment. 3 A. Right. 4 Q. In the '30 to '64 time period, was 5 there a body of scientific knowledge out there 6 concerning the known carcinogens? 7 A. Yes. There were known carcinogens, and 8 b 10 and actually this goes back to 18th, 19th century, 9 sources: Chemical constituents, chemical causes, 17 Carson writes her classic book, "Silent Spring," 18 and that gives rise to the environmental movement; 16 pollution and environment. Remember, Rachel I 1 15 the 50's you've got a general concern about 14 of this, and this becomes more worrisome, and in I 12 being related to environmental exposures, 13 occupational exposures. So there's a long history 11 with scrotal cancer in chimney sweeps, you know, 19 you've got lots of concerns in the aftermath of 20 the atomic bomb about radiation and genetic, you 21 know -- the mutagenic effects and carcinogenic 22 23 24 25 effects of radiation. So, this becomes an important field, in and of itself. Q. . Was there a general consensus in the scientific and medical community concerning A. William Roberts, Jr. & Associates (800) 743-DEPO
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• . • 1 understand. 9 153 You've used "relationship" on some 2 occasions, you've used "link" on other occasions. 3 if called to testify in this case, exactly what 4 phraseology are you going to use to show the 5 association between smoking and disease? Is it 6 "relationship," "link," "causation"? Are they 7 all the same in your mind? B A. I'm not quibbling over words, though 9 that's also a time dependent question. Because if lo you're asking me that, you know, question about an 11 earlier period, it might be important to analyze 12 the word more carefully. But if you're talking 13 January 1964, the first Surgeon General's report, 14 it -- the conclusion of the report, which is 15 accepted clearly by the body of the scientific 16 community, was that cigarette smoking was a major 17 cause of lung cancer, and that the word "cause" 18 was used. And if I've used "link" or other words, 29 there's no meaning to it in the context of the 20 surgeon General's report. It proved a causal 21 relationship or a cause. The more important point 22 is that, as I said, is that a minority view with 23 responsible scientists in it did continue after 24 the report. Not everyone bought into the new 25 paradigm, even though the majority by that time a A. William Roberts, Jr. & Associates (800) 743-DEPO N iP
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• 24 suggesting Dechert, Price & Rhoades might consider 25 doing this. You could take that as evidence, if 18 allege it. You would have to -- and it would take 19 more than a snippet. You would need 20 confirmation. 21 1 have seen in my whole historical 22 work examples of the misuse of primary evidence. 23 So, Ned Dodds could write a letter and, you know, 160 1 may or may not be doable. It depends on the 2 nature, number and quality of the documentation. 3 Sometimes you can go to Cornell University School 4 of Medicine and find lots and lots of document 5 about the history of the school and you can go to 6 University of Maryland School of Medicine and find 7 it has a very spotty archive. So, I -- you know, 8 I.-- there are really a number of assumptions, all 9 of which would have to be positively answered to 10 do that: The number of documents and how get the 11 documentation was, and cross corroboration, and so 12 forth. 13 Also, you know, there is an 14 implication in your statement that while maybe 15 they knew something that the rest of the world 16 didn't know, well, it's possible, but you would 27 still have to prove it rigorously and not just A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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154 1 clearly did. 2 Q. And is it your opinion that it's 3 the retrospective studies which served as the 4 primary basis for those conclusions? 5 A. Oh, that's totally incorrect. 6 (~. What is it? 7 A. It was -- the retrospective studies were 8 among the weaker links. The retrospective studies 9 of 1950 and 151 and 152, and other retrospective 10 studies that were done in later years, that 11 suggested a statistical relationship. The 12 retrospective --,much more important were the 13 prospective studies which were first published, as 14 I recall, in 1954, and then these studies 15 continued. 154 was the first two reports. But by 16 1964, the Surgeon General cited seven reports, 17 three of which were published after 1960. And, in 18 addition, all but one of the earlier prospective 19 studies had been continued. So as you continued 20 to monitor events over time, put more patients 21 into it and see that statistical associations grew 22 stronger rather than weaker and that these 23 differences bare out, then the earlier studies 24 assumed greater significance, and of course the 25 development of clinical epidemiology and the A. William Roberts, Jr. & Assooiates (800) 748-DEPO
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i 9 161 1 you wished. Someone from Dechert, 2 Price & Rhoades -- let's do this the other way 3 around. someone else from Dechert, Price & 4 Rhoades might write a letter and say, "Maybe we 5 should do this." Ned Dodds would read it and say, 6°i got your memo, but that's a dumb idea; I'm 7 surprised you even thought of it; let's drop it." B And the person might write back, "You're 9 absolutely right; I don't know what I was smoking 10 that day and that was the stupidest idea I had." 13. If you were to pick and choose that first letter 12 selectively, it could lead to erroneous 13 suggestions and implications and conclusions. So 14 you really need all the evidence in hard, rock 15 hard unassailable evidence to make such a 16 suggestion. 17 We also have to remember, putting 18 this in context, that the tobacco scientists, 19 they're chemical scientists and very good, but, 20 you know, they're not biomedical researchers, and 21 the world's scientifia community is investigating 22 this very, very intensively, and I personally 23 would be surprised if anyone could find evidence 24 of notable scientific results that were 25 unassailably established and withheld from the A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 159 1 known to cause cancer at what specific time in, 2 medical history? 3 A. That's a doable study if someone wanted to 4 do it. I haven't done it. I can't answer the 5 question, you know, that one would ask and tell 6 you what would be found. But on the surface, 7 without reflecting on it, that sounds like an 8 eminently doable project. 9 Q. Is it also possible if you had 10 access to the documents to go back and look at the 11 tobacco industry documents and determine when they 12 knew certain carcinogens did or did not, at least 13 in their mind, in their research, cause cancer? 14 MR. NEWBOLD: Objection to form. 15 A. I did lose you on that. independent of 16 objection, I did -- 17 Q. Assuming you had access to all the 18 tobacco industry documents, as a medical 19 historian, could you go back and review and 20 determine at what specific time a particular 21 scientist within a company or what particular time 22 a company knew what carcinogens were in tobacco 23 smoke, for example? That's a different question. 24 MR. NEWBOLD: same objection. 25 A. well, as you know, I haven't done that. It A. William Roberts, Jr. & Associates (800) 743-DEPO r m ,
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• • 163 1 if any statement were taken out of context. The 2 responsible historian would be very careful to put 3 any statement in context and verify it before 4 drawing those conclusion. If those assumptions 5 are met, I believe it's a doable study. And there 6 have been such studies with other industries. 7 Q. Now, you say -- you don't say; a 8 yet-unidentified lawyer 9 "beginning in the early 10 "beginning in the early 11 that raised a scientific 12 may be life threatening. 13 early 1950's and January says in your report that, --" and it's page 3 -- 50's, evidence appeared concern that cigarettes At no time between the 1964,'when the Surgeon 14 cieneral's advisory committee's report was released 15 was there a consensus within the medical community 16 that cigarette smoking caused lung cancer, heart 27 disease or other life threatening diseases." Is 3.8 that -- I mean, I assume this statement still 19 applies today since you adopted this report. It 2o applies to all three of these, lung cancer, heart 21 diseases, other life threatening diseases. 22 A. Let's me just see that. 23 Q. That's what I underlined. 24 MR. NEWBOLD: Just note -- is the 25 question, did he write that in the report? A. William Roberts, Jr. & Assocfates (800) 743-DEPO
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r . . 162 1 scientific community would have made a difference 2 if they had been released. 3 Q. I'm not asking you to jump to the 4 conclusion as to what the effect would have been. 5 I'm asking you, as a historian, could you go back 6 -- and you have to assume for the purposes of my 7 question, you're getting a complete archive of the 8 internal industry documents. But assuming you 9 could do that, could you look at those as a 10 historian and write a report as you have done 11 saying, at this given point in time, this is what 12 this company knew, based upon what I have 13 reviewed? 14 A. That is possible. Sometimes companies will 15 help you, because they publish, you know, annual 16 reports and research reports and divisions will 17 have reports. So sometimes the record-keeping 18 that a company would do and the reporting it do -- 19 it would be do, would help you. So it is 20 potentially doable, but I do want to emphasize 21 that it is not an easy job, you need a very good 22 set of records, an accurate set of records, that 23 they have to be complete, you need verification, 24 cross verification, and they have to be assessed and it would be totally inappropriate 25 critically , n II~ A. William Roberts, Jr. & Assoolates (800) 743-DEPO 1, I
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r r 164 1 MR. MAISTROS: Well, I know he 2 didn't right it because he said a lawyer wrote it. 3 MR. NEWBOLD: Is the question -- is 4 the question is does that appear in the report? 5 MR. MAISTROS: Yeah, page 3. 6 That's not the question. The question is: 7 Q. That's really your statement? B A. I would concur with that. It was the early 9 50's that the retrospective studies came out. Now 10 you have to put a time dimension at this. The 11 link with heart disease came with the prospective 12 studies. so if you're saying early 1950's, I'd 13 say lung cancer. Mid 1950's -- 14 Q. Well, that's why I broke it up 15 because the sentence starts with the time period 16 and I want to make sure that you're saying that 17 time period applies -- that statement applies and 18 that time period applies to all three of those does apply to those -- to lung cancer 21 and heart disease and other life threatening 22 diseases, but the statement does not make clear is 19 diseases. 20 A. It 23 that evidence for lung cancer was obtained earlier 24 than evidence for heart disease and other life 25 threatening diseases. The retrospective studies A. William Roberts, Jr. & Associates (800) 743-DEPO
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! • 0 167 1 constituent, you wouldn't have had those positive 2 results. So scientists -- and the Surgeon 3 General was also puzzled by the low 4 concentrations. 5 Q. Are you familiar with the 6 categorization of the different chemicals as 7 either being cancer promoting or tumorigenic 8 promoting or precursors? Is there a body out 9 there that establishes standards for those terms? 10 A. Well, you know, there is a whole chemical 11 industry. I'm not part of that and -- 12 Q. You're not a toxicologist? 13 A. No, I am really not at all. And certainly 14 as different carcinogens are being identified and 15 as the potential worst culprit of all, benzpyrene, 16 is found only in these low doses, they don't 17 explain the biological effect of cigarettes, it 18 generated discussion of promoters and 19 co-carcinogens, and maybe it's the interaction of 20 the two, and this discussion is also part of the 21 Surgeon General's report. i'm not a chemist 22 myself and I've really gone as far as I can in 23 terms of describing this. I don't work in'this 24 area, I'm not-a toxicologist, and I could not 25 start giving you all the different definitions A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 165 1 published as early as 1950 raise a very serious 2 question that cigarette smoking may cause lung 3 cancer. The connection with heart disease and 4 other diseases was an observation and finding from 5 the prospective study of !54, so we need to make 6 that qualification. 7 Q. okay. And earlier you testified, 8 before the break, that it was a significant 9 finding as to the existence of BAP in tobacco 10 smoke. I think you said 53, '54? 11 A. Benzpyrene. 12 Q. Right. You didn't say this. I'm 13 just asking you this. 8o don't think I'm trying 14 to trick you. Is that the first carcinogenic 15 compound that was identified in tobacco smoke? 16 A. That's correct. To my knowledge. 17 Q. 8o as far as the medical world and 18 the medical -- 19 A. Actually it may have been '54. i,would 20 have to check the date. I would not want to be 21 quoted. I think it was '53, but may have been -- ] 22 think it could have been '54. 23 Q. Does the '64 report pin the date 24 down? 25 A. Oh, yes, it did. But I'm just not A. William Roberts, Jr. & Associates (800) 743-DEPO
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• i 0 166 1 remembering. 2 Q. No, I know. 3 A. But, you know, it gives all the dates, all 4 the citations. 5 Q. So if I found it and read it -- 6 A. Oh, sure. 7 Q. -- I could find whether it was '53. 8 or '54? 9 And it's your understanding, based 10 on your review, that that was the first 11 carcinogenic compound that was identified in 12 tobacco smoke, RAP? 13 A. Benzpyrene. That's my recollection. 14 certainly was the most significant, because it had 15 high carcinogenic potential. Could a different 16 carcinogen been identified before benzpyrene? 17 It's possible. I'd have to go to the Surgeon 7.8 General's report. I don't think so, but I want to 19 be accurate. I don't remember for sure. 20 And also, as I said, there was a 21'problem interpreting the data because the amount 22 -- the amount of benzpyrene was at a low level. 23 It was not sufficient to explain the known 24 carcinogenicity of cigarette smoke. The skin 25 painting experiment, if benzpyrene was the A. William Roberts, Jr. & Assoalates (800) 743-DEPO I ' N I N v
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• . 169 1 process of removing it from a product? 2 MR. DODDS: I'll object to the form 3 and to the scope. 4 A. The medical community or the industry? 5 Q. First the medical community. 6 A. Now you're talking -- your question said 7 medical community, and I'm not sure that the 8 medical community would be involved with product 9 development. 10 Q. As a medical practitioner, would 13 you be concerned if your patients were consuming 12 known carcinogens? 13 A. Well, I'm not an expert on carcinogens, so, 14 you know, I want that to be clear, but speaking as 15 with a general knowledge as a physician and a 16 historian, the issue is much more complex than 17 your question allows, because there are many known 18 carcinogens that the government knows about and 19 tolerates, because they're at low levels, and the 20 danger comes at high levels, not low levels. if 21 you were to eliminate all known carcinogens from 22 life, we wouldn't breathe air, because it has 23 oxygen, we wouldn't drink water, because if you 24 drank too much water you would get sick and die, 25 so that whole issue needs to be tempered by dosage A. William Roberts, Jr. & Associates (800) 743-DEPO
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. 176 1 the original scientific literature. It's very 2 complete and very useful. 3 Q. was it accepted back in the mid 4 50's to the early 60's that the identification of 5 known carcinogens was an important factor in 6 determining any causal link between a substance 7 and a disease? 8 A. As I've said, I'm not an expert on the 9 history of chemical carcinogens and haven't 10 studied that, but one -- but the identification of 11 a carcinogen in a substance is now and was then 12 considered insufficient to say that the substance 13 is carcinogenic. You still have to prove that the 14 substance is carcinogenic. Once you do, you start 15 asking the question why. And lots of things we 16 eat have known carcinogens. So the presence alone 17 would not be the issue. You would have to show 18 that the substance itself is carcinogenic, and 19 also you would have to interpret the dosages of 20 the nobody carcinogens. 21 Q. Isn't it true that in the 50's and 22 60's and even today there are some carcinogens 23 that the government, United States government, and 24 international'bodies, have characterized as 25 unacceptable at any levels, in any doses? A. William Roberts, Jr. & Associates (800) 748-OEPO
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• • 168 1 between producer and co-carcinogen and promoter 2 and this sort of thing, but that is an area of 3 active inquiry and there are fine scientists who 4 could speak directly to that point. 5 Q. Are you qualified to offer an 6 opinion as to whether or not a substance, if it 7 was a known carcinogen -- it wouldn't matter to 8 the public health community or, in fact, maybe the 9 producer of a product -- that if they knew 10 something was a known carcinogen they would do 11 everything they could to remove it from the 12 product? They wouldn't wait, for example, to find 13 out if it was in the proper dosage amount? 14 MR. DODDS: I'm going to object to 15 the form of that question. 16 A. Could you ask that again. 17 Q. If there's a substance -- and let's 18 assume for the purpose of my question that 19 benzopyrene is a carcinogen -- okay? 20 A. Uh-hum. 21 Q. -- if that substance is known to 22 exist in a product, is it fair to say that the 23 medical and scientific community wouldn't wait to 24 determine if it was in sufficient quantities to 25 cause cancer, they would start to work on the A. Wllliam Roberts, Jr. & Associates (800) 743-DEPO
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0 • I 175 20 you know, research -- researchers have discovered show me where it is 4 Q. And that would identify at least 5 the known carcinogens that the public or that the 6 medical/scientific community were aware of in 7 January 164? 8 A. That's correct. There's a whole chapter on 9 that. 10 Q. And that at least in January 1964, 11 was there consensus in the medical -- 12 A. Excuse me, by the way, not only A chapter 13 on that, but references to all the original papers 14 if•someone wanted to pursue it in more detail. 15 Q. You mean like -- 16 A. It's all cite specific -- 17 Q. What person first found that there is was a certain chemical in -- 19 A. t9ell, you know it would say something like, i in the 164 report or you can 2 in that report? 3 A. Sure. 21 benzpyrene, with -- you know, one, two, three, 22 four five, five references in the reports, 23 nitrosamine, six, seven, eight, nine, ten, with 24 the reports ta the five papers identifying 25 nitrosamine and so forth. So there is citation A. William Roberts, Jr. & Associates (800) 743-DEPO i I
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0 • • 170 1 and by amount and what it interacts with. We all 2 are exposed, with the knowledge of the government 3 and FDA and organizations, to substances that have 4 known effects if misused or if were present in 5 large quantities, but when they are at such low 6 levels, it often it doesn't matter, and that needs 7 to be taken into account in assessing that issue. 8 But I do want to emphasize that, again, I'm not a 9 chemist and I'm not a -- I'm an internist and I'm 10 a historian of medicine. I'm not an FDA regulator 11 and, you know, how low is little? But I do think 12 that qualification should be added to the context 7.3 of the question you're bringing up. 14 MR. MAISTROS: Let him switch 25 tapes, because I've got about fifteen minutes and 16 we're going to run out. 17 THE VIDEOGRAPHER: Off the record 18 at 3:35 p.m. 19 (Brief recess.) 20 THE VIDEOGRAPHER: Starting tape 3 21 at 1538. 22 Q. On page 4 of the report, entitled, 23 "Expert report of Dr. Kenneth Ludmerer, it is 24 stated that, In the third full paragraph, fourth 25 line from the bottom, "Between the mid 1950's and A. William Roberts, Jr. & Assooiates (800) 748-DEPO (,,1 U N N
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182 1 A. No, I haven't studied the tobacco industry 2 in any way, shape or form. Those twelve to 3 fourteen hundred articles or whatever they come 4 to, a thousand to twelve hundred, are all 5 scientific studies and not advertising, not press 6 release, not tobacco company documents. 7 Q. We'll see if we can finish, okay? 9 B You mentioned the Sloan-Kettering Institute. 9 A. Uh-hum. 10 Q. What is your familiarity with that 11 institute? 12 A. Memorial Sloan-Kettering, it's a major 13 center of cancer treatment and cancer 14 investigation located here of course in New York 15 City, in Manhattan, Upper East Side, across the 16 street from New York Hospital, Cornell Medical 17 Center, worldwide reputation. 18 Q. As a historian reviewing the status 19 of medical and scientific knowledge concerning the 20 causal relationship between smoking and disease, 21 would it interest you to review internal company 22 documents suggesting that there was an effort to 23 keep scientists such as Widner quiet by funneling 24 money to the Sloan-Kettering institute? 25 A. Well, as I've said before, there are two A. William Roberts, Jr. & Associates (800) 748•DEPO
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• 01 172 1 subsequently other carcinogens in the Surgeon 2 General -- if you wished to know precisely which 3 chemicals, the easiest referenae for that is the 4 chapter on this in the Surgeon General's report, 5 which will list all 15 or 18 or 19 or whatever 6 they are. So, 1953 onward, the carcinogens in 7 cigarette smoking have been identified, but 8 science is quantitative, as well as qualitative. 9 It's not just their presence, but their amount, 10 and they were there at such low levels that the 11 levels detected are insufficient to explain the 12 known carcinogenic properties of cigarette smoke, 13 which we knew it had from the skin painting 14 studies. So it raised very serious -- it raised e 15 lot of confusion. There is confusion on that 16 point. 17 Q. i just want to make sure, as you 18 read the last sentence of the paragraph, it says 19 "the inability to identify these unknown agents 20 was also considered strong evidence against the 21 causation hypotheses in the So's and early 22 1960's." 23 A. By some investigators who were looking for 24 biological credibility, and yes, you found 25 benzpyrene, but, you know, it's in such low levels A. William Roberts, Jr. & Associates (800) 743-DEPO
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. i 171 1 early 60's researchers were unable to identify any 2 agent or combination of agents in tobacco smoke 3 that could account for its alleged cancer-causing 4 activity." By that statement -- you've adopted 5 this statement; correct? 6 A. I've adopted this statement. 7 Q. Well, you didn't do the report, so 8 you agree with that statement? 9 A. Yes, I do. As I mentioned, the report was 10 put together by staffers who were listening to my 11 ideas, and that's precisely what I said before -- 12 Q. That's not my -- 13 A. -- before the break. That you've got 14 benzpyrene. The good news, if you're trying to 15 understand lung cancer and try to put it together 16 with lung cancer, if you're trying to come up with 17 answers, on the one hand you've identified 18 benzpyrene and that's a known carcinogen, but it's 19 at these very low levels that don't explain it's 20 known carcinogenicity. So it raises -- that's 21 what the sentence says. 22 Q. Are you talking about that they 23 couldn't identify carcinogens or they couldn't 24 identify levels sufficient to cause? 25 A. No, the levels. After 1953, benzpyrene and A. William Roberts, Jr. & Associates (800) 7a3•DEPO ~ . 0 , N ' N)
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• 0 2 Q. That's what I want to clarify. 3 Because as I read the sentence, especially the 4 last sentence, it sounds like you're saying that 5 the actual carcinogenic agents, regardless of the 6 amounts, were unknown. You're not suggesting 7 that, are you? 8 A. No, they were not known, but it was a 9 question of dose. It was a question of level. 10 It's like saying you're a fellow who stays trim 17. and you don't want to get fat and you were to say 12 to the doctor, if I go out and eat some cake, am i 13 going to gain weight? Are you going to eat the 14 whole cake or a single bite? There are dosage 15 issues in everything in life and it was a dosage 16 phenomenon, a level phenomenon. And they were 17 just -- it's so -- it's such tiny quantities that 18 the quantity at which they were directed was too 19 low with the knowledge at the time to explain the 20 carcinogenic properties of cigarette smoke. If 21 benzpyrene had been discovered at the high levels 22 they were anticipating, then that would have tied 23 together more easily.. But it was there so low, 24 it's like youlre saying to me, I put on 40 pounds, 25 but I literally -- and I'm not misleading and I A. William Roberts, Jr. & Associates (800) 743-DEPO (U Un N iP
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174 ~ 1 only had a bite of this and a bite of that. Well, 2 something else must be going on. 3 Q. And I'm not asking you to rewrite 4 this, but would it be clearer to me or anybody 5 else if you rewrote these last two sentences to 6 make certain that you're talking about the levels 7 of the agents in the smoke as opposed to the 8 inability to identify agents? 9 A. I think that's a very legitimate point and 10 I appreciate you're making it. Reading it now, it 11 is unclear the distinction between the actual 12 presence and the level. And I think it's a 13 legitimate point. 14 Q. And if you are asked, could you 15 offer an opinion as to what specific compounds 16 were known between 50's and 60'g or not? 17 A. oh, easily, and I wouldn't try to remember 18 it, because for all the time I do reviewing, that 19 they're the chemicals slip through like, very 20 easily, but I'd -- you know, the Surgeon General 21 has that. That's easy to reference to it. It's 22 in the Surgeon General's report. 23 24 - u 25 Q. MR. DODDS: Off the record.• (Discussion held off the record.) Again, if I wanted to I could look A. William Roberts, Jr. & Associates (800) 743-DEPO
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178 1 it to yourself. 2 A. Okay. 3 Q. This paragraph discusses a -- it 4 starts with at the top of the page a third 5 technique called prospective studies, which you've 6 testified about? 7 A. Uh-hum. 8 Q. And in this particular paragraph 9 the report says, in the second to last sentence, 10 "At this time scientists were able to obtain 11 cancers on the backs of laboratory animals, but 12 all attempts to obtain lung cancers in laboratory 13 animals exposed to cigarette smoke had failed." 14 Well, first of all -- 15 A. I'm sorry, where are you? 16 Q. I'm in the paragraph below that. 17 I'm in the largest paragraph, third paragraph. 18 A. Which page? 19 Q. 5. 20 A. 5. 21 Q. You're on the right page. You see 22 that sentence at the end of that paragraph? 23 A. Which sentence are you referring to? 24 Q. "At this time...° 25 A. Uh-hunt. A. William Roberts, Jr. & Associates (800) 743-DEPO MUMMEMOMMM
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• 0 1 raise issues of company behavior and would 2 affect my area of the study of knowledge. 3 let's also keep in mind that it's a large 4 demonstrate that they're true and I'm just 5 unprepared to accept allegations without any 6 evidence. 7 Q. You come to Louisiana in January, 8 you get on the stand and you're presented a 9 hundred documents showing destruction of 10 documents, suppression of evidence, buying off of 11 medical associations, would it matter to you at 12 some point whether or not that type of conduct 13 could affect medical and scientific knowledge on 14 the link, association or causation between smoking 15 and health? 16 MR. DODDS: Object to form. 17 A. What you have to keep in mind is the 18 context of this controversy. This is not an issue 19 that is being studied by tobacco companies alone 20 or tobacco scientists alone. They did contribute 21 to it and in many cases published articles that 22 were injurious to the tobacco industry by 23 tightening the case. You have to keep in mind 24 that this is one of the most intensively 25 investigated scientific issues of all time. A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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l . • . 177 1 A. Well, as I've said -- 2 MR. DODDS: Object. Outside the 3 scope. 4 A. That's way outside -- you know, I have -- 5 way outside the scope what I can -- that I've 6 studied or that I'm prepared to discuss. But, as 7 a general internist, it should be pointed out 8 that -- and I'm speaking in general, in my 9 knowledge as an internist, that -- that as we have 10 already said, the carcinogenic potential of 11 different substances differ. Some carcinogens are 12 known to be extremely potent. others of less so. 13 And that observation of a range of toxicity among 14 carcinogens, that's correct, but that's really the 15 extent of what I'm able to say, and I couldn't 16 start telling you which ones are which and when 17 were they detected and, you know, what cancers 18 will be produced by this chemical. But 19 carcinogens do differ in their potency. That is a 20 correct statement. 21 Q. And in page 5 of this report, in 22 the third paragraph -- and, in fairness, you 23 should read the whole paragraph. I'm only going 24 to ask you about the last two sentences, but it's 25 hard to read it out of context. If you could read A. William Roberts, Jr. & Associates (800) 743-DEPO 0 m I C U N Co
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• . 180 1 Q. Did you review the studies that 2 Auerbach did with the smoking Beagles? 3 A. Yes, I did. 4 Q. Does that.have any relevance to 5 your report? 6 A. Well, it's relevant because he, as you 7 know, attempted to induce lung cancer in Beagles Et through actual inhalation of smoke, and it was 9 part of this effort to see if lung cancer could bE 10 studied within the framework of the 500-year 11 tradition of experimental medicine. But at least 12 before 1964 those studies were largely 13 unsuccessful. other sorts of changes, but he was 14 not able to produce clearly unequivocal lung 15 cancer by smoking. Had those studies been 16 positive, my suspicion would be that there would 17 have been quite an ado made of that, but his 18 studies generally did not. They're very 19 significant to the historian because it shows this 20 effort being made to try to study lung cancer 21 experimentally, but it was not a successful 22 experiment. 23 Q. Do you know if Auerbach ever was 24 successful in'inducing tumors or lung cancers in 25 the lungs of Beagles? A. William Roberts, Jr. & Associates (800) 743-DEPO
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193 1 tobacco industry, would you have any problem 2 ethically with representing plaintiffs in tobacco 3 cases? 4 MR. DODDS: Objection to the form. 5 A. Well, first of all, as I said before, I'm 6 not a paid consultant to the tobacco industry. I 7 am an -- i'm a university scholar who treats his 8 scholarship seriously and I've been paid for my 9 time and my ideas. 10 Q. You didn't even write the report 11 you're testifying in this case about. 12 MR. DODDSs You're arguing with the 13 witness. 14 Q. Did you write the report you 15 testified in this case about? 16 MR. DODDS: I object to the 17 interruption of the witness. 2t's unprofessional. 18 MR. MAISTROS: I object to him ].9 saying he's not a paid consultant. 20 MR. DODDB: Well, you may not like 21 his testimony, but he's the one under oath, and if 22 you have a question, put it to him; if you would 23 like an answer, let him answer. 24 Q. Are you paid? 25 A. I'm paid for my time as a consultant to the A. William Roberts, Jr. & Associates (800) 743-DEPO
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0 • • 179 1 Q. I'm trying to figure out what. "at 2 this time" means, first of all. 3 A. Actually, as we sit here, i'm just raising 4 the question if I saw this. Certainly, in 5 general, it reflects my views, but a number of 6 cases happening at the same time. I don't know if 7 I saw this statement or not. And the questions 8 that I had -- myself have about it, don't at all 9 deal with the general substance. It deals with 10 some of these specifics and qualifications and 11 things of that sort, because I'd be surprised if i 12 didn't correct some of the -- or catch some of 13 those things on my own. If you're talking -- "at 14 this time," in that sentence, "at this time 15 scientists were able to to obtain cancers on the 16 back of laboratory animals, but all attempts to 17 obtain lung cancers in laboratory animals exposed 18 to cigarette smoke had failed," "at that time," in 19 that sentence, refers from -- to late 1953 with 20 the first skin painting experiments, positive skin 21 painting experiments, the Winder and Graham 22 experiments through January of 1964. So you can 23 scratch out "at this time" and put "from late 1953 24 before the first positive skin painting, through 25 January 1954.". 0 A. William Roberts, Jr. & Associates (800) 743-DEPO 0 @ 0 I
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1 to, was the greatest scientific figure 2 entire controversy, and to 192 in this suggest that -- I do 3 know many -- I do know biographically, as well as I 4 scientifically, of some of the scientists who were ~ i 5 -- who did not accept the epidemiology and who } ; 6 insisted on laboratory verification. In a couple ~ i • 10 individuals let their funding source interfere 1]. with their ideas, again, is incredulous. it's ; 12 like saying that someone -- Fisher is the Einstein R , 13 of 20th Century biology. It's like saying that 14 rinstein let his funding sources determine his j 15 views. it just defies credibility. , 16 Moreover, all views are -- have to 17 prove themselves in the marketplace of scientific 18 ideas, and that's exactly what happened. It's not ~ 7 of instances I do know that they had grants or 8 contracts or they had some sort of association 9 with tobacco, but to suggest that these 19 just that someone says it; but it's subject to 20 critical review. 21 The -- again, I can't speak at all 22 to company behavior and I wouldn't, but I do think 23 that this type of context has to be brought to, 24 bear on the question you're asking. 25 Q. As a paid consultant for the A. William Roberts, Jr. & Associates (800) 743-DEPO i 0
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• 181 1 A. I ever not followed that forward beyond 2 1964. ; s 3 Q. Did you read any literature on ; s 4 tobacco's reaction to any of Auerbach's studies? f i 5 MR. DODDS: Objection to form. 6 Q. Tobacco industry. 7 A. Other than the one frank statement that you 8 and others have shown me, I have not read the 9 response or views of the tobacco industry on any 10 subject at any time. 11 Q. Well, you did list among some of ' 12 the twelve to fourteen hundred articles you read ( 13 some advertisements by the tobacco industry, 14 didn't you? s ti 15 A. I'm sorry, I didn't. 16 Q. Did you list any advertisements 17 among the -- 18 A. No. 19 Q. -- twelve to fourteen hundred? 20 You didn't look at any• 21 advertisements? 22 A. I did not study advertisements. 23 Q. Press releases? 24 A. 25 No, I did not study press leases. Q. Budgets of the tobacco companies? A. William Roberts, Jr. & Assoaiates (800) 743-DEPO I
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. • 13 times, new patients are enrolled, some 14 different -- so there are multiple dates, but the 15 first one I believe was 1954. 1.6 Q. Would it be pertinent to your 11 there are actually a number of publications over 12 time. As the patients are followed for longer 10 published in 1954. But it was continued. so 187 1 prospective study done in the U.s. with the 2 American Cancer society and their volunteers, 3 which was one of the very major steps in 4 ultimately demonstrating that cigarette smoking 5 causes lung cancer. 6 Q. When was that study? 7 A. Excuse me? 8 Q. When was that study? 9 A. My recollection is that it was first 23 ' MR. DODDS: Objection to form. 22 A. Well -- 19 colleagues of Dr. Hammond to embarrass him in the 20 medical and research and scientific area as a 21 result of his studies? 17 conclusions in this case if you could be convinced 1.8 or shown evidence that the tobacco companies hired 24 A. I would give the same answer that I've 25 giving all afternoon: Company behavior is a A. William Roberts, Jr. & Associates (800) 743•OEPO
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• • 1 Lack of foundation. 2 A. Again, there are many inaccuracies and 3 incorrect presumptions to that compound question. 4 First of all, studying company behavior -- the 5 questions you are asking, number one, much of it 6 relates to company behavior and not to the state 7 of scientific knowledge. I'm not an expert in 8 company behavior, that's not what I've looked at, 9 that's not what I planned to look at, and even if 10 I were interested, I'm too busy with my own 11 works. It's -- company behavior and the state of 12 scientific knowledge, which I'm here to testify 13 on, based on my work from 1988 and '89, are two 14 entirely different beasts. 15 Secondly, we also have to know -- 16 secondly, as I've said, just as a general 17 proposition, if any statement, whether admirable 18 or disrespectful -- you know, if you're making any 19 historical claim, the need to have good data and 20 confirmable data, verifiable data, make sure that 21 it's not an exception or taken out of context, all 22 of those qualifications are there. 23 And, thirdly, I don't accept the 24 premise of the question that people like winder 25 and the scientific communities could be quieted or A. William Roberts, Jr. & Assoalates (800) 743-DEPO ~ N- W ' N A W Ln W 0)
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0 1 INDEX 2 WITNESS PAGE 3 KENNETH M. LUDMERER, M.D. 4 MR. EVANS: (Direct) 8 MR. MAISTROS: (Cross) 94 6 7 8 9 E X H I B I T S 10 Plaintiff's Ludmerer 13 12 NO. DESCRIPTION 13 1 CV 14 2 Expert disclosure 15 3 Article entitled, "A frank 16 statement to cigarette smokers 17 4 Article from British Medical 18 Journal, London, Saturday 19 December 13, 1952 20 5 Editorial from the New 21 England Journal of Medicine 22 6 Notice of Deposition 23 7 Report in Scott case 24 8 Defendants' Joint Expert 25 Reports Index Volume 4 A. William Roberts, Jr. & Assooiates (800) 743-DEPO
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184 1 what are the consequences. You know, if there was 0 • 2 some trivial experiment that for some reason 3 wasn't published, it probably wouldn't.have made 4 the difference, so you would have to ask what are 5 the consequences as well. 6 So, what you're describing does not 7 sound like very respectable behavior in terms of 8 how, you know, company scientists or Dr..Windner, 9 but I don't have any knowledge of that, but if 10 you4re trying to persuade me as a historian, you 11 need to show me real data and you need to show me 12 confirmation, and not just, as I say, a little 13 snippet from millions of documents that very well 14 could be taken out of context and be, frankly, 15 incorrect. 16 Q. if you had documentation from the 17 tobacco industry that they wrote where they traced 1s the history of an effort to keep scientists such 19 as Hammond, Widner, others, quiet and you had the 20 opportunity to review those documents, would you 21 do so for the purpose of determining whether or 22 not your conclusions in your report in this case 23 were, you know, quote, placed in the context, 24 unquote, of the times? 25 MR. NBWBOLD: Object to the form. A. William Roberts, Jr.. & Associates (800) 743-DEPO
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r 190 1 You've got all the medical schools, all the 2 teaching hospitals involved, in different 3 departments within teaching hospitals and 4 universities, from basic biology and biochemistry 5 to epidemiology and public health. You've.got the 6 university scientists involved, you've got the 7 research institutes involved, such as Memorial 8 Sloan-Kettering. You have the National Institutes 9 of Health involved and various institutes. You 10 have independent clinics, such as Mayo Clinic 11 involved and others. This is -- you have the 12 various scientific health agencies and foundations 13 contributing to this work through their funding 14 and through their expertise, the American Heart 15 Association, the American Cancer Association, the 16 American Public Health Association. These 1'7 activities are being conducted, not only in the 18 United States, but Britain, France, Germany, 19 Japan, South America, across the world. And to 20 think that the viewpoints of the tobacco 21 companies, the influence, the magnitude of this 22 scientific activity, one way or the other, which 23 has a life of its own, hugely funded, defies 24 credibility. 25 Q. It's possible to conceive of a 0 0 4 A. William Roberts, Jr. & Associates (800) 743-DEPO
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• 183 1 dimensions to your question. As a historian 2 testifying on the subjects i,m here today to 3 testify on and will testify if asked to, if this 4 case goes to a trial, it would not have been 5 pertinent. The word is not "interest." The 6 correct word is "pertinent." It wouldn't have 7 been pertinent to my subject to start B investigating internal company documents when I'm 9 interested in the state of scientific knowledge 10 and the scientific community. It simply would not 13. have been pertinent. 12 And that, secondly, as I have said 13 before, I don't want to misstate myself. I don't 14 approve of company misconduct.. I don't approve of 15 suppression of scientific data or trying to go out 16 and get people as is being suggested by these 17 people. But as a historian, I'm saying, I don't 18 know if that happened or not, and for you to 19 convince me as a historian, one -- and if you're 20 asked -- asking me what would be needed to 21 establish that, you would need some very good 22 evidence, and it would be more than a little 23 snippet from one document. I would really, you 24 know, need to'see good evidence that this occurred 25 and then, in some cases, there is also an issue of A. William Roberts, Jr. & Associates (800) 743•DEPO Ln W A I
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• • 12 their views. if anything, it would just tick them 11 to be quieted by anyone. They're going to express 186 1 stopped by the tobacco industry. Everything I've 2 known about medicine and science -- and you're 3 talking some very great individuals -- from my 4 personal involvement as a college student and 5 medical undergraduate, now as a professor of 6 medicine and as well as through my study of 7 history, tells me that you're talking with some 8 bright, in many cases brilliant individuals, with 9 strong minds, strong wills, strong temperaments, 10 who are on a search for truth. They're not going 23 a lot about him biographically, but his importance 16 of science and of the nature of scientists. so I 17 just don't accept that premise without evidence. 18 Q. Y7ho is Dr. Hammond? Do you come 19 across his name in your research? 20 A. Dr. Hammond? Dr. Hammond is -- I'm sure 21 you know, was one of the very important U.S. 22 investigators of the subject. I don't think know 15 side, I believe strongly misunderstands the nature 13 off. And to think that any company could quiet 14 someone like Doll or Hill or -- someone on either 24 in this context is that he and Dr. Horn were the 25 two principal investigators and on the major A. William Roberts, Jr. & Assooiates (800) 743-DEPO L" W J
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• r 191 1 circumstance where the tobacco companies hired 2 individuals to go over to Europe in the 1950's and 3 60's to retain scientists that may be adverse to 4 their interests, just so they could be on the 5 tobacco company payrolls at a later date? 6 A. Could you just say that again. 7 Q. Do you think it defies credibility 8 to assume that there's a man, hired by the tobacco 9 companies, whose full-time job was to travel 10 around Europe, hiring scientists who may be 1]. adverse to tobacco company interests just so the 12 day might come where they say, "You can't testify, 13 you work for us; you're on retainer, you're our 14 consultant"? is that beyond belief for you? i5 MR. DODDS: Object to the form. 16 It's beyond the scope. 17 A. I know so little, you know, company 18 behavior and what's appropriate and what's 19 inappropriate and so forth, that -- and I 20 certainly haven't looked into it -- that I really 21 can't give you a conscientious reply to that, and 22 so far out of the scope, but I would point out 23 that some individuals who had contract grants from 24 tobacco that I know of, such as Dr. Fisher in 25 England, who might be the person you're referring A. William Roberts, Jr. & Assocfates (800) 743-DEPO W Ln ~ N
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S Kenneth Marc Ludmerer Curriculum Vitae November 1999 i I. Personal: Born: January 13, 1947. Long Beach. California Citizenship: U.S.A. Spouse: Loren (married August 9, 1987) Children: Jordan Suzanne (b. February 15, 1995) Lindsey Francesca (b. October 4, :996) Office Address and Telephone: Washington University Jepartment of Medicine 660 South Euclid Avenue St. Louis, M0 63110 (314) 362-8073 (314) 362-8015 (FAX) klaamereL imwustl.edu (e-mail) Home Address and Telephone: .' 42 Rio Vista St. Louis, MO 63124 (314) 993-1811 (314) 872-7157 (FAX) II. Education: A.B. Harvard College; magna cum laude, 1968 (History and Science) M.A. The John Hopkins Universiry, 1971 (History of Medicine) M.D. The Johns Hopkins University, 1973 m. House Staff Training: (Barnes Hospital Medical Service and Department of Medicine, Washington University School of Y/edicine--St- Louis, Missouri) Intern, 1973-7d Junior Assistant Resident. 1974-75 ' Sehior Assistant R'esident and Chief Resident. Washington L'ni%•ersit}• Mediral Service at the io'nn Coc:rtan.': _rerans .knminlstratlUn HWpttfll. 19".>-"b ' N _- N A W Ln N B
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a- . • 188 1 different historical issue than the state of 2 medical knowledge. it would not be pertinent to 3 my study of the state of medical knowledge, from 4 the public -- from the published scientific :> literature to know whether or not they hindered 6 him in some way or they assisted him in some way. 7 That's really not pertinent. 8 And then, secondly, I would say 9 again -- and I will say it, because I think this 10 is important to the integrity of history as a 11 discipline -- and I will say it every time you 12 have a question that suggests it -- aside from the 13 fact that behavior, company behavior is different 14 from the state of medical knowledge -- two 15 different topics -- and I'm not speaking on 16 company behavior -- if that had happened,.I'm not 17 justifying that, but before we start assuming it 18 happened, one needs to have good historical data 1.9 that it did. And from the three court trials that 20 I've had and the four depositions that I've had 21 that you miscounted as eleven rather than as 22 seven -- but there's been enough experience to 23 have heard this before. 24 25 A. Q. . I said seven. And, you know, these things, if true, would A. William Roberts, Jr. & Associates (800) 743-DEPO ! 0 . ! I
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• 0 194 1 law firm. I'm paid for my ideas. 2 Q. Are you paid by the tobacco 3 industry? 4 MR. DODDS: Asked and answered. 5 A. I've asked and I've answered that. 6 Q. Are you a consultant to the tobaccol I 7 industry? 8 A. I'm a consultant to the law firm. I've 9 investigated questions. I stand behind this 10 testimony. The testimony is mine, and it's no one 11 else's, even though a couple of little typos got 12 into this report, which I do apologize for, but -- 13 Q. I'm not talking about the typos. 14 Your testimony was that -- 15 MR. DODDS: Could you let him 16 finish? 17 A. To answer your question, I'm available to 18 anyone. If you would like to retain me for your 19 next case, I'm available. 20 Q. You wouldn't have any conflicts, 21 sort of rules or ethical sort of rules so that i 22 could pick up the phone tomorrow and retain you in 23 a tobacco case on behalf of smokers? That would 24 be okay? 25 A. I have one allegiance. That's to my A. William Roberts, Jr. & Assoolates (800) 743-DEPO i
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• 1 C E R T I F I C A T I O N 2 198 3 0 4 ~ 5 I, ABNER D. BERZON, a Registered ' 6 Professional Reporter, Certified Realtime Reporter ; 7 and Notary Public, do hereby certify that the 8 foregoing witness, KENNETH M. LUDMERER, M.D., was 14 15 16 9 duly sworn on the date indicated, and that the ~ ~ 10 foregoing is a true and accurate transcription of ; r 11 my stenographic notes. R 12 I further certify that I am not employed by ; . 13 nor related to any party to this action. ~ 17 3.8 19 20 21 22 23 24 25 ABNER D. BERZON, RPR, CRR A. William Roberts, Jr. & Assoolates (800) 743-DEPO
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195 1 ideas. I don't know your case or their case. I 2 have one allegiance. 3 and the research that 4 stand for, and if you I'm a champion of my ideas I've done and the ideas I thought it would be useful to your case to have an the causal relationship cigarette smoking grew, historical account of how between lung cancer and I could just as easily 8 give it for your side as the other. Yes. 9 MR. MAISTROS: I have no further 10 ti k T ques ons. you. han 13 THE WITNESS: Well, thank you. 12 THE VIDEOGRAPHER: This concludes 13 today's deposition. 14 (Time noted: 4:08 p.m.) A. William Roberts, Jr. & Associates (800) 743-DEPO ti ~ w ~ m
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0 Dr. Ludmerer may also be asked to comment; on the opinions expressed by Plaintiffs' witnesses, and bases thereof, relating to the state and evolution of medical knowledge of smoking and disease. 0
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i 197 1 SIGNATURE OF DEPONENT 2 I, KENNETH MARC LUDMERER, M.D., do 3 hereby certify that I have read the foregoing 4 transcript of my testimony, taken on October 18, 5 2000, and have signed it subject to the following 6 changes: 7 PAGE LINE CHANGE REASON 8 9 10 11 12 13 14 15 16 17 22 23 24 A. William Roberts, Jr. & Assoofates (800) 743-DEPO N W, Ln 4- 00
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~4.~ . Publicadons- continueu 0 "Time and'vledical Education," Annals of Internal'vledicine, in press. "Reflections on Chanxing Standards of Medical Authorship," The Pharos, in press. Clinicvoatholo¢ic Conferences edited by Kenneth M. Ludmerer and John 2v1. Kissane: 156 columns edited for the American Journal of'vledjcine, May 1981 to June 1998. List available upon request. W Ln N k0
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U. .1 X. Editorial Board Positions - continued 4. Editorial Board, 3tttals of Internal Medicine 1993-96. 5. Editorial Board, History of Education Ouarterlv 1993-96. 6. Editorial Board. Bulletin of the History of Medicine 1996-present. 7. Editorial Board, Academic Medicine, 1999-present. XL Visiting Prof ssorships and Lnvited Lectures: 1. Symposium on "Biology and Politics," Swarthmore College, 1982. 2. Harvard Medical School Bicentennial Celebration, 1982. 3. AOA Inauguration Lecture, Washington University School of Medicine, 1983. 4. Visiting Professor, State University of New York School of.Medicine at Stony Brook. . 1984. S. Visiting Lecturer, Georgetown U niversity Summer Seminar in the Medical Humanities, 1985. . 6.. Plenary Session Lecturer, Organization of Studont Representatives, Association of 7. Plenary Session Lecturer, Society for :'esearch and Education in Primary Care Internal Medicine, Mid-Atlantic Region. 1986. • 8. Visiting Professor, Temple University School of Medicine, 1986. 9. Visiting Professor, Albert Einstein College of Medicine,1986. 10. Visiting Professor, University of Michigan School of Medicine, 1986 11. Visiting Lecturer, Kent County Medical Society, 1986. 12. Emmet Pearson Lecture, Southern Illinois University 5choolAf Medicine,1986. 13. McGovern Award Lecture, University of Texas-Galveston School of Medicine, 1986. 14. AOA Visiting Professor, The Johns Hopkins University School of Medicine,1986. 15. Plenary Session Lecturer, Washington University School of Medicine Alumni Day, 1986. 16. Symposium on "Flexner and the 1990s," University of Illinois College of Medicine at Chicago and The American Medical Association,1986. 17. Visiting Lecttuer, Georgetown University Summer Seminar in the Medical Hutnanides, 1986. 18. Visiting Professor, University of Pennsylvania School of Medicine, 1986. 19. Plenary Session Speaker, American College of Physicians and American Society for Intemal Medicine, Missouri chapters 1986. 20. Keynote Speaker, St. Luke's Day. St. Luke's Hospital, St. Louis, Missouri, 1987. 21. Keynote Speaker, First National Conference for Teachers of Introductory Clinical Skills, 1987. 22. Annual Lecturer, Carroll F. Reynolds History of Medicine Society, Pituburgh, Pennsylvania, 1987. 23. Visiting Professor, University of Pittsburgh School of Medicine, 1987. 24. Saffron Lecture, Medical History Society of New Jersey. 1987. 25. Keynote Speaker. Symposium on Technology and Medicine. St. Louis S,cience Center, 198".
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PUBLICATIONS • ok : Genetics and American Socie;,v: A Historical Anoraisal (Baltimore: The Johns Hopkins Press, 1972). (Second Printing, 1974) Learnin¢ to Heal: The Development of.krrterican Medical Education (New York: Basic Books, 1985). (Nominated for the Pulitzer Prize in History and the Bancroft Prize. 1986). (Paperback editions: Basic Books, January 1988; Johns Hopkins Press, 1996). Time To Heal: American Medical Education in the Twentieth Centurv (Yew York: Oxford tniversity Press, 1999). is Selecte i4rticles: "American Geneticists and the Eugenics Moverr,ient: 1905-1935," Journal of the Historv of Bioloev. 2: 337-362, 1969 "Genetics, Eugenics, and the Immigration Restriction Act of 1924," Bulletin of the History of Medicine, 45: 59-81, 1972. "Charles Benedict Davenport," in pictionarv of American Biogrm,hv. Supplement 3 (New York: Charles Scribner's Sons, 1972), pp. 214-216. "Cornmentary," in Bruce Hilton and Daniel Callahan, eds., Ethical Issues in Hutnan Genetics: Genetic Counseling and the Use of Genetic Knowledge (New York: Plenum Publishing Corporation, 1973), pp. 402-407. "Eugenics: History," in Encvclooedia of Bioethics (New York: The Free Press, 1978), pp. 457-462. "Reform of Medical Education at Washington University," Journal o the History of Medicine and Allied Sciences, 35: 149-173, 1980. "Reform at Harvard Medical School, 1869-1909;" Bu let'},r of the Historv of Medicine, 55: 343-370, 1981. "Writing the History of Hospitals." Bulletin of the History of Medicine, 56: 106-109, 1982. "The Plight of Clinical Teaching tn .america. " Bulletin of the History of Medicine, 57: =1S•"q. !98:. N ~ LA w N - - ~P W Ln Ln 11
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IV. Post-House Staff Experience: Post-Doctoral Fellow. Department of Internal Medicine, ~ Washington University School of Medicine, 1976-78 Research Associate. Deparanent of the History of Science, Harvard University, 1976-78 Chief Resident, Internal Medicine, Barnes Hospital and Assistant Director of the Medical Service, Washington L:niversit.•SchoolofMedicine, 1r18-79 V. Academic Appointments: ` Instructor of Medicine, Washing'on University, 1976-79 Assistant Professor of Medicine, School of Medicine, and Assistant Professor of History, Facuity of Arts and Sciences, Washington University, 1979-i986 , Associate Professor of Medicine; School of Medicine, and Associate Professor of History, Faculty of Arts and Sciences, Washington University, 1986-1992 ! Professor of Medicine, School of Medicine, and Professor of History, Faculty of Arts and Sciences, Washington University, 1992- Vl. Professional Societies: Diplomate, American Board of Internal Medicine, 1976 American College of Physicians --Elected Fellow, 1985 Ametican Federation for Clinical Research American Association for the Advancement of Science --Elected Fellow, 1990 Association of American Physicians (elected, 1999) American Association for the History of Medicine --Council, 1984-87 History of Science Society Organization of American Historian American Osler Society --Board of Governors, 1988-present --Vice Prcsident, i 992-94 --President, 1994-95 ?'.or•orarv M ember. ' .1dedical Histon Societ."of Ncw-lersn• iiistor} of Education Societn W N f+
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VII. Honorary Societies: Phi Beto Kappa Alpha Omega Alpha Sigma Xi VIIL Awards and Honors: College: Honors at Entrance Harvard College Award for Scholarship John Harvard Award for Scholarship Research Prize, History of Science Department, for outstanding Senior Honors Thesis of 1968 Medical School: Henry Strong Denison Award for Research Recipient of Research Grant from the National Genetics Four.dation Post-Graduate: Selection of Gettetics and Americart ciety +by Saturdav Review for inclusion on its list•ofthe year's ten outstanding books on scientific subjects 1973. Nicholas E. Davies Memorial Award, American College of Physicians, for it outstanding contributions to medical humanism," March 1997. IX. Research Grants: American College of Physicians Teaching and Research Scholar, 1980-1983. Henry J. Kaiser Family Foundation Faculty Scholar in General Internal Medicine, 1981-86 Research Grant, Henry J. Kaiser Family Foundation, 1986-89 Research Grant, Josiah Macy, Jr. Foundation, 1989-94 and 1995-97 Research Grant, Spencer Foundation, 1992-93,1994-95, and 1995-97 Research Grant, Culpeper Foundation, 1995-97 X Editorial Board Positions: 1. • Consultant Editor and Editor of the Clinicopathologic Conference Column, America Journal of Medicine 1981-1998. :. Editorial Board. Journal of the Historn• of ~tedicine and Allied Sciences 1981-83: 1988-90;1996-present. .. Editonai Board. The "rharos i9o6-presen:.
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XII. ivtiscellaneous • 10. Vice-President, Alpha Omega Alpha. Washington University chapter, 1987-90; President, 1990-95. 11. Health and Public Policy Committee, American College of Physicians, Missouri chapter, 1987-1989. 12. Consultant, The Johns Hopkins Medical Institutions' Records Project,1987-present. 13. Board of Trustees, °vlissouri Historical Society-St. Louis History Museum, 1987-93; Executive Committee of the Board of Trustees,1988-90. 14. Board of Governors, American Osler Society, 1988-present. 15. Faculty Senate Council, Washington University, 1988-1989. 16. Co-director of course,. "Medicine in Modern Society," required of first-year students, Washington University School of Medicine, 1988-90. 17. Committee on Publication Policy, American College of Physicians, 1988-93. 18. National Advisory Committee, Clinical Scholars Program, Robert Wood Johnson Foundation, 1988-92. 19. Chairman, American Heart Association, St. I,buis Chapter, Community Research Peer Review Committee, 1988-1989. 20. Chairman, Library for Intemists Committee, American College of Physicians, 1990-91. 21. Advisory Board, Culpeper Foundation Program in the Medical Humanities, 1992-93. 22. Task Force on Medical Education, Acadia lnstitute-Medico College of Pennsylvania, 1992-96. 23. Consultant, Medical School Objectives Project of ihe Association of American Medical Colleges, 1996-present. ln N . (J . .A W Ln Ln ~ ~
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XI. Visiting Professorships and lnvued Lectures - continued 51. Lloyd Stevenson Lecture, Insaure of the History of Medicine, The Johns Hopkins . University, November 1993. 52. Radbill L-cture, College of Physicians of Philadelphia. November 1994. 53. Lowell Davis Lecturer, Northwestern Universiry School of Medicine, January 1996. 54. Invited Speaker, American Board of Internal Medicine, Annual Meeting, July 1996. ' 55. Nicholas E. Davies Lecture, Annual Meeting, American College of Ph-vsicians, March 1997. 56. John P. McGovern Lecture, Centennial Meeting, Medical Library Association, May 1998. 57. Twig Visiting Professor, Rochester General Hospital, September 1998. XII. Miscellaneous 1. Regular service as a book reviewer for the Bulletin of the Historv of'-Viedicine, the Journal of the Historv of Medicine, the ,[o_umal for the Historv of Science, CJjg, Medical Journal of American Historv, the American Historical Review, aro , jik, Reviews in American Historv, Journal of the American Medical Association, cience and the St. Louis Post-Disoatch 1977-present. 2. Regular service as a manuscript referee for the Bulletin of the Historv of Medicine, the Journal of the History of Medicine and Allied Sciences, the Annals of Internal Medicine, and Joumal of the American MedicalAssociation, the American Journal of Medicine _the Johns Hopkins Press, the Universiry of Pennsylvania Press, Princeton University Press; the Free Press the University of Minnesota Press, Indiana University Press, and Rutgers University Press, 1977-present 3. Regular service as a grant referee for the National Library of Medicine, the National Science Foundation, the Hannah Institute fdr the History of Medicine, the Wellcome Trust and the National Endowment for the Humanities, 1980-present. 4. Adjunct Curator and member of Medical Advisory Committee, St. Louis Science Center, 1985-present. 5. Participant, second annual British-American Conference for the Successor Generation (sponsored by the Johns Hopkins University School of Advanced International Studies and the Royal Institute of International Affairs), 1986. 6. Nominating Committee, St. Louis Region, British-American Project for the Successor Generation (sponsored by the The John Hopkins University School of Advanced International Studies and the Royal Institute of Intemational Affairs), 1986-90. 7. Consultant to the New York Hospitil. 1986-90. 8. Association of American Medical Coll:ges.New Pathway.Program.Evaluation Committee. 1986-90. 9. Participant. Conference on "Medicine and Societv: Citnical Decisions and Societai Values." Cornell l:ntversir<• Medicai Coileee. 19S". !
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r KENNETH M. LUDMERER (M.D,) Dr. Kenneth M. Ludmerer holds joint academic appointments in the Washington University School of Medicine in St. Louis, Missouri, where he is a Professor of Medicine, and the Washington University Department of History, where he is a Professor of History. He graduated magna cum laude from Harvard University in 1968 and then studied both medicine and history of medicine at Johns Hopkins University. Dr. Ludmerer received a Masters in History of Medicine in 1971 and his M.D. in 1973. He is the author of Learnin_e to Heal, nominated for a Pulitzer Prize in 1986 and, in 1999, of Time to Heal. Currently, Dr. Ludmerer practices and teaches internal medicine as well as history of medicine at Washington University. Dr. Ludmerer is expected to explain the principles of historical analysis. Specifically, he is expected to testify about historical analysis of developments in scientific and medical knowledge.. He will describe his application of these principles to his research on the state of scientific knowledge and belief regarding the relationship between smoking and health from the early 1900's to the mid-1960's. He is expected to testify about the state of medical knowledge of smoking, cigarettes, disease, and a possible relationship between smoking and disease in the Unites States from the early 1900's to the mid-1960's. Specifically, he is expected to testify that, prior to the . early 1950's, there was no reliable scientific or medical evidence that cigarette smoking posed a serious threat to the public health. Dr. Ludmerer is also expected to explain that, beginning in the early 1950's, medical and scientific articles began appearing n the leading scientific and medical journals suggesting a possible link between cigarette smoking and lung cancer. He is further expected to testify that these articles primarily concerned statistical studies, which were not considered sufficient under then prevailing medical and scientific standards to prove that cigarette smoking caused lung cancer or any other disease. He is further expected to testify that the studies began a bona fide scientific controversy as to whether smoking causes serious disease, including lung cancer. Dr. Ludmerer is further expected to describe this controversy, including the views of various scientists and scientific organizations and how these views related to one another. He is also expected to express the opinion that this bona fide controversy continued at least up to the publication of the Report of the Surgeon general's Advisory Committee in 1964. Dr. Ludmerer is also expected to testify how this controversy was addressed by public health officials. Dr. Ludmerer is expected to describe the circumstances surrounding the creation of the first Surgeon General's Report in 1.964. Dr. Ludmerer bases his opinions upon his education, professional experience and expertise, his review of the pertinent primary and secondary literature, and other information reasonably relied upon by members of his profession. L, N ' S ` jOWNTIFF W
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M. t•{siting Professorships and Invited Lectures - continued 0 26. Keynote Speaker, Centennial Celebration of the National Institutes of Health sponsored by the Associated .%Iedical Schools of New York. 1987. 27. Visiting Lecturer, Heberden Society, The New York HospitaiComell Medical Center, 1987. :8. Plenary Session Speaker, Society for Health and Human Values, 1987. :9. Annual Lecturer, Cardiovascular Council of the Central Research Society, 1987. 30. Visiting Professor, Indiana University S:hool of Medicine, 1987. 31. Visiting Professor, Department of Medicine, University of Michigan School of Medicine, 1988. 32. Workshop in Doing the History of Medicine. American Association for the History of Medicine, 1988. 33. Phi Beta Kappa Inauguration Lecture, Washington University, 1988. 34. American Intellectual History: A Conference in Honor of Donald Fleming, Harvard University, October 1988. 35.'Keynote Speaker, Sesquicentennial Celebration S,vmpositun, Albany Medical 50. Conference on Medical Education and Health Sen•ices to the Poor and Medically Cninsured. Ame:ican Academy of Arts and Stierices December 1993. Ln N W 1991. 46. Overholser Lecturer, University of Missouri School of Medicine, March 1992. 47. Keynote Speaker, Annual Associates Meeting of the American College of Physicians, Michigan Chapter, May 1992. 48. Keynote Speaker, Plenary Session. Clerkship Directors in Internal Medicine, November 1992. ' 49. Keynote Speaker, Plenary Session, Association of Program Directors in Internal Medicine. November 1992. College, November 1988. ~ 36. Austin Flint Lecture, University of Massachusetts Medical'Center at Worcester, November 1988. 37. Conference on Documents and Interpretations in the History of Science, American Philosophical Society, December 1988. 38. Symposium, "The AIDS Patient and the Health Professional; Cornell University Medical College, February 1989. ' 39. Commencement Speaker, The University of Anzona College of Medicine, May 1989. 40. Keynote Speaker, Stanford Health Policy Forurn, January 1990. 41 Plenary Session Speaker, Symposium on "Medicine and the University," Centennial Celebration of The Johns Hopkins Medical Institutions, May 1990. 42. Lattimer Lecture, The New York Academy of Medicine, September 1990. 43. Annual Lecturer, The Buffalo Academy of Medicine, October 1990. 44. Visiting Professor in Medical Humanities, Universiry of Arkansas School of Medicine, April 1991. 45. Logan Clendening Lecture, University of Kansas School of Medicine, September ~ - N W ~ . . ~ ~ rP
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Publications - continued "The Rise of the Teaching Hospital in Arnerica." Journal of the History of Medicine and Allied Sciences. 38: 389-414,1983. "The'vledical Schools of vew York and the National Enterprise of Biomedical Research, 1850-1987," Bulletin of the New York Academy of'vledicine, 64: 216-236,1988. "Patients Beyond the Pale: A Historical View," in David E. Rogers and Eli Ginzberg, eds., Public & Professional Attitudes toward AIDS Patients, (Boulder, Colorado: Westview Press,l9'9), pp. 7-18. "Charities or Businesses? American Hospitals in the Twentieth Centttty," e' w' American Histotv. 18: 267-273,1990. "The Origins of Mount Sinai School of i4iedicine," Juunal,gf the History of Medicine and Allied Sciences. 45: 469-489, 1990. ,' "Methodological Issues in the History of Medicine: Achievements and Challenges," ee s of the American Philosophical Socfetv, 134: 367-387,1990. 6 ~ "Joseph Erlanger," in Daniel M. Fox and Ita Rezak, eds., Nobel Lattnates in Medicine or Physiolo¢y, (New York: Garland, 1990): "Washington University and the Creation of the Teaching Hospital," Journal of the American Medical Association, 266: 1981-1983, 1991. "Watching the Doctor," Reviews ir.AttteFican Historv, 20: 386-390, 1992. "The University of Michigan Medical School: A Tradition of Leadership," in Joel H. Howell, ed., Medical Lives and &ientific Medicine at Mi.chi,pa~n 1891-1969, (Ann Arbor: University of ;Mlichigan Press, 1993), pp. 13-27. "What Will the Education of Internists Be Like in 201 l?," in o ess" a Res,p,onsibilitv Professional Accounta¢j(jty What is the ABIM's Role? Report of the 1996 ABIM Summer Conference (Philadelphia: Amer.:3n Board of Internal Medicine, 1997), pp. 59-64. • "Instilling Professionalism in Medical Education ° Journal of the 4rttetican &dical Association. 'S'_: 881-882. 1999. ~'Retlecnons on Timr to iieai," 3;~1. Rercr er QCtobe,r 1 qqq. Dn. 2•3.
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Respectfully submitted by: 0 Robearn Simon, Peragine. Sn#h & Redfearn. L.L.P. 1100 Poydras Street, 30th Floor New Orleans, LA 70163 Telephone: (504) 569-2030 CERTIFICATE OF SERVICE I hereby certify that a copy of the foregoing Notice of Deposition has been served by hand delivery or by fax this (,'{ ~day of Ckj r• 2000, upon: DEFENDANTS' LIAISON COUNSEL: Scott E. Delacroix, Esq. Charles F. Gay, Jr., Esq. ADAMS & REESE 4500 One Shell Square New Orleans, LA 70139 Phillip A. Wittmann, Esq. STONE, PIGMAN, WALTHER, WITTMANN & HUTCHINSON, LLP 546 Carondelet St. New Orleans, LA 70130 SPECIAL MASTER: Dominic J. Gianna, Esq. MIDDLEBERG, RIDDLE & GIANNA 201 St. Charles Ave., 31" Floor New Orleans, LA 70170-3100 otiert L. Redfear Plaintiffs' Lialson 05unsel ocT-Ie-zeoo 17134 +5e45959925 76% P.13
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Si 0 the complications; 25. Copies of any and all medical release or patient consent forms that Dr. Ludmerer distributes to patients prior to the following procedures: needle biopsy of the lung bronchoscopy, with and without biopsy thoracotomy mediaslinoscopy exercise ECG pharmaoologic stress testing stress imaging, including exercise echocardiography and stress nuclear imaging cardiac catherization cystoscopy intravenous pyelography CT scan with contrast Video•assisted thoraooscopy (VAT) VAT wedge resection for histological evaluation of SPNs These statistics should include morbidity and mortality rates and descriptions of the complications; 26. Any documents, including notes, and electronic communications, pertaining to your expert report; 27. Any protocols, procedures or "standing orders" for histories and physicals of asymptomatic adults utilized at your hospital, department, clinic or private office, Including information regarding measurement of blood pressure, blood tests for lipids, urine analysis, spiral CTs, stress ECGs; spirometric measure of lung function, immunizations, NMP-22 testing, or urine cytology: 28. Any and all forms used at your institution, department, clinic or private of8ce for obtaining the medical histories of patients; 29. Any Information regarding procedures and/oi tests performed during a history and physical, or as a follow-up to a history and physical, of an asymptomatic adult N w r which are reimbursable through third party payment; N w ~ w oCT-1e-2000 17:34 +5045857925 76'/. P.17
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disease. Second, I reviewed the primary literature -- articles published in the scientific literature i after 1930. A summary of the opinions that I expect to offer at trial is set forth below. Overview of Opinions I expect to explain the principles of historical analysis. Specifically, I expect to testify about the historical analysis of developments in scientific and medical knowledge. I also expect to testify about the state of medical knowledge of smoking, cigarettes, disease, and a possible relationship between cigarette smoking and disease in the United States from the early 1900s to around 1964. Beginning in 1950, medical and scientific articles began appearing in the leading scientific and medical journals suggesting a possible link between cigarette smoking and lung cancer. There were varying views within the scientific community regarding these studies. I expect to describe how these views related to one another. I expect to testify how the findings of these studies were addressed by public health officials. One response considered by the public health community was the reduction in tar and nicotine yields as a possible means of reducing the risks associated with cigarettes. Another response by public health officials was the creation of the Surgeon General's Advisory Committee and the publication of the first Surgeon General's report in 1964. Statement of Opinions and Basis ' I have concluded•.based upon my review of the literature that there was no credible scientific evidence linking cigarette smoking to lung cancer or any life-threatening disease before . 305111.3
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• Mayo Clinic, expressed misgivings about both the accuracy of the statistical studies and the conclusions some scientists were drawing from them. For example, Dr. Berkson asserted that significant design problems still remained in the retrospective and prospective studies that made their results unreliable. Dr. Fisher also criticized the notion that these studies established causation. These are only a few of the many scientists at the time who questioned whether the scientific evidence of that time established that smoking caused lung cancer. There was also disagreement between public health officials and research scientists about the proper way to proceed in the period between the mid-1950s and early 1960s: While public health officials believed that it was better to be safe than sorry, and that cigarette smoking should be assumed to cause lung cancer even if it had not yet been scientifically proved, medical researchers, although certainly concerned with the public health, were first and foremost scientists who felt that they could not make a judgment as to causation until the evidence warranted it. These areas of disagreement continued in scientific circles up through the Surgeon General's Advisory Committee's Report of 1964. In conclusion, although the question of a relationship between cigarette smoking and lung cancer had certainly become a major concern between 1950 and 1964, there was no consensus during this time period among medical authorities that cigarette smoking was hazardous to health. I base my opinion upon my education, professional experience and expertise, my review of the pertinent primary and secondary literature, and other information teasonably relied upon by members of my profession. 305111.3
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• EXHIBIT "A" 1. A copy of Dr. Ludmerer's most current curriculum vitae; 2. Any and all of Dr. Ludmerer's original records pertaining to his treatment, evaluation, or examination of Gloria Scott and Deania Jackson 3. Any and all materials, documents, writings, or other tangible objects, Including computer data and databases, that Dr. Ludmerer relied upon to form his opinions in the case Gloria Scott et at v The American Tobacco Comoanv et al or Intends to rely upon, including, but not limited to, any and all medical records pertaining to Gloria Scott and Deania Jackson, any and all articles, books, book chapters or other medical and scientific publications or data (published or unpublished): 4. Any and all complete original file(s) pertaining too the case Gloria Scott, et ai v. The American Tobacco Company. et al., including, but not limited to, any and all expert billing records; 5. Any and all complete original file(s) pertaining to the case BianJ,cenship, et al v. Qhilio Morris.gt al.. Including, but not limited to, any and all expert billing records; 6. Any and all complete original file(s) pertaining to the case Richardson, et al v. Philip Morris et al., including, but not limited to, any and all expert billing records; 7. Any and all complete original file(s) pertaining to the case Reed, et al v. Phllio Morris, et al., including, but not limited to, any and all expert billing records; 8. Any and all materials, documents or writings that are not reflected In the deponent's curriculum vitae and are related to or arising from any research or other scientific endeavor conducted by the named deponenl the subjects of which are smoking and health issues, smoking cessation, medical monitoring, or routine screening tests; 9. Any and all materials, documents, writings, or other tangible objects provided to Or. Ludmerer by Defendants' Counsel or other expert witnesses in this litigation or any other INigation.involving smoking; 10. Any and all materials, documents, writings, or other tangible objects that Dr. Ludmerer has pertaining to plaintiffs, or any othe,r matters relevant to the case Gloria yott et al v The American Tobacco Company, st al., obtained from any . OCT-7e-2a6o 17:34 +9045a579Z9 W N J O
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CIVIL DISTRICT COURT FOR THE PARISH OF ORLEANS STATE OF LOUISIANA No.96-6461 DIVISION K DOCKET NO. 4 CLASS ACTION CLAIM GLORIA SCOTT AND DEANIA JACKSON VERSUS THE AMERICAN TOBACCO COMPANY, INC., ET AL. FILED: DEPUTY CLERK IHi1 HHII1lififiNaHiMafYlialKiKHY4YHf/1KaflNafllYHiiKaMINNiYMlylfai11K1L1f1afl11Kff RE-NOTICE OF DEPOSITION TO: Phillip A. Wittmann Stone, Pigman, Walther, Wittmann & Hutchinson, LLP 546 Carondelet Street New Orleans, Louisiana 70130 Defendants' Liaison Counsel • PLEASE TAKE NOTICE that plaintiffs will take the following deposition, which has been noticed in the Blankenship case and is hereby cross-noticed in this case: Deponent: DR. KENNETH LUDMERER Date: Wednesday, October 18, 2000 Time: 10:00 a.m. Location: Dechert, Price & Rhoades 30 Rockefeller Place, 23rd Floor New York, NY 10112 Telephone (212) 698-3500 The deposition will take place before a court reporter or other person authorized by law to take oaths. The deposition will be taken for all purposes permitted by the Louisiana Code of Civil Procedure, including use at trial. The deposition will be videotaped and recorded stenographically, and will continue from day to day until completed. Therefore, this notice is deemed good and valid until which time the deponent has been completely deposed. The deponent shall produce for inspection and copying at the time and place of the deposition the documents designated in Exhibit A. You are invited to attend and parlicipate as you, deem appropriate. OCT-1e-2000 17:34 +sea5esnrs ~
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. i . (~i orri et al ; 20. Any and all reports, summaries, memoranda and evaluations that Dr. Ludmerer has prepared that relate to his opinion in this case Richardson, et I~y. Phtlin Morris. et at.; 21. Any and all reports, summaries, memoranda and evaluations that Dr. Ludmerer has prepared that relate to his opinion in this case Reed, e]pI v. Philip Morris, et A1.; 22. Copies of any and all prior deposition, trial, congressional, governmental and other testimony (including affidavits) by Dr. Ludmerer, relating to the etiology of lung cancer, or testimony related In any way to the issues of medical monitoring, smoking cessation, or smoking and health; 23. Any and all articles, books, or book chapters written by or contributed to by Dr. Ludmerer that are in press or otherwise not publicly available; 24. Statistics regarding complication rates over the last ten (10) years at any hospital, department, clinic, institutlon, or private office in which you practice, or have an affiliation with, for the following procedures: needle biopsy of the lung • bronchoscopy, with and without biopsy • thoracotomy • mediastinoscopy • exercise ECG • pharmacologic stress testing stress imaging, Including exercise echocardiography and stress nuclear imaging cardiac catherization cystoscopy intravenous pyelography CT scan with contrast • Video-assisted thoracosoopy (VAT) • VAT wedge resection for histological evaluation of SPNs These statistics should include morbidity and mortality rates and descriptions of oLT-Se-2000 17:74 s5g45g57g25 967; P.16
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. EXPERT REPORT OF DR. KENNETH M. LUDMERER, M.D. i Background I am employed by Washington University as a Professor of Medicine and a Professor of History. I hold joint academic appointments in the School of Medicine and the Department of History. I received my undergraduate degree at Harvard University, where I graduated maetta u~r laude in 1968. 1 then went to medical school at Johns Hopkins University, where I studied both medicine and the history of medicine. I received a Masters in the History of Medicine in 1971 and my medical degree in 1973. I am board certified in internal medicine. I have published threebooks, more than thirty original articles concerning the history of medicine, and numerous book reviews. My curriculum vitae, which is attached, lists these publications. I have also served on the editorial boards of seven professional publications and have been a peer reviewer on a number of medical journals. I understand that defendants may call me to testify in this matter on the issue of the evolution of medical knowledge of smoking and disease. In conducting my study, I followed standard historical methods. My research had two parts. First, I reviewed the secondary literature -- that is, the literature that people wrote after the fact. I reviewed this literature both to gain an understanding of the general history of public health and disease and to leam what other people have already concluded about the history of smoking and Ln W is N 1 305111.3 A ~ PLAINTfFPS EXHIdIT :
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0 11. 12, 13. 14. 15. 0 16. 17. 18; 19. ' OCr-1e-200a source; Any and all notes or memoranda pertaining to Ms. Scott or Ms. Jackson or any other smoking related case; Any and all notes, memoranda, audio or videotapes prepared by or at the request of Dr. Ludmerer pertaining to this case Gloria Scott e_t al v The American Tobacco Compa_qy, et al.; Any and all correspondence, including electronic mail, between Dr. Ludmerer and Defendants' Counsel and between Dr. Ludmerer and any expert for the Defendants; Copies of any an all presentations and public statements, including those made for the media and for legislative or regulatory purposes, dealing with the etiology of chronic diseases, lung cancer, bladder cancer, COPD, coronary artery disease, smoking cessation, routine screening tests, or medical monitoring; Copies of any and all lecture notes, outlines and course materials that Dr. Ludmerer used in teaching capacity involving the causation of chronic disease, lung cancer, bladder cancer, COPD, coronary artery disease, smoking cessation, routine screening tests, or related in any way to medical monitoring; Any and all documents, including but not limited to, copies of correspondence exchanged with persons or organizations, relating to the etiology of any disease associatedwith smoking, environmental pollution, occupational exposure, smoking cessation, routine sueening tests, or medical monitoring; Any and all critiques, memoranda, correspondence, articles and other documents authored by Dr. Ludmerer relating to the potential role of cigarette smoke in the causation of chronic disease, lung cancer, bladder cancer, COPD, coronary artery disease, or related in any way to medical monitoring or routine screening tests; Any and all reports. summaries, memoranda and evaluations that Dr. Lddmerer has prepared that relate to his opinion in this.case Gloria Scott et al v. The American Tobacco ComeanV. et at.; ' Any and all reports, summaries, memoranda and evaluations that Dr. Ludmerer has prepared that related to this opinion In this case Blakenshio, gt al v. PMlio 19:74 .5e45e5?925 76 P.15
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• 0 30. Any and all documents or literature, incduding, but not limited to, brochures or posters, relating to smoking and health, smoking cessation programs, smoking , cessation products, smoking cessation methods, medical monitoring or routine screening tests: 31. Any and all documents relating to grant proposals or applications made to any entity for any funds to study any aspects related to spiral CT scanning, cancer biomarkers, and any screening for lung cancer, bladder cancer, heart disease, or COPD. ~ N N W U v .rI OCT-1e-2000 14:3q +50a5857925 7f•, P.1s
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! • The first new type ofstudy was an animal experiment conducted by Drs. Wynder and Graham. In attempting to obtain laboratory evidence that tobacco smoke could cause cancer in mice, Drs. Wynder and Graham condensed whole tobacco smoke and painted the resulting tar on the backs of laboratory mice. Forty-four percent of the animals treated obtained cancers.' Drs. Wynder and Graham did not believe that their animal experiment proved that smoking causes lung cancer. Their narrow finding that tobacco tar could produce cancers on the backs of mice was confirmed at least 15 times in the literature within ten years. Researchers also attempted to go one step further and produce actual lung cancers in laboratory animals exposed to cigarette smoke. None of these inhalation experiments was successful. The second new type of study involved attempts to identify known cancer-causing chemicals, called carcinogens, in tobacco smoke. Although researchers identified the carcinogen benzpyrene in tiny quantities in tobacco smoke in the mid-1950s, it was widely concluded that the amount of benzpyrene in tobacco smoke was simply too small to have a cancer-causing effect. Between the mid-1950s and early 1960s, researchers were unable to identify any agent or combination of agents in tobacco smoke that could account for its alleged cancer-causing activity. The inability to identify these unknown agents was also considered strong evidence against the causation hypothesis in the 1950s and early 1960s. 2. Wynder eta l., "Experimental Production of Carcinoma with Cigarette Tar," Can.cer Research, 13: 855-64 (1953). . 305111.3 . 4
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_ .... ..~....~.. t iBRITISH MEDICAL JOURNAL : LONDON SATURDAY DECEMBER 13 1952 m6cft4?7&,~, 1299, opcniug pages of this issoe Doll snd Bradford xill report the results of an extension of their inquiry .. during 1950 and 1951 to patients In Bristol, Cam• bridge. Leeds, and Newcastle-upon-Tyne hospitafs and a continuation of it in eight of the London hos- pitals, The method of Invutigation, described in the first paper, was to obtain notifications of patients admitted to hospital with cancer of the lung. stomach, SMOKING AND LUNG CANCER Six years ago the Medical Research Council called a conference to consider whether the remarkable increase in death rates from lung cancer, as indicaMd by the Registrar-General's statistics, justified a search -for the causcs of this phenomenon. At that time many were sceptical about the reality of the appa• rent rise, attributing it to the increasing use of radio- graphy in the diagnosis of thoracic disease; but for tunately the conference was not deterred by such ,doubts from advising researches both of a statistical and an experimental nature. Among the conclusions arrived at by a Symposium on the. Endemiology of Cancer of the Lung held by the. Council for the Inter- and large intestine, who were then questioned about tobacoo•smoking, and to match each lung-cancer case with a patient of the same sex and age group suffering from a disease other than cancer. In the extended inquiry the almoners visited the provincial hospitals at intervals and interviewed patients with suspected cancer of lung who happened to be in-patients to- gether with matched control patients having other diseases. The final classification was usually based upon the diagnosis at the time of discharge from bos- pital. In addition to obtaining the history of tobatxo- smoking, the almoners asked questions about the proximity of gasworks, methods of beating, places of residence, and previous history of respiratory diseases., I . This second report is based' upon the whole stties national Organizations of . Medical Spiences at, Lou= from the start of the Invesdga6on It now comprises , vain in July., 1952, was a statement of belief that a j,488 patients with carcinoma of lung; of whom 1,465 significant part of the apparent increase is'absolute. were paired with control patients having diseases In England and Wales the graph of death r>ltes shows . other than cancer, and another control group of 1.278 ~o siga as yet of levelling out, some 13,000 deaths which included patients suffering from cancer of the aving been registered in 1951.1 It may be. irue that stomach and the intestine. Comparison of the 1,465 i large proportion of the cases now being certified' 'patients suffering from lung cancer with their matched would not have been diagnosed if they had oocurred controls showed no significant social class diHer• • 10 years ago, but the fact remains that,. out of any enees ; but there were fewer resident in Greater random sample of 400 men now aged about'SS, at London (791, compared with 900 among the con• least 10 must be expected to die of lung cancer within trols), more resident in other urban areas (500, against the next 20 years, in comparison with 200 from all 394), and fewer resident in rural districts (155, against other causes, even though death rates remain at their 164). Since tobacco consumption is rather greater present leveL This merits serious atten6on,•and it is in London this inequality. would tend to reduce any well that the studies initiated by the General Register excess in usage of tobacco by the lung-cancer group Office and Medical Research Council ate yielding mther tban exaggerate it. In the interviews with some ' results of great importance, unpopular though they pairs of patients questions about brands or tobacco, must be. filter-tipped cigarettes, petrol, lighters, and cigarette- Dr. Richard Doll and Professor A. Bradford ~I1B holders were added to those described in the first published in this Journal two years ago' a first report report about frequency, quantity, and duration of of an inqu'uy, most carefully conducted among 2,475 smoking: Non-smokers were defined, as before, as patients in 20 London hospitals, leading to the con- persons who had never consistently smoked as much clusion that "smoking is a factor, and an importnnt as one cigarette a day tor as long as one year. ' factor, in the production of carcinoma of the lung." Among the various quantitative measures of smoking Their results were confirmed in almost all respects employed were the most recent amount smoked, the by a similar study of 684 cases of broncbogenic-carci-. •maximum amount ever. smoked regularly. the esti- noma by Wynder and Graham in the U.S A° In the mated total amount ever smoked, and the average i n y4F Mrd1 : io~.19so, r, 739. • amount smoked daily over the 10 years preceding ~ If. .,mtr. mrd. An. 1919. 143, 329. IRrnW=o}~,19s:,:.r1o. illness, and of these the first and last were judged~1nld.,l9sxr,9u. to be the best. PL~IINTIFF'S' " EXHIBIT ` : ', 4 :..............~ 2-20.:
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0 • The third type of new study was a new type of statistical study called a prospective or cohort study, which is a study that begins with a population of people without lung cancer and tracks their health and their habits over a long period of time. These prospective studies found an extremely high association between smoking and lung cancer. They also found that smoking was unexpectedly associated with many other diseases. Taken together, these studies sparked a fundamental disagreement that lasted for years between experimentalists and epidemiologists -- that is, between medical specialists who felt that laboratory experimentation was necessary to prove causation and those who accepted statistical evidence. Some scientists believed that the new science of clinical epidemiology, with its new methods and sophisticated statistical techniques, could provide direct evidence of causation. The medical specialists who believed that positive experimental results were necessary to prove causation noted, first, that nothing was known about the fundamental mechanisms of lung cancer; in other words, no one understood how lung cancer developed and grew on a cellular level. Second, the required experimental proof was lacking. At this time scientists were able to obtain cancers on the backs of laboratory animals, but all attempts to obtain lung cancers in laboratory animals exposed to cigarette smoke had failed. These medical specialists were reluctant to accept causation when medical science had yet to identify anything in tobacco smoke that could account for its alleged cancer-causing activity. There was also disagreement within the statistical community itself. Some of the founders of the field of biostatistics, specifically Sir Ronald Fisher and Dr. Joseph Berkson from the JOS111.7 Ln N W N A. W U1 J t0
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A list of cases in which I have testified during the last four years is attached. I am ! charging S300 per hour for my work in connection with this case. Kenneth M. Ludmerer, M.D. / ~ 305111.3 u, N W . 7 X, W N OD N
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Defendants' joint Expert Reports Index - Vol 4 KENNETH LUDMERER, MD - Professor of medicine and professor of history, Washington University
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• the early 1950s. Beginning in the early 1950s, evidence appeared that raised a scientific concern that cigarettes may be life-threatening. At no time between the early 1950s and January 1964 -- when the Surgeon General's Advisory Committee's Report was released -- was there a consensus within the medical community that cigarette smoking caused lung cancer, heart disease, or other life- threatening diseases. Rather, the issue of whether smoking caused disease was the subject of debate, with reputable scientists on both sides. The early 1950s was the turning point in the history of lung cancer research. Between 1950 and 1952, at least five retrospective statistical studies were published on the relationship between smoking and lung cancer.' All of these studies found a statistical association between excessive cigarette smoking and lung cancer. However, these studies did not conclude that cigarette smoking causes lung cancer; in fact, most of the studies were careful to state that causation had not been proved. The years 1953 and 1954 brought additional developments in the history of lung cancer research. During those years, three new types of studies were conducted relating to smoking and cancer. 1. ee e. , Doll & Hill, "Smoking and Carcinoma of the Lung," British Medical Journal, 739- 48 (1950); Levin e_t al., "Cancer and Tobacco Smoking," Journal of the American Medical Association,143: 336-38 (1950); McConnell et a,"Occupation and Personal Factors in the A,etiology of Carcinoma of the Lung,"~ Lancet, 651-56 (1952); Mills & Porter, "Tobacco . Smoking Habits and Cancer of the Mouth and Respiratory System," Cancer Research, 539- 42 (1950); Schrek e a., "Tobacco Smoking as an Etiologic Factor in Disease," Cancer Research, 49-58 (1950); Wynder & Graham, "Tobacqo Smoking as a Possible Etiologic Factorr in Bronchiogenic Carcinoma," Journal of the American Medical Association,1,43: e, 329-38 (1950). w ~ ... . , . . , N 305111.3 3 ~ w cn J J
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i ~j~V 21 t995 FLORlDA SfIsTI: CICLn R/rotit en*nyuLmJ ~{O nks 4ve1(i.a adcpubGdry n. Ntay W r dµ rnaHO/ 6 h loao ry GddvML.(arwerYLrea ary . . , AWeulbwnduneCbydaandprofaJwdrLnd'a{• IkrtrptrinimurnrolrtµrdaA. mrlydaLtlrErKnf .aar rourtl. rla.~.a''•'.~. Pa MI b.lk.. wt uy Wku1 • M)inl nrlnl',fR. d/..Y b/ R/1dY rn LfOMINIn rL00{~ i .. 6ediuqlKadxGtLydiuvinM4 At the rnr 4mm•n kel R 6 LIOe pubGc Nlemt lo a9 nkeUon b Ur fu1141fmLrM doelan ud nwrtblckmnu 4.re µi0fid) 9r<aioecd tk ./dm.d dpd&.ev of tbne a. . puwati I , f~slvhkaSNoddn jdel mt: 1, TII nMwl manl If riKW )..n fdkstw wrJ yowlll...«n N L.1'...rn. ' LT•Uhukw•v.~al.owMW..ualtlnntul• by.kl lk n`r k 1 T.1 P.n Y.n pwf p.r dl"u oatlry L ew of W ev.a . l TYiI NaWlu Cor foAp b Lk dt•Mk woLl4 nld. a dw..wu .pll rl6 w•d /om la ael .ar d.a7 .6nuprcudrWrt.Mk.ldndMMlUrydtkWEMh - 6a¢rtku Y IeMLrd /i.a'.rw rkdub. we ramt.n Lrnnln peepkS bn1LA at. buic lapoe• r'bSry.p.nmuynl u rKry aAawMldmiioe kombuSrcu. • W. klk.w the produvj" Ltr rn eot LJwIOw w bula. ~' , M•c dnn Lr .M .M)r.itl wnµnr .bxly wilb Ibor+6cr wk p b to W<qwd Ox pubGc k.ld4 ~ (w new da 7D])an kbrc<MI Cl.a rd.o[ rtW~ 1 fo.•uda~Rwwatlnd.Atartlk.e.r.eerludqb{ • Oneyan a8fu4n kld k mpW6k fa L.rWaLJ eray lrrr dIk Imaabod).O« by aa Orr d Wyn kre ben .rb.Mexlbrlrkdaidma. , Rt(I/OIt1101 PM nfNO Ol 14! /MIt. rM nR aa nJIR\r • aaSL~wLSAeddmebfwped.lYlaurdrrub. '• diWrktNlbYfdocr WMtn1>Y4 ... )dYy pwpkbM.alfkdpYbltrGYCdob1[I0 m<dlb[ • pWeT tcea~a uoaru.i b~ tbs lami nperts /kn b 16e ralnr•. ~. W. w Ck1t4( .Id a/ rWNU. N dr IaoW dIM LI. dpLw1 d toktt. ar W kd6. Tw /nlq /+rdal rY • .m d e.rr k L.ldirla r..kt k rbnd~ klq a.. • MWdbIMM+L.wp.k.. • '.. . 2. r...k frf.....r..wula/n . Wt w.ro) w.r adA.t Ltl.Cl d C, sAmlpN. TW Lnq .0 k Le.. a i0u(L4IS9tSttY r[s4tp1 COkN(RLL 3 L diut<d6r'r.r.rA .Nddn dtle C•mdml t91 k r . rludn d oLCnA.11. LtrpkJ u/ rMa1 n"~ L'. .Yld.r{a.dlleaA/br)!sW drdmdbtlbEe• ' Ma/ l. h dCUem Idaq. A p.af.(/W.fdld m C.a.e&Lr. dan. uA N.atla.m k Ldld b.r.. .a tah INH. Tk+t drNbb.W ./.bt 6t Qmebtw .e IbnrndvLdd.. • ' TD'n dlwral 4 ktq krved knor n klitn tk qnpk in a140cE Ol Lm. Witrt K In01 OE Cdf aIYC .Ed Mbll • abr.dado.ba[k. TOBACCO INDUSTRY RESEARCH COMMITTEE' 11/1 CMCIRC CTATC IIIILOII:C. NCq YOCC 1• N. Y: . rwrwrr..aovl..ut/pl1~oM ' . . LL.ry.../.•u.. Iry11 I. (wN /w4M ~ a•u.. arnw...aoon waurw. 4W rbr. 1. - SPONSORS - .v.rtr ro..oca ao.ru cebn.anR u.oturo. U.e1. WL.. a.e4n.t~G 1.4eYlAa LOMart r.l•aA.•KaMa~ rAn4MO lO1.CN µOM[Y YMptbyl K11 rYYY. W.ln. r~G G LY a.C..•. ML•t `
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EXHIB/T 3 52324 359i
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'1l00 qr.c. 13, 1952 SMOX1Ntf ntru ; Among f-3S7 men with lung eaneet ottly 7(D.596) T6ndon, county boroaghs, other urban distritxs, and were non-smokers, compared with 61 (4.5%) among ruial districts viere, after corrcction for the dHfeiing JQe, same number of control patients with other dis- age distribudons, 5.1, 6.8, 8.4, and 10.4 respec- ies ; and at the other extreme 25% bad smoked 25 dvely, and the percentages of smokers of 25 or more ~more cigarettes a day (or the equivalent in pipe clgaretted daily were 14.6. 9.9. 8.9. an¢ 7.7, but the tobacco), compared with 13% of the controls. Among proportions smokiitg 5-24 cigarettes daily showed : 108 women with lung cancer 37% were non•smokers,' no consistent differenee according to urbanization. against 55% of the controls; and 11y6 bad smoked Tho'se who imoked only pipes coatributed 10% to 25 or more cigarettes a day, against gnly.196. of the sdtokers in rural districts, however, compared the controls. ' The figures for patients in, Greater ' with 5 % in Gteater London. : London interviewed during 1950-1 sgreed closely '.Whereo do we go fromm here ? Statistics. it is said, with those for 1948-9 which were analysed In the first cannot ptove 'eausadon, but- neither could Koch's report In men the contrasts between smokers and postulates, although the lives of millions are aHected non•smokers were similar in the provincial centres to ° and •controlled on the assumption that they have those in London. • From the.28 women aeen In the sstablisbed beyond question the causative agents. of provincial towns no oonclusion could be drawn. Esd• . certain Infective diseases. 'All that these things can mated death rates for Greater London. in groups of do is to show that the probability of a causative con• men who bad smoked different quantides of tobacco nexion between ari egent and a disease is so great - ~--ealculated from the patietits not suHering from:::. tliat we are.bound to take wbat•prevendve action we cancer as a liasis for smotiing habits En the popula,.: oen,- accepting the theory as though the proof were - don as a whole-indlcated that mortality from•lung : absolute until further research leads to some modifi- cancer may iricrease in• approximately Simple: pro~ , catioa.. It would aeem that such a position has now 'por6on with the amount smoked. beend reached with lung careinoma, in that tobacco = No appreciable dif(erences.:*ere foand•, betweep.„ bas been ineriii'tinated as the vehicle conveying an Y.5 . a; padents with 'lung c~ncer°arid pthetierits ;in.:.agent responsible for,a large proportion of the cases. the regular ase bf petrol lightera (43 and,4196) qt of,;~The netura•'of the carcinogenie: agent is not yet "• band•rolied cigarettes (11 and t996}. ' atather-fetlfer _= kriown:. benipyrene has not been found in tobacco, . ,.;. . .. dents with lung cancer had"ever•nsed a ctgaietta ; and thoagh the arsenic known to be present in most older rexulady (59b, atainst-l2M sad.orilv`thiti,' `.lirands of el¢arettes has been susoected there is as out of 504 had smok2d filter-tipped cigarettes, .ooqi:.. '.yef ao'. evldcnce to incriminate this. Intensive 'ne- pared with 15 out of 46y•controls. Thoygii 4ucon-;=,search on the chemical constituents of tobacco and clusive by themselves, these difeienccs point in We ; of tobacco•smoke is now needed, and it is surely same direction as does the imding that among, men ., Incumbent upon the tobacco manufacturers to do this. ~ with lung cancer a lower proportiori of smokets bad:` (t is g reaionabte expectation that if the carcinogenic sntoked only pipes (4y6, against 7% among.the male , agent'can bq isolated it can also be removed, so that controls who smoked), suggesting partial removal of srqoking will become a less dangerous occupation sa active agent before it reacbes the respiratory traot. •tban it appears to be now. In the meantime the Analyses of the answers to quesdons ebout proximity • younger generation will have to decide, each for him• of gasworks to the home and. use of --eoal or.gas in self or herself, whether the additional risk of contract- living-rooms showed no appreciable differences. ::: ing lung carcinoma •ia worth taking. For a middle- Rather fewer of the patients with htng cancer iived 'aged•rnan lung cancer diminishes his dxpectadon of in the country ; but the difference does noi eppear to living 20 years• by about one•twendeth. The appor- be large enough to account for thti observation by •.Gonment of responsibility for that to smoking and Stocks' that eountyborough death rates of males other factors such as atmospheric pollution can be were more than twice those in rural districts for the roughly estimated, since the statisdcat picas of the . country as a whole during 1940-6, and that •London puzzle now seem to fall into place faidl well and . ' rates were two and a haif times those uf rnral dis- ' make sense. .If the annual total of deaths of inen from tricts during 1947-9. Ibll and Bradford Hill con- ;ung cancer is, taken as 11,000: of whom seven out of •. dudc in this connexion that ".it wo ld seeqr likely each 1,357 would be non•smokers, the total male non• that some agent other than tobacco (~resent perhaps smokers dying annually would be 56 ;'and if the pro- , in domestic chimney smoke or in the exhaust fumes portion of nod-smokers in the population at the. ~ of cars) is at least partly responsible for the excess relevant ages is taken to lie 5%, the remaining 95% mortality in towns." The percentages of non-smokers would also be exposed to the same risks from causes deduced from the control patients resident in Greater other than tobaceo-wbich gives a total of about
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EXHIBIT 5 52324 3606
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52324 3595 EXHIBIT 4
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'.INTEB]NJ.:S£-55lUM=3-j. 1OU15, NOV. 3D-DEC. 3, 1948., . O! T7R Americ ~, Medical Association ~OES NOT LEAVE L(2RARY t 1 :. . Srbsenllicw, $12.00 Published Weaklr at . SinE4 Cep7. )S Cmu VOU.R/E 137, No, S SJS Narth De.rbore Sunt. Cbicato 10. Ili•aoiu µqY 29, 1948 .i.ta.-.cr. Lc:,VZ Li.:RARY Jur, S'48 THE JOURN2 ORIGINAL ARTICLES dRANSIENT CEREIRAL PARALTSIS ............:...121 a. N. licY.rint, M. D., Londen, [n/land TNE NEMIPLEGIC PATIENT.....VI Cewaneu Eaar6J. Le..an, (MC), • U. 3. R., /nlla6tlrhil. . REVASCULARIEATION OF THE NEART ....................17/ Cl.vee 3. leck. N. 0.f Evtan. Stanten, M. 0.; llillia lutivenak. M. 0., aM [vlene Lliter, M. 0., CL..I ana PSYCNOTMERAPT.IN EVERYDAY PRACTICE .................111 [a.ar6 41u, N. D., nlladalrnia ASNORMAL PRESENTATION......166 N, Na6nall Lr. ,Ir., M. 0., Rich. oene, A. TREATMENT OF ASTMMA........ 653 lansl Olwvssien. J. Rarve7 Ilcct, M. 0., Oallu, tctas, Moderater SPECIAL ARTICLt CARCINOMA OF LUNG..,....... ISS Ed.are D. Ckvrchill, M, O., k11en CLINICAL NOTtS FLUID REPLACEMENT.......... 161 Mencel E. licht.nttein, N. O.i Chicale COUNCIL RE/'ORTS Cevncii on Phanac7 and CA.alttry 162 Ne. snd honaffidiai Rs.Ni.a...163 ORGANtZATSON SECTION evral Nealth Cenfv.nca........ ,..67 qthln6tan Lettor.......s........177 GOVERNMENT SERVICES ln7 ...................'...........7e PuH ie nulth 7orriea............ m MIIS111snauvt ....................c76 RtGULAR DErARTMENTS M..iC.I 1w,t .....................176 Marriaeas .........................60 6.atht ...........................W1 Farei6n L.tttro • Leneon ......................... IdS /rat11 .........................6115 Mediul' Metlan lietvru t67 ...... .... EDITORIALS AND COMMENTS Medical EaYinatioa aAt Editnrial An.evnees.nt........... 161 ' Licant.rs ......................N7 MNieal LLare1 ......... ........ /Sl MNtwla6al Abstracts............ 666 Scvn7 md tictett ...............663 Current Noelcal Lltaratrrs....... e1/ ~ CLRCINONATOUS ULCERATION...ISO Yit.ins ane N.larla .............666 'Inek 6otieao........... .......... 613 ~ [ede Oaris, N, 0„ Onah. , Natlanal Cancor Institvte........ 166 Qv.ries and Nlner Ratn........... HS ' ,.r ~ Willius & Dry's -H 1 ST4 RY of the H EART New. This jreat.nor,r-intere/tin; as qnfy history can be-i/ "mutt" nadin; for (very doctor who would appreeiate and praetice the art a6 weB a6 the ecieaee of inedicioe. You will surely Brid thii new book delightful reading and a/tirnulatinf experience besides. You . cannot help feel a deep pride as you trace the efforu of your predece66on-Uom antiquity right down to the twentietb century-aa they grope painaukin`ly, often brilliantly through the cea. turie/ toward the Correet anatomiul and physiological picture of the heart and the eirenilation. The authors have assembled and /et down in fa6dnatin6 style a truly remarkable collection of historical and biographical data, dealing with the development of theot•ie6 pertaining to the heart itself and to tht eehopnition of such entities as aneury6m: pulle, hean block: the perie.rdium /nd itA diseases, ete: TLe di6tinetive features of baeh'/ueceeding eivilisation .re carefully eoliaidered: especially u re;6rd/ the advantages or diiadvantaeee offered to medical research during that pqdod This is : book you will read thOreu=hl,v, then br6wldin often fvr sheer relaxation. Irr.wno,lTlwoSM.D.M16M.1'r.~S..:rCw"Iu..i.C..6Lq.N.t.C1:...dPnh,+.tNN:1rM.r.rwM.• .+a ..d Tn.u 7. Du. 11./. SIl.: Md::w L..rlm~ S.qw- G..+Lab 11d. CYwt Arri.u r,.lr .t M.a:.,. Muo r.:.tu:a ab i.w VV e•. il.",.,J. Ilae. . . , . .Yw-/.. M,d- See SAUNDERS Advertisement on Paaes 2 and 3 1
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jwnrrAb OF MEDICINE between the agcs of forty-five and sixty-four ez perience an incidence of lung cancer between four and thirty-four times as great as that of nonsmokers of the same age, and incidence increases propor- tionately to the average daily consumption of cigarettes. If auch figures as these have been unduly pub- licized, the public, medical and lay, shows no sign of taking any of the relatively simple courses that would undoubtedly reduce the incidence of lung cancer. if similar data had incriminated a food contaminant that was not habit forming and was not supported by the advertising of a financial empire, there is little doubt that effective counter- mcasures would have followed quickly. It is not. insufficiency of evidence that accounts for lack of such measures against tobacco tars, and it is de- batable whether or not a little more "alarm" would be amiss. It is true that the causative mechanism underlying the association between tobacco and lung cancer is not known, although there is ample room for speculation in the presence of known car- cinogens in tobacco tar; also, little is known about dosage, filtration of smoke and other factors that bear on the subject. However, if control of cholera had not been initiated empirically, but had awaited demonstration of the vibrio, active and useful pre- ventive measures would have been delayed fifty years. The situation affords unusual opportunities for the vast tobacco interests to support impartial re- searches into the effects that their products may have on human health. , REFERENCES . 1. $1il37S~ EJ w19Slaeo and reMie, about canetr of lun.. lrit, .1r. J, 2. P.aer, R, D. Smokin..ad luna tanaa. !7•it. .Ir. J.7:S99, 19SS. S. Johntto.. L amokink in lung ctntcr. IN, .1t. /. I:S0r, 1955. 4. Dnll, R.. aad Hill A. a. st.dy of attioin.r of t.rdnoma of lunf. d.it. af. J. l:I2f1-12a6. 1952. S. ainy.h, H. Smokina in lunr oa.ctr, ari4 .lr. J. 1:307, 1911, 6. Doll R. and Hill. A. a. an:uHnr.nd etrdnnmt uflvnr, arif. M. J. 1:f79.}ia. 1950. l. \l'yndvt. E. t._ and Grab.m, E. A. Tob.ecn rmoNa,~ as po.aible tuoM c factcr in bmnchioKnic car<iadmn .ud~~' of ti. huadnd nd eThtr•four 6rm'td carn. l. .4. ]r. A. 117:779•71e. 1950. i111TrNESOTA CENTENARY THE hundredth anniversary of the Minnesota State Medical Association was celebrated last \fay at an annual meeting attended by more than 4000 physicians and guests. The program included ad- dresaes (all of which are published in the August Sepr.. I issue of dfinee.rota dfrdirina) by Dr. Richatu of London, head of the Papworth aud i•.. Alamein rehabilitation centers it.rr„ tuhr. patients, Sir Ak;ander f leming. director . Mary's Wright Fleming lnstitu:e of London Dr. Alton (khsner, ehairman of the Departnic Surgery at Tulane l'niversityy of Louisiana b of Medicine. Not tht least interesting featu the meeting was the exhibition of a typical dot office ofa hundred years ago. Medical advances in Minnesota in the pt marked by this anniversary are all the more pressive when considered against the backgrc of the evolution nf \finncsota frolu a tcrritory state. Ten years before the organization ni Minnesota State Medical Association on July 1853, there was only one civilian 'doctor wes Prairie du Chien. Today, the names of the Str leaders in medical and surgical research and prac are bywords in the rest of the nation and throt out the world. Confident that the next century will more t, match the notable progress of the last, the Jour congratulatet the \Iinnesota State Medical At ciation on an anniversary extraordinarily full meaniog to'all concerned with the -advancenlent medical science, MEDICAL REHABILITATION TaE Bay State Medical Rehabilitation Clin put in operation at the Massachusetts Gene: Hospital in June, 1951, has presented the accounti of its first two years of service. During this pe6 its patient-treatnient visits have increased fro 3153 in the first year to 5363 in the second, a tot of 448 patients having been admitted. The disposition of this group has been broke down into 114 patients with degenerative and Il with traumatic-conditions discharged, 90 still undf treatment, 74 who were referred for evaluation onl) and 60 who discontinued attendance for one reaso or another. In the degenerative cases 38 patient were returned to tvork and the rest aided in othe ways, such as the institution of a home program o referral elsewhere, and in the traumatic cases 6; patients were returned to gainful employment anc the remaining 48 otherwise aided. 52324 3567
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EXHIBIT 6 52324 3617
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I : ! ~ 6 a i 1 .~ E I ~ s sep~Rxs ' ~ 1
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A 2+9 A1:a t t EDITORIALS The New England Wournal of Medicine . OfGcial Orssn of : Tat %Ltss.causcTTS \taolcat Soclsn and Tac Aecw HAUnalac \fr:DtcAL Soclcrr Owltaa aY THE MGssneaustTTS \IDteAL SoeIEtY Aem Pveusaco W[aCLY VHDrR THC JValsalcTlOR or TH6 CoHHITTaa o!a taL'aueATlons ' Richard \I. Sm4h, \I.D., CAeirmu ae. P.O'Htrt. \LD. Conrad tt'na.lhoeh. M.D. nrr Cnpe. \I.D. R4chard E. Au. hl.D. Jnrph CarLM, \t.D., Enrtoa - AHOCUf[ E>RUts nnar 't. Lanmm, 1[.D. Dunald Nuno, ]I.D. Thwdore H. tnnlla, \I.D. . C1art 11• Daviea, EntVTlrt EpITOn . R..nrn tYl.atr). .bu.r.a Eu.roe Jamra P. Ba-lerJ. Iluuc R[run N.mtut . \bhnn C. 1'aire, Jr.; Hunnn, \lanaoen EotTOaut soAen Cur t.tn<, V1.D. S'ernen P. tS'illlam,, M.D. err R. t'teu, M.n. Ileniamin CaHlcman, \I.D. 6at \I. Greet, h1.D. Ilu.h R. tearell, \t.D. .irht O'H.ra, M.D. J. F.nYlebrn DunpLY, M.D. . nder 11 Gdby, M.D. Robert W. Bnak, 11.D. beet I ewqJale. M.D. llnrmen L. Btumpre. \LD. ener U. Ivner, \t.ll. F'r.nk N. Allan, M.D. teeY R\bxriaon, M.D. IlarveY A. Kelly, \I.D. neell t a•anJ,. M.D. !.anedon Pa,rvns, M.D. Deerint C. smith, \l.n e . rRtprewninf the \ew Hamp,hire \IeJical Su:inY. ' tVnMarTCon Ttaru JdAO pcr Yur in aJcance. pcante paid, for the ItrJ Sutr• (nnc-year nttraa, 'f preeiou, .nbsaribera, end medieal 0 S.VJ hr Yesr.;; Canada. f•.Ap per year (9uuon iunJtl; breitn. Ynr. lunr-urm raur: t'nited Sutu 2/'eut J,S.rA, 3 Yr.re edt, 2 Yean {17.BD, 3 1rHt $:S.BB: lorritn. 2 1'ears i20A0, 3 tb. btr rplusee auailable to retultr eubatribers rhrorlrh Ilni.ebity aro6lm., tIJ S. Fim sircu, .tnn lrhvr, \lichltan. tlare.ru. wber than oneinH nutlu, chvulJ be recrired .et later a nam nn Thuuday, tArre wrtke bc(vre Jete uf publication. rrt. Iovayut dosa oot hold italf ¢rpouible for rutementa made by r ancril•atw. •oYYVI1CaTlona should be addrened to the Rer L.yG.d feurwJ e/ firrnq S Fenwsy. Bnnon 15. \luuthuutu. Telephoae F.Ed-JWl. 16S each of these factors is not known -especially since the evidence linking cigarette smoking and lung cancer is incomplete,. The medical profession, should therefore "beware of putting extravagant accounts of rising cancer death rates and their causes before the,public." .1re these accounts extravagant? Smithers places stress on the lack of knowledge of the extent of the true increase in lung cancer. At the same time, he states that the recorded increase is due in large part to changing age distribution of the population and improved diagnosis, with the implication that the true rise in incidence has been comparatively small. In view of lack of knowledge needed to settle the point, speculation in either direction is inde- cisive, but many competent people consider the reverse situation to be much more probable - that the startling rise in lung cancer during the past few decades is real. They compare the increase in car- cinoma of the lung with that of other internal sites - for example, the large intestine-anJ point out the disparity in the percentage increases (133 and 3.5, respectively, between 1940 anJ 1950).' In ad- dition, they question whether diagnostic measures have improved to anything like the degree necessary to account for an increase of 133 per cent between 1940 and 1950. However, this trend is a secondary consideration, since it forms no part of the evidence incriminating tobacco as an etiologic factor. In the United States anJ in Great Britain lung cancer accounts for between a twentieth and a thirtieth of all deaths in men of middle age. Consideration of present incidence anJ death rates, quite apart from past experience, is sufficient to justify coneerll, Whether undue concern has been or is being raised among the general public is to be questioned. The latest study of Doll and Hill4 based on 1465 patients with cancer of the lung and 1465 matched controls, was carefully contlucteJ and yielded evi- del)ce of an association between cigarette stttuking aild lung caneer so strong as to be considereJ proof within the everyday meaning of the word. Even CANCER OF THE LUNG I: a recent issue of the Bririih 31.dira! Journaf oithrrs; radiotherapist to the Bron)pton Hospital r Diseases of tlle Chest, expresses concern about . e'•alarm/e that may be created among the general iblic by undue publicity accorded to recent sta- .tical research on carcinoma of the lung. That iethrrs is not alolle in his concern is evident front :ent correspondfrice''x in the same journal that lutt'ed the comprehensive study of Doll and Hill' rlier in the year. . Srnithers contends, and these. 1 alsti the 1•i~ic ar plmenti of other correspondent$, •t, a' ',i+'ph .•ne can guess at the nature of some c factors responsible for the increasing fre- with which cancer of the lung is given as.the ;• r:ause of death, the reltve importance of ; ~ a PLA1Ni I L'SBIT~ before presentatioii of this work, evidence in favor of such an association was strong, deriving especially from a previous investigation'by the same authors' and front an investigation of 684 cases by 1Cynder and Graham' in the United States. Male smokers -40f 5~ NTIFF'~ ~1~ : L ,{IATAIatJ'JatLaNa.EOJt -~M ~
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'A ' R ` IRG lf. :-' ND LUNt? CANCB SMOKIN(} 11101 ,/ t;100 deaths ot men due to those canses, compared • patient's genetal oondidoawithoutacthally arresdng ~: I with 10.000. attributable to tobacco. By similar the progress of infecfion...But it is not clar.why,." _ reasoning, with an annual total of about 2A00 deaths if peritonitis still exists, it should tall to sbow aoy o[;:. among women, of whdm 37 outof each 10g•would' , the usual signs. There are no reasoas'for suppostcg ::<' ,. _ be non•smokers, the total female non•stnokers dying' that antibiodcs have any action except on bacterie,' ;~ would be, 685. and, taking 60% bC the female popu- , and in very mixed Infections of this kind they ofteq' lation at the relevant ages to be non-smokers, we eliminate the sensitive majority, leaving a minority of :'~•: txn eaiimate that the total )ung.canoer.deathi. of resistant types which are not necessarily bighly patho~: ;: ' ~ women due to causes other than tobacco wouidd be genio. Whenever srreptomycin is used there Is ahvaY4 about 1,100, as for men; tbe,other.900 8eing due to - thee possibility of acquired •re5istance,.and tbe turn sa^`,';.`r~ tobaooo. This seemtto dispose of the Idea that there foi the worse,taken'.tiy the patient described is a sex difference In susceptibility to lung cancer, the Mr. Lake may.well have followed escape of bacteria:..= ' large eacesi'of male mortality being explicable by: from the Intluence of.this drug, with consequent re• greater use-of tobacco among cten:.: •~ newed multiplication.~ As a possible explanation of 'Ibese are tentative estimates abich may have to the absence of signs it may be assumed that restrained • be modified when the British Empire Cancer Cam- . or Iow-grade infection fails to excite the reflexes on.,. • - paiga "has' completed its field ' study of cancer of-' which these signs depend. Whatever the exglanatior the stomach and other organs in'North Wales, the, this warning is one'whieh should be heeded, and fqr..':'; l.iverpool hospital"region, aud the:Isle of Man!.`The . ther. pubif4'hed experience; of. the sifent progress of•'. =,~;s> " large apparent urben excess.of lurig•cancer mortality, ` infection during antibiotic therapy'would be helpful.;: and its correlation~ with'slze" of town!' Is not fully~ • Prophylactie use of antibiotic§ is another matter,''. • explained by the apportionment suggested above, and , because it is arguable whether in given circumstances' it may be'that•o.ontinual exposure to.atmospheric• pol•,:; it is indicated at a1L. It ia a common piacdce to give': ,? lution by'a carcieogenic subsfabce; 3dc6 es txinzpyrene- :.peniciiliq;before and after a clean operadon for tbe; lowers the tbresbold.of resistanceao: tobacco6 smoking.. .dua1U purpose of protecting tbe operadon site against i ' ' In that case the total. contiibut l ou:of.atmosptieiic:•: .accidenta:~ntamina8on andd of preventing cbest•: poliution to the deaths`would•'be greater than appeaTa:-;comptications. it sometimes fails in The.latter pur-''': , from these estiniates:.: Bufwliether:•tliat is so ot not,pose, and w6en It does so the infection developing is„" ,; , there is now enough evidence to justify';much: more. -penicillin-resistani and consequeatiy much more dim. .'; energetic research into 'the harm[ul constituents'of cult to treat. It is evidently impossible to Jay down ~ ' For mo.re the air of towns. thas a century the . hard-and•tast rules about this practice, although there General Register Office has called attention so often : are certain typea of patient in whom it is clearly to the high death rates from resp'vatory diseasea in cated.: Penicillin covei is cettainly. necessary for' our northern towns that we tend to accept this as a.dental bxtracdon or tonsillectomy in a rheumatic sub. ' oaturel"phenomeoon Is it aot time that abatemept ject. It is equallyclearly indicated in operations in i=: of atmospheric potlution was added to the regular septic field, where any interference may otherwise responsibilities of public health' departments instead' cause an a'cute execsrbadon. This.applies particu•, of being lett to a few:enthusiasts regafded rather as larlyto the surgery of Infected bone, and the use not. ~. troublesome.cranks by the Ministry of Heaith 7. ;:•qnly of penicillin but of other antibiodcs has, greatly facili)ated major operations on the lung. OperaGoris '• L which 'aierits serious consideration: He cites two the local.than on any general effect. There is no -cases, in one of which the prophylactic use~ and in similar pro•cedure for operations on the stomach or ,_ sal employment" of cbemotherapeutic.ageats, calls antiseptics preparatory to operations on the colon is attention. again to a trend in present-day therapy "sound .and established practice, but it relies rather on -i , s P• P g g ABUSE OF ANTIBIOTICS ' on the alimentary tract are. in a different class, since The lettec from Mr. Notman C. Lake in' this issue - here only tbe'normal fiora is usually to be feared. tin a inst the " unthinking univer• Tbe use of sulphonamides or antibiotics as intesdnai a rote ( 1307) th~other the therapeutic use of antibioGcs obscured oesopbagus, nor is there the same;need [or it, the the development of serious complications. The ex• flora of this area being much. scantier and thelactor ~ ample of therapeutic use and its consequences poses of distension by gas inoperative. Whether systemic W' a distinct problem, and one which does not appear antibiotic prophylaxis is indicated in such operations ~ to have been generally recognized or 'adequately may presumably depend on the features of the indi- studied. It is understandable that partially effective vidual case, but in a straightforward gastrectomy the f chemotherapy should abate fever and improve the necessity for it is at least doubtful, and if there is "' 01
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" M N S ~ ~ w N 0 a w • f ~ ~ Y j i ..1 ,I , 6 R ~ f f s i .i p~ Ss/ 1'j(!.i F~ I 3 ~ RF e^ ~ !
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52324 3629 EXHIBIT 2 ~
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-xuXiur _ biol. t]4; C.eeet I functioo: oat.l pra s. itraios. rtntas of a. C.acer 2. 700R\AL 0P TRC 2:ATi0YAL CARC6R INlTITt/T6, YOL. tt ,~.~s,..r . . 8ock &ad Moore 401001-31-10 . tLATL f{ 00 O1
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. , 410 DOCK AND atoosa Fmuaet4-Qepre.mnttitive verrueoae popilloma. Many of such lesions would prcbably progrcat to hwmivo carcinoma. : Ftoues S.-in'vaaivo aquamoua carcinoma with pearl formation. No1e vertucoee papiilary structure similar to that in 6gure 4. Ptovae 6.-Invasloo of bodywall muscle by aquamour rareinoma. Ptovea T.-Seation of regional lymph-node metutaaie. bfetaatssee to the luoga were eoMmon, while meataataaea to the liver atnf other organs were rare. a
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408 BOCR AND IrOORL - (!f) T.ac:msa, E.,'Corruea, E., and Srarteea, M.: InAuenoa des rqone X eur t' action anc6ripoa du m{tbylebolanthpoa. Compt. pod. Boe. do biol. 124: 935-956, 10,17. (!p) Csunoax, A.: The coesroino8enle activity o( eipratte tobacco tar. Cancer Ites. l8: S 10-317, 1038. (SO) OoaauAN, A.: Pituitary tumon In rodents following ehan8ee In thyroid funotion: A reriew. Cancer Rea. 16: 99-105, 1966. (11) Wrxoea, E. L., Oa.aAr, E. A., and Caoxtxoea, A. B.: Experimeotal pro. ductloa of nroinoma with eipe.tt. tar; tata witb diderent mouu etrsine. Cancer Rea. IS: 448-448,1966. (lJ) ANpeaTOx}, $. B., and Eaacors, J. Hs Rerponw of aeren Inbred strains of 'eJce to perout.ncoua appilatlooa of i-matb7leholsothnn.. l. Nat. Gaccr Iart. 17: 461-496, 1966. PUrs 24 Ftauns 1.-Mouse from group V illuatratis6 exteatof trauma caused by "rasdpaperia8:' Ftovae 2.-Mouse from group XII IBuatratin8 extent of Imdiation. Tbe frradiated ' area ta indicated by rearrin8 aod lack of pi8meatation lo the hairs. . Fiauas J.-Mouae from group X abow,io8 a large quamour-eell eareiaoma aod eeretal papflbmaa. Tba approeimate Irradiated are. fa ladicated b7 tbe square. I 110
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>iunr Would ve verrueox ac lunp were JOCRYAL Or TIIE NATfONAL CkNCER 1Y9TITOTE, VOL. 22 PLATE ib r
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. :,• th.t a rriFhrenn: KT9nt. ...... an_ rhourhl hinr nn Aert I;a1 rf oW :Ia and nutmap •! "a Grw M,hluhed :'%yr. Cnmrory to populor : eirhp ih, lot or the habit y IohieW 11,: runlCnlCo mien of the .r iu eTUle there fr usually •r R. II'. Au0 in the Arrnu .',.lJir LAror.. The Biologic Effects of Tobacco MA~' With Emphasis on the Clinical and Experimental Aspects Edited by ERNEST L. WYL'DER, rc.D• Head• See7'an of Epldemioloey, and Atsoeiate. Sloao•Ketterine tnsdtme for Cancer Reuarch Foreword by Joseph Garland, at.A. Editor. TAe NtW Ent&+nd lournel oJ \fedierae ~osror,. • l.i'riLv BROWN AND COMPANY • TOAOHTO APB 001136
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• wtrrrE ut CANCER OF LL'NC - CHURCHILL 4i1 FLYEGt S has been considered pneumonia should be viewed with aESPasintatv or ntE ExPES7 co~SCt:nxr suspicion until they absorb. Assuming that the clinical manifestations ar.d roene• Paralysis of the recurrent laryngeal or the phreaie °ee~s examination point toward the possibility of primary nerves, obstruction to su•allo+ring, cardiac ur.thmiah cancer of the luny, it is usually <les+rabfe at this point pericardial effusion and obstruction in the superior vena to olace the problem tsefore an expert consuhant. $y an cava are late manifestations of inediastinal extension expert consultant is meant some physician or surgeon of the disease. They usually contraindicate operatiou. esperieneed and iantiliar with the d+erapeutie mana;e- 1 aE5P0YSIatLiT1' PON E.\eLl• MeOSOs75 ntent of the disease as well as with diagnosis. This state- ~ While the burdea of responsihility for the early diag- ntent may be challen;ed by those xho ++auld estend I nosi: of cancer is commonly pictured as restin; on the the responsibilty oi . the ;eneral nxdial adviser to ;eneril practitioner. thi> is by no means ahn.'s the p,ittin•, t,e:her fra{mentanY hits of technical data de• csse. \f.nv patients t<da}• luce no regular medical r+`'ed irem several dutere.^•t sources. The re_son for the adviser and oitentimes place themseh'es directly in statement is that further dia;no;tic measures. ahnost the hands of specialists in one held or another. The without exception. provide information r.at bears direct• , patient's own emphasis on secoudary manifestations of 1S on therapy. If these measures are pursued sokly to the disease m1y cause hint to be directed to specialist, e>ubfish a dia;nosis, their contribution to the ultin:ae u•ho are in a position to lose precious time if tlte false problent of therapy is likely to be missed and iead to scent is followed. Cough from any cause nu}' focus the unnecesury repetition. There is no Ix«er example of attention of the patient on an in;uinal hcrnia he has thtY than bronchoscnpic esantination. tolerated for rears. or a;;ravate a prolapsus uteri. the Brnncnofrop}:-The purpose of bronc4oscopyY in symptoms from schich have lon; been accepted with eancer of the lun; extends beyond the remo+'aI or a:r:;• resi;nation. There is a danger that surgical treatmesn• tnent oi tissue to contirnt the histologic dia;nosis. The sound in itself but irrelevant to the real i,;ue• may be broneltoscopist notes: integrity or paralysis of the vocal undertaken. The wheeze may lead the patient to the cord; : the exact position ot the grotvth with reference to specialist in aller;r, or hemoptysis send hint to the mlxr• the leeel at which the bronchus must be sectioned if culosis specialist who has been known to undertake a surgieal ablation is undertaken: any widenin; oi the long and laborioos search to exclude pitdtisis by bac• an;le of the carina formed by the tn-o primary bronchi teriologic analysis or prescribe a trial period oi bed that mar suggest ini•qH-ement of the subcarinal lymph , rest. A patient with pulmonary osteoarthropathy based node; fixation of the region of the growth. and the gross • on primary caucer of the lung has been known to follow chancteristics of any presenting tumor or ulceration. An' • the devious trail from the expert on arthritis via the expert appraisal of these and other bronchoscdpic find• . exodontist to the specialist in physical medicine. Even ings is essential to the final decision re;arding treamtent. ~ the neurosurgeon may come into the picture and coniuse Unless the examination is carried out by an open,tor a cerebral metastasis with a primary brain tumor. who is accustomed to make hia obsercatiots in ternis of . All physicians, whatever their held of concentration the feasibility of a surgical attack on the iesion. the or specialization. must be alert to the early signs of bronchoscop,v may hive to be repeaSed"by one who is. internal cancer if material progress is to be nude in Bronchoscopy can be espected"tovield a biopsy that the control of the disease. This is particularly tnte of provides mjcroscopic coqArfisanon oi the diagnosis in t primary carcinoma of the lung with its varied nuni- 60 to 70 per cent of,casci. In other +vords• 30 s^ 10 per festations. cent of primary e}iicers of the lung are so situated that nESPO\SIa1L7TY oF THE aOENTCExoLOCrST they,annot be re5ched by the biopsy forceps. These pro- It would be a rare occurrence to arrive at a diagnosis p?rtsons are baud on series of cases heavily weighted of primary cancer of the lung in the absence of abnormal• with advanced ind inoperable ases. and so are not , ities discernible by roentgen examination. Precision in applicable to the disease in early and surgically favor- the interpretation of these abnonnalities thus runs a able stages. `egatis•e findings on bronchoscopy may be close second in importance to an alertness on the part of no signidcance if it is recognized by preliminary of the physician in recognizin+ early symptoms. A roentgest localization that the lesion is inaccessible: ior ' di ^ 4 I' • I Ib O h t im r• and s•m oms d other hand. ne^ative findin t ma he e~tren+el i > pt oes not mean srmply tal.tng a roent. . R Y Y, fp genognm. A. eompreheosive roentgenognphic exqnti• tans if the area under question is radily access+ble. Inl- t nitton iticludes lateral fslms and Nuoioscop•v ih addifion provements in the optial'siatem of b'ronchoscopic I to the usual anteroposterior exposures. Oblique ex- snstruntents have made visual; tation'of the se,rnunul 1 posures, spot films, grid films and totnognphy may be bronchi of the upper lobes feasible. ' required. Only atter comprehensive Hudv and after C~'r~o9ir Aferhods.-Increased precision in ehe diag• emm, full weight to the clinical manifesniions in con• nosis of the disease is provided by methods for recogniz- ~ ference with the referring physician, should one measure in8 malignant cells in the sputum. In 193S Dudgeon i a course of delay against the pursuit of further diagnostic and t1'rigley = showed that this method was reliable, and investntion nunv subsequent observers have confirmed the practial It is beyond my competence to discuss the details usefulness of the teehnie. ; of roentgen diagnosis. of pulntonary cancer. While a The method has been ntodified 4nd its effectiveness 1 surgeon or interntst may develop eonsiderable skill, in mcreased by exan»nin; a specimeo of. secretion secured visualizing the patholoeic lesions displayed on toent• directly froei'the re~ton of the lesion at the time of . t genognms, a precise diagnostie examination is a matter bronchoscopy. This requires accurate localization of the f. that had best be left in the hands of the hiehly skilled suspected lesion to a bronchial xpntent by preliminary ipteialist ln 'roenegenofo~. However. In order to fnain• roentgen examination and insertion of an aspirating tain his position v+s•S•vts the surgeon, the roentgenol•. tube into the lumen of the corresponding bronchus. ogist must continually check his interpietatioiisscith the Cells obtained in this manner appear in graler num- actual pithologie changes disclosed at the operatin, Snrian b. ll..e~, .4 rOt lC table• HL. SIa1K, J• 4Oea, i Oiel. SOtrSL111 <otJ tqi e e a,nostsc roentgen exam+nat+on in the presence of ssgns examp e, m« rtam segntents ot t se uppcr o n /
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aAcco -u1 r.nd clinial . :r.ndvt mcas- :revcadon of a tobzcco. It is :v not only pro- -ti6c Ynon•ledge Contents Psefaa ForeW'ord, DY JCSEPH t,'i.Ut:.A\~1D yii L 1 CHi:hiISTRY, eY ALVtv 1. KosAS: . 3 Pbysical Sute of Tobacco Smol•e 3 Factors InAuencin; the Composition of Tobacco Sraol•c 4 Tob2cco - Addicices - Gzareue Paper - 0 Smol•ing Conditions -Contpounds Present in Tob:ccv Smoke 8 Aldchydes-Ketones-Acids-Alcohols and Phenols -Alkaloids - Othcr itiuo:cn Com- pounds - Hy'dro::rbons - \lisccllaneous Or- 8anic Compounds- Inornnic Compounds Efiect of Filters on the Compo;iuon of SmoL•c 23 2 PHAPWACOLOGY, aY CHUALES J. KESSLER 35 Compounds of Phar-tacolocic Intetest in Tobacco Smoke Pbartnacolocie Action of \icotine 36 I 37 Nicotine Absorption-Xicotine Metabolism and Ezcrction-Centnl \en•ous Systcm-Periph- r..l Chcmoreceptors-Autonomic GnntGa- Pfeuromuscular Tr:nsntission-Azon Relkz and Sensory Nerves -tirculztion - Hean - Po- ri ppt; 001138
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0 • , : . . .~ cOfTt/OFT. tM. lT L[T7L3. LlCWO eNt COYfaNT IICNTI lI/LtY[...0 faT OI TFII TOOL IY tiCili O7 .N7 IOtM t•IT '~ ALL NlNelil VOt01 MAT a LLILeeCti! SW TlLY1//10N IN etiT77IC /% OY ?ML TVfL11NtL { uatalr er ee.etm c.ntso c.u Ne. 71-l6el ~ TNt[! NOCT nuT u1TIOY 1.lluAd dwduenwlr ie C'..JI lr UrJa, l n.+ C- Ca f.ey ( Cte.l+) ri+yd. l.Ridd i. Or.r ln'rc. {y I. t A. CAurcAllr LI. GeL.. TtIFTLO IN TNL CNITtO ITATii OI lYttlC. ROtE1LT C BA^Ext Assocare Clinial Pr (The Gcttfoinre.^.in: E, C1mEi'. HAx)4O~ Professor of Biornc:: Director o( Sutist;u (Cc:ur and EBec: ) CtkxiES J. KESSLE! Head. BioloFy Dep: Lecturer ia Phariaac (PharmacolotY) Ar.vtr+ I. KosAx. PH Assistaat Professor I Postaraduate Me: (Chemittry) FtuNCts C. LowEL: ssoeir,to Professor Medieisse (AUer,yy) r Ap8 001137 -
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• r...r .f.J. w..rt c~ LA. ^.7 402 eoclt AND Yooaz to dotermino whether use of secoodary agents would make screening tests for earcinogons more sensitive. Sinca the beginning of these experiments, successful induction of mouse- skin tumors by painting with cigaretteamoke condensate has been re- ported by Englebreth-Hoim and Ahlmann (10), by Orris ee al. (11), and by Passey ef al. (12). The study reported bere serves to confirm a growing body of evidence that cigarette smoke is indeed a mouse-ekin carcinogen and to emphasize the importance of using a variety of techniques when a "weak" carcinogen is studied. Materials and Methods Almost all the "tar" used in this experiment was produced in a manifold- typo smoking machino with a falling water column as tho negative pressure sourco. A 35-cc., 2-second puff was taken once each minute until the butts were approximately 23 mm. long. This machine di&ered signifi- cantly from that used by Wynder in regard to frequency, volume, and other charncteristin of the puff. The pressure oerrw time curve for the puff resembled a positively skewed curve instead of the plateau-type curve used by Wynder and by Orris af al. A small amount of tar was pro- duced by a manifold-type machine with a plateau-type pressure oersua time curve. Cigarette smoke, condensed at -20° C. was washed from the collection 9asks weekly, with the use of the smallest convenient volume of acetone. The acetone solution was condensed under reduced pressure. The con- densed tar was redissolved in 15 ml. of acetone per original carton of cigarettes to give solution "A." Since the recovery of "tar" usually was about 4 gm. per carton, solution "A" aas approximately20 percent "tar." Experiment A was designed to determine the effect of variations in painting tecbnique and the effect of irritation upon the experimental results. It was also intended to determine whether a variation in dose rate would produce'a large difference in the nature of the response. For this purpose, Swiss female mice were divided into 8 groups as follows: Group I: 30 mice shaved on alternate Mondays just before painting with "A." Group II:30 controls treated as above, but painted with acetone. Group III: 30 mice shaved the fint Friday of each month, but not painted until the following Monday; painted with "A." Group M 30 mice shaved when it appeared necessary; painted with "A." Group V: 30 mice rubbed with sandpaper 3 times weekly just before painting with "A." The "rubbing" was just vigorous ecough to induce a elight degree of bleeding (fig. 1). Group VI: 10 controls treated like group V, but painted with acetone: Group VII: 30 mice that were neverehaved; painted with "A." Group VIII: 10 control mice that were never shaved; painted with acetcne. •
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0-Z 0 CONTENTf a. 51 52 54 .tv 63 64 ,u :i- 0 ; 83 EBects on the Upper Gastroiatntinal TnC 140 Normal Gasuointestinsl Tna-Abnorm>.1 and D'ucased Gasuointestinal Tnct-Functional EI• fcrs--Organic EUccu-Muugement of Dis- ease Edecu on the Lower Gutrointcstinal Tract 48 6 ALLERGY, sY Fw.cu C. Losvt7.t 151 Criteria for in Allaeic Cause 153 Skin Tests and Si:in•Sensitirint Aatibody ' 155 Qssancous ?donifcstuions 159 Respintorj Afanifeststions 160 Vas.wlar }.laaifesut.ions 163 7 CAUSE A\'D Er'iECT, nY E. C{'YLER HA?Idto.sD 171' Gnsation 171 Artificial vs. Natural Situations 175 Epidemiolo;ic Rcsrrc5 176 Retrospoc,tive Studics 177 *rospccticc Studies 180 Studies of Restricted Population Graups 132 Assoauion vs. C3uvtion 183 Time Trends and Gco:nphic Studies 18s Causative Factors Ha%in; Multipl: Ellcas 187 "Mutual Causation 188 The Experimeatat .lpproacb 189 Author Indcz 197 Subject Indez. 201 ^_--=-~ --r--~--~--•a ~ ~ ~. . . w ' APS 001140 0' w , s!
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!b7 CANCER OF LC.1C - CfILP.CtlILL 75 eases• or 7.5 per cent nf the uhnie. Dcspite this gloomy picture. wbich ios.ibly is attribuohlc in part to the war years, the ca,es <ousidered facorable fur thora• catomy increased fronl S2 per cent hl 1937 to 25.6 per ceat in 1944. Furthermore. raec::bility increased from 5.1 per cent in 1937 to 13.5 per cent in UJ•t.i. These basic figures from the 3rompton Ho.pital are si;nificant beause during this period a vfgorous surgical program was beir.; pressed by Edwards. Roberts. Price Thomas and i3rcck. Their importance lies in the base line pro- vided hy the poptdauon of a!args hospital admitting persons with medical and surgical diseases of the chest. The range of applicability of surgical procedures pro• vided by reports from surgeons in the United Statu is more favorable• but these reports are heavily weighted by collecting of patients from a wide area because they were judged favorable for operation. T!tey do not ac- curately represent the state of affairs relative to the disea;e as a whole. Nine reports (.adams.' Burnetr,• Clturchill," Clagett and Brindlcy,"Graham,10 Jones." lindskcg," Ochsner, De3akev and Dison! Over- holtls) published since 19:0, record 1950 cases. In 782 (40 per cent) of these thoracototnc was done, and in 432 cases resection was periormed t22 per cent). It should be recalled that the tint total pnetlmonec• ulmonar tom that launched the stlr-ical attack on y y y p cancer was performed in IM (Graham)" and that >urclval rate could be conlputed.Five of these 43 pa- several of the series of cases referred to date back to uents rcere surris•ing at the end of three years. 0f•18 that year or shortly thereafrer. There is an encouraging paticnls for allum a tive year survival rate could Ix trend toward a higher proportion oi operable cases in eoulputed. only I waa alive. .\ot a single insnnce of iur- the more recent reports and in current eaperience. vi+'al as long as one year is recorded for 244 umreate<7 l1'hen An attempt is nLZde to e>tinute the proportion !Wrents." It seeuu reasonhle to suppose, therefore• nf patients who die in huspitals as an iulnlcdiate result that rnnnval of tile lungbearin;theprimarygrolcth rids 1 I'• t of the uperati:ln or its attendin; complicatiuns• the cl+an,in~ back~rounrl procidcd Lr technical improve• melita. chenlotherapv, bltaxl transfusb+u and uthcr ad• juvants to surgical nlana;ement uttiry>itatea yearly cor- rections. In addition• the rauuval I-i ,rou~tli; that are nut localized to the lung has carricd a higher mortality rate than is encountered n~hen dcaliug with the tnure iacorahle localized gro+ctlu that are cu~niqq to the sur- ;con with increasing frcqueocy. 1'he 1947 repurt of Jones," based ou the experintce of the prtYedin; four years. ;ives a better index oi +vhu is goin; on now than a sunuuation of earlier experience..1 total of fiitv. two pneultsunectonlies with hut 2 hospital deaths yielded an actual operative mortality of less than 4 per cent. This was accomplished ost tile basis of performing thoncotomt• in 33 uer cent of the cases diarnosed and 1. A. v. A. n., :t, INI pulruwlary eancer can now he made celun ;ent to that of partlal ;natrectauv for malilfnant leaions of the steuach (3.: Irr cuu. \layn Clinic. 1915), and considerably In,ler than that of total gastrec:ontv (16.7 per cent, •llayo C!inic. 19+5).'1'he «aec:ability rate for ma!ignant Icsiuns of the .tonl:eh. i.e.. the ratio of patients n~ho undergo resectiun to the total patfents in +rhem the dia;uuaro is :nade, il ume+lhat hiGher (33 per cen(), Yw;•i:nf ~.per7uur;.-Carciul iollolvu17 statiities lhu nlcasurc tile sunival expectancy in puhnonary uuli;nana• treated by surgical resection hsve not as )et lece!etj ort to even an approximatiun of accuracy. It is probahly more informative to consider that Graham•s pauent. in whonl a total pncumoncctonry was perfornled for stpuntous cell carcinoma in 1733. is still alive and well than it is to attenlpt to interpret the pre!iminaiy analv.es that have been placed ou record. There are several variables to be considered, not the least oi which is whether the , ow~th appeared to be localized to die lunz at the time of resection or +vhecher it ;ave evidcnce uf having extended to the mediastinum, either by « gional metastases or encroachnsent on eon- tiguous structures. Ochsncr• Dc3akcs• and Dison' pcnurnled resection in 43 cues in which the growth +vas nn csfdered to hace :•xtended Ixvoud dle lung and (or w hich sumcient time had elapsed so that the three czr u pat.nll ol cer.am cuntp tuuous ol tile d sesse tlut accclerate his death. The relentless progress of the dis- ~ttltirlated catlcct contlnues. This concept that the local primary ;ro+vth not onlycau:e; distressing synlptonu• as in cancer of the rectum, but acce!era)es death. as in obstructing cancer of the pYior+u or taopha;us, is well known to surgeons but necrls far greater emphasis el.cwhere in the profession. Sur,,ical treatment of cancer is too often harshly judged as l:eing futile on dte grounds that it fails to produte a lauin; cure, rather than ol+ the fact that it makes the best terms possible with a diaease that is already hopeless. Another variable in the reports of survival centers in the patholu;ie classiricatiun ui the peculiar tunsor known as bronchial. adenoma. Arguments as to whether this l li i h h d i li i l asm s ma gtta.nt ave o scure « ru n c ti ca earrying ottt pncumoneaomv in 20 per cent of'the total neop casts. Sfltsilarly, in 1946. Adalsts' on the hasis of a 31.4 f'cts abo tt which there can be no difference of opinion. per cent rate of resection recorded a hospital nlortality Cliuica!ly, the bronchial adessonu pursues a Icisurely rate of 3.3 per cent in his most recent thirty consecu- and protracted course• and when rcsected. recur- tiee resections• rence or subsequent disaelnilsatiott is practically un- These 6;ures are stardin;, as they shosv that the knots~n• The tmvor is nre in comparison with the forma opentive munality rate of total !7tlcuntonectomy for ~~clusi noof i feu•ccases wh nethelsurvival e.cpmtaney L Aloq. /.t hl::uq Luy Tu,..r.. 1• A. & A. ssol w•sas follou•ing nperation is being tabulated will adord an tsl'n. sl n•a unduly oprimistie interpretation of results. W, t- i. Iiuru:M M CtNun. I'. +V : OiN.rm:iali.n .r /rMr.,r.n t: urcM.:.a ). n.rat,t s„a, laurs+rn tA:•r.u ddjurmtt Surgicaf 3lrasurcr.=Es:tension to the ll i lik • i h 1/" i l h l l r ar esa chost na s e to occur u it era •• la. Onteul. t D.: CnMiM .f :N Lunp Aqery, I:/N'III P Y• Pe P tDr0 iuo. 11 squantolts cell cancers. The'pain caused by this eatension. Cl+nn. 0. T.. +e1 IFeMe C. R Jr.: FMahlqm,< C.runMU. . s. ain. wn. .l.,r.K. aa, us.ue u,:rs n... in inoperable cases nuy Ix alleviated by section of the !: ~ IL DqA+n\, E•+.. T hRVnN:, M[, - rtostal nerves or may require chordofonlY• Drainage' . Il. . C: Surr,t+l Mnsu .f nnAe..~ /r+n.nulrAa Caninuns. 1. A. M. inte t+ A. s~Maauj'n7 rso, im 19.7. of an abscess or enipyelna -inay reduce. a productive y It• UMrbr. Q C.: inn.IN./mit,Caninnnv. Ann. Suq. 114,447. j. 17. (on.) If•a cough or minimize the burden of infection. The effects 4.0 .rreNr. R. H.: A C.n,nM Mqu.ndinr Lunt R`wlu. tF+..f L.• Irnn.liw.w•< C++~ ~ C*nl 9:117JI1 tM...1un.1 IM7. 177 ra SClbn+nn. A. P.: CMrn,eM TM.nrI 11. Cu4rm. C. A.. MI Sinn4 1. 7.: Succmrul }.w..d .f +n t.nir. <a. An / IannrnH. a111L1/ f)+n.l It++. Ut Ldbn C T. an~ Lunr br Camnwnt .r ro. A. }l. A. tol l Il)t IOeL •11 slnntl:. amnurn Tlrr+nr /.r ar.ntanenrt C+rarunna, )• ,L I/t7. , 7c. A. a1a:77114-11 IDrr. :a/ 04
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! Carcinogenic Activity of Cigarette- Smoke Condensate. I. Effect of Trauma and Remote X Irradiation''s Fatx G. Boct and Grancs E. Mooae,s Ro.udl Park Menoriol lmtitu+e, Bufalo, New York Summary In Swiss mice pcinred with cigarette•smoke condensate, benign and malig. nant skin tvmon were produced in all groups, regardless of coincident irritation. The data indicate that qualitative difkrences in laboratory results probably ort not due to minor diffnences in skin-painting tech- niques but may be due to differences in movie slocks empfoyed. In Swiss female ond C3H mole mice, intense irradiation af a small area in- creased the sensitivity of dlstant areas of skin to painting with cigarette• smoke condensate. In this case, X irrodiation apparently acted as a systemic initiating agent of carcinogenesis. The Swiss female m.ice were much more sensitive to the combined treatment than were the C3H males-l.,Ves-fr~ 'i•1r1%9. . 1 In 1953 Wyn¢er ct al. (1) reported they produced tumors by applying cigarette-smoke condensate to mouse skin. Although Wynder and his colleogues duplicated their work qualitatively and extended it to wher species (2), other workers failed to confirm their observations (3-6). Many studies relating irritation to carcinogenic processes. have been published since Deelman (6) observed that wound healing accentuated tumor production. Inconsistencies in the experimental results (7, 8) led Berenblum (9) to propose that the variation was due to timing of the irritat(on. He suggested that irritation could exert a promoting effect after-carcinogenic change was initiated by other agents. No evidence exists to indicate that the differences observed in tobacco-tar studies are due to the minor irritation caused by painting or shaving. However, we were persuaded that controlled investigation of this possibility should be undertaken, inasmuch as Wynder's experiments have stimulated use of mouse skin to measure carcinogenicity of tobaeeo products. The experi- ments described here were conducted to determine whether the divergent results could have been due to diHereaces in painting techniques, and also r swrnd r« sueevu,c .uurt u. tsa rteppw4dmPrtbreVdtewul.T.hesbdmerRrrtlC.mmnW, . r TLe uJan r. W.GW 4 tdr. YJ.m 14Wwd.ed 14. Juer euber p erp.am ud 1uN.ear em..r.a+anwruw srwa Xn. Deh. Hkte..v e1 tn•t.aqe. r mncE r 1!. reswsl .vt. ' deteor-8l-te 401 ~. .r, .S ..,
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*~i 7"ol,ilcco SmuLin; as an l1riulo,.:ic I'acror in 1)islaasc. I. Canccr' Rui•r.rr St:Irntc, \1:T)., L,,.u.4• 1),u;la;, \i.T)•., Grnr•~r, P. 11u.l..lr:u, :1I•I)•, n~u SluSr,% Ual.curr•, ,11.(J. CJiniri:n:• corm lo be in w:rJr di-a^rrrurent uu •lc rr,rlp aa 1!)13•:U,hr• (~) in \cu• l'orh rcport• t?:: tv~tliv:r :,i;, lntt:rru Iblcrr!•V :uu) caucrr. cll on 1011 Ir:it:+lr 1r,tlicnL, n•illt t:urC('r of t!rc Uth?I:e: fl) a: •1 )•iplauL (:1, fur t:uuul,.'~•, crru<id• tnuulh. Uf lLc..r• aU Nt-tc)urn•:dl of uLr,ru Cscrpl crcrd au+uLil:g ::n irnprrrt nI :•liv'u;;ic fat Ir,r in c:m• our u'rrc hra.•y slnul:rr:. \cytly ull Of the wcn tcr of thalcr: ,• .lvldtscm (:l) Jitl srNl spc• u•rd Ihrt•t to lurutp ci~:rr.c u day• 7lti, ,surpri?iue- cifc:Jiy the r.l:,;ioa LclNCCU awokirt, :In.l r.iuccr, h• lli~h pcrcrnt:r;c of c•i, tr +orokcn n,:,y be at• Iwl he LclieecJ that the only pzlLo!v;;i: e!fe'et uf tri!+ulcJ in part to two f:tct;. I'irnl, ihc lnrn u•crr hc:,+•y sr.rnl:i•le i: toagr;,ir:l uT thr pl„urua. TJ,e priaa(r patit'nt.' who o•crr prciuu,al,h• in gouc) cli:lici::n's 1Nralt or t•ica' ia A uwm: ri: •.! IT 10 nvrwuue cw.Jhion aud Nl:rr uould ht• cspcclrd to al7lr:rrnt t•; (`:urrrou P) lht( for et't'n• expert hrcfa•r eigure ru(Lcr ILau I6e che:iprr ci+~rcllts. n uho h:,n,:r. IuS•rtco fur cnncrr of lht hw;;, lhtra Srcand• thr s:utl;' ac:la :u.rJr in l0ls• u•hcn iwo1:- i, anollu•r t•spcrt a'Im s,r„ lu',actv ia rlot tllc 'iu;;uf ll'r;;vnrn:!p,r,,ulationac:aJiCcrrnt ~ e:,u,c. from Ihc prcarl::• lu sl+i(c u' lht•ac two fnttori• the I •lIC'1710Lt: Ul' bTJ•U17\G C!( \11'1C•t\CJi nluldu•r af Lt'aey eie:r an:u?t.ra still ac.nta to bc If! U!' '1•UC,1t:C(1 utmsn::1!y hi; h. liloutl;,,t.l! t9J roJmrtcd tL:lt nt:ulynil •tlirnls uilL C':,IlcCr of Ulp loll~llc Un'J Ip1,:,rY6 Iu C\CL'ai. ~ rae tlinit'n! itnl.n•::iou' ar•r 1,•a,•J to :: !'t•uad- }lt' con,idrlcd IuIr.irro. in /ch:,tl•ver fnrnn, :m iru. rrr•ttl¢ cxtcv on u:dicidual csJ:rriantc ::ad on lht•' isurtaut rti:+l,+••rr fr.t•lur. Til: litcraurc ou the ` clinical hiatur:en o' i:~dit.iJcs) pstitata. PNr es•IIN• %rn:•:inr h:d,it~ of phlicnla with c+•ntcr of (6c Jip p 1?crm;rnn (:~I o•r:tratd c..:arcr u1 ti,r'rrn;ll m„IJ of l6c tun• t:r ac.ti rca'itucd irr detail ha 1T:u.<c ~ cord., in a lu:ul a: yuirs o!J who a:nokrtl Lr•:trily - lcco (lul rl't~• !(1 ll' '(1 1 ( , I , : ( 1 • . e a .lu 106 il p\rcar, nec o +ir,d in!::J!•J the amoLu. Lt tolarael, nu It:ntor Jr• oo:,tnkrrs •rlnon; loaliruta with Ihcac tumor; varied ~ 1'e,apcd in an idcntiad Itcin seho did not aual:c• fimn 100 to 10 per ccnt in Jil7rrrnt stndi,;a, with ~ Hcocn acA rroonris (6) ccport th:tl brar•cho;;t'nie all ns•cn;;c of 40 per cent. The u'idc 1'arijhility in car:inolna w•ai (uunJ at autopsy in only uno a'om- rrtcnla~cs Ihrooa Juubl On ll:c La•Ilracy and the un at tht: U!i.•u 1'ical' Sanilariont, nnd shc had riv p I aignilitante of the sl:rli<lits. . rn a hiator; of cxtvaicc strrd,ia~ ci rirp:rrrllcs for t • ]atki ou :md Jatt.:an:r (11, rryor:cd iu IOa t l.r.rt . mtrc •han 1L}•c::rs5 i'ri;,Jcll at,J 1,t::cnthcl (1) de•' ! tl;'per cant of nlcrn tcill: eauere of llse I:r n-N a'urc rtri!,.J ci`LL (•:lirntr Ao Jcsrlr,pt•rl cnur:cr of Iht su:u{ crs. rn >pitc Of IJ:ia app•rrr•tltly hy;h prrnrll• ' n,oidh !n!!Ouin; lJ,u usv ul rhrutng tulr:cru, ' agr o m:u~,ri ihrg (1:) cru<itrrnt rnun+g nuh. '...r a.. finr~.: u/; l+d.•r .r t r 1•n:frrl,t uiilt canc.•r: rr.diciJ- I on: of lh taiaor r.:u,a•i ,:1 rantcr nT lhc ?:u) u.c. UaJ Jnalnriha nre IN! V ,la 5 5 1 in t t i 1 ' ' Ya, ~ . t ,cr 1 :iD L ttr• r 1 1 hll ,•ri• +a nr.l rr;art, it a: nr- rsvu:a cau:c. iti;;n c!iuical ituprrnsEt+as, hat thry t,nly I•aint the t;ay L•.: Idrnn.uul (3) ia 1:i::u found lbn! ?G out of 30 : rd atu:lirs on srt•tq i 0111IIIrl,lx. ~Tarr' 1t/:ll•• r.ai,•rd Sr •,•recnlr u'i:h lan•u••Cd cauc•t•r u•,m I.I rrlr:•rlcd on tLr alnu',ang lutbila of Tt;. 1 (- E "• tirta. l,artirular t;•pt of c::uarr. sLCULrJ rc;ularlc, and ur:.l Of Ulcw hvxeile: tig114• n!crlicttc. inlwli•d Jurir,; smukiug• Arkin • 1N• tw V,L LM,! ;U(d:.S.d .ill, ttK ,atqnoral Iltt,! l\'n,ut•r (t::) in ('hiro:ra rrl.+rtt•J in 1!I:h: thal }1 •r/l.l'I,i.l,llnllr:IUlOtitOl.T+f.IJIfI1MTI,J1„Ir/':rrlLNrrp/ r n1 pcr cavtt ltrlirnla u ilh i•:uIR•r.c! lhr hme . ' I 1 .•.nllr.'ll,.auriwr,r.r:•arr.ullnltl•vir,.cy.luw.u,IJu. „nwr'a. rrfN'r tie uyitiuu Yt 1)•1:,~ ol lltr ('rlfratu tti'rf,thfuril~ ,I:IUI.t•h. 'lhr:e UV(wCh. 1a. /Ir:t6)• /111 ~ b..;::i,•r,li,rn: olllCr,, t:rvn< (ht' t'IIuIP~Ir n.'f'ttllir,lnCC 4f' ibll:,Jy .I:r•fi:•J1.rynlE,.~I~on.::.p:,,,Jrrs.19+~. linn uf..lulc,reo ..lunLr. Ilnn•wl,.,ul: (l/) in \fan• N . tfl i Ot .
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Cr•Ill:r>; r! rrL -Tu•'.u.r•n S uml.~ing anll (•rurrrr 53 ! • n s tc •J !II' IIL! I rI,Ir0,I: Lf I I,1• t+„rI rl 1 ILI tl,'III \ 1.i16 nli:cr tmm•r> i. Icprr.,•ul,••t in ILc Ii;;lltr• Ly :In irrvv.-ul.rr rur.r. TLr i,r.,ut,ril,t• u! 16: cltrrl• 1!1::1 Ihl• agr Ifi•/ri!,•t:ial, it nrll nurlu:l! na•1 Ih::l ILr I,:Ilirnl..:lh• a!Ir•Irrh~r•nt•no: ::rnulr. fhr. II••Irrn;••uicil~• .rimv' fr..m ILe facl Il.at the itl 16i+ I:I,:pil:ll (:IU inlo Ihrcr di<liuc! ra\•;:• IL•.. n:n,u:y, rrlrl.ur., of l';vl!11 1S'::r I ol,d tf :,I:,I Lf 16c Sluui•Ir••\InrriO:lu N\•nr. .1 •"r•uud u!,•analiun t6:ll com I,t• rh•ricrd'froul Ila'/i;urv i: 1!r.:l ILr :I.r di.l r:lnlliurn fl:r I i'r t•liu- i:.ll ;truuln Ililfrr tn an :,Irprrrcdr r t•x(cnl frnut I hv pudnd. Tiloiv Ililirrt•nr•rc ar.• Frr:rlr.l in lhr Iutt•t•r ~rmlp.:ul•! ul:l; In:.,;ld)' br rttrilnlb rl lo carp• min:bt•roof SS•nrblll;lrll trlrrnu:iu lhc ruup:. T!a• a};t' di,lr!.ntinu of the Conlrnl al:rl lhr tlliuiC:r1 ernu}iL : rr tlJ.w ccprrvw•d' in ri;;:lrr :: hy utcnu• of lhc ael•r,l,t• ;.,t• aul) ihr slandarll drt•i:t- liuu. it lla% f0u:r! Illol lhc:lrilhtntlit nlr:,p fn: tht• e;cA of Iht palicnls scilh C:wt•cr of the 1ung. !arylls aw1 ~p)I:Iryyl%, Onll'lip (.i1.aG, 3•?.37, ancl R.71 rrar:) du unl dilTtr ~ienif cautl} from llull for lLc tonlyd guup (.il.flS}•rur.). )u tuutnul, Ihc.tend• arJ dt•\'iAlinu o! Ihc lhrc. Clinic:J , nup: (5.O5, G.DO• a.ud i.1•2 ccar.):Irc dcGnil••h• loncr 16:n1 Ih:ll for 111c cnnlrL•I (11) Cra• Thr :Igr tli.lrilr:lliuu- Jur + the 16rre cliuit•al gru:t},., diffL•r Ilx•u, ul Ica>t iu aur tYSpcc!• (ruw IL,II fnt' thr Cuntrul. lit•iJnill;•, it i+ ncc:•sctrv lu rli:ninalo or tnini- nlizr lhc Cari:llinnc iu :,;r dieh'iLulioo, 6rfort• ~ tnuqalrirp 16r smol:i;le Ilalti(: iu thr Ciinical and f I On.r. Lne..+,l Ar.t . 'rLn L.Iv Wur•. So• 10 0 4 40- 171 33 !1 30- 1" 30 33 Gn- 6: c t 70- 17 t 1• TAIIt.t: 7 rcurtsi.ter• ur ?b:nlal.tTc .t. u 11c.trr CIO tnr.rn: 5tlnr.er.: n IS'u171: }I ¢,, Acconnl.G ru AGr:.tsu Tm/: nr C.tsnal .C,1. nr .rltr Y19 .IU WYCY .e I I Lip 1 47 48 lA 4 •1u iutiArn6J •J.,crralian it IL:d in tLa f/a- licui. lril!/ Iul,l,.r., in ul!/rr ,ilc., lhe ublcr rucir 30•37 anJ GII G:r yeac: L,t.• u luwcr fn•rcl•uraq-c of Ci;;wrllc alnui,rr, lLt•u tr:l•u 10•3'J. TLin 8ndingg urrv II•• cnrrrLllt•.I wilh 11c\all y•. re} orl (IO) ofr loo 40 EO 701 /ro o-~ < 40 30 20 l0 t--OCScr:itce•tcntr•ol 2 • L\jr.Q 3 • L.cTn,• v.: phcryru 4 • Lip . Avere2e S Seanderd doviecion 1 51.95e10.6L 2 5l•:6 s 5.98 3 5257 : 6.90 4 5L]2 _ 7.9L 0 t L 5 10 20 l0 0 80 90 05 9809 Cumulativa fn~•,r'rmy . Fu.. ?-Tln af. di.vil•,. ;iml ut p+l{c. e ds will, anrrr ol 1•:,rl•„I. Altr,. Tl,r Irrvrlti.,r r„r\'e rrlV•'Mlllf the ftr dIr1111,Y- lib,• nt llu i1{ enr.tnd n.ltirub.,ilL olhd luumr..'1'L.• irfe.f/r L,rilc ur ll,e aln'r i„Jn.d.rn It..:l ltv n,e di•lriSnlinu i, nnt nnr,ual aml lt:al Ibe p.ltvnl,.re a brlrrop:uruud tnmp, eli.alll IYtl.\ 1? •n:1L Y1.1 •III RYnr •r tpLn I+nu eed r:t.. L.aa Manvl Lir S0 luo 40 100 0 .7.f 77. dy 70 19.: Gi fi! !G • +0.7 Ga 7s II le 0 M 0.01 0.06 ,i:,d3r+,lrt•r Lia-r It:a. Itr n.IN p+...a.v (r • 0 01• 0 bN. 1 r.,an.~. i.,SYSavnll; :~f r tl.+ tls r-.L.a r:n.a •r Iw ^1...+• al Nln 41.: i:• < O.nll I Llntttd grnujlr.'p;lhlr .1 prrsrnl: a tlctniktl anal;•- I •i, r( Illc pcrrraltagr nf ciptrrllc eulolrr< in trLila ( 1••Iti.ntc.ltlu:lrLcCUncnlJe/lL•oullhitlul•It•.t!lol, I rt•cll N6tn a••c :nif racr art- rnntro!L.1. lhr p.r~ 1 ~ r:•pla;;Y c,f riP:rtCtlt• rnmlt•{,a iu I,lru wilL t•ancer af I:n,tlt anQ Id:aryll.c i> drfinitrlc Lighcr lb:ln iu 1 rh" 1•,nfrol gluyp (1' - O:u1). I••or t•aurvr of lLt• t hIII . Ihc prrcrnl:l.r of ci~a:rlle >luukcr< is pr,tl • al ~r hi~htt (P ~ U.0:7). . .. Arl illt•rt•:uQ ill rlg,lrtl:t Co;l•:111:'IIIOII. Ihl` 'n-tatl•} popal:tril}' of arln "kille nli,ht Ll• t•sp.ttt•l lo alT.et Ihr }'unn~n•r ulc•r uwre lll::u thc u1Jcr.• OL11L•rl.rcturx hari• lu Lv tou•i,irrrd in Cmupat- iuL^. 1hc ctinica( au.d tu::lrol ;;rvap,. Il:a•uuir?t a, lL: p.lli:ntx tcith lmnort ar. dcriv.+l' L-ul:(11:. ra- lirr \(i,1+ir<t aild frn:u cilv. tawn, am! f.cm, it it urcrs.ur lo nnni.lcr thc ~.•,•,:np!:iF:di.IhLllllrnl Of palirnlv. t•nfurlun:dr!;'. \!.da' un 16i. f;iClar %
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CANCER Of LUNC - CHURCHILL provided the disease is still localized when sur,icay treatment is undertaken. Many aspects of pulmonary cancer tllx are recorded in the vast literature on the subject are of interest only to students of this particular lesion. I shall consider only certain practical aspects of diagnosis and management that are vital to further progress in the control of the disease. They shoulil be of interest to every doctor, if for no other reason than that he hinsself is a likely andi- date !or cancer of the lung. Pulmor.ary• cancer is almost as common as cancer of ttu stomach. and its greatest in• cidence is in men (80 to 85 per cent) be:ween the ages of 40 and 70. raEVEYT:08 Nothing is known about the cause of the disease that can be translated into effective preventive measures. It is possible that an actual increase in the incidence of pul- monary cancer has talien place during tlle hrst half of this century. Several statistical studies support such an in• terpretation. On the other hand, Boyd. I who is in a po- sitlon to speak freely of the shortcoatings of pathologists• thinks the disease was not recognized twenty years ago because it was not looked for. At auy rate, evidence that pulmonary cancer was on the increase led to several spec• ulations about causative agents. and among other thingsr. cigarette smokinQ nas incrsminated. Further knotcled;e about the nature and tlu mode of action of carcinogenic agents, and a careful recordin; of tlte smoking habits of ample nuinbars of patients with dte disease, provide no factual evidence on which advice to give up smoking for J. A. Y. .. u.r :r, Iht This complaint always should he cxplored with the query whether there has been a notahle change in the cough habits. It is the eough that 'hangs on" in an unaccustomed manner that should alert the physieian. He should not he misled hy the patient who "drops by" to askYor a cough nudicine. An acuie infec-tion of the respintory tract oftentimes (!0 per cettt) provokes the first signs and sympto,ns of bronchial ohuruc:Eon. The event may pass clinically as mild pneumonia that responds promptly to chemot4e:rapy or ,ubsides spon- taneously. Whether or not a rrxntgen examinat•'on is deemed necessary during the acute phue. it is esseutial that localized pulmonary infections he follv+.ed by rocnt- gen examinations until the lung fie!ds have cleued. A persisting shadow, or one that shows colla, se of a segment of lung, indicates further efforts tmvard diag- nostte investigation. Krrnopeylfs.-Hemoptysis, when it occurs (5 per cent as a first symptom. and sooner or later in 40 to e0 per cent of cases) is ahvavs an indication for thorough diagnostic study. Blood in the ,puturn in the early stages of pulmonary eartcer usually does not take the 'form of a brisk or profuse hemorrlu;e. It is more companhle to the small trickle of blood that is detected as "occult" in lesions of the gastrointestinal tnct. In the sputum the amount of bbod seems insisniticant; the re, tlarity and persistence of its appeannce are highly significant. I-femopn•sis ir likely to be the symptom .that brings the patient tothe pfsysician (30 per cent). LorJ of 1Vrigfrr -_Loss of weight is surprisingly corts- this reason can be based. Exposure to radioactive ores mon and many times seents out of proportion to the has been correlated with a high incidence of the disease in size and nature of a tumor t)tat is still localized. Loss c!assical studies on European mine workers. It may be of weight need not he interpreted as a sign that the well to bear this in ntind. tumor has disseminated but• of course, becomes accen• DETECTtoN' IN .\Pt.1RENTLI' tt'ELL PolCL.\T(DN tuated as the disease progresses. ' At the present time there is onlc one practical way to Puirt•-Paid (:0 to 60 per cent) when severe is go ahout detecting early pulmonary ancer in the appar- usually a symptom of extension to the parietal or medi- ently well population. and that is by roentgen scre•.nut;. astinal pleura. It suggests inva;ion of the intercostal This method will disclose silent neoplasms in the perirh• nerves or• the first dorsal root of the brachial plexus. ery of the lung. The increasing use of roentgen :creen• A. cottstant dull pain referred to the hack is presumptive ing as a public healtls measure for tuberculosis ax evidence of inediastinal invasiun and as such points Ending is bringing a few of these uyntptomatic cases to toward an inoperable sta;e nf the disease. Discomfort li;ht. It will not disclose the early endobronchial and other sensations arising in du chest for which growths that have not as vet mcroached on the lumen the patient annot alsnrs fsnd adequate verbal expres- of the bronchus. When Isronchiaf obstruction occurs. <ion are often deseribed as Nin. but not of real severity. st7~r ptoms usually bring the patient to the doctor. They mav arise from an indammatory reactfon, the dis- ~ However, the age astd sex group of men between the tortion lirodueed by partial ateleaasis or troln medi- aqu of 40 and 60, wherein lies the greatest incidence of ustinal involvement. puf,monary .cancer, is probably,dse most difficult to se- ff•Grr::.-_T1te noting of a wheeze { l0 to t5 per cent) cure in tvutiue tutierntlusis si'recning. ,Uso: the repeti-. ma,v (re an arly: sympiom tlat is ofteiuimes transient.• tion of the examination at intervals• a precaution neces- It diners frotit the tvhceze of asthnu 6e being localized sary in an eAectice cancer eontrol progratn, is beyond as unifateral In,tb by tlte patient and the e.•raminer• the range of nettssiry in checking for active ttdxrculo- Plrfntorrury Urtroriir4Yapurhy. - Pulmonary osteo- ais. About aU a physieian cat do to exclude cancer oi archropathc with clubbing uf tlse Bn,ers and joint pain the lung in a persodie health examination is to inquire is usually a late ntanifeanuon• but may lie the presenting about symptoms that may be pettinent and secure a ro- symptom of a slowly growing and otherwise silent entgen examination of die chest, prefenhly by fiuoro• cancer. xopy. OETECTIOY ./Y LAsLY fICSf AND f1';frtn>ff Pleural E(azien.-Cancers that originate in the pe. The early. symptOms of,.pulmonary carcinoma ate' riphery of thrlun; are oftrntimes, asymptoautic until so t:ammonplace that they ttu-v no't Ix taken set`fously ffnedtp extecid pleural s tfa~Thtsle,rnt iironnitesteds4y ples,nf either by the patient or his physician. Cmryh.-Cough is the first syntptom in 'over Italf eRusion• dy'spsa and at times,pleunf pafh or dlscont-' the cases and a continon (90 per cent) manifestatiofs for?' While it may be the first, and therefore an early in later stages; but every one coughs. more or le:s. ItapfJening in the clinical course. it discloses a late and Patients may be unawbre of the fact that they enugh. inoperable. stage of the Cisease as far as treatment, is concerned. Specimens of the ffuid obtained hc aspintion 1, tire. tv.: s... R....n. r.. rs. R«rnr tr.sw .r erMa~l chancteristially are bloody and contain tunlor cells. Car6nem.: tr. a bll. rfn~sun• PMbadrr.4 4rJ17-Jtr ts•ats me Small pleural effusions that Dersist alter an episode dwt
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/ TSE 310L0GIC ZFFECTf OF TODACCO iiphe:al Vessels--Coroaary Flow-Aruu Toz- idty-- C/uooic Tozicity pthu A7kaloids and Bases in Tobaceo Smoke Mis;.etlancoas Compoaenu of Tobacco Smoke Tbe Tobacco Habit 3 TAE CARDIOVASCULAR SYSTEM, aY ELtL'st McDEyarT Axa 1xvMo S. tiVtiGnt Phpsiologic Ettecu Hcart---Periphenl Blood Flan•-Blood Sugu -Allcrgy Diseasas of Periphenl Blood Vesses Thromboan.iitis Oblitaant-Peripheral Artezi- oselerosis-Arterial Tnuca-Raenaud's Syc• drorae-Cerebnl Vastulat Disrses j oa; vity 4 NEOPLASTIC D1Sc^,kSES, bY Er<:;FS I_ 1VYN-aEx C31nic21 Data I;ung-Lisynz--Onl Co.vit}•-Esophagus- Othet Types of Caneer Ezperimcntal Data • Pret•eative Measures and Outlook 1,Soderation of Smokint Habiu--•Filuatioa-- ?.fodifinsion of Tobacco Tx-Outlook 5 THE GASTROINTESTI\AL TRACT, 3Y.Ro3EaT G BArsEtuu:+ Pharmacolo?ie Considerations Componenu o(the Smoke-Act of Smokint-- Habituation and Tolerncc-Emotional Status -Baul vs. Ambulatory Status xu Si 52 E3CCt Nor Dis: fcct 54 easc 63 6 F3cets ALLRC 64 cl;u:i: 83 Skia T: Cacanc 7 R•spir. Vnscul: CAtJS~.' f 91 Qusoti 102 Arti6cic 102 Ff idcm 118 itetrosp Prospce Stadics 124 Associa' 33 T-uae T1 ClusatiS }rfntuat The &xI 134 Autbot Inl Subject In . APS 001139'
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xst q.. Neoplastic Diseases BY ERNEST L. WYNDER agarer.e smoLag, : ready besa su•estc Loobasd snd Doe:i facu esub(ished by smoYcs in the arat LUNG C.cNC P"Oti EC f.J tl , CISnC.IL AMD STAT)577CAL SSVD(PS HAYE OrTZH AIDED IN dcte.-aiaing the cause of t disease. Sucah studies an cuncntly rrsponsible for linking c..-ttaia types of ancer to sobar..o. The iaferences that may be drawn from statistical studies as such, partinilarly as they refer to ausotRer, selationships, are cval- tuted in this tezt in (bapter 7. Well-eonduaed sutistial studies, whose results ars compatible with the epidemiologic lnowlcdge of the discaie investigarod, a in my opinion esnblish t ausa eftect rclationship.betwr.n .a agent and a 3ivcr. discase. In the followir;g pages we x-at to eza..-tine to what eztent. if ony, such a relationship is borae out in respect to aaesr suspecmd to have been iaducd by tobacco and its produtu. Clinical Data LUNG During the past four years the most ezunsive epidemiologic surnys ever attempted in the cancer 6eld have been carried out on lung cancer. Tbirteca separate «erospeetive and twro prospes- tivo studies• have been published in various parts of the world, which all show s.n association bctweca smokinc, particularly • Rdumea 4. 20. 22, 29, 31. 35. 39. u. e7. <i. $7. Jt. 61- 63. 6t. 102 Strh Prneat ao+dy (US.A.) Doll and HiA' ' (EajLsad) McConaeU cr eL' (Enrknd) Wyndcr tad Cors:el (US.n.) Watwn aed Cbatc• (US.A.) 8rataw er a1.• (USA.) t.er'nP (US.A.) Koalumie! (Fiesaad) Sado.~tr cr.L• ( Tou)) • fncludes ody t: mecr data. t E rcPtsseats C; cdcnoarcoocu an t'Speei5t re(crt abuining tobcco d . S'Adceocudnoe
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404 80CK AND 1t00A8 . •. , T.eu 1.-Edecl ef yaineinr kckn e~~ bn en r seaenee to citare7l.-emek. Group Number of miee iivin6 emontha Number of mice with ekiD.eaacer Number af miee with aarcinomas orpapWo. my , Miea nith akla tumora (prrunq I-ehavo6 bin•eekly immediately i before paiotinb •.. •.. 28 21 IIi---rhaved monthly 3 days bea• fora paintina •...... 28 1 6 l8 IV-ehaved"whenaeeeoaW".. 28 2 ,6 29 Y-"sandpapered'•' immediately before painting ...... 27 7 to 31 VII-aever shaved ,.,.. 30 6 9 30 Tctal of rzperimental Oraup. •. 141 J6 . dd t7 Ii-controla (or group I . . . 30 0 0 - VI-cootroir for group V. •. 10 0 0. - VIII-eontroleforjroup VII . 10 0 0 - Tests 2-EQeet o/ mowe elaek and remote Xy~ierodialian oa ruponee to eiperdte•emoke . Group Number of mice ltdn66 Miee with skin tumors after 64 week$ Number o tumoes+ numberof 3e I Number of akln cancers b d • months Number Percent ta e n tXj040) o serve ~°ujoy Ia-Sxbupaintedooly•.•••• 49 13 27 31 2 X-Swiss irradiated and ' Daioted .................. 66 44 68 126 17 XI-Se'ist irradiated controls• 36 0 - - - XII-C38 Irradiated and ,paiated .................• 42 12 29 33 1 XIII-c3S irradiated eaD- trol....................... 19 0 Doae Iavef of Cigarette Tar Used in Eaperfinent A Mice of group IV, which were painted only 5 timea a ireek, gave a response similar to that of the animals painted 10 times a week. Like- wise, in animals that were never shaved the tumor yield was comparable `to that in shaved animals, even though the full-length hair reduced the' expoaure of the underlying akin. These data suggest that the dose rate employed in expetiment A was mazimal. Such results would be ez- pected if the inaetive residue of tar applild to the animal was of sufficient I i r e tu sh co ero th:
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Tgi ltoLOCtC EFFZCTS DF 7oBAcCo and that inversely there ue more havy smokers aatong the luag 1 canar patieats. The perrcatage of nonsmokers among lung aa- ~ ar and control patients as found ia diIIeraat teetrospeetive studies is tbo.m in Table 4. Some diHerraas ia the studia may be aecouated for by the fart that not all stsrveys were carried out i (ow.ulrr r,yall a c.cuKTlts woRta Fnuu 11 <%G 0 /o to 30 .o wyeder. E L aod CatnGeld J.W ) so Rcletfoa bcn•eeo releBre mortalitF aod amouat.cloked. (From ;~:..... by speei64interview and that some siudies did include bistologi- a)ly unproved eases. It hu been repeatedly demotutrated that the morulity rate from lung cancer Is proportional to the amount of tobacco smoked (Fi;. 17). Cutler and Loveland 11 receatly ealeulated the expected incidence o( lung cancer among satokces and nonsmokers (Table 5). The prospective studies, too, show aa increased incidence of cancer among smokers over non- ~~t M M4~..aw W T1Cer/ Mw~/ MMMa11Y1owGwq.y " .ww w 133 o..ft uw.r L... tti..r...l H1I/M 4e I W/ W H$~YnM IMw /OMI N M) PP0 Sadowty , Wyader L. . DoJasdH t3Z7oKe.-S, a uwellu in..^ide~ec i among pip 7Lesr d 8( TYpe (Ftovl N
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9 i (OO BOCR AND YOORZ irrndiation. In this instance, irradiation possessed "initiating aetion." In both investigations, however, the effect of X rays could be ascribed to direct action upon the affected cells. Tosebnor, Gottlicb,. and Spritter (18) irradiated mice with 650 r of X rays whiln protecting a small area of skin. Subsequently, painting with methyleholnnthrcno produced moro tumors in tho protected area of irradiated animals than in nonirradiated controls. [fnfortunately, details of the quality of.irradiation and exact location of tumors in relation to the irradiated area are not available in their report. However, the data of Taschncr et al. appaar to bo qualitativcly aimilar to those obtaincd by us: In our experiment, cells which eventually became malignant wcro beneath the lead shield and received a very low dose of radiation-of the order of 2.5 r. Tobacco tars, when applied after benzo(alpyrene, have been reported by Hamer and Woodhouse (4) and by Gellhom (19) to possess mild cocarcinogenic activity. However, since tobacco tar alone can give rise to skin tumors, neither these results nor our own eliminate the possibility of an additive carcinogenic e[fect. Ac;ordingly, two hypotheses can be advanced. One might suppose that with a weak carcinogen a slight exposure of ionizing radiation or a chemical carcinogen could have a large effect upon the observed biologic response. This would be true with certain dose-response curves. An eltarnative ezplana- tion would be that intensive irradiation of skin (or other tissue) leads to systemic sensitivity to carcinogenie agents. An indication that the lstter may be true is provided by experiments of Gorbman (20), who found that irradiation of C57BL mice with the head shielded acted as a cocarcino- genic stimulus in the development of pituitary adenomas. While Gorb- mon be,lieved that irradiation could have acted as a generalized atrea+or, its action could equally have been a more specific cocarcinogenic one. Experiments have been initiated to explora this possibility. Strain Senaiticity to Cigarette-Smoke Condensate Wynder et al. (f() observed that Swiss mice were more susceptible to cigarette-tar painting than were C57BL mice. Their report is in line with studies of many workers who bave observed differences in skin • sensitivity to carcinogens among various mouse stocks. The field has been reviewed by Ander+ont and Edgcomb (22) who studied the response of 7 inbred atrains of mice to painting with methylcbolanthrene. The present data tend to re-emphasize the importance of this factor in experi- mental design and in interpretation of reaults. WAth a weak carcinogen, differences in sensitivity between strains might account. for quaGtative diSesences in experimental results.. Significance of These E:perimenta In Eoaluntion of Hawrda to Human t Beings The data in this investigation support the experimental dqta of other workers suggesting that cigaretteemoke condensate is a weak mousealtin . . .. . .r....J a 1b R....d C.. 1.....
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• ( .cco ~ NLOTLASTtC DISLASbS =oa f the ltmg I , TABas S :ag lung eaa- :ctive studies :y.'CS m2y be -c arried out i I GtSES OF LUNG CdNCE+t EXPECTED TO DEYELOF lER IA00 SMOKERS AND 1A00 NONSMOIKP..U WL'ae Alales 40 Ytan of ASs (From Cus)a, S. J. and Lovclaod. D. H!*) ar .cs .e ar tct rt .r .ot a A'w ~MWWM) i~ o/ D" iw.iwf awaL,e Mw. ~..Ln t..tnt WL~t ;ypl ~.1 wal t Sado.rsky rr oi.N tE 10 30 . 7 12 4 Wyada acd Gtaham" 50 3 32 2 13 1 Doll sa4 HIII= 45 3 29 3 11 1 tmofcrs, ss may be seen ftom Hammond and Hom's datas"'st u Mell as fsom the British data of Doll and Hill.20 While ths iacidence is arcatest zmon; dgs.ate smokets, it is &lso c.:ater amons pipe and d, r smol•ers thut among nonsmokers (Fg. 18). Thae data show the imporunce of studying all types of smok- so •Yked. (From .;ude bistologi. :oasttated tbu : to the amount end sr recently :soa; smokers :ies, too, sbow .:r3 over non• ~ $0 g$ s0 J p o p ~~40 Qo .............. None Pip• Cipor Type of Smokinq ,F,cvtt It Trpe of mtokiag and es,imated aenual lunr aneer tnontlity. (Feves Wyoder, F. L, aad CornReld. J.42) 105 t APt9 001144
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~ e fe rip0rruw,mald of 1 .43 pilloo- u i f I Itice .ith ekio tumon (p~e) 21 is 29 Ie ta cipartllNnlokt mbrro Kumbcrof no17~ skin libltr Ot ea0cere ice in. observed •xpt. bBtoiop• ~ (t00) rul1Y ~ 2 l25 33 - I sent A a week, gave a s a week. Like- was comparable hair reduced the tat the dose rate ta would be ez- : was of sufficient .Y...1 t:.r 1rdbw CIOARCTTL TAR, TRAUMA, AND X IRRAOIATION {OS volume to interfere with tho absorption of additional quantities of active material. On the other band, the data from experiment B disclose that purification of crude cigarette tar permitted increased exposure of the target cells to earcinogen, probably because a smaller volume of inactive residue wu applied with a greater amount of active material. In this case there was less interference with movement of the agent to the sensi- tive cells. In this regard it is of interest to note the experimenta of Twort and Twort (13) who found that dibenz(a,Alanthracene was less active on mouse ekin when applied in mineral oil than when applied in chloroform, a volatile solvent which would leave no residue on the skin after its application• Effect of lrritatfon on Resufu No qualitative differences in the biologic response to cigarette smoke was demonstrated by any of the groups of experiment A. The total tumor yield was comparable in all groups. While the number of carci- Damas varied from one group to another, the number is toqemall to war• rant drawing conclusions. Two ezpetimeata comparable to that of group V have been conducted by other workers. Ludford (14) icariFied mice with eandpaper before and alter painting them with coal tar. He found that acarificatioa of the painted area decreased the number of observed tumors, while painting after scarification produced a slight retardation in the development of cancer. On the other hand, in an expetiment by Riley and Pettigrew (16), mice brushed with stiff bristles, after being painted with dibenz(a,Aj- aothracene, had more tumors than did the controls which were painted only. The design of each of these experiments differs from that of group V in the timing of the irritation and in the intensity of the agent. AC- bordingly, a comparison of our data with that already published is probably unwarranted. Still, it appears that the quantitative differences observed • by investigators studying cigarette-smoke condensate are not due to small differences in the method of tar application. Effect oJ Irrodiation The results of experiment B are presented in table 2. Nearly All tumors observed in the irradiated animqb appeared in areas that were tAiclded from the direct X-rsy beam. The irradiated area usually was covered with a anr which was quite apparent, even in albino mice. A comparison of the mouse of figure 2 with that of figure 3 demolutrates this effect. The effect of local irradiation upon the dovelopment of tumors in distant areas of akin cannot be explained on the basis of present data. Mottram (16) found that X irradiation increased the number of papit-„ lamae produced in skin previously painted with benzo(alpyrene. In~ this respect irradiation acted as a "promoting agent." Likewise Shubil,t • d af. (17) observed that exposure of mouse skin to the d-tay emiuioao7 Tb70/ produced tumors when tben s)t9n was painted with er.otqa oil :aker T.L r7. R4 r. rJ,..rr IfH .._ W 01 N N '
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• screening tests '+n of mouse- .as been te- d al. (!!), and .-firm a growing skin carcinogen baiquea when a d in a manifold- .-gatire pressure dnute until tho ditlorcd si, ifi- ,v, volume, and ic curve for the 3e plateau-type t of tar was pro- pressure eersut m the collection ume of acetone. sure. The con- iginal carton of :ar" usually was :0 percent "tar." of cariations in ~ ' otcperuaental .ion in dose e response. For n as follows: just before tinted with month, but .vith "A." try; painted weekly just ust vigorous l). lainted with d with "A." red; painted .d..1 Or L.0wr CIOASETTL TAR, T1tARHA, AND .L 1RAADtAT1ON 403 Tho cntiro backs of the mice wcro sha.ed with an Oster electric clipper (size 0000 head). The back of each animu was "painted" with 0.25 ml. of solution "A" using a 0.25 ml. syringe. The viscosity and volume of the solution were such that it flowed evenly over the entire shaved area. The animals of groups I, lI, IlI, V, VI, VII, aod VIII were painted 10 times a week, while animals of group LV were painted 5 times a week. To produce solution "B," the condensed tar was treated with 1 volume of acetone and 8 volumat of petroleum ether or beptane. Tho upper noopolar layer was decanted away from the aqueous residues and woshad with 1 N hydrochloric acid until the washiogs bad a pH less than 3. The beptane was removed under reduced pressure, and the residues were d't.solvcd in acetone to make a final volume of 3 ml. per original carton of cigarettes. This procedure was intended to concentrate a fraction that would contain the bulk of the polynuclear aromatic hydrocarbons. Ezparimont B was conducted with 5 groups of mice as followe: Group IX: 50 nonirradiated Swiss female mice; painted with "B." Group X: 65 irradiated Swiss fomale mice; painted with ;'B " Group XI: 39 irradiated Swiss female mice serving as controls for group X; painted with acetone. Group XII: 45 irradiated C3H males; painted with "B." Group XIII: 19 irradiated C3H males, controls for group XII; painted with acetone. Physical radiation factors were HVL 0.1 mm. Al (100 kv. unfiltered) and a dose rate of 780 r. per minute at a distance of 20 cm. A single dose of 2500 r was delivered when the animals were 55 days of.age. At this time the ~do:sal hair was in a resting stage of growth. The animals were placed in individual lead containers with wall thicknesses of n,- to ;f-inch; in each of which there was a 1 em' window permitting radiation of 1 cm1 of the dorsum of the mouse just anterior to the tail (fig. 2). With this dose of 2500 r delivered to the skin, the dose scattered to the interior of the mouse under the lead shield was found to be 2.5 r. Experimental animals were "painted" 5 times a week with 0.25 ml. of solution "B" by the same method used for solution "A." Controls were painted with a similar volume of acetone. To keep the hair short, all the aeimals were shaved as needed. ; All animals in experiments A and B were painted continuou3ly until they died or werx moribund. Without knowing the experimental groups from whicb the skin lesions arose, we examined the lesions microscopically. The first akin tumors appeared in about 9 months. Fifty percent of the mice lived 15 months or longer atter the start of the ezperiment. Rnults and Discussion The data are presented in tables 1 and 2. Tumors were considered carcinomas when the cells invaded the panaiculus carnosue. Metastasee to the lung and reginal lymph nodes were frequent, whiqe metastaees to the liver and other organe were rare (figs. 4 through 7). Y.L ff, Nw ; rJ...rr ifH . , .
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I NEOlLASTIC DISEASES i eanecr rate. On the othc: hand, difereaces in smokiag babits ia l these tsro uw may also attaunt for the diderence. Doll and ~ HID y bare sbo.+o that tbem are mazy taorc nonsmokers amoog farrnen than unont people living in cities. In a rncrst susvey among upstate New York farmersr* 35 per eent were found to be nonsmokers, whicb is about tvrix the number expected from I a city population. ; Tbe correlation of smoki•sg and lune eanar appean to apply particularly to tbe epidermoid types of-lun_e ancsr, a•hich in the male, of cousse, arc the important ones. in that they a=unt for 90 to 95 pcr cent of male lung anars. In a studJ"P of 41 male patients aish lung anccr who were nonsmol•ers, adcnocarcinoma was found in 29 per ant of the cases. Adenocarcinoma of the lung is considered to be less closely associated •ith smoking than are epidermoid typ~ s•" ' A mere sutistial usociation does not in itself prove a auso- ten ara a tive usocintioa In the foAowin hs oi u am g p p . , p g n - outlined w•hich, takea together, sucgest tobacco u"3" eause of- lung eancsc. 1. Vidcsprcsd inerase in age-specifie death rate from lung • anar: Lung ancer has increased sharply throughout those , countries where a great increase in tobacco eonsumption, parsio- 1 ularlyy eigasstttes, hu oecvrrsd. Notable exeeptiosu, sueb as Ice- t 1aad,'s where there is a low eonsumption of tobaeco, rc•emphq- siEe this point. 7. Predominant inerrue }n incidence of lunt cancer among males: The predominant malc ratio of lung cancer is compatible with the long-term smoking habits of the two sexes. 3. Slight increase among women: The gndwl iarsue in emoking among women beginning some ten or twenty ycin ago i AP8 001146 .
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aa CANCER of LC.CG - C9L'RC.YILL I. .. v. .. hers antl ,ho+v !es, Jr,cr•cnute :I~an~e than those ex- pec:oratcd in thc aputuut. hlcrbut and C:cri' examined bronchic,! +teretiuu, ubtair.ed bv dtis proadure b~• the Papanico!aou techtlie in YJ com.cutive ca,es uf primary pu!mmnary earcinoma. Cancer cells teere demonstrated in ?2 cases. but biopsy slxcimens oi tissue .hutved r.neer in only I I cases. Bronchoscopy falled to di,elose cancer in 7 cases in which cancer cells were prese:u in the a,nirated secre:ions. .\e, tite resulu of cytologie studies are of question- ab!e sipniiicana. and posince results are valid only when the interpretation is made by aa esperienced observer. A positive nnding by the q'toloqic method is not as t'et gitzn the Iveight accorded a direc: tissue biopsr. It is one additional link in the chain of evidence tltat requires clinical or roentgenographie support. Oronr/rograjlry.-Instillation of iodized oil is rarely a useful aid to the diagnosis or localization of pulmonary cancer and should be used only to answer some highly technical question. The ill advised use of iodiud oil as a general diagnostic measure or simply to demonstrate bronchial obstruction may obscure or complicate subse- quent roe::tgenographie studies. There is little to be learned frotn instillation of iodized oil that annot be observed with spot dhna, grid films or tomograph,v This ii true. not only for pu!monar.• cancer. but in othef diseases of the c!' est as tvell• the tsotable exception being hronchiectasis. Even here the chief value oi the broncho- ;nm lies in the planning of a surgical prograns, not mercly in arriving at a diagnosis that usually can be estab!ished by other means. Diprrcuuiutiorr of Primary and .1lrtaftatic .1'royfomrs. -Because the ltm; is so commonlv a site for the de- celopment of inetastues from primary growths in other nr;ans• this diagnostic question is one that is raised repeatedlv. When a primary or recurrent autonomous cancer is actually present ebewhere• the likelihcod that the pulmonary• lesion is a,econtary deposit is, of course• ;rat. Multiplicity of pubuonary lesions is also strong evidence of inet:statie disease. Merely the history oi the surgical ablation of a malignant grotvth in the paat• if a reasonable period of time has elapsed without evidence of recurrence of :he disease and the lesion iit tl e lung is a solitary one. should not close the door to a con;idention of surgical therapy. The roentgenologist is likely to raise the question of a metastatic origin when the abnormal shadow lies in the periphery of the Iuug and is spherical. 1Yhen such a lesion is encountered. and it will commonly be found in a paticot with few, if any, clinical nunifestatimts, a. painstaking physicaleeaminatlon must be arried' out not only to detett a primary source but to be certain that other nodulu do not exist front which a biopsy can be ohtained more readily than from the one in the lung. In view of the frequency with which renal cell carcinoma casts a solitary mctastasis to the lung. pyelography should be camed out- The ultimate dectsion as to whether the pulnsonary• lesion should be approached sur- gially is Isaied on a careful weighing of nsany variables that never take the same pattern in two different ases. r+lexassder' has assembled the experience of sevenl sUrgeons with the removal of ntetastatie neoplums'in' the !ung. Y,. :.• LIP tr doseiv simulates primary neopi.r•ns of the lung as tt inav produce bronchial ubstruerion, hemoptysis. ma!ig- nant cells in the sputum and positive bronchoscopie tindings. No one ot these is commonly present with peripheral pulmonary metassases. although hemoptysis is not as rare as it was formerly thought to be. Di(frrrntiatiou o( PrirnarY Cancrr Of flle L:ury and TrrBrrrrdoiis.-A round and apparently "stabilit:d" focus of the adult type of postprimary tuberculosis may closely resemble an early peripheral neoplasm. So also msy the rare postprimary nodule of hemic origin that is characterized by dense fibrosis and in mar,y instances by a retarded tendency toward roentgenographinlly demonstrable calcification. Art intensive search for tubercle bacilli may provide an answer in the first men- tioned form of the disease, but will not produce positive evidence in the latter. Depending on the collatenll lines of evidence, sur- gical exploration Of the lesion may be required. The operator should not commit himself to total pneumonee• tomy, however, util further evidence is obtained at operation. Taking of a biopsy sprcimen of the dense hbrotic nodule of henlic ori, n may be accomplished by resection en bloc for immediate pathologic diagr.osis. Taking of a biopsy specimen oi a circumscribed nodule oi adult type postprimary tuberculosis should take the fonn of a lobeetomy, because these lesions are nlled with caseous material heavily loaded with tubercle hacilli• When earried out with technical finesse, iuch a "biopsy" oftentimes proves to have been a remukably effective nsethod of treating the tuberculosis before frank avitationis established. Summry._This review of the responsibilities oi the expert consultan makes it obvious that he should have nt his command a number of diagnostic ttchnics that range from areful case history taking and physical exaulination to thoncotomy for biopsy Of a doubtful lesion. These responsibilities must be faced in logial sequence and cariied through without delay. On the other hand. the consultant may indulge in certain as- sumptions relative to his responsibility that are not altogether warranted. Attention is eaUed to these be- ause they nuy retard the development of that close relationship between practitioner and specialist that is desired to promote progress in cancer eontrol They also directly inAuence the extent to which the patient will respond to the educational efforts that urge him to consult a physician in regard to arly symptoms. One of these assumptions is that the expert must in- variably exclude any possibility of cancer, however re- mote, by resaning to major diagnostic techniei without regard to whether the clinical problem under considen- tion indicates their Isse. Another false assumption is that a presumptive clinial diagnosis always must be ex- tended to histologic confirmation despite the fact that the course of nsanagement is obviously not going to be altered by the reading of the microscopic slide. Finally, in deciding on the course tlut the management of an advanced ase is to take, surgical exploration is aften- tisnes proposed as the "only cHance" and u such, one that cannot he denied the patient. In their quat for scientific exactitude the members of the protesslori rritist not confuse the scientific precision with which certain A rare form of inetuntic disase results from a Pans of the evidence an be formulated'v,ith the broad metutasis to thr tvall of a bronchus. This occurrence responsibility of weighing evidence as a whole. Courts of r. H..ha r. A.. tM Clal• l H.: 1. A. N. A& rMar IMN01: IAr.A IJI N4. 4. Ai,ta4n. I•. +se HpeM. C.: r hu.h~j R,,stN. IM SW:trrr Hetuutw sut.,eY ,d Qn,ee..u, S.rr.. Gr.•c a o1K a33I77. 14 IA.FI IYtr. law may exact severe or. even capital punishment if the evidence as a whole is judged valid "beyond any reasonable doubt." ft ii the responsibility of the con- sultant in conference with the family medical adviser to !
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ta,vt t:r FL !Q RERL.fCc: lc.t'r-LlCili E.~'STEI,V 461 blUaq I of chemotherapy are trar.sient and incomplete when the problem may or may not be solved by surgical pro- pncumonitis or abscess is peripheral to a blocked cedures. it patient is likely :o corne to the surgeon bronchus. trith hiqh hopes that fi the growth can be resated his The ODrratimc.-Tne.op<ration of total pneumoncc- liie •.cil! Ix saced but that ii the operation cannot be tomy is so standardittd that it tcarrants little commer.t. periomud he is doomed to die. Even a limited faith Tlx lun; is mobilixed, if adherent, and the vessels in ally alternatire method o( mana;en:er,t has been <.ecured b,v individual lisatures. The bronchus is divided a-mph:ehdestrured. It is less disturbin, to the pa- ar.d closed by ia;errupted sutures. Sonic operator, place tiem t and to an apprchensive familt- to s,xik oi surgical nnphasis uu the use of stainies; steel uire sut:res. but oper:uon a, one of setcral oic:jwus of maiu;entent the imporr-nt tr.hnical precauuon aphc.rs tn iie in the thae nta'' •`•at'e to ho Ilur,ued. It can be ecplair.ed to acoidance oF necrotizina clamps aud utures. Tite closed the pauent that eerta1n inrms oi his di:ra:e an best bronc!ti;l suurp is coverctl bt• a Bap of plcura. a mobil- I~c'uana,ed bY sureical procedure atd othcrs bc radia- itcd intcrcostal muscle and 'pleura or a irce ;r.it o: tion therap,', nitroan mustard, and so on: titit sonte- lun, tissue. tfux> it is nece>earc actually to look at tile diseased The clsest is closed without drminage• Irtin; ;i,c dead arCa and deten••tine its po,ition and nature by thonto- sp.ue to (x oblitaated Inrttq ltc or¢inixin, e.udatt and tnmyheinre tile decisian as to the ntost etTectice tuethod partly by displacement of t4e tttedia.tinwn. rite ai tile oi manaeentent for his particular case can be made. dlaphra;m and retrxtion oi the clicst wall. 4aue sur- lChen sur;ical procedures are found impossible. great ~eons end that thoracoploslr is adcisaDle in mar•}ca,es comiort is dcrived front the knouded;e that some con- aiter a certain amount oi tinlt has elapsed. Othcrs rrelr structive course can be taken, even though the chances find it necessary to earn- out this prucedure, iertainfy ni success may' be slight. The patient tclll rarely con- it should be done iur ;ood reabon, if at all. cern himsalf about tile an;nitudt of this chance if he is The age :roup oi potiems eoneerncd brin;s a>ubstan- lett le, itel that ecunthing possible is being done. tial incidence oi cirdiocascular complicatlons. Cardiac There is no short cut that can teach a surgeon u•hat arrhrthmia, particularly auricular flutter, may oceu to sac and ho+t- to say it when he is faced by patients in the postoperause period. For this reason preoperati ie "'tth inoperable nuli;pant diseasa, He may elect to preparation with qusnidint is recomnxndedd remain on the purely technical level, a posttion that I I i 7 Blood last at the operation should be replaced in ~ertainh' Is the least troublesome and time consuming. volume, but, because of tile dangers of edenta in the remaining lung. additional fluids arc administered in moderation. Oxygen therapy is usually emploved dur- ing the first acenry-four hours. The total hospital stay after the operation has been greatly reduced and now rarely exceeds two weeks. Early ambulation is beneficial and there is no danger of incisional dehiscence or hernia. A tcell administered anesthetic is vital to the patient and the technical steps of the operation. A few anesthet- ists continue to magnify the technics and complicate the procedure with cuntbersome appliances• but as a general rule anesthesia for major intrathoracie procedures has settled down to sundardized intratracheal technics that require little comment. The important qualities dernand- ed of tile anesthetic agent arc, first, that it have at wide a margin of salety as possible and, second tlsat fulf anesthesia can be mainained svith a high percentage of oxvgen in Ate mixture. Poiition on the table, incision, instrun)ents and ottier details are matters that are best left to the operating surgeon, who,is assumed to have sufScient campetence to undertake the procedure. The surgical excision of aneer of other orpns be;an with limited resection and extended to ndical resection. In contrast, the surgery of cancer of the lung, exeept for a few sporadic attempts, started with total pneu- monectonty. This in part aecounes for the uniformity of results that have been achieved. It is customary for surgeons to take the position that total pneumonectomy is the only acceptable form of operation. If the mortal- ity rare of total pneuntonectomy is ahe same as that of a more limited resettion, and the life expectancy rate or disabi(ity of persons with one lung equal to that of persons after a lobectomy, the matter can be closed. As fong as any disparity in these values exists, hoa•evct. the question of the place of less radical procedures in drefully sclected cases must he kept np¢n. XOtSVAGrC.U. TREATStENT As long as only I or 2 patients out of S that come to the surgeon have resectable growths, a patient should be informed before the consultation that his particular ,t ntav be found that this is tile only position that can be taken in certain situations. On other occasions, the surgeon may be the only person in a position to guide the patitnt and his immediate family through a trying period. This takes time. \1'hile the e~ploratory thoraco- tonn' ahat reveals an inopenble grotvch may be com- pleted in three quarters of an hour, several hours must be ipent with the family, the patient and in conference with the physician who is to take over the daily mana,e- ntent of the case after diuharge front the hospital. Surleons talay, struggling to keep abreast of a heavy load ot technologic datail, uniormnately find little time for these matters. 1f they are to maintain their position as doctors in contrast to artisans, dte responsibilities entailed must be faced. Clinical Notes, Suggestions and New Jnstruments FLUID AEPLaCENEAT MtTN XALf STgENGTN SOOIUH CNLOAIOE SOLUTION MARYEL C- IICMTEESTEtR, N. Q. tAicata. Loss of fluid in inrestiial o4ttrucrion results frem two de- relol.nents folbwing onset of the eomlitins Rnt, frank loss of secrtrions oecun» a result of (4) Vomiting..(b) ,tagnatieqof secretions abuve `thr sevd of' ut>sruaion and (c) sueiion or ~isA+onast inssiiutnl r91en dte paticnt is nlaceA under ntwEe- mmt. Seeonl loss of ineon+e is sustained as a result of atleren- tion fronr foo,l and becerages. TYie unmmr, of loss in the 6nt of Ila•e deretnrmmts rrrin Willl ttrc rolmnet t'ornited. su^.nant in tLt intestinal fnmm and »annml Ly snaion or sidtan¢e. N'hatcrer thit .blume nuy' 4e, it is comryndl 4P x?Itr nilh o .anie Lid inoreanie sub- sancrs the nro•t imlr•naut of .hia4 is .•limu oldoride. The aon- crTVUion of tile Ylt., in the Caftnmmc.linal ;ccrni,ms is a0- rr.w .4 n,.n.w N t.rpr. $ynF~e•rrm l'.irrr..p )HJiul btM1 •uC rb C,J, em,ry CnJ,uv Se1..J d HN,but. I
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9 ('rnrrrr Jir.rrrr•h - TADLF e. \l'!tuen sSU 1'eAreSiaGt: llv >It:UCU.tTtt tcu 11r.try' C7e.VU:iT: StroKr:ci I. ' S\Llit: ?\U (blCnCn \!I:S nt71I C.t\Crat . frar.l . • ' ' rr.rrM... vr rctlt•., lu x tnn'!r'ra!r nr Frt•nlrt rslcrll. ') in> Irt•r- erul:lg• is npn•.etdrJ hy a hnrirnul:J lin:. ,1, iu Piglcr 1, cun'.• arl• dr,rn'n In ,Lott' the linlil.. uf sipuifr:luct•. TLr pcrcrn!rw• nf ,mul,cr• a:rnrrus palicut, u•ilh Umlun rd Ihr .tlnn::rt•h :rurl torlullt arc hiehcr lh::!: ILr tnultnl, llal Iln• Jilf• n nn. an: not staliaic:Jl y ,iguifir,lnl. '1'his I:tck ur aurola- tiou brln•cctt lho inciJcnch of r~qart•ttc mnnking and of lumnn o! Ilrc upprr clierslit'r lract Innp Le due to an in;uf cicnt tnun1ar uf p:dicnl, or Io tLc als,t•ncc of Liolv;;ic rcl:llir,n.hip Lattcrrn s:twkiu„ xnd lhr occurrrncr of l6r,r 1;'p.•t of tunwrs, In coutTa,6 lllr ;,roupa of palianb tsilh luctor< of I IIC lun;, lary•ns anJ phar}'ned anJ thr fip Ictt r a signi(ictntly hi;hcr lx•rccnta;c of sruuLcr, (GS,::, J'c!i!,rs,t rri111 rdln•r rlrrnrrra n.r a Crrntrnl gr,:np.- crtll:l:;c is sigui6t•anllt 1Li616,•r Ih:ln lhal for the In Pigrirc °. Ihc nrlllrol qrnnp a:Ixrnt•n N•ilh cunlrnl grunp. ollrer ltunori. nf u'ILvnl IS.41srt tcnl slurd,c4 )',tlirnl" n'illl caucrr 0! Illr lily diltvrc.l, Il.rt,• tOrrVM sr nwn . iN.l R111. Xrp. olher tiln ~ S?? 456 06 Lcnt se 7:1 s t•rrcnt :nd phJrynt 73 65 4 Up • IIG IIt7 0 frlsm Ir.lli.•ul. nill, "olllvr ltrnlmt. "in a 6i;,llrr !n•r. ct•ntn."c of e.hiLr• ulrn. 1N tl:i. r:lcial di!ivn•ncr in lllt: rliuical :tuQ t•uu!rrr! ;;rlllq., rc.pnlniLlc fr,r lLt• tc!:Ilivt•Ip Li;h !r,•rccnlupr u: ciw:lrrllr• .ul;,trr. nrmrn~ p:llirtd' trilh cauc¢r t•! lllt• lilr? '1'lu. rlnl••. linu c:cl Lr :unnt•ri J r. •ily Ily r~rlul!ia: I hc cnl- urrrl !f•Airtll, fP.ln Iht• conirtll ;nnq,. "1'hr t.~llilc Isllirul, wilh C+tnCt•r of ILc lip L:rr! Ilrt oenl ci;;arr•llc Smnl.t•r< xnlan;; Ihnrn .I, el,:n- lut: t•ll In 30.11 pt•r cent Itrr tLr n!ti l r mrn rl i l ll ul l:rr tu:unrs.'Phe di1T••n•ncr in pt•rtctd:r:r> m.ly I,c cul.. sirlrrrll ns Pro11:166• %lati.titalh• :i~niCalul (/• . 0.01•:). In cr'nlrn•l, the ;(roull: r.t lln. nhilt• Icl. liruls ttidt clattr of Ihc rracralorc tr:lct h:lA .i••. IIiGt•aullc clc•ealell pcrt•culaer, of eis;.lrcllc ..Ut. .. I.• L:Ir 2.1.1 sa 0 91 s ltrt o• u::r.v li ' InIJl,.lr • runu.r.7. 1 r c Y.011. I ,1i1.r rL.. It.. r••.b.J pma.:. (t • OALO.f:r. Ut Ihc lIG palirn't eilh r:nl•cr ol' ILc lijr, ltotc- CN'rr, all ur 11111 lrt•r ecal terrv n'hilr. Tlli.c pt•t- and of Illt l:lrt•nx nnd ph,vcus (!11.3 !•.•r trnl). of ..rt'ctal (rrllurnr; drlnlm:lun, and Pcnud• 1 11 L 60.9, and G? ~ per crnt, rc>prclivrly) lhan Ihw cuu• rrs. It may hc concludrd lhul the diRt•rrlrcrs in lrol ;roupm of palicntx (IS.S per ernl). racial rlislrihuliou arc not rcspowi!,Ic fur lhr cL. Tbrre is thrn a eorn•Inlion Lctn•ecu eir:lrctte s.n'ctl JiiTcrrnrt• in the >Inakine hahils of p:llic:ll• smokin; xnJ the ineirtrncr of exnttr of lhr lip and trilJ/ eanrrr of the rc<yiralor}• lr.tet. of the retpir::lor;• Ir.lct. ls the eorrelatiml of hio. IncidanlaB;•, it ncl;• he notrd that the d,lt,t a! lotie si, tifieanc..' IIt•forr eonsiderin^, this prohlcut• Tnlden cxn hu Ir,tt•.I lo dt•It•rtuiuc tt•hcther l!tcrr i• oee hxm to stuJy in nsore dclail thc Validily of the any dilTcreneo iu the parccnL•I-,r of ei-,:uvlta sntoL• eontrul Froup uted. ers lunon; n•hilc aud eolurcJ p:tiicnts• In nlcn tt'i:t•1 Raeinl rfitlri6ntinn.-In tcsting the valiJity of "othtt lmutln," for c.:lmPlu. ei•;:tr.•trr i:nokin;c: the eontrol grnup, wnny faelors tanl Lt• eon.iJcrcd• waa oh,er.•trrl in .Sn prr cent of the tt I:itc and un1?' In tl,tit studN• otd;• raee ond k;r n•errlrsIcd to Je• a; pcr cent uf lbrr folort•d ,m•n. The Iertnine tt•itctbrr Iheso foelori snlq• 1ro rt•nlton,ilila nn:d}'•is ,!mu•t, x. utight lie rspcclctl. Ih,li coL+n+l for thc• eorrelulicat af d;:lrvllr: smokin,:mJ cant•tr rnct; haJ a,i;;llifl:nttly lon' Ilvrccnl:t,c uf ci".:rol:c of Ihc,rrstrintor;' lracl antl lip. stnc!:rrs. The racial dirlrihulions of control ntud elinicJl :I,t AisAibrdian.-:\ >:•cond factur lh:tt h:l,; Iu groups nru presrnletl in Taldr ?, tclsich .Lotc, the he enn.idrrerl i; a;;r di,ttilmliun iu Ihr rlinir;ll and prrccalx;t• of tclritc pulirula in lltr dilTrh•rtt ~ruul+.. cuulrul graup•. ,1 dt-luilrJ an+lly,ii of tll,• a_r Ji•- of mcn tt•ith e:utct•r..F'or thc rontrtml -,roup, !t:t.t trihliliun i: 1xeK•Idrd ill Pb;urr S. Thi. pr.lp!t pcr ernt of lltr nten t•'rrc w'hilr. No ai;tuiGcont :htins lhr fn•plept•v Ji..1r111NtIqI1 CSIrVI', 491 :IrII!1- e;tri:ttiun.s frotu !his perc.nla~,r were uL>vr.•t•J Grr tnelie j+mL:tLi!itc p:ipa.'1'hi, h pr uf Fr?p!t p•I!"•r p•Ilicnls tci111 tuttiots of Illc lung (s!>.II p,t crnl) 11at'Ihc :nlt:qila l• nT f:rrililaliu_•.Ihv cl.InpnriJru, 1 p,ti, nl. -r9r/, Lu _ t' . rcjm•.cnlaliwl' nf a uartrrll Ji=triln.li0n )' „1•1~. ~ slraighl linr (0hrvk, aa), tn N W N AN
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NIOfLASTIC DISEASIS d;uette saotia;, and lua; aaar. Such i wrrelation bad a1- seady been sut;ested by studies published in 1928 aad 1939 by Loobard and f?oerfar' and by bfueller?e The two outstanding facu established by these studies are that there ue more aoo- ~ jmoYers in the cant.rol _noup than among the lua; aaeer goup, i Tuts t LUNG CANCER .(MONG MALE NONSMOlCTRS AS RFlOR7ED 8T DIFFERLYT U.'Y£STlGATORS • (From Wynder. E. L'r) toCeet N~b+roJCeuu Nonimul•rrr • Ty1e Lunr ' L+iAt NlL. oJ)ateti strdy Ceeeu Coenole.wrrCoRtrol tnror.f rfevl fzs.+ 0 sucb ~zve I prernt study f79 710 (US.&) Doll add Hill' US7 U37 (Eatl:ad) . McCoaasll n aL' 93 93 (Eai7az4) Wynder and Corn6cld' 63 . 133 (U.SA.) Wauoa and Coots• 265 465 (USA.) Bmlow et aL' 493 493 (US.t) Levia- 490 2.361 (US.1,) Koulumie! 902 313 (Finlud) Sado+sty a d.• t77 613 (US.A ) Tonl 5.019 6.616 1.4 14.6 E oa)yf Spccihe 0.3 4.! E.ti3 Speei6e A 33 Nooe 441 3.6 6.3 E aod A Speei/k t•1 20.6 Not p.en Speelbt t3 13.0 EaadA Specide 1.4 ti EandA Sped6e 79 269 Not A+'en Routiae CJ 11.0 E 336 Routiae Neae 472 31 11.7 Not given Routine IJ 11.4 • lncludes only those rtudies that reported oontrol data as well as lung eucer data. f E rcprcseate epidermeid. aaapludca and unelauibed. A reprtseeu adcaoearsinoau aad terminai broochiolar aareinot.ti j'Speei6e' refcn to etudics that .ere dooe witb the tpeeial purpose of obtaining tobaaco data. S Adeoocueinoaaa o( the lunt werc calculated upantely. 103 AP8 001142 m ,
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.:~--'----_ Scui:cr rl rrl.-Tu!wr•en ,CnrnU,rg rr,rd f'ancer 57 0 ~ aanli:d rei,Ir•Iler I!lal •rrrol:iu~ rc rlir,!a;irul in caot•rr. Lrl u. r\'adlate nLrtLl•r Ihc rciJ nr.c i. '1•I,e ol,a•n'cll rorrrialivu hctnrro >ul•il;in~ :nr,I elarcr can l,r txldninid in st•err:J n•ap. 1 ir.t. il IILIt• lie t•Irn.lllrrl••I tll.%l Illr tY,rrl'I.,IIUI, I> a rr•>nIt of forluitun• c.r t•hsnct• Llr•Inr.. 71r Ir,ls fur xl:r. li,lical >i;puific•:mrc iadic:,lcrl lo a Inr;;r c+arnl Ih:rl l6t• ol,•r t:rJ rcnull, arr nol dnt• lo 16,• xrcidrul, nf ,c:uqdin;. A sccund rxplnnafion for the rorrclatinn ia thol il a•as not a tlircN trl.aiaa•hifa Imt :m iudircc•t anc and n•a: d, p:•nJ,•nl upou auclr struud,og Glctnt> :Is mcc. aec, occupz:tion, rlc. It it nrrc possildc to ol,tain a eontrul ;rou,n +ehich n•e\ csaclly lhe s:un,• as thr cliuirul ;roups in all fa,ctor> csccpt tu•o- t6e prc.clur of canerrand smoking-it u•oulJ hc posuhle to lcst dtfinitrh• n•hcthcr lhrrr is a dircc•t rrI,ilinnship bt•t,crcn ILcsc tn•u facloc.t. Such a control gruup is (icquclutly apprn:,clrcd in csircri• menlal n•o••k, but rarrly in clinir:d slndies. Thc e•hancrt of uldainin; an iudirect rcl•Ition= s6ip dcprndrnl on s(eondarp factor, can Le nuini- miced to a eonsidcr,ILlr Je,ree. TIK• firsl slcp is to select •lhr control -roup srilh a full anrl drl:lil.d noni,•'."c of tlre Ila.d situntion in rrprd to .nrh .jelors as the tvp;• of palit~nlf udmillyd anJ thc utrthn,l of.tal;iug hi>,tnrics. In Ilris siudy, fur t•s- ample, il n•aa ncrca>:Irr lo colnidrr that cancrr und noncanerr p:dirnli nrrr sclcetcd front dillcrcnt lo- talilics and pnpnlalinu: aoJ, thvvforr, timtcnurrr patients could tlnl l,c usctl as a tonlrol. The secnud stt•p in con.<idcrin; Ihc possl,ility of indirt•et relationchip is l,}• tecting aud oomparin; thr control :md Iht• clinic'aI group in as many.tt•c• ondary• factors os pn<r7)ir or as seem kasibe. In 1114 teork it was po,sihlc to lest age and ran. An aualyris of thcsc two lactors indicatni lhal 111c coutrol Lroup was ursuitahlr for esuctir of the lip hut cnuhl be u>cJ fur eaucnr of the rcr:pintuty I tract. 1171rn ner'anJ ract u•erc aqualired in lhc c•mdrul and e:inieal broup+, lhc„• alill renlaincrt a I•tali,lically si, lific:ml cur,c6lliun Lcht•rcn srno/,= ! in1 anJ eauccr of thc Inng and of the larpnx anJ 1 . pharcnx. 1 •1 tLirz) and irnporlnnl strp in minirniain5 indi• , rrrl rrlatian>lii1r> 1. Ilir Coluparisnn o( the slali?ti• ' tal <ludic> in dilfct.ul in>titluiuua bv dilJcrcnl iu- I\r•ti;;aton. Thc mlifurtuily of lln. flndiny;t ob• 1 I:linrd Lp \Ili/lcr ind ICy•ndcraiul Cr,,haiu, and in ~ tLrprr,,vnt>tud;•i.<iulllrv..i\r.7•h,•rr.lillrrntains / .li;;hl Iru.•ihi!ilr Ihod wu:c nli ,tru:c s.rntul.vy I r;ur n•In,linrd Ilrre:uut• iu all lhtre incrsli atiuna .ull h••nllell in :In iullitln•I trl:diun.hip hrlu'1•t•n ~ l,in;; aml c:un~rr ~d Ih,• Innl',. Thr cr,rrvl.rliun hrt.crrtl >Innl,iug uurl canrrr i:, S I ILru, prt,l:ald unI Ibtr to (nrlt:ilun. nr 4rraud:lr.• fnrtw... It >r•rld• I/l:nr,ihlr, lhe•rt•farc, In fur.:mLdr; tllt• Ily•(Tlht•.i. /hal tliPrC is a dirirt rc1./11M1:,•l~it) Lcl nceu c•i;;:lrcl Ir.umli:liz:nnl c:uu•.•ro!;6c n.pir- :rlnr~v tract and 16at cie.lrc;lc•;Inokiue uray Lr:r c/rrcin• g,-nir np-ul. '1•6rrc is ar.nl6r•t :r•p,tl lu lhr p:r.! Iom. 1f oi":,rrllc slur.: ibg i, a G/rcinqet•nic al~ •ul, Ir9n• daugrrnu<i<It,i, liahit!'I'lris rlVCdion oonld unl lie considrrrJ frnul lhc prrsrut Jal:l. Sun/c irlb.ruln• lion Can llc ohlr.ined. ho,rrrt•r, frotn othcr>hli;• lir: aud rxpcriulrnb. In uninlal ospt•rimcnt:dirm, applicalinn of a slruu.- Carcmn1gruiC agcnt In•oJucrs lumr.-r> iu ncarl;• all dn• ani:unls, hul a n•cak ap:nl ciu•ra tu- mors in oufy a frn• animaL. - It is n•c!1 known lL:rt Cigart•tlc vnrokiug is a•iJc. sprr:ld. The cantrol aronln iu tLr prr:cnl >tud~• aud in 11'yndvr rlnd Ca•ah:lni i\rurk str~yr>t, tlalt abunl Ilalf of lLr mcn are uu+drrutc ar.J Ilrn\•y ci;:lrclle srnol:ct•..1cco:din;; lu Qrc )narL,liiy sla- li.aics of lllc 1•:lilt•J Slalc•i (:L31, 0.1,1! p.•r rcnt uf 16c drallis of I:u n Ila.tl 40 %verr tiuc to cantti•r oi Ihe rr.I,inrttriy .;yylcm. TLir rcl.,tircl; lolc y, rc.vt¢;;r of IlralI,; Lt• r.wcr: of ILc rr:pir.;,ory Ir,ri a, cmn- p:rrcd In the 1ce;1L prrcenl:,tc o.' ,nwl:er> iirlirallr> lhat smul;in;, is. :11 laust• only a u rak carc•ir.ojrnic aecllt. SCmJL\ltl' .1ND CUNCLUIONa 7•hr smoking La1,i1; of S: nmcn n•ilh car:h•r uf ll:; hmg and 79 uu•n will, canccr of the Iarynx :ud phnra•nx n•crc comp:ucd n'ilh Wc inlokiu;, L•ahil. of a emlIrol Froup of b:•1 f lai;l;l<u•ilh n,i•erllanr. ou+ Iuluors..S r,lati\'r!y hith pcrccnlag: u! riga- reltc stookcta aas fuuurl atnu:l= Ihr patia•utA with Canccr of Il:c rcylir.aorr Iract, aa r•oulpnn d in th;• Conlrul. Tl:i, pd.ilit•e curra•la:irr., Lclrrcrn Il:r in• cldYard of ch.lrcllr sn.Ul:iag :Itvl tln• inrirlrnrt• of r,mc. r of Il,c rr,lrir.lI.•n• Irlc::lpln•.Ircd D:I,rl.olll slali<lic:alr nrol Li.r!Ir~icaliy 'I'I:r:rr i. strune cirarul<lanti:a c\•iJcerv t!r.,t rigarrltc smnl:iuR wu an rlinlu'-ic Lrctv: iu t::utti•: .d:6r r.- spiralur;• tn:cl. Itlil'liltC\CE3 ut CLr•:• 11:"C-1:?, 19t3. {. l.lr.rrT, F•xlv 1)r•r I1rux:Li,a:ra,:,...'rr li.yao-r- \t},•- rheri. 3. 1nlh.ns, 11'. \r. Tnb+..•n iar.r'.ir;.v C9{oi,~,t Au,!y• C. ~:. 11Ixr.13:7A, ~laa!1 7• I^t9. . G. Il...e:., E. a,A t.mvle, It. N. T.•L.....r T.rr .k, I'.;. ri. xn•nlal rd 11..11!.~.,I1>Pib.,h:.:, Ma. I. 1'anrrr. I i;:1.S C, -? I, 7. Fuu•ur,l.l., 11. I., a•,a I
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0 TgZ 7I0LOOtC EFFECTS OF TOSACCO iag in an a:alysis of its possible reLticnship to luag csa=. The sotu~ asotu for the apparent greater oorslation of dgareae :mokia 'g ts a with lung caneer art not eatuely clear. The foUowing points may be importaat: 1. The greater practice of inhalation among cigarette smokets. 2. The possibility that eigarette smokers are more likely to be bary users of tobacco than are cigar and pipe smokers. 3. Ggarette tobaeca may be prepared somewhat differently from that used for cigars and pipes. 4. It may be that cigars and pipes filtc: certain ur partic:a more thoroughly thaa do ciguettes. S. 'I7ie diRercnt burning properties of cigarettes may produc tar unlike that obtained from smoking cigars and pipcs. - Doll 11 recently sbowad that in the absence of smoking the sez ratio of lung cancer and the urbao-rural d'utributioa would equaliz:. The preseat sex ratio, raagiog between 10 to 20 to 1, is ~ campauble aitb the lone•terra smoking habits of the two sexes. Studying female control patients in the caacer-aee group, Wyn• der and Graham•' found that 80 per eeat bad aot•sr.:oked eaa- sistently for 20 years, in coauast to 15 per cent for the males. Only 1.2 per cent of the females bad smoked exeessively, in contrast to 19 per cent of the males. It has been predicted that as the younger female gcnendon with its eztensive smoking habits reaches the cancer age, lung csncer may also increase considerably In females." Lung cancer is reponed more eommoniy in eities thao'in rural areas, which might be explained in part by the fact that most thonde snroery• eeiiteis are in ciGes; and ruial population eroupi may gnvitate to these centers in their terminal phue: HueperTa believes that air pollution is responsible for the hi¢het urban lung . 106 L_'1M.r v I these rve HilJ =Fa• fu:ar.z t among ai be ao:s- a Ci.y pc. Ihe cc pa:..:aa: sss•le, of < 90 to 95 pstieau u was four, luag is c thaa are A mc^ tive asso outli.ed lung enr.: 1.Wi: anmr: I countries ulariy etg )andss w sitt t5is 2. Pre males: 7 ivith the 3. Slis smoti.-1g
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i 864 Canur Raearelt 9, Dott g, ead Hy. L 8. SmoEast sed C.edoems of LaaC Prelimlest7 H.pott. 8tit- Mad. J,1t77t-tL Ubo- 10. --. A Stud7 of the A.tio6p at Ca:dnoma ef 16 Luac. Ibit. Sat41-1d 19lL It. De:rau, Y• Loat!'.udsom. ia Tuland. Leecet,1:94f-t7, IIJO. 1L Earrostv. Eademiolup ol Hnoebiel Curiaoms. Leo6 7:31L 19St 1!. Eacqao. L ?L C4atette Smoks ud tbe facidwa ot Prim.r7 NcoPlum ei the Loet ia Albiee Sfioe. u9:J61-41. 1t8L 14. Fto6A C. bL YLe Ptodactioa of Tamon b7 Tebreoo Tee. Cum Snareb,1a9M0. 1NI. 19. Gasu. 0. Srox5is0urrinem aai 1'Jrk: CreecSaa ds Lanpatxbw. Seb.eir, m.d. Wcbaar34 fl:9af-a4 1961. 10. Ha.rta. P. C. Gro.th-Pcaiuring Edeets at Etfnetr of Tobano as )Loe. LAXA. 91:ISO-,fi, 19lL 17. Hofrwxn. E.: Scan% H- T.: sad Zca9ax; E. Heo- beebtoatra sV aperimeatQlea GacL.abtstseguot dmch Se.r ..axLiedeaec HerbueR asd Pan¢s. Deotxb4 med. Weba.ebt.p:97l-N,19tl. 19. S~+otu.a, V. R.: and Soar.aa. H. C.aoer bf &Ltiea te L'aya: Tbm Ne. Tlryn in fadu. Mah. Patb.10:561- 91, lPtb. 19. IaYOan, IL (eitiet T.a) Studies oe Cucioopmie Cbemleal Sobctaees Tna.. Soe. Path Japoa. 37:e6S- 7t7, 107. 90. Yoeseearti >L Smolcot aed Palmoeaq Cuenoma. Acts ndiol. 79:ltS-9o. 1971. tL Ls.c+. )d. L: Gota.rss+, H.: aad Gnuaas, P. R. Cum sad Tob.av Smajing:, A Pnlwiaar7 Seport. JASf-A..1L7:L1WA 19DO. !L LoszrL L: Ses*an. IL L; D.xta. l. H.: sad Neiox. C. L. Tbe Edect+ of Hrntbiat To6.ao Smolu oe Stteio A 3f1ce. Cum &sftre5-}:iL7, I9U. Lt. Le-Fa-.oa. 9berdie Erwwee .aa I4abfi dme! Tebek• teerpimelaat beim Y.aisebea. Fnaklmt- Ztacbr. Petb, MtJU-!9, I9X 9i. XeCoxmtit. IL H.: Cosaox. IL C. T.; aad loxts. T- 0eeupetioo.l md Penoael Fettars is tSw Aetioiop of Carcieoms of the Laal. Leeat;1:931-Sa, 1L1L t!. )fc\.ur, W. D. Tbe Tar Is.CKecette Smolu eod Its Pouble Eteets. Am. J. Geocer,,16:19ot-14~ 193L !L 1lat& C. L, ead Poasa, !L X Tobeme Smoieet 8.l its aod Cum e(tbe 3toat5 so4 Sepa+eoq 5,7aem, Ce., eV Bseueb, 10:dd9iL 1960. t7. Barre. A. 8. lsokaPt.aa ts6.4aia ezpvimeotal !aL fart. med. aPer. artvd. daav, i:17o-if, I9JO. L7. -- Dutr3 Tabak beim Yuidehm eet.iekelte Cv efeem. Zte3t. L Ynbefenci. Ji:d91-?L i9ll. !t -+. EIT~6aco oemeoiaor~(tsoa. Be1 iort- med eqe. atod, deoer, 13:9d7.1ft li7l. 39. -. Der TebJt eL knrb.eesea{.ada .ltses DretsL med- Wcbeecbr, 9J: Ual-71. 19n. SL --. YnbM+xwmds BeayToa. te*anoee r Tab.kt.et 2tacba L Ynbefoneb.1/:S96-PI, 19l9. 9L -, rrrb.m.ucesde Eiobeit da .aar2iedey. Tab.ktea.. DxAat3e md. Webambr. 99:9W7. ll». 33. S.aowu7. D. L: Gauut. L G.: wd Coc»m.o, J. A, Sulietial Aaeoe.tioa bet.aaa Smokia~ md Caece eI tSr Luag. L NaL C.a«r tart, 33: ttst-80. Uts. Si. Sasc L; Batss, L L: 8au ua, G. P.: eed Douw.. S. Tobeem Smokint ee w Etiele& Faeter ie D've., L(:amr. Cum Re+eueb, 10:1P-89, 19l0. SL Sacsaa, 0, sod Werrarrar, L&pn(mmtelk &hrat mt Fey. Tebek and Xnb. Ztaebr. 1. Le6. fone6., f9:/11-19, 19J7. $6. Soawa., S. Oba:+.tiou ea Aaimab P.fetad .il Tobeom Taa. Aas L Cancec. ii: p-H, 191a. $1. W.em, L. md Smaxess, A. E=petimeotelle Cetrt• webaocas eot barwtea Geaeu U7pi.e5ce £prtt<t• .ochenmpa. ]SOaebm oxd. We?<n.edr, q:taot-a: 1980-d1, 1917. 3L W.usa, IL $ Tbe Bwpyteea Cootmt al Ta.. .1ir. 8»t. l. Caae.r, 9Ndl. 1L7L 39. W.nmr, W. L Cum ef tbe Lunc: Con.ident;ee d b• tidaaae sad Etiolop. New Yerk Yed.. 9:13-19:10.1 W 40. Wr.my E. L. and G..aar. E. L Tobecso Smeliy r s Portble Etioktie Pwenr fa Semebiermie C.+dwar. A Study o15u Hoodted sud Eiibt7-Foar Pro.ed Ctn J..LV1.1tl:5:9d0. 1989. 41. Wixnss, E. L Somu Pr.etial •bpa'ts el Caaat P..+e• tioa. New Eag. J. SSaaL 1ll: f9t-dm; bTb-9t. I9sl IL WTxeQ E. L, aad CoLrnaa J.: Cum af tbe Le+t a P4netuu. Ye. •Eet. J. )ftd, 4tlt H1-1. 19iS Fta. i.-tia 97 CATn Rt d.l.. &91ae7nff an3aoms. Fta. L-Pbalamfetotespb of oe:euom.. Na tl CAFt st Jf7 dyi XJL Fta A-Na 11 CAFt. 371 darl. Ad.epe.d ea+eieoms. Fta f.-Pbetomicrotrepb o( cudeams. Na. 94 CAP, .tS71da7nx911.. . Ra f.-Na 9T CAFt.1T1 daTs. Adnoced eudsoma. Fta. L-Pbotomimop+pb of looftb roenitoa tnidplsat o( tvmor trem No. 67 CAF:. Xt10. 11 I]
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! T8E ltOLOGtC LFFECTS 0F TOiACCO is campauble with a SGght iacsase of lung anar among (emaks. 4. Predotaiaant iaaease among urbia population: The higher rate of incideace of.lung aaar among the urbaa as compared with the rural population is compatible with the greatr; dgaretse consumption among dry dweDet:."•'r• ^ 5. Age distribution of luag eaaar. 13e ebancteristie peak of lung eaacer in the la « Bhies and early sixties fs, as pointed out by Clcmmesen et aGt• and l.evin," compotible with the latro- dur;ion of a carcinogen some thirty to thirsy-Bve years ago. This falls 3ato the time period of the first major upward swing of ciguetta eonsumption.te, N 6. lnerease in the smoking babit, particululy of cigarettes: Considering the latent period of aacer, the ine°ease of lung aacer is compatible with the increase ia the sale of e3garetses By itself this faaor means little. In addition to the other factors listed it is importiat; and, in the abseaa of an inr.use ia eiaa- rette eonsumption, tobacco could not be reguded as a major factor in ihe devdopment of lung eanocr. 7. Concepts of epidermoid earcinogcaesis: Epidermoid an- eer, eiiher in animals or in man, is but rarely found in areas not exposed to extrinsic irritation." Certainly it eannot ba dcaied that tobacco smoke does serve u an irritant to the bronchial murosa. The frequent history of chronic cough among long-term tobacco tuers serves as a point of eviden--. 8-..Cliaical ezperienee: The statistical tobacco data have not been surprisint to clinicians who have had the opportunity of seeiag many lung eancer p0ents and have taken detailed his-. to~&s. Staoking histories of lung aacer patienu have served well as an aid in diftereatial diagnosis of lung conditions. 9. Tobaeco a proved animal carsinogen: Condensed eigarctte 1t)i 1 t =okt has cdu: whiU' thc tar wa 10. No other eaa sut,;est no c aoeiatioa found. The stuisticz: all of these pOL1' of husaan carr,r ancer is stIIl dc and Kircboff.ss i pollution are pr.• iacideare: pu'.ica ratt in iadL•s•.riial cnogrnic to ma: that hold the tob; however, u to wt lung cancer and a coincidental o-- Several oScial tetrsce at Louva tioa,1c the British . Soeiery.° have rc: lung eaaar as e: cina. in a tseent assoeiatioa bctwe as to be eoaside: woPd.~ a la tertsing tob 7ng, "a". pttSe of other factors in : I.- u, AP8 001147 W N I 0) ~ N
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0 intin; Action." dd be ascribed .h 630 r of ently, painting utccnvl arcn of unatcly, detai)s t in rrlntion to cerer, the data obtained by its. talignant were .fiatioa-of the ajpyrene, bare :Uborn (19) to 41cr0 tar alone otrn eliminate ~ordingiy, two with a weak ical carcinogen csponse. This tatire explana- issue) leads to that the latter rho found that Ia a cocarcino- SRtile Gorb- nlized stressor, 0 einogenic one. . tsate r susceptible to -port is in line •renees in sUn Thi field has rd the response inthrene. The actor in experi- lel- carcinogen, for qualitative trds to Human I data of other eak mouse-skin *.,t C. trerr 1 ' CtOAngT7R TAR, TBADMA, AND X IRRADIAI7ON 407 carcinogen. Sinco tho smoking characteristia of the maahince that have been employed to produco cignrotte tata di(for in various rppects, it is dear that mouse-akin carcinogonicity of cigarette smoke probably is aot dependent upon small :artations in puff eharsctetistics. The cocarcioo- gctlic effect of X mys may provide a tool foc the detection of such very weak carcino;cns. It hos bcoa pointcd out tnany times that animal exporimentation un- not.be used as a direct measure of the hazard to human beings aasoc~ated with an envirramental agent. This is particularly true in the present series of experiments. The irradiation employed in these studies was not comparable to that of human environment in regard to quality or quaatity, References (I) WrNDCR, E. L., GeARAM, E. A., and CaoNINOER, A. B.: Experimental pro- duetioo of carcinoma with cigarette tar. Cancer Res. 13: 855-864, 1933, (r) GRARAM. E. A., CeoMVrass, A. B., and Wrxass, E. L.: Experimental pro- duetioe of carcinoma with cigarette tar. IV. Successful eiperimenu with rabbits. Cancer Res. 17: 1058-1066, 1957. . (J) CAUrastL,J. bL: Brit. Empire Cancer Campaign, 33rd Ann. Rep., 1955, p. 104. (4) HAUnn, D., and Woonnovas, D. L.: Biological tau for eareinogeoio aetioa of tar from cigarette smoke. Brit. J. Cancer 10: 49-53, 1956. (6) PASSSr, R. D., Dasoat, F., Lswu, G. E., Ros, E. M. F., Mtnnt:TOH, F. C., BoTUxn, E., PtArr, B. M. G., SIMe, P., aod Hnosa, I.: Cigarette smoking and cancer of the lung. Brit. Empire Canoer Campaiga, 33rd Ann. Rep., 1955, pp. 59-61. . (C) DLLLMAY, H. T.: Tha part played by injury aod repair in the development of oaneer, with some remarks on growth of experimental cancers. Brit. M. J. 1: $72, 1927. . (7) Rosea, H. P.: Extrinsic faeton that in6uence earcinogeueaia. Ph7aiol. Rev. 24: 177-204,1944. (dy Sevarx, P., and Sict, J.: Chemical eareinogenesia as a chronic toxicity test: A review. Cancer Res. 16: 728-742, 1956. (9) BsiLYaLQM, I.: Irritation and carcinogenesis. Arch. Path. 38: 233-244, 1944. (10) EMCiwassa-HoLY, J., and ARLMAMN, J.: Produetion of eareiaoma In ST/Eb mice.ith cigarette tar. Aata path. et microbial. aeaadlav.41: 267-272,1957. (11) ORSIs, L., VAM DvvRSR, B., HoaAR, A. i., Nsuou. N., and SeaMttt, F. L.: The carcinogenicity for mouse skin and the aromatic hydrocarbon oonteat of eiprette•amoke condensate. J. Nat. Cancer Iost. 21: g57-561, 1958. YAlaL7, R. D., Bo*uxo, E., PaArr, B.M. 0., and Hmesa, I.: CI`arette . smoking and laag cancer. Brit. Empire Cancer Campai`n, 34th Ann. Rep., 1956, pp. 1546. ' (1S) Trogr, J. M., aad TwoaT, C. C.: Comparative activity of sdma carcinogenie hydrocarbons. Am. J. Cancer JS: g0-8S,1939.. (1O Lvaroaa, R. J.: Skin regeneration sod cancer. Brit. J. Exper. Path. 10: 193-19e,1929. (16) RtuT,. J. F., and Psatouw, P. W.: Acceleration by meaqs off prolonged mechanical trrttatioa of eareinogenesia in the skin of' mice painted with 1:2:S:6dibenunthraeene. Brit. J. Exper. Path. 26: 63-66,1945. (1g) MarrsAM, J. C.: Production of epithelial tumoun by a combiastion of beta radiation aod painting with beosp7nne. Am. J. Caaev 32: 76-79, 1938. (17) Savsts, P., Gotaraas, A. R., Rtresm, A. C., and Lneo, H: Lateateareinogeaie action of beta••Irrsdiatbn on mouse epideimia. Nature, London 171: 934-936, 1953. r.L aa. N., s. rN,.nr teae . ,., Ln N W to 0 U) ~ N ~
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I vatvtIJr CANCER OF LUNC - CNURCAILL months. Applied indiscriminately to advanced cases. roentgen therapy contributes little either to sur~ival tinte or relief of physical suffering. The nitrogen mus• urd compounds produce transient and incomplete re- gression in about one half the patients treated.' Castra- tion and the use of estrogenically active substances have been exolored on the basis of the unequal sex incidence of the disease, but no indication of er?ectiveness has appeared. The cr,lcial decision therefore lies iii the judgment regarding the applicability of surgical pro- cedures. INDIC.ITIO\'S THAT Tllt CAxCER CANNOT 11E ExTIRPATED Ertrnrion to Plnrrn.-A pleural eBusion. usuallv bloody and containing cancer cells. can be interpreted as dennite evidence,fhat the cancer has extended beyond the bounds of surgical extirpation. While patients with this fornl of the disease suffer front shortness of breach, progressive anemia and cachexia. they usually are not subject to set•ere pain or distressing cough. Aspiration NlVefJt S determine whether the "only chance" offered by surgical treatment is in truth a reasonable chance, or whether the ar.cer is surgically "out of bounds" beyond any reasonable doubt. ALTCANATIVE FORMS OF TREATSIC.VT There is no possibility of obtaining a lasting arrest of the disease unless the entire erorrth can be extir• paced. Rqcntgen therapy appears to halt the progress of a few cancers of the lung temponrih•. Occasionallv actull re;res,ion tales place for a period of several ; of the fluid and replacement with air afford partial symptomatie relief. ' (f the diagnosis is in doubt because cancer tells can- I not be dentonstrated• the replacement of the pleural F. Extension to mediastinal lymph nodes is difficult to esublish by roentgen exa+nination alone. Presumptive roent*en evidence tstay become determinative when combined with bronchoteopie fixation of the growth and pain referred to the back. Lymplmtic Dfssnniralion-Diffuse spread in the lymphatic channels of one or both lungs with the de- velopnsent of sltull nodules immediately beneath the riscenl pleura may be defected on roentgen etamina- effusion with air may bring pleunl nodules into view on roentgen e,xantination. A biopsy can be obtained -u'uh the aid of the thorscnscope or by a limited thoracotomy with the patient tlnder local anesthesia. A pathologie confirmation of the diagnosis is desirable in this type of the disease• as radiation therapy may be helpful and as a general rule heavy dosage should not be administered without accurate knowledge that the disease being treated is cancer. Ertrnriou to Lrmph A'odrJ.-.~In e.cacting palpation of the supraclavicular iossae, neck and axillas should be carried out in every case. The removal of a palpable node with the patient under local anesthesia may con- firm a prestnuptlve clinical diagnosis and at the same time demonstrate that the cancer has extended beyond the limits of sur; al extirpation. This is a less trying procedure to the patient than bronchoscopy and can be substituted for it not infrequently. tion. Thoracoscopy an'be'an adequate substltute for a ' formal thoracotomy. ffc.mtogencus Afetastasfsead to t.he lirer ouy be sugg ested by the increased size or palpable nodular- ity of that organ. Peritoneoscopy is a simple procedtire that confimts tlte tliagnosis. Headaches or other eerebcal symptoms call for a pamsnking neurologie examination. S. Rn^.d,. C. P.: Rn,u Adtuen In Tru[w,.nl .1 6n<n• 1. A. Sl A. 1ae[ JUsJos //.n. JI1 17n. 4S9 including the determination of the visual fields. Panful dpical Syndronta--Pain referred down the arm, a Homer's syndrome, and roentgen evidence of erosion of the Srst and second ribs are often referred to u Pancoast's syndrome. It is usually productd by a prinur-v cancer of the lung in the superior pulmnnan- sulars. A cancer e.`.at produces this syndrome is beyond the bounds oi surgical extirpation• and the severe pain cannot be relieved by local resection, or division of the intercostal nerves. The pain is oftentimes escruciatin; and the course of the disease agonizingly slow. Reliei should be sought by tnctotomy or hi;h chordotomc. Hirsologir Tppr n/ tlfc Tnnlor,--The prc;nn>iA inl• lowing surgical extirpation has notlxen fulh• cnrrclated with the predominant cytologic chancteristics of cucers of the lung. The evidence that exists• hosverr% confirms the reasonable hypothesis that growths with highly un- diRerentiated cells are rapidly invasive and « nd to metastasize early. The salue nay he said for the so-called ou eell type. Significant results achieved by the surgial extirpation of ancers of these morpholo;ic tvpes are rare. A biopsy that demoustrales a highly undiaerenti- ated or oat cell cancer is presusnptice evldence £hat com• plete surgical extirpation is a remote possibility. Nrr,-r ParelyriJ.-Paralysis of the recurrent larvn;wl nerve is eridenee of nlediastinal incasion at a level dut precludes complae surgical ablation. Cancers that have produced phrenic nerve pdsy nwv be resec:able grossly. It is significant, hosvever, that dehsner, Dc3akey and Dixon' analyzed the survival period in their cases from the standpoint of u-hether the growth was limited to the lung or had extended beyond it by eneroachment ou contlguous structures or by regional Innph node me• tastases and found that only 2 of 27 piticnts with such extension demonstrated at operation sunis•ed bcyond a three year period, and noxe beyond six ccars. ' SCRGICAE TREATSr£\T 0perabiluy.-.Tlte experience of many different slr•• geons in the United States and elsesehere has been sur• prisingly uniform in the results achieced by surgical extirpation. Apparent differences in the statistical tables that record this experience are usually artifacts de• veloped by the terminology emploved: the calendar years covered by the report,,the selection oi cases and other variable factors. An analysis of the results of surgical therapy cus- tomarily starts with those patients that are referred to a surgeon for consideration of operation. Thi> base lino ignores the large number of patients in whom a diag- uosis is never nude or whose disease is judged so far , advanced that surgical consultation is sulxrAuous. )t is thus inlpossible to detennine with exactitude the extent to which surgical procedures can be an eBcctive control measure in the population at large. Surgical efforts have rarely been measured against the ma;ni- tude of the problem as a whole. Few surgeons, partic- ularly those whose cases are assembled front a private clientele, appear to be aware of the selection that has taken place before their own "seriei • was assembled. In 996 asa With the elitsial diagnosis of bronchio- geqie arcinoma at The Brompton Hospital for Diseases of the Chest in London; fr6m 1937 to and including 19•k, only 1~.3 per cent (152 cases) were judged suit- able for a thoracotomy. In cases in which tlioncotonry was done, extirpation of the growth stas performed in i Or1•nn. A.: Dd.S.r. St. fnJ ni.en, 1. L: Prnnan Canrer d Qr Lrnp J. M>t. A. 1aa[ JflJ-r Iekl. 11/ 1947 In.,run M nrwntl pn••nanh'uw N Ihr avlMr. AIS,t1 Hql- J. amt• V 0.: Hnnrl;qrnic Caronarna. L.M. E. n w1a Dal• Ip.YnM. 1//7; Ana CAn. SanAinu. f•rnl. I:!I OSr Iil!. It/.. t 1 I I
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0 ! .cco ~ wzll re- :yd7ri ia rsr- -: ~ Yh: re~t _» afcw oc• ; caaxr, they : nor do they : of iuag an- ss bern shoav ;cat c..-u there --e of tob:cco ia pcpalations : t.tie p:xd'upo• :: 4:'to smokes :_oaes arise in =uuoa Yet .kin%. iung smok.iae is.an ::Optneat : ban prevented ! : pathogenesis .rsvcntivc medi. : of this report. ::acet is already :t tiaks in most : by Glemmcsca' :_g cancer death : dau from Den- : 6). rrt:oPLAsTtc DtstCASSs Lt:ng esaat trtrresasu one of the grntea probtcts fsc':ag tu ia csncer today. In view of the tac, that tabaab is reguded ts "a" far,ar in the development of this anar, grrn cSort I t ' Fr,uu 19 . t i i Prod+'cttd inercue in deatb nte from lua= anar. (Ftoo Cudcr. S. ). aad Loveland. D..B.tr) must be piiad in turtaiLng exposure to suspected arcinogcnic agents wbicb must exist ist tbbtceo mtoix, as will be diseusscd. . IA1tYXx Cliaiea) statistical data on cancer of the lzrffa~ sre by tio meaas as eztensive as thos: for lung caaar. Scbsek ct el.,'T in III 0
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-----_~,r-=------ 0 (rtrrcr.r Iir.trnrclr ~ _- 34 ~------'_-' Qa uri_iu:rl ar0 :tn adtlilinual n'a..nl !nr ditcl:liuriue" ~nr Li:. a rl•rv%i+ u:, lt.l. ttttc r:ql oL::liurvl in ft•t'iCtciu•rt lltv ~~' ' rcrard.. LI prrt'iou•>t'I'li.•+in lui.6r„piIal.Srltrt•I: hrric mgnificaurc for Ihe high percrnla c o; riy.+ iptttit'rl;'). nn~!.111a1rrn(:a)(oul'•IILaIIhcgrmlp•urpaticnl< tullratnnLineillp:dirnt<uithtanct•rnflht!ip.r j Ofll+e: i L c.,::crr of tile Iun- and InrcilC hatl ILr t lulc Durn:ial nnl agt at ur,a! ph:ln•n.v. GI !..,. ~rrcrul:r_r nf tnnlhrrurta am! Iht .nu[• )x•ttcul• It•lrc..of bminriilappcaralllal Ihrtlct'vlripn•rnl,~ of ci~:rrcllr .+,. H,r uf rnr.tl rlnrllrr.. a•' in cu:drul r,rmqr.• It is r:mct'r in an iudit'idlr•d tlt'pcad.: nnt only on IL: i ctmrrr.. tc:r. ;u p!.;rld••, thrn. I1,::1 Ihart• arr nn >irniCcaul tlif. earcmngrluc ngt•nl lud aL.o on ILr n-Yr 4f Ihc imti. mm:l,cr of iutLr;,••:..4fra)"rrrliatil,nli•mUflcitu~ul1 t•idn:d:llthrtimt•ofllrCGt.lalro.urctollttagrur, r 2111, uaanpl:•n, tcilh crncci m' tile .ir::V•r)• Ir,lc'1 awi +,f nallrul It in. thercforo• or ilnportnt:cr lu int'rslig.,R~ 11,,. t•. uLl;+in ,. ft•<I Patit•III... TLr )prt•vitnnly uh>crtt•d corrtlatimr I+c• agc at tt'Lich tile palitnls tlnrlt•tl lu atunht•. I aun!•cr.. Thc hisloq• of lhe dnratiou of slnu!:in, tt;n o!,. T,11?t•£• s laiuetl as iudirattd in the rprr>limmnirr in 1'al•L- I ( apprnra tu Lr ; Tlll. Dcu trnuc t<Ir Tlrt: Aot.tT 0%<I:7 (it' SuLtraetine (lie dur•Ilitm of ituul:ing frmn Illc a_•• Il Ilravr ei,;.trrth (:IG.11:17rTr ~tlu!:I~:• i\Inl•Ia:tTl:.151+ of the II:IIIrJII e:rvC an ea111na1C Of tll,: aer :tl On••Q I tOry Ir•rct. it ... 1b:m'') n t'.tTU:.T- of alnokiu;. It would hat•c bean prcder.d,le to hat'•• the .n-okL:e I~r.w. at \e.PU.n .r.a" ... ru•aa.rt .le[rrr.an •r.r.+.f 5nw6.d Ikaavavnr a'^t^r tGa.Ju~ t.,un[ n L 3o tt s e 7 ^3 : e.. ; u hr.m+-A 31 :1.6 C G Su T r I p!:aryu• Lip TS IB 7 6 3 31 t o 4 0::.tr ailta :31 31 3 7.7 i7•0 10 1 T.1nl•}: b 1'.tru:~Te•ttrra lhintl.r>rt• Clctr,crrc c•vnacc 1. c.tu.t I'uo'ctu Tt'sln::e ur TI:,: Iil;rn•.tront 7n.tcT M.u.•n a.a ac.•. u•.amf \a. ar •.+.r..• S.r[ ar naa.• t..:[.r. \.. rnvm Lurt:: prct'nlt~~es 47 30 6s Oth•r rnal 33 46 77 T,•1.1 1. $0 63 La:•n, anJ pli•rqro<: ta+ea f:u;'ns 1'h.rn nt Inr; i~. an•1 p?4rvnt \:.•p?Mr3n ' Tta,l 01!rr rart Tnlal crnl;.1'his Glr•h. t'IYllo fllnli:r~ w, cig•vtllc smr!,i: tratl alnl (il•. nr.• ti.•c eorroln 1 i, m I c:un r•r• I} p. , n, Oau•r fe.tor• ci,-ar:utd pipr •, licul• n'ilh litr/.% lun' p, n, . Thc-t Gudi,:c•... it•rt rd In,c iuwi•L Ihr rc•ult of 1! •Inul•cra in Cans• : t••...•.nt • .t.nu (.. , o,ust la t •) ' r rc' rrc r~atllittcd 1•y' c•r.•.. r nl Ilrr lijl ha~l at >i,;niGr:inllv hi;;li !tcr.rtit• ~ liu:c, iit Ihe' cliuiral :mttps n s.r u! iudit•i+l?ell> fruln tur:ll sdcliout (N lltr ccnl hiolny or nolop+y} Tablr N'nlntu•a t)It• nplyl.rr „! . t.arp.,:r•.! lo yG pcr t'rnl lit: aII r:u.rvr p:ltirnitl• palirtul, tcilh hi>tnL,t:iv'Jh• prot•rd luinnrs •mr1 Il:r C•+irm r; llr. • '6' 'Phr. p. rt.:lrta};c .r•f. u,uthcmcra atuon;; p:rticnli rulul•i6g fii.ti,rit•s r?f thrsc indiritlual:. It i< .r•t•a ~ Thr r',nvavld l•. ill. .r„rcr yt,a•.!i hac Lul nol niri:leficuUlly lh.t( uf• lht \•: je•lirut: taith cauh•r of Ih,• luut i Ii.Iipd un I1••••1• t• I•rr cvt•i a. r,,:up.:rt•,I lo'ai IK•r t•t•nt). Tho>r lunrt• Ih:.n hall (J7) h:r•I Iht'tli:t~noai:l•nu~rtnt+l L~ t i'Jnq•.,rc •.ill, II thr ~r:r. arl•!lir rli.lriletIiun of Ict. Li,•Ir•t• tir :rnlopa'. ••!IC prtt•t•nlatr uf ti;:at•~Ib ~ n•rJ 6.1 t rnf lln~ lip:,n.lltf t•.•nln-l lt.dit•It1. .nn.t•rr.: in lhr lrrncrd mtd nrrultrut'c:l r:nc• n; r•• r b y I +.,. . 'f y tttcrl. tile iuci-lt•ncv of ei;acttt atul•4ittg nntl of The prescnl fintlin~s failc-l to coufintl :rn auti+i• e:rr.crr nf the rt•~piratury tract e:uluol ht altriL- palt•tl louger tlltration of tlnnlang an+1 nn L:t " :c• th, ectrauenni Lletor of yt•o;rali tie tli.• ' a~t• at onstt of ci~:trclle rtnnl.in; for padtenG ni:l. IriLnlinn• eancer of thc rcapiratorc lract• tri'Is - lli.:nl•w ir rfnrt;frn:;.ln ot.lpnn'rr•-\ol all I'+• $ .1 •'' 1 11l 1• "Il f• 1 Il l suc JS 31 T ': eij eliniealnudtheeontrvl~roups.l'hic:+~'tr:+gct:cm• J J 3 1 ~7 hi;h• and it may ir.dicalc tht wut!iehi:ilc of 13 • i tl nlcllrtxl ust•din t)cticin; lhc ntv al onsrl• ~7n p Js 70 slantl•r'ftl tJrt'ialiotu for lhc four erol:pJ carir•! • a 67 73 31 . 0:1 Irom 0.3 10 S•G ycars and did uot tlillct ti~nilic:r:d• frotn each other. l IlllcrrcYp••11r11IIIeh:tlR•Iil[!IrCttly':lalohlaa't•1•:,~ I 1114f,.. OIISCta of Slllolane. f1'hcrt probahle w:zt a I~r••r rr• Fi~arc i alr•n Ccnl:r;rofcrrorinlLerepurtcddurotionaudin_IL,. (l0-•:u Cip.,r,::, t!l•fll'Kl egC at OntCt. . • I slllo%rri for I+.iC -'Tn61c 4 prctenls tile accr~;r dnralion and Ilw ;,rol1p.. It i.. , apC of ontcl for jt:ttienta in thc eliniCtl Ynd rootr.•1 ~ rr,lnr•+lory lr:~. g•utlp.. Only lhe nlnderole and hrat•y cig.lrrlt• hracy and m••: Sn16la•ri t+rC Ooll.tltlrrrll in tI:C t:tl:lv. tl I ii 5r•Oh Ihat f01tL•u!. Iq CI•i. i' thc at'tra~r duration for the fonr gronp< uf p:+• of Illv lil+ h.,~! .. licnlsi<approciln•tlclylllaiamc(':7.G-31.'.yrar..:x nmdt,a+lr..wo„ The ili;,hl di!icrcnccs in thr accraes•> are not the hrlitf Ih.,l nific:lnl. The duntliuu of aulokin; enricd cou•id:•r• 1 au,I r:urrt•r:f t6. ahh• (fromu I to GU ycara). T)tu tri.lc rau:: ic r:• I niGt.mcr. I•,~I ; Acctcd by the hig6 aandard tlt•viatioui fur Ih~• ~•Inrl r.,rccr o! 11 . dur•Ilion (7.9-1113 years). There tt•ere no ii-ni5. ! ll;;urc J.,L.• 1 caut Ailfcrcntt:c in lhc itnud.lr.l tlc~'i.ltinn:. lour 6roup.. cnrtlins In Illcse resuli.. thc dnralion of ciearr:b, ':ttlt! ph•In•r,s. .. srnol:ing for p:dicnls tt'ith eantcr of the rrptralo•y' `) nouimo!.cra i d .l a l.7, and ln.J I n for p:tl a traet ia not apprccial•ly grt•,Itcr th I trith other tumors. The I[\•Ctap^C 1gC at onset of Sn101al1a ttai aj • proxi,natrlg :l grart lor tile patitlttt in hoth 1L•• 52324 3601
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TNt ltotoctC zrfECTs oF ToaACCo are cosnted a asmsber af 0C"SpaCatS, which have b= R'ell rL` viewed by Huerxr's and have also re:eatly bern studied in svr- vcys by Wpade: aad Graham" and by Brsslow cr CLs The rertat diaial studia clearly iadinte that though therc ars a few oa capations which lead to an iaerwed tsisk of lung caaar, they annot acrnuat for the great inerease in luag cancer nor do they play a toie in the development of the great majority of lung rs. cer eues Air pollution may be a co-factor. Benzpyrtae hu bttn shown to be present in city al:;'•- " howere:, at the proscat time thr,a is no clinical statistiral evidence that in the absence of tobacco smokiag the incidence of lung caaee: is higher in populations living in cities thaa in those living on farrs There must eaist iateraal factors which reguJate the prtdispo- sition to lung aacer, for ceraialy tot eve:yone who smokca develops such eancers, and orasioaaDy these caacus uise in the absence of any noticeable factor of extrinsic iniutioa. Yet the tact remains that in the absentt of to:,acco imoking, lung ancor but nrcly develops and that, therefore, smokiag is an importaat link in the chaia of lung cancer development In the history of medicine many diseases have besa prevented by rtmoving a givea link, even thouth the eatirs pathogeacsa of the disease was cot understood. Measures of preventive mcdi- aae,.to be outlined in grcater detail at the cad of this report, secat particularly urgeatrot only because lung cancer is already the most common cuuse of cancer deaths among males in most WeStbta countries but benuie staiis.tieal studies by Clcmmesen' and by Cutler aod Loveland" predict that the lung cancer death rate will continue to Increase, as deduced from data from Dca- muk and the United States (Fg. 19 and Table 6). 110 x l.:rg aax r ts cs wcr toda u"a"fiacrc coo .eo »--. ..~ hcdicud tacn and t.o.el. 5.7& must be placed ir aEeats whic5 mt:s, uarxz Clinical stacisL: means as cateasi% APB 001149 .
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. ... lrs n rYRYWt (Os) t'+a@fWt tG.w.1 G.en• Y.. d.L. Y. dein T/Cj 31 t A/C{ 30 1 T at a 3 T/C 3t 3 1 A A/C q 14 a e T/C ~i 10 ! A rb 10 A/C 14 10 T et It 1s e T/C 14 1t 3 A ta 1t A/C T is so tt 14 et e T/C 3 Is 14 7 A/C 1 1 14 T 47 :e ss tb T/C I is 10 1 A A/C r! 11 Ie is 0 T/C 41 is 10 si A A/C is a is is 880 TABLE t .VrtJIANCI Or LIAOb IX CAPI Mlea ATrP2 PA1M• rNG wlTt CONDr?tI3D CiGAtttrL TAr. C1070H On. AND AQ20N1:' CGflCGf RL.re07e111 I ' advaattd stage: mavive ulcen . ! 10, 11, 13, 14, was obser+ed, S8 per eent developed eaaeer. oa of theee leaic Twentyfi.e of the earciaomu occurred in & ~on of highly ma: TIC ~ t0 11 31 A/C t7 LO ' : T 3 tt' ~ {! 34 T/C 3 -ts : 13 3 A is r' tt ' A/C 3 • t! T/C 0 f4 1! 34 A/C 3 e4 • T~ Iv/r,ur.?fC ~ W/a.W .L..1.a a. rtw,.A/G ~ ..1.rh..1..wL Y,.M,.aY rYWiw eN4 w tM 64 O•n 6111.4114,11 i'ttill.l.Y hMNY.Y.I,ll..1N.11 M tM r/1e~++ .N.NM ,.La,l.•..ie.a.~e.ar 1Y 1. MYl is t.Yw 1 W t°q.uN pw,b ,. b.FO...` b LL,. 1w .r W Yaa ,e Li,Uiq,a wri4a:. •Y IS,a Y IY aY, N t/N yrYYs. t(Lt«.a.YIIYW L11r~.wlaY,Ia, broad•bued, clearly outlined wart, varying in sise irom 0.1 to'0.4 em. iri diameter. Inmosteases these warts were well-defined nodules, occasionally bud• diog before sloughing abd ihowing definite. craters.' Cancer Jormation.--{)! 81 tarred mice, 44.4 per cent developed epidermoid eaacer of the skin. The first was aoted gros+ly during the fortysecond we¢h: t3e mean time of appearsace was 91 wxl•s. Of 62 mice stt7l alive in the tar group at 13 months, the time at which the first groa anar . males and 11 in male miee. The females, altSouFh Pownward invas their average weight was about 4 grams lesf than wioa through th that of the males, had a longer survival time in the '3erentiation, and mtheethl: 16th month. `!t is not possible 1' per cent of the a :d 14th months, : ° , I I ' ~ ^ . :L Oa oae occasio e • e a .4 t° .. '.u thought to ba.- .... a ..... r r...+. t-uhing (rom eic ~ W. r i1 C.. .u.... ••••W, r11°IMw. Caass t.-Mo°tb of 6eet I'ast appear*+x* of peidl~ aad eueoomes in CAF, mice p°intad .itA a eiruate 1411 °celoee .olutioe, and a p°up a( C.tFt min punted ..ts acetone elo°e. All of thne ieeiaes wet lub.equeelly pm,d 6ietotpaio117. In tw° iastaaeq .hen a nneer ru founJ i° a tumor .6ieb appeuad te°.lrto be a popilloov, lix m+'th ef deatb wu taksa u tbe tlme ef 6ert appannee al lbe eu~m. 4u group of aaic ims. ( letiane yroup.-- f up. Nme-s0 pe ad of 24 months, i .-ed group. No It. 'imice. The epider eughoutthe e3pe .:izal+ 1n this grot tar group than the malea. Of 41 male and 40 femal. 'm about I gm. tr mice started on e:periment, at 12 months 34 fr• :Sough. at the otls male and only 28 male mice were alive. At 18 4e weight of the m months the respective figures were 46 and 19: In 'a greater than in the control group twice as many males lived for Iy ~.loetonr/croton oFa months as females. x originally, treat 0f the cancers, the majority-47 (73 per cent). ~tsdditional paintir -had previous papfllomatour growthsa however. e Y ct the 7th montb number arose from loali3ed ulcerating sites. T•-o rcent-were still cancers, which bad been classified as papHlomaa at i%ir became rougs autopsy, were discovered upon histological essmi- Wted. application nation. The eaneen were always found only on th'e eisteinoma+ appea painted ana. and in advaaeed eases oftea rptrx.l lfdhyleholanfArne laterally beyond tad area of painting. Six mice b•0l :e were painted ° two separate skin eancen. Prior to the develnl. •nlylcholsathfene meat of the typial eaacer, a loealised thiekeni"t Sty all developed t and ridging of the epidermis sutsoundiog the It fir:t papilloma pdpilloma ia the shape of a'rbtled, puekering.e;'a .•-t, and their aver was noted. During this proaeat of initial iavuwn. 'ets. The respectiv the papilloma proper sloughed off and left a emall a were 1g and 16 ulcerating eater. These craten widened and con•. j rranspfanlation.- tinued to ulcerate. They' frequeatly becsa:e >Td group have b necrotic and grossly infected. The rima a?d bi' y et ancer was tnz: also became more fully entered and hudeaed. la 5. p:SuntxB befc AP8 001242 (p, 9, 1t. 1. t4Gation. Of 31 n tper cent develop 4pm in the 7th rarlmllon aif.- ~ caomu. The 1t ~~ '.u in the tar:ed 1 . . .. . _~:- .I:w .. i', ..r_.~. _.. . ^IN, 52324 3612
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0 ® I AW~ in CA,SCER Of LUNG - CHL'RC111LL 455 able. Since manr as!hmatic children have a Mnntenl 1)rn!dwd than does the act of couphlnp. Rest u tssamal. Chroral hypcrpla.ia in their navqharvn< even thouplr their «•n.ils Indrate. Nnldeh)de or o.l.vne fur ehe cou(h art helpful and adenoida have been removed. at!emnts have been made, drugs hut should Iwt be u.rd to the point af decrcasin( respira• thereforq to get rid of the I,vmIJv,W collmio!, in dK na!o• tiurt or drpresan0 the center. \utrition is +rather imrartanl phanu by u-e nf radium or rocntem therapy iostrad of factor. Attention should be paid to Amd intake, minerals ard mr(iol trulmrnt tTnrrrolo tt!st't Ortsnos: Is nte ytnMaid tnsue awe or effect? De• Tcri: I presume !he anntianer has in mind nhcther it is cause or ciect in relatian to dK asehma. That is deiatable. Lymywid hyrerNana le cons{daed Sy !omt as b.in( part nf the allerey picture, and thVCiorr prr,lubly may he uusal. li the 1)mphoid usmt it !ar;e err!uph to eau>e ob•tNnlon, it may mduee asthma relle>I,r• ud under thnst cireumuances should be rtmaxed by means oi radim, ronuccn n.s nr sur• preal lrnrmeat. t1'hether dK ericct oi ndsnn is eKrifie or nonspecine is dithcull to insuCr. The eurrent !Kliei ie Uut ii it afints or LeneBts the astlmu, it drcs su nv,~~~;lr its non- rpccihe ertect, iust as roen!prn trUmRUt oi aahim pirm ncCr OIt posterior part of tht thora.~ die splca, or dw I,m,; 4+Ks tomnimes temporarily helps thc aithnutie paticnt, pnaurnably Ihrnuph a nonspeeihe pro!ein edect. itCTIDS Ur s1'1VdTIItTIC na 4,a.1nea11•dTnrilr HQ,tI SnFrS Qt:rynns: P:case di;cnss rtu;{aal ar ehcniiol sectiun ot tht /rmratlKtic or Nnsyninctlxtic dorsal rKrvrt in arthma. Da. Tcn: As wilh any chronia iulnetahlt Jirpase, a!lhma likpw'i!c har rtm Ilto ;amm oi manc su(pcslcd rtmtJlcL One of theee nas bkKkinp a( the parncm(utheties either by mcans of alcohol er by fu ,inl re,crtlun of the pulmonary plezus. Tiu/ is a radical procedure frauclu wilh cauiJarah!e danjcr. Ii I remember Nrrccll!', perhane 15 per cpnl or nhrte oi Ihose paticnts died dthcr at the time oi the oMrallon or nnt lon; aireruarJ. I do not remeniber tLt exact IKrcniu;e, bnt it is high enouah to Ihow that it is a radical and Janperous pro- etdure and thould not be prescribed for the 7urnCe Patimu. other essemul foods. Severdy aslhmaue patinttr may do wtll wr intnvNOus injectiou of amira abd products and dealrost f2 liters in tweury•-(our hoursl onl). for oue to ttvo da). The . diet is thee increased to the pomt of•calorlc adeVUacy. Aside from qmplumaue measures- trnlment ihoulJ bt dirccted aCainst the'nase or a0ainst the allerpic iactor. This muns above all a sorrect ditpnosis. 11any factors mal• he rtsronsible lor the asthma. Inha4ntt, foods, dru[s nid iniection rna.' act alone nr in combination• I belitcr that food ir not as frcquent ae eamtanl as mhalanu or infettion. but if tiiere are food allerrens they should be determued anJ eliminatN. t1'htthcr or not in(enion arls a, a primaq• eaelunt, it is certain that mieuion is important iu producing aathma. For that reason the antihiaties aid the sulionamide drup by their effects on acute alM chrm& infecnons of the re.pinlory tract play ah impornnt role in comroilir4 asthma. Education and the to- olernion oi the patient are necrssaq. Entphaais should be placed on the fact du1 athma it nnt outaroan but thu the ratGer the Nliau is fnn. piten a correct dia;,!ons and treueJ, the better the results eill bt. Special Arficle PRIMARY CARCINOMA OF THE LUNG eDwAaD 0. CHV1ChIle. M. p. Ieeen I think that Dr. Car would probahlc aCree that it should be tnia arridr 'u the tat)eh of a anitt lo he OrVubrd by the used only as a last resort and nut the Ntinn should be warned Amrrirmr .f/rdiral Auneiarion in roorrrerien tcilh the dmeri- about tht limited pouibililies ni etentual eure or rnnissimL ton Ct+rrr Serirtp. THe rerirr ir draipnrd lo eid 1,r r4e mrfy Some patirnn, honaer, did pcl remissions for pcrisals ,'aryin( diagr,oait of rnrtrrr, mid,7lrrrrby la gein nmrr rpru&-r trnAt irom six monlhs to se,enl )cars. in rrennnrae. mtT rot rStntST n'IT!! •tctracr Qt'tst!os: Is there an!' ha;is for the dunr•v that an anhma due to aiy allerpen may he ae;nvand by any olirrr protcin? Tlureiore. shou4l a diet hieh in earAuh,rdra!e and low in pro- !rin bt recommeded in vc, ine such a padcut? Da. Tt'rt: I am tat sure w!ut this oveslinner lus in mind. I tupMsc he meam, if a patin:t is allrrpio to cme ia,rl, shnuld )au remove othtr protein ineds front the dic!? I do ,.'•t lhink that is necnsary. As a rrde, if there is pcciric +Cn-itieaiun, it is lo ont !aod or tn a memhtr of a foal Drnup• rather thau to all protein InadL I do nnt thlnk that I tnndd reennmcnd a dirt low in protein auJ hiph in arladq'drate. saunnne Dt. Rncrar A. Cooee \ew Yarko I shall try to ium tip the diKttlrimi nnthe treatmene of asthnu. Thereart two phasra to the treatmmt. Ond is Yymplona!ia. the olher is etialogie or against the cause itself. Symplnmat$ therapy is baeed at d!e physiolopie procedures of pttting air in!o the )un=s ant clorin( the broochi, Ont !nnlwd is tp Irosen tht !e!ueinus snrclfau in the bronchi. The dni( par evrellaKe (nr !hat is ievbde. lChat a npld effect is nenled the salium salt nuy IK >;iayt intnvnansly. Aminophyllint, in my tarerience. (in•s reYei to man•r patients n•id! severt asltnna. The rertal adminielraliun ol S to 10 praius(O.S to 0.6 Gm.) ddrer in soltnion or as a sup!asilury nitni assures a ni;his rett. Givrn intratowml); it it uwn pron!pdy elTuctiva. Eldredrine (orlll=•) Primar.• carciuoma of the lun; Is a conunon disease that is usually not di(ricult to detect even in its early sta;ei. The constrtxtive results of surgical extirpation are iarorahlo when conqnred u'ith other visceral malig- nant tumurs, and, n!ore iaq)ornnt, s:eady improvernent i., bein; recorded• lit the Inst decade the !nedical profes- siou has made real tsrogreas totrard earlier diagnusis of thit disasc. and there are many reasons to believe that the cimo la; betlueetl ollset and reCO'a1tlt1olt q'III be still further reduced. Durin; the same Ixriod many of the technienl obstades to the successful surgical nunage- na•rn of puln!onary cancer have lxcn surnlounted. The operatit•c tuottality rate at first aplKarad iorn!idable be- cause advanced and oftentimes hol!eless cases x•ere being approached with technics that tcere inadequate at the best. As technical problenu u•ere solved and ntdre iavor- able stages of the disease reco, lizcd. the operatice haz- ards inre Leen reduced eorreslwndingly. The problem of prinury farcutonu oi Ihe lung is hotv that encountered in all efforts for cancer cnntrul-tarlier diag!!osis. It is doubtiul that t!lore radical surgical treatment can be devised that can materially ilnprove - and epinephrina are the dru;s of thoice. Epiniphrina 4aque•' restdts. atthou;hiurther jxrfeetiou oi'techlfies and.sup- o h i i U v may e used in a spray or for nleet on• For prolonged effect in)eairnn ol epinephrine in oil or (elatioe are reconi- -mended Bron<hnscork eaamimnbn slvmld he dmr odlv an seleeted easrr,-as tReaicc a>leritiat nf muens is nnosily leCUrtd in this wa)t 1'msihly tIK prelimilury trealmrnt alnl itKdiea11E11 may' be as Trirr!Ire' as the aetul a\piratiext• The nld f..hi,med u.e nf il+'a: ynq. .huuld nnt'IK netrhv,Led• The bronchi arc hcner umpliul L% the act of ru,nitiq^„ whidr tcr.lr T's enp•esr the ruvunus ph ,. irom tlm brnnehi nwre triemtcely portit•e.nseasures tuay gain evn) Ixuer inunediate results in tlx. poor risk pattents, tllat. nou•.!.nrkt up the s!nall . group thtt sucarmb after o)n:ntion. There are relatively fetr patients today who do nar hate a reaaonable chance of treatherin; a radical reu!ncal of tbe Iximery ;rowtH wN•wao w er Snrr... 1(annt Unf..r• Dr, Ca„re6dl ) I,u 1•rdn 'tt, and OQVf M J,e 4neral ivrenat Seruur, Aarumrvm Geeeral tlY/nnaL N01M' 1MS A1Aii:R(AL 6ti;V BE PPOTFC?FJ BY COPYRIGHT LAW (TITLE 17 U.S. CODE)
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• • :CO I ttLOfLAS7IC DtSLASLS :=z fcmales smoke hss induced cpidermoid cancer of the sldn in aain:ats to : Tbe hfgbe-r which the tar was applied.° i eamparod . 10. No other esplanation for the statistical relationship: We _r egusne can suggest no other feasible ezplanation for the statistical as- sociatioa found. :risae peak The statistical smoking data are compatible with the data of pointed out aA of these points of incidence and with our geae:al knowledge = the isco- of humsn cucinogenesis. Ilse relationship of smoking to lung z ago. 71is ' aac.-t is still doubted by a few, such as Hueper" and Rlgdoa j swing of and K?rcSoC.'s Hueper believes that industrial farars and air pollution arc primarily responsible (or the increased lung cancer : cigarer•.tt: addcnce, pattics:larly br use lune ancer bu a high lxqueacy sse of lung rate in industrial areas. He also states that it tobacco were car. : dgarsnes ; cinogeaie to man one should encounter more cancer of the fsngen _tir faer.ors that bold the tobacco. No one has as yet advanced a suttestion, - in ei_ra• however, as to why the established statistical association betweea i najor lu>ig cancer and smoking could be a false posicve and merely ~ a eoincidcntal one. ~ •rmoid na- Several o6eiil bodies, such as the meeting of the Lung Con- :3 arras not feresce at Louvain. sponsored by the World Health Organin. : be denied tion," the British Ministry of Health;' and the American Canest : brooajal i Society,a have regarded the correlation of smoking tobacco and ; lone taro ; luag eanar u established Ihe New Enjland Journal ojMcdi- cine, in a recent editorial, considered "present evidence of an :a bave not :)mnity of etailed h'u- :ave served a :d eiguene association between ei,aiette smoking and lun, eancer so strong as to be considered proof within the everyday meaning of the . . w'ord." e In terming tobacco smoking, and particularly cigarette smok- ing. "a" cause of lung cancer, one does not deny the presence of other faaon in the development of lung eaaeer. Among these ~ 109 ~ t i APB 001148
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0 • 0 • Eov, xed, ro:ssHt~ e etiena Hleeim 7~ . ,. rluma ead nn. fsan. ~ la.os;aaiea x:[lu-K ., aad c mr.ar- A. a. ll,.,: Ie lS7eloma, J. Qis. laetd i Wtmra Y. Tbe Eadoorll.4 ,d Flum. hot.ia Fa,m.t:a •. 1. C1ia. It t.hL fs..tip e :. 8: aed Lewv. & D. Amh: Ia.FroaSoaEry+r.Ebl.a C. S:.ed a•ouT., L 11, mal Svum Compeneeu er a. tev-aiastiua, 70:tlts•1~ & D. Furtber St,d..e tL :t lmmaa. Avtuo.. J. S1 .: md Busua E. Amin..teit s of Some lmmuae Auaria , 1ak4 t P. Eladropbontie Stud:e r .bit liva. 1. BioL Cbem. l.Mc ,d Llu+e.mtriJus.l Stud:e r 'v. fMd., pp. 311-U. ocu.r. C.: and B.as inau in Ts Cuee of 1•I~ i Fatb.51:30'7-le, fel0A .: aad R.uta A. An Imm.nr e. lotdn F,netia,.. eeL ~ 855 ;-._rr•:~•.;;Yti r.~+r~~~"•^`• < AP8 001237 I _t~ O~-ql Experimental Production of Carcinoma with Cigarette Tar' ERMEST L. WYYDER,t EVARTS A. GRAHA-M, AND ADELE B. CRONItiGER (D.yortwM aJ S..rny, R'.aiineeo. C.irr.ney SeAed eJ SL tnJ t{e D'vtinw ,JCluumf 1.,rri y-6eo sJ tAt 5(aen..Cenuy lRtiAa. eJ lh. Jf,waul Cnun Jer Caner end A9wd Di.rw, Nev Yutk, V.Y.) srn'bed epithelial prolifention. Subsequently, many di8ennt approaches to the problem were undertaken with various types of tobacco, diHer- ent methods of tar prepantion, and different spe- cies of animals. Many of those studies were carried on for too brief a period of time or with too few aaimab to be regarded as signi5unt Hof7maaa aod his a.ssociates (11), for instiace, painted aaimaL for only 14 days, at which time they noted hair loss. R•acker and &hmincke (37) observed pco- liferatioa of epitbe6um in rabbits' ean 41 days after a subcutaneous injection of pipe tar. The first recorded experiment with mice aaid ' with tobacco tan as the suspected atcinogen was the one just cited by HoHmaaa and co-worken. The more detailed of the subsequent studies are listed in Table 1. This table attempts to summarise the methods used in the various studies and the re- sulte obtained. In many instances the method of study was not described in sutficient detail to give, all the information considered essential. jEp is sur.ey of the literature it is found that. befon our stu Y, e oro.~ous attempb to 1t ' ~~+*~r tn~ee wtth to The incrcasiag frequency of primary cancer of : lung in many parts of the world has amused -3t interest in this condition aad has stimulated eucb for an explanation. In 1960, Nynder aad i6sm (40), on the basis of a clinical and statis• J investigation, presented evidence of a real sistioa between lung cancer and smoldng, es- ntly of cigarettes. Thex data have been well asntiated by a large-scale British study by. 1 md Hill (9, 10). Both studies showed that tbe , o( developiag cancer of the lung increases ia ,tt proportion to the amomt of smoking. Ten a nrcent studies reached similar conelusions 11, 13, 20, 21, 24, 4E, 33, 34, 42). In 195°., The meil of International Organizations of Medical mct's convened a symposium on the endemiolo- dlung cancer and agrecd that the present evi- 7e points to a relationship between lung cancer :eigarette smoling (12). iobacco is alsb thought to play some ro1e in the products were succes~s uZ m! e~produetion o a 1 f dadion of canar of the larynz, oral cavity, aad sevrn eptaermotd caaeers uI fse i ?6agus. .4.lthough the studies of those telation- s an not so complete as the studies on lung xr, the mlJected data are suggestive (33, 41). IEe increasing incidence of bronchiogenic ear- wa and the avu`lible evidence relating smok- .to it and poisibly to cancer of other sites led us Jdertake the experimmtal work reported here. J investigation is directed toward determining rbontory animals whether there are careino- t factors in cigarette smoke. Pssnon Ix+aneanors 7eoy attempts have been made with tobacco dacts to induce cancers in a variety of experi- as1 animals. Tbe first was reported by Brosch ?G0 (4). He painted guiaea pip with tobacco 1e" for an unknown period of time and de- ~'fliW iewtit.tioa.u supported b7 a reeen'S gnntlhom 6tfoeal Caaae lartitute ef tht X•ational Lutitutes af h PubGe.ltoltk Ser.ie.. - Deant Addreu: Uemorial Cmter for Canesr and Allied Eut Sittysiahtb Street, Kew Yerk rl. \.1;. il'•t•i•ed for publ',otlon.l(mi a, 160.7. . ' ve ga on attempt to induce pul- monary tumon in mice with tobacco smoke. Lorens and oo-worl•en (22) obtained negative re- sults in this manner, Campbell (S), and especially Esseabe•-g (1S),'however, claim to have found a significantly higher percentage of pulmonary adenomas in the ezperimental than in the control group. It is doubtful that such a finding is impor- tant. At any rate, so far these methods have not induced traf proocbiogeaic careinomu. The majority of the investigators worlliag with tobacco tan used rabbits as the experimental aai• mals (14, 23, 4T-34, 36). In view, of the faet that the present work deals with mice we shall only brie8y Gst some of the studies with rabbits: ItoHo ' nported the production of carciaomaa in rabbit ean alter painting the ean with a distillate,of tobacco (48, 30, 32). Sugiurs.(~8), in attempting i,~ ..
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_ti Crurrr_ _lir_rurde IL,I, a ('LrrinY TO..a.v in ('.ra+-r vf lL. \L,..tl.. Irn,xl Cm,Jmd'a,x l:n;iru0 arxl a( T~Jwrrr. Xr..,.lr uYw J. 1.\I..l., 115:31 ~"•7+. 191I, . 1fiR, rill• ?(..7 d/64w•rrr•. I•• )•8i.l..wr u! '1'umu• .i b. ,(enG. Itr•n'.nr. f aw.r .111, \Iwrllr; (Im C.«• aeaiu•1 Ilrr f•nnC, 11rit. J. '1'dulb..\ra 1'r,rL 11.J.J..lo2:1.:./!.I1. 90. ]If.un.la. t•. };, \'urL eim,ul $ip.baenrnurh r,,.l • ~ • •9. Ilvnnx:•nu,'J. C. ('arMV d Ilr T,.nt,r, . 1'rtrr~'Lhlr I,uxp,nLal.., Zlv'4r. L I:o-:L,Inr.cL., 81a1;-9:• 1?II. • fL(:vtt•LU.F:..(.,f.wu.P.iwou...i:..an.lllrr.t, . ln. If •lnn.'Gv A••ridni.,lrr Icu:rqrLL'u •wil wA )L 1- TLr I:•Jr •,(in ll•r 1'ruLnii.u ~f J..r Li/q+n• nr..l %,u~p•r,lJ..I.,.Ix~i Ilarrrl.^n,. Il.ul•aLr Caner6J.11;;..J-aertl qn,r, I!ra• ~ \I,...+lvln. f, S[Gl'a l, K. Ol..:nvli•,n. ,.n •\xim,rl. 1Liu!,.I 11. Ju•e..%,(•..an•I lv.•..n.~'.C.I-f.unrr,J Il,e Inry'n-+: TrJ.nc-..rTat.,(nr.l.C.nrrr.2l:11-/7, 1nv1. ll.lunra•iu'I:vi,ln,r:..Ir:h UI,.Lr;up..~2:1.1•k:.L'rll. iG. Itnn'n„1. 11. ArcL.~rarn,;••,.Jr.llrntprrvP.Cr.on,~.aau. . '1'Lr ley'u. arvl l/• Ili.'a.es• Y. JI. 1'InL,I.•Ip!,in: T.I•altler. %I,ehf. I. Arrl•.Lx.ei., (9::is-T.. 1Y.7. ; 1Y, U. S+a,xLr. Co., nT.17. 97• 1:Gluri.l. TL. lncrra, iu Cars.r v( 11, Lun;. lur.rl, 1 1•J. .txeLe,.L,ar..I II.I'IinUrl•CaRrrr••//Lr 011hr $22:114G-7, 197:, ' ' r.,m;. 99. 1Ln,uw•..1. C. :~pmm.xr.•Crll EpilLrliouu at the hq,, r 14. llnn.CYIC[. IlrLUav. TIx• (laerrya110mrI In.'i•6;rxr ur •lluda•ld'.77Ca,r..J_1.31..1.,717G:G•Gt, 19, Priuurp• Lxuy Caorrr. Quart. 1. \Ird.,1:71-/n, 17.1a•. 0. 11l LLdx• 1'. II. Tal.,lnd•.Lrauc4 und Lnu;ruorri....na 13, Cntr6}:unrs.'1'vl~tv`n•••lin;andC.bCer,Jllrl•ung. Ytahr.(r /:rl'l•dunc'Ir..19:i7•aJ,19:17. I Il llns lpr-_ , am. J.:nrC., 6f):7t•1 01. 171.. . ' On, IS'rxntn, }:, /., ad Gnuta~, E. l5nrr, 67:7J, 1Ijrch 7, lllc acp,nn :- IG. Mr:\.aLLt, 11'. Il. Thc l'ar in Cit.rrltr Sn•nkr atrJ Il. 1917c prrrnul ewmmnicaliun. • Ii..atL'f 10 1'u•.iLlr 1:111d.. 1m J. ('autrr, 16:13n:-11, 1A1:. Dt. SCPat, lt., .nJ •1U.lacs. C. 1L St.lirtical Anrl;.6•,.! . 17. llnnvl~~, }', 1. Canarrarxl Srnul)r.C /1wLil~.(nn. Sur;.. 9,I07 Admie.)onl to the Tmxor Clinic of Crlrun. (I•,- ~ trll dilt:it,r . 92:J0-(,7, 10+1. ' pIInl, I6nra, lllinair, duing 1717. Canerr Ilnl•arc6, nuruliCr Ol 1,,. 16.I1t'trtn,SC,(•.Chsuj4diaralTlmrunanJ.Sllirdl7i.caaa, l79-16,1913. ~ OnCOfll:c•cti p J::. iprix;(rlJ Ill.: l'Larlr. C.'l7rnrua., 197l. 9:. Srrbu:[, )t. A Cr.,pLir 1616r.1 fvr CemN.r;np (rre.~~~l.c•. • t. I On~C 4.r 11::. 17. F1unr,C.SLTLrI'n.Lmlia'n!Tumvr.L;~TvL:,rru7ar.. .nd\L:rn.dCvulnJand L'aperiweulalGrvnp..lluiwu iI110qn1 G! h C.nrcr flr•eam4, 1::'%t•7G, 1411. Li ' olnG;•. (1n prr..,) 90. S.nn.'.1:.,a.nl lt•ILL!naa•1!.1'Lr DiaLsnli•lr,. of \Ia• 33. ~• In;.vilLmit Prctpx"ncp 1h :iLnliona. IIum.4 ~' nIi10liC ibrlln• lipnaxt Tunwra, p. 901. Uiwlllro, \,T.:ItelcrarRt Pre.:, Uivl., 1971. ' InaCrtlril0lilI: 1"11. 7(. R'rtua,lt..l.1'.dLoln;;•vfTum-i,.l•unJ-m:IIutlenvnL Je(ctn•iut'tlLr. 91. )Iclrte, F. C.?7rr Grn.l1,•pralucinC Efrrrl. uf 8clr.rrU & Co., lAd., 1715. ; of•1'eL.,erur.a)Gev.J_i.11..1.,9:U0-1?.1!?S. 33. (liiterl St:dr, Ilurrau of Crnaut. %Inrta6ly Ft.lid:-, `) fnrrJificrrnra. 1:. ('dYaY/:LL, J. •1.'I'In EI!.Q rJ );alrYWl,(ie.v~ frt•,r1 )n• 1J:IV. L'S.l-M•Crlrlnanl I'tini{u;Qlilr. lr•.UCI• I ,flllil•IPO)11.- nltl0lll' t1:La• t• . ~ 1[,rn~irlo Jrt•;r ' CUllura•a ~9, 1::• I, lion of Crll d:'•: bblCl Of a4n•L' ' ~ li.hrtl on 1LL• 6,r ;mss•Ih of lhv (o nr,nna iu nhit!: uu•lhod ir nnt :p nihlr to clalvtu'i: b;.9oml• ollrrr I ~ indrx,.lhr inlr•r i (3) fronl Ihc 6•:: I I Intenuil•• . . . I I I +Jc)s;• in rYll rlit ' ILia crilit•!I t:.r~• . I Irart \o: 71nJ.-n: ndlr..• .. i• 52324 3605
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T8L 310LOGIC LFFLCTS OF TOBACCO as=311 sample, bave noted a si.: tiar smoking patt= among their laryageal cancer and their lung cancer patients. This was also found in the stndy by Sadowsky cr ai." from the National Cancer Instituta Of 273 paticnu with cancer of the larynx. 96 per ant smoked, and 35.7 per eeat had smoked cigaretus either alone or together with pipes and cigars. This compares with 92.6 Tust 6 C.tNC£R OF LUNG, COfdNN.(OEN. M.(LF.S, (Fmm Ce_mexe. l!) Canprnd amwt nrmbrr of lruhe 1951-55: 241 1956-60: 362 1961-b3: 507 1966-70: 660 1971-75: 808 1976-80: 919 1981-E5: 979 1986-90: 1007 per cent and 88.3 per cent for 477 lung cancer ases, and 86.8 per cent and 72.5 per eent for 615 controls. These data shew significant difterenea brntten lar)ngcal and lung eineer eases as compared with the eontrols, but not between laryngeal and lung eaxer cases. This study did not distinguish between in- triasic. and extrinsic laqngcal cancer. %Vynder et of.t' arc at pment investigating ths etiologie factors in latyngeal cancer ia eo-opention Nith workers in Sweden. and India.. Preliminary analysis indicates that the tobaeco consuraption among intrussie larlTgeal cancer patients is the same as in luog eancer..'Ibe toa bacco consumption by extrinsic laryngeal cancer patients seeras 112 xsor to be eqaally bavy, bu: and pipe smokers. Lzdi: and tobacco chewing w- ated possibty ait.4 di: women show a sL-ong : tsinsie larynse al lesioa: dicate that at least ar atfected by factors not the ctiologie pastera i may be of impor.anr thertnore, sugsat a ^ in the laryn_leal a:.r. These f,dirigs indlnu c.ompar:sons ano:g d possible avircr ±ea. and statistical meaas. It may be asked a•: not increued as sf:a factor, since aar.r associated with snoc that there has be-.a c cr in Entland durie uc to be considered: 1. There has bea aneer in the Unitec lung cancer. United erease of 47 per e: 1930 to 1945. Tbcr, : bidity data* ars coc in laryngcal qncer Apg 001151
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. M.~ . ...~- ~ ,. ~ •. T8I fIOLOGIC LFFECTS OF SOaACCO abould be used, to compare lung eaaar and Jaryageai uaar ineidcser. 2. Data on laryngcal cantxr iacidence do not reflect the pos- uble changing ratio of intrinsie and atrias9e lesions. The forme: may be more closely laEueacrd by saoke inhalation. Ia India, whero betel atrt nsd tobacco chewing an more prevalent than ogartnt smoksag, extrinsic luy-ngeal aneer is predominaat_ Further studies in this field must sbarply divide the two typa of lesions bcattse of possible diRerenas in etiology. 3. thhe: cavirvnmeatal factors which may Induena Iaryngeal ancer may play ao role in the developmeat of lung cance•.. Ex- eesrive alcohol consumption and eertain dietary de6ciencies may be of etiologic sig^?bcance, at leut in the cztriasic type of Iaryaz anar. 4. Laryngeal epitheliun may be more resistant to estriasic araaogens than broachial epithelium. Ptesent data, further- more, suggest that pipe and cigar smoking arc more closely sssociated witb ancer of the lar}az th.-a with anetr of the Itmg. In this regird it must be realiz~d that the rate nf change in tobaav consumption has been towards cigarette eonsumption, mone so than m over-all Increase in the tobar..o consumption. During the time pcrfods of increased agarette consumption dur- •ing the last two deadu,.the per capita consumption of pipe, dgar, and eheving tobaeco his decreased. P/hIle awai8ag the 6nal results of present studies, one can only guess the rasons why.laryngeal cancer has not increased as sharply as lung aneer, as we have done above..Howpver, on the basis of data already avat7able, there can be no doubt that there is a de:nite statistical association between tobacco smok- Ing and cancer of the Iatynz. 114 OIAI- t:wl: Thz.roisa of the ora2 c ys also rer'-ate are so far c aborvsd an a oon, and G, with cancer nifr:a»t)y gr: eKIIts N'IL~1 e aaat of thc poiat that t tzwoking ms, iag With Iur fuund that 0 ttsas of tob Dau on sidenble in: yvire t:ombi te=Jy dec tor In ana iagly eamat eaersive .h: showing thc with cancer tobaeco is I eapcer to 0, anr.r of t: area of Int u, N PS 001153 W N A W a~ 1
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0 • J36 -j!r 3 CAa•CER AXD roa.icco Cn.Ga;sio. Aan st:UaAaY I. Eccessive and profon;ed use of tohacco, especially cigarets. secros to be an impor.ant factor in the Induc• tion of bronchiogenic arcinonu. 2. Among 605 men with bronchiogenic arcinolua. other than adenoardnoma. 963 per cent %rere moder• ately heavy to chain smoken for nuny yvrs. compared with 73.7 per ce.it among the genenl'male hospital populaticn without ancer. Among the ancer group S1,7 per cent were e.•ccessis•e or c•hain smokers cons- parld to 19.1 per cent in the general hospital group aithout cancer. 3. The occuftence of arcinonu of thelun; in a male nonsmoker or minimal snroker is a nre pllenomenon (2.0 per cent). 4. Tobacco seeau at this tuun to play a sinu'lar but somewhat less evident role in the induction of epi- derntoid and undifferentiated amnonu in women. Amoug this group a grater perceange of nonsmokers uill be found tlun antong the nten, with 10 of 2S fuing nonsmokers. S. \inetysi.; and one•tenth per cent of patients uith ancer of the lungs n'ho had a history of smoking had smoked for over twenty yars.. Few women have smoked for iuelf a length of time• and this is believed to be one of the reasons for the pater incidence of the disease among men today. 6. There may be a lag period of ten years or more between the cessstion of smoking tobacco and the ocr.tr• race of clinical symptonu of cancer. 7. \inety-four and one•tenth per cent of ttule patiena with cancer of the lungs «•ere found to be c'Igirct smoke.rs• 4.0 per cent pipe smokers and 3.5 per cent cigar snickers. This prevalence of eigaret smok- ing is `rater t)tan among the general hospital popu- lation of the santc age group. The grater practice of inhalation among cigaret smokers is believed to be a factor in the intteased incidence of the disease. 8. The inAuessce of tohaaro on the development of adenoarcinonta sernu much less than on the other typa of bronchiogenic arcinonu. 9. Three independent studies have resulted in data so uniform that one nar deduce the same conclusions from each of them. ADOCNDt: ar Since dle daa presented in this paperr were tabulated, 45 additional inttr.ieW s of Isullepa tiena with .epider• moid or undifferentiated cancer of the lung have been obtained. L' ight of these patients have been interviewed by Dr. J. L. Eltrettlssfi froat the Cniversfty of Ioua Hospital. 9 were gism our qucsdonwire by Lt. Col. J. II. Salyer from Fitafmow Gaunl Hospital and 7 asre reported on by Dr. E. J. Sftabart from the Vet- enns Adminlstation Hospial. Hines• II4 Amoeg thex 24 asa there were no noasnsoken or Iight smokert 13 atcessi.•e smoken and 4 smokers 7 hat • T cluits smokers. Tnentr•otte additional patients lave to Qraenee or•abseece oi anca, npecially Since only been interviewed by Iliss Craninger on the Barna Pattents suspected b' their physiciatts of havtng cancer Hapial Chest Service. Among these there were I ue admitted to the institute. ' aott.ntoker (a . 72 yeu old blatkimith), 10 haty' sntoken: 6 e.cetssit•e smokers and 4 chain smokers. .These 43 asa, which indude reQorn independently made at two additional centers (L'otvasity of Ioua and Fituimons General Hospinl), shoa the satne trend noted in the larger aertes. s.UOl:1SG-LEVlX ET aL. LA. tt. ,~ . .rrr.L,e CANCER AND TQgACCO SMOKING A Ir.f.i..rr eao.rt YOereN L INIM• r.0. nrMAM GOtOSrtIM• Y.O. .r PAyt L etiMAtOr. K0. w.w. K r. The published litentttre on use of tobacco and its possible assocution with hunun cancer fails to show dearcut consistent obsarntions. Reviews of the liten- ture for the past twenty years reveals that it is often conflicting and that it consists for the most part of studies which are inconclusive beause of lack of ade• quate sampla, taek of random selection, lack of proper controls or failure to age•sundardiae the data. Potter and Tully s have rePorted a higher proportion of smokers in patiena tnth cancer of the "bucal a,ity° and "rapintory tnct" antong mala "ovrr the age of 40" who w'ere seen at Massachusetts aneer clinics. Since 1938 a history of tobacco usaga has been obtained routinely from all patients admitted to the Rosu•ell Park IIcnorial Institute• Buffalo. These hi,- /rUaN ^ ~w hn..up M ra:.a .6. w e.a ..rk.d 1f Ut+ .f ..ti~r. tories are part of the regular clinical history and are taken before the final diagnosis has been established. This procedure is eotuidered apecially intportsnt front the standpoint of ercluding bias. Approrimately half the patients admitted to the institute are subsequently found not to have cancer. Special attention with respect to the history of smoking has not lxsrs paid to any single group of conditions. so that these tecords' may be pre- sumed to be free from bias which might result from preconceived Ideas as to relation Ixtteeen smoking and a particular form of cancer. The histories record the date smoking /xgan. dun• tioa, type of smoldng and amount per day. The relia• bility of the quantitative aspecu of smoking obtained by a history is of course highly variable. It is presumed, hou•eeer, ehat such errors are not selective aitls respect a'Iy aAwl w.w~w, .1 t7i.Ywi O.. v~ D..N a.N..4 In~ W O.m~ M'GKrt CwuY, Prw. a NaY a...,m. \*. Yrt hu O+snrnl M tia& •D.. i.wr C. t:rt.• De. 1.reA f. Nwer...I.e Srw O4n C. W...• M O. Wt M W ea..U hM1 lt.r•.nJ ISwir.M1 uawM MbYs.r a.uY1Y Or r..r" M lav r.1.w wA Yr rb.e wr• g...r Y w 04 M••uq M W wMr. ' t• ln.,.. t ~wa Tdtr. tL L• Ta. lsi+t+1 Aw..~~ ft W C..~.e er.ybw i. tt...rbwwti Aa 1. fM X.1Y aa/4c4b. 1941. I , t 1
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Si'r:mta d al.-Esporimtnta! Careinoma tei1A Cfqarelk Tar . 881 e was 71 weeks. r -roup at lt atr aMK a. cancer. ! cmueed in ft. .males, although grams less than vival time in the } . f Fsd.anced stages the cancers appeared s.s gross- The method of transplantation was as follows: The e massive ulcers with defuilte rims (Figs. 1. 8, S, tumor was ertiscd from the li.iag host, and sma11 •.t,10, 11. 13,11,1g, 1B, Y0). Histnlogical esami- healthy piecea were cut and placed in either a ,tion of t5ese lesions showed the usual chancter- peaipllin strptomyein solution or a uline solu- (b of highly ma8g-ant epidermoid alan cancer tion before being traasplanted aubcutaneoualy .4o+rnward invasion of epithelial cells with e:- with a sterile troar to the lateral chest region. The !:ion through the basement membrane. lack of other cancer was transplanted in our laboratory jerantiation• and many typical mitotic figurea directly ftom the Gving animal to another CAFt ;,rs. 4, 4, 9, 14, 15, 1T). moux with a sterile troc..r without first placing rar/crolon o,7 The tar/croton oil group was the tumor into a solution. The ho.rt aad the mouse pm in the 7tb month after the onset of tar to receive the tumor were previously injected sub• pLatioa. 0f 31 mice segregated into this group, cutaneously with 100 units of &ydroeillia,i this !per cent developed papt7lomas and 9.7 per cent dose was repeated for S days after transplantation. yanomu. The lesions did not appear earlier For every third generation since the sirth genera- ua in the tarred group. The first papilloma was tion, the tumor has been ezcised, minced, and i ted in the 8th month, and the first cancer in soalced in either dihydtociliia or rynerobiad for 1S- ~ s 16th moath. 43 minutes prior to transplantation as a protective It is not possible to evaluate these data because measttre against infeMion; subcutaneous injeetions i'per cent of the ani®als died between the 14th of antibiotio have been omitted. Preliminary data ; d 14th months, subxquent to marked weight on the rate of growth of this tumor ahow that L-- ;--- ; scOn one Qcuioo, one group of twelve animals transplants without the intermediary soaking ia .6 to „ a thought to have eeceived an overdose of tar, antibiotic grow to approrimately 0.d-1 cm. in 1S- ..+' dtiag from excessive aeetone evaporation. 21 days before ulcenting and being retrausplant- y group of animals died after haviag convul- ed, whereas transplants previously soaked in anti- m. biotic grow more slowly (}-1 cm. ia sisc in Y9-4.S -.n.nor ef p.pilbmr •leam"s Proup•-Thit'ty animals comprised tbis days). This tumor is still an active epidermoid nr. .;u a e;r,r<ne tar/ 'np. Nine-30 per cent-were still Gving at the einoma in the 13th generation with 100 per cent miv pau W aiS 1 o( 24 months, in contrart to 0 per cent in the takes (Figs. 6 aod 19). ~+ubuqueatlr p~•J nd group. No lesions were aoted in this group o'~ L°~p0d V'mice The epidermis remained soft and pliable DISCUSSION ,etpee.n<e. sagbouttheexperiment.Theaverageweightof Ea+afvetion of eulAai of prerenl rludy. Tbe . . ~ak in this group through most of the study bask principle in tar collection was to simulate tale and Y0 female u about 1 gm. more than in the tarred mice, human smoking habits as closely and as practically 14 months 34 fe• iough, at the onset of the e:periment, the aver- a•s possible. A popular brand of cigarettes was ,-ete, alive. At 18 t weight of the mice in the tarred group waa t used. The temperature factors were found to be ere 46 and 19. 1'a : greater than in the acetone control group. similar to those encounter d in buman smoking. maln lived for lg ladons/eroton o,1 proiup.-A group of fourteen T'he frequency of smoking (3 times a minute) a originally treated odly with acetone received is greater than that encountered in the average -27 (7S per cenl) :dditional painting of evton oil per week stsut- human smoking. In view of the fact that this in- nwtbs; however, a; k the 7th moath. In this group thtee mice-41 crease involved no significant tempenture eratiag sites. Two tceat-were still living at 44 months. The epi- ebanges, the more frequent puffmg rate was d as papillotnas 4 mit became roughened and thickened following chosen forthe practical purpose of obtaiaingthe re- tistological esam{- rated applications of erotoa ot7. No pap,7lomas quired amount of tar more rapidly and economi- found only oo tbe arciaomas appeared in this group. CADy cases often spre.d YeAyfaSofantAmu Orvup.-Twenty-five CAFt Since we assumed that the caecinogenic effect of ting. Si: mice bad :e were painted with a solution o( 0.8 per cent tobacco tars might be owing to a summation effect ,r to the drerlop• thylcholanthrene in acetone S times a week. of subthnsbold.nrcinogenm or that such a factor ~lised tbiekening rj all developed eaciaomu within 4} months. might be ia the" ilkaloid fraction of the tan, the susounding the _ first papilloma was noted during the Oth whole condensate was used. Acetone, an eatab- 'ed. puckering tia { aad their average time of appearance was 7 lished aoncarcinogen, was found to be the be:< of initial iavuioa. -U. The respective figurea for eareiaonia farma- solvent for the tobacco tar apd, therefore, the tar )d and left a smaD t were 12 and 10 weeki. ' wts admin'utered-as a tu/acetoce'iolution." widened and coa franrp/nnloffon.-Two of the cancers in the , b C equently becux ed group have been successfully trans lanted & r mb eauon el anptomrrie wd yso dlGn piaha. p . ss b ' tn a be rims and rancer was transp4nted for 4 generations by ' N Combinat;eo ol,tr<ptamyeie .nd pen;e~t¢e br scbeal<r I and hardened. la • p. Suntx$ before it became grossly infected. tm , W N iP t W i o, Fa Apg 001243 w
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0 0 ACCO :otte2 amoaa ::u. This was :.the National 3e lar}mv, 96 ';arettes either --s with 92.6 t Ls ases, and 86.8 iesc data show ;; cancer cases s laryngeal and :sh betweea ia- ct aLrs ue, at ; 2geal cancer in sa: Preliminary =ong intrinsic cancer. The to- : patieats seems TILOfLASTIC DISZASZS to be equally beavy, but with a slightly iligber proportion of cigar and pipe smoke.m Iadiaa data suggest an assorition of beiel aat ( aad tobacco cbc.+iag with ancer of the estrirsic laryaz, usod- t ated possibly with diet_ry de5cienciex Swedish datss• " on women ahow a stroag association of dietary de6ceaeia with es- tsasic laryngeallesioas. The latter points att emphasiud to ia- dicate that at least certain types of laty-nseal anner seem to be affected by faaors not found among lung anczr patients. Thus the etiologic pattern is not the same, though tobacco smokiag taay be of imponance in both diseases. Preliminary datas* fs.z- . tberatorr, suerst a relatioaship of heavy alcohol coasumptioa I in the 1arynseal cancer paticnu, particularly the extrinsic type. These 6ndin3s indinte th:t before we caa make de6aite etiologic comparisotu among different types of cancer, we must study all possible environmental factors that can be surveyed by elinial and statistical means. It may be asked why mornlity from ancer of the larynx hu not increased u.sharply as from lung caocer if.smokiag is a factor, since aacrr of the larynx has also br.a found to be associated with smokia_e. A recent British study" shows cleuly that there has been no incrcase ia mornlity from laryngcal aa- aT in En_land during the past sizty years. The following poiats are to be considered: 1. There bu beea an iacrease in morbidity from laryrgcal anar in the United States, though it is not as marked as for lung cancer. United States vital ttatistia'.' have shown an in- creue of 47 per ceat in mortality from laryngeai cancer from 1930 to 1945. There is a greater increase. however, when mor- bidity datar an considered. In view o( the higher sc:rvival rate in laryngea] canccr, morbidity data rather than mortality data 113 AP8 001152 '
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Wrlmrs d al.-Esperimcrttot Co7einoma toitJt Cigarr7e Tar 863 ~ Ssary to have ttely one-baY ge 71 weeks). us finding of aarimum in- o the human -about onn• V ` ~, k.Wak content of vuious typea of Europeaa :eananr F•>d+tso tends to place less emphuis on this faor• t tar iavertig... ,ric element. HutQ cigarette paper, 9avoring. aad d the elinital: Rtting agents have beea suggested as etiolo lp'c iven to both. man in tlte production of eancer. but it must be m tbe tobamo {•::trd that clinial evidence hu alw pointed to :atioa between ~•7ar•simoliag, pipe-azooking, and tobacco•einew- d. It ba.s beea :. x ar posstble fadors in the produetioa of uncer ke may induoe' '• tbe teryir.tory and aLmeatary traot. t ezpersnentd r 73e aetual eucinogenie agent or agents in to- iogen has thus' .ero remain to be identified. Studies combining • a 4boratory :'srmic+l and biologic efforts leadiag to their idea- I iation are urgently needed. Should one be able s observation,' identify definite carcinogens and succeed in re- :e relatioaebip ar{ng them, or at least in reducing their quaatity r, in that tDe •tabacco, proper preventive methods would be at tisbn us with ..nd. Such studies may furtLer our understanding ~ identify aad .:buman lad animal eucinogenesis and may lead thin the tan. :t6e development of practical preventive mear gni8cant fact n against eaneer. d on cotonary ato rc arcy *+ rising eU oa with ~ little work cause recent emphuis on ur bope that he. tobaceo- t_ aad physi- ancer in aai- stohavea raumatic it, tcer to aay of the posi- •upeet that genie is not e identified ;u)d not be rs (7), and be detected :by',of the reveal any :rciaogeaie cepted bu- ,-yt nrcinogen, u peaeat in tobaeco. but recent number of duths occurring during the 1ft and .nd3e.s by Daff and co-workers (8) based on the 14th montbs, although within the period of obser- SMfARY AND CONCLDSiONS 1. A eigarette tar condensate was obtained with 'moking machine which simulated human smok- ; babits. Tbe resulting tar was dissolved in ace- ae and applied to the baeka of CAFt axin in a xage of 40 mg. of tu/acetone solution S times a xk. Control mice were paiated with acetone. t. Of 81 tarred micp, 50 per cent developed ip:llotnu. The first lesion was noted in the 33d wk, iad the mean time of appearance was 56 "v. 1. Of 81 tarred mice, 44 per cent developed hia- bgicaUy proved earcinomac The flrst careiaoma v observed in the 42d week* aad the average Se of appearance was,71 weeks. Of 84 mice alive , It months, 38 per cent de:doped eancer. Seven- sane weeks constitutes approamately one-half of 2 life Ipan of CAFt mice. T6is corresponds •sghly with the fact already noted that in the -an about 30-SS years of smoldng; or approa- :ately oae•balf the life span, are required for the -iductio4 of bronchiogenie earciaomia. . t Oue eucinoma was transplanted for 4 gener- bos and another one is currently growing in the 1k generation. I• Control mice painted with aeetone alone -•ed no slda lesions. At the end of 4o months of enan o mary umoun a oe. r ueg . :nting, $3 per cent werq stiU Gving, compared to 70; Isat lpe.. . . • . : per' ceat in the group painted wit$ tobacco T. Cooesa. E. A.:lawa P. W. St; Sumr>a. E.c and Han, ~B. L Tbe Bole of Tob.aeo SmokinR in the Pmduettoa,of _. t• T3e group of mitt painted with croton oi1 in. Gn°n• 1• 8rt., 3?asas-sao. Is7i e. Dur, K E.7 D'ou. R; end lsrx.v.r. E. L Caaeer of ~lition to the tsr, starting in the 7th moath, tye Lm,g ia Bepwo to Tobaeea. BriL l. Canue 6: t-m, _aot be properly evaluated because of a greater 1931. ~ APB 001245 vatton no aaeler.t:on of cancrr formation waa noted. 7. The group of mice started with acetone and receiving croton oil beginning in the 7th month showed roughening aad thickening of the epi- dermis, but no tumor formation was noted. 8. Al) CAFt mice painted with 0.3 per cent solution of inetbykbolanttuene in aoetone devel- oped cancer within 4} months. The first papilloma appesr.d during the tlth week, with average ap- pearana during the 7th seek The frst carci- noma was observed during the 12th week, with a mean time of appearance of 14 weeks. 9. The resuits obtained with CAFt mice estab- lish condensed cigarette tar as a carciaogen for mouse epidermis. These studies provide a tool to determine and isoLte the possible earcinogenic agent(s) within tobacco tar. At present it is not known which fraction or fractions in tobacco tars are carcinogenic. Combined chemical and biologic studies are now in progress to search for such ageats. Such studies, in view of the corollary clini- ea1 data relating smoking to various types of ean- cer, appear urgent. TEey may reault not only in furthering our iztowledge of carcinogenesis, but in promoting some practical aspects of caacer pre- vention. ACCrO~iLEDGDg:rTS TLe aotbors wi.h to espae tde'v se.titude to Gaka B. Cook ltfa7 Ger C+ow. aad Gatnde Curol of Wubiartea Uni.erdty School of 3edidne. Depertment of Surra7, St. Icu6, alo, for tbeie tr~ninl..wtaaoe. BEFERENCES I. Bns.a.cet. L Tbe Xabaniim of Cu~inosm..is: A Study of the Signi6nem of Co-o:onoemie Action and Aeleted Pbmomea._ Caneee BneueS a:eo7-14, 1e{I. s. Boasa. I- ead Loosae, A. N. To6aceo Tar+ Aa Psperi- mmtal Io.e.tiptiaa of IU Alleged l:ueooeeaie Aetion. Am. J. Goeer.1/:ISIS-t1.10sL S. Basaaw. L De.e Crjatette Smaldog Caaee Long Gnar! Catifoenia i ReanA, h I-r. test. 4. Baoua:.A.l3weti~emdesraimmtelkUata.urbm- em me Pathoeeaem and Fti,teatnnie der maBgnen 6esehwel.te. P4ebon MeS. patboL Aaat. a. Pbnial.. 1e4:lt-41,1000. a. C.+mcs, l. A. Tbe EQeeta of E:bamt Gaw from Intrr. aal Combu'tion EtMion aod of Tobacoo Smoke apoa 1Gasm with Speeid &renace to tnctidenee of Tamoun of the I.ung. Brit.l. E.per. Path. 37:1~e-64 1aSe. e. --. Ca:daoeaoie Ae.nb P,eeat in t8r Atmo.pben and Iadd f P i i >6 187d L T .
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~ 1 ~in;r•lirrl}'). I pf Ihc7ap:dirnt.+rilhrnrttrof IL•r laryusand GI hall tmr+ilit•c Irinlr•in. /flu Ilctrvul:r~, rd e;;•+reltr.rmtkers in Ihr lic,lind. e•i!!t Pr••v+d 53 ( nppraxiu+:dd~ tl.r .unr (st atrl TI prr n•nl, rr• 1lr,Jcrs ('.S) ulracrvrd lhat, in •r sru,11/ of JY1 ~ c:pxrr, tt:,a 701xr tvrrL )l k tn !n- mdcd ILat tile nm.J,cr o( Ir.dicni> nillt lun:nr, nf tile P1,:,r.•m :,nd nnuq.6:,rs•ux u'a., .r, .cwall Ih: I it i+ uul L••. I .il,lr lu r,hl:+in xdi.G,clu: i• prrrud:~~r• u( ei;;:.rel I,• I i ,t > , . ir ,.i r o n ( ., tn . . , n., • nrors. Fi;;nrc 4 shon•, thc pcrccnl ,c of n:ild. Inlvlrr.ttc L ! appvar, lu hr a corhrlalirnr l,(:lc•'rt•n ,nwk•ralc arnrl .:c ! )„-at•y ri;;:trcllc snn,kinF fur tanccr t.( Ihv rc>pira• turc lnrct, it .•rt•uls nt•tr>.Ir;• lu (*un,i,lrr iu tl,•tail 11 •nol•il ^ I~ l il ~( II •~ li • l v~ l! II •• + .,c t. , a+ • ILe • nu ~ / (lh-al ci~.rh•llci a tlat'). aud hrat•y ci~.rrt•Ilt' swokrra fur patiruls in tile eliuieal 41114 IILC cuntrul grouPs. Ia ia st•rn t!tal pnlicnla n•ith e:.necr of tile rcipiralor}• tract liad :t (+iphrt perccntn"c of LutL hcary• and mndcrulc cioan•ttc smoht•r, Ih.ul lhc eontrul. lu und::r..t. lltc•;ronp of nicn !+i11L eau!rr of tile lip had 1 gre;dcr prrccnln~r of m7,d anrl nmJrn,lc .mo!;rn. 19rt•,r find6,~, Irtn! ,upl orl lu lLr I,rlicf Ilc,l lkc ar ocialiou Lcl+crilt ,u+o!.in,^, antl ccuurr af tLc re>pir:rlorc tr:rct h:r, hinlup c>i. ~ niGcanor, but tllr corrclaliun hcltcct.r. auwl iu~ ~ and cunccr of lhr lip i. ola}• iucidcdl:J. tkc ~ lirrcorrrlation Lt•lureu nousnrohingnue) Iltc lLrcr li:e I typa of canccr. Ot6cr f.,etorl that lurce to he emuidcrt•d are ul• ei,:u uud pil+c alnukinp. Fi-vnrt• 3 iurlic:dc. Ih::l p:i• tieuls trilh eane.r of the rt•api-ltury iract hud rel:t- t 1' •• I ( Lr I nr ~ nn pcrctnta~cs of r.(ar and pqK• ,ntu~nr~.. 1'1 I' 1' 1 j Scsi W:n rl 7•ubu.rn .Cnrnf in2 ruul ('mu•rr :rnol;rr.:. (,'oml,i:7r anm:in~ L.:L,Is.-)u:,.nnlrh a. Iht•rc 1'r.urc i al.o en:npart> lhe nou~ratd;cr> in ike fottr , uupi. Fnr cnnccr of tllr lunp. uf lhc.l,rvno. and pilaq~ts. antd of thi lip, lhc Ixrcrntagrs nf uon,wolz( rs u•cre 1c>s lhan fur ollrrr Iurnnr: ( U.G, 13.7. and 10.•"r pcr ccnt a> owup:vrd to 4t) ~!rvr tenl). Thii finding is not <urpri>ine. Since Ihr (irr• rious Lndiue xas a poiilit•e corrt•laliun brut-iru ciyaratle rnnokine tutl wmcrr of tile res(riralon• trncl and lip, nue nru1J!t•xpt•et nn arwci:tb,l urpr t< a tut wp, as m thr camt nf thr f>rrrwu>!v 11. arrrrr! ln+r iuridrncr of nun.m°!crts, nrr al+p,vcully lhr rr,ull of Ilir higlt pt'rtt•nta;,•r of ci.l:trcttc „no.cr; in'tanccr of tLr respimtun• IracL UISCCSS10\ i'lfrrirlr of filr•rnhur rili ri.rr uf tmllrv! gruul•.r.-- ( 1'hc prc.rnl ritnliu~, arr'tlclx•nJcut uport1 llu• >:a- t2i.liral tnrllroll of :•ctling Iqr a ctnutrulFrr.r:p lo ~. t.•rr.p.,rt• a•ilh ll,c cliuic:d ~rnup.l'I,i: tnrl6vd . r"••I fur>1ud;•io;; 1(rc h•(ali•qnhipnf >urnhiu; :uu( ' r.uit•rr In• •rvrral int~r>li~alur>. p:dirul: t.ilh t:rucrr of thc lilr. only 11 +ccrc u•oln• cn. Tfu cvrnpart.) Ikt• xrnuking lubils of t/rrsc pa. licrnl. u'ilh 3U:1 tvnlnd n:ru. )krfk ;;rvnp, 1cu( yr- pru.irualcly Ihc >anic I,a•rn•ttU+er of nuntl.cr, of luLareen (I!).•il snd 01.4 pcr ct•nt). 1'Lcrc +eas, I tt ... ws j .1, r) €r;' 1 • >1 ~..: ....r I s~ ur• i~ aa ,r ao q n c u> l.rpntal• Fie. 7.-lTi. p,•nenupr 4l mild. inalrratr. u,J I-r:..]' rir..o-llr >m4leh L.r nil6 Gu~[rr 4r variwu utb. 0' hvr Sitaa ;--.- .. . i 27 6.) 10.0'/. s Lvn -~ E r. c w V 0v z.c 3.7 i. Lerynr and Ph.rynX O5.•0 i.•O.t Lio 0.9 2.6•2=6x IOtS.r sit.ca r..~..~~_. n 1.5 8.8 lls :G % Lun ° 12 L5 .Ei Lervm: and ahervn>; • 0i 6.8•6.8X ' c . 1 3.4 tt2-A.t 0 S lo 15 Percen:e1a Fra. s.-hdu J.o.. tLr lKSeldArlOt nirK AIUI r:pr •IMt• In~ t.R [•dlir,J1 Aili, r•,nhT 4! Y.flC+ra rllYs. 11•tn'rcrr, a uwch hi~hrr prrecnl'a„r of pipe ,mnk• ~ rr,an,r~n;; lhr snwLrr, u•ilh caurcr thau in Ihoir of ~ . I In• cunlral ~rarqr (7S. tS ani( :15.f1d,r;r crnl) and 1 tuuch Inn,•r pcrt•rntnge td ci-arrtle snwkt•rs (t.IG a, cnrni,:,nil l° .i!1,f11 I,cr t.,•nl ill tkr cnnlrul). 1'he rMtln,l i:n•ap nas n,.l. lwtcrccrl rnlirrly a.:ali.. 1 r
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NLO?c.AST1C DISEASES 0 :m:-al nar.t :tla't the pos- s. Tbe foracr .fon. Ia Indi.a. •r.vaicnt thatt 7redomiaaaL :lc two typa 7. :aa lar)agal t caacer. Es- ?:icacies may =sic t}pe of : to e.'tP.asie ita, further- :iore closely :,aect of the _ of change sptica. wisumpdon. =ptioa dur- :oa of pipe, a, one aa :; increased :ou•ever, on doubt that seco smok. OR.IL t:AVSTY There is a Ecnaal cL'ainl 'uaptrssion that cpidermoid eaa= of the onl avity, Kith the exception of cancer of the pbu7ax, is also nlated to tobacco eomumptioa. though the data on this an so fu only fragmentuy. '13e study by Sadowsky et c»+' sbowed a usociation of aneer of the b'p, toogtre, buccal mu- eosy and itoor of the mouth a;th tobaeco smokmt. but not wit]z eancer of the pbarynx (Table 7). These data show a sig-I ai5aatly grater number of eigar and pipe smokers among pa-~ ticats aith cancer of the oral cavity thaa among paticnts with ean= of the lung and larytu. This would seem to underline the point that the practice of inhalation associated with ci¢arette ~ smokia; may accaunt in part for the, ater correlation of smok- ing witb lung and Izr)a_c=al eancer. As early u 1915 Abbes found that of 100 pstieaes xith cancer of the mouth nll had besa usr.s of tobaaa aad 13 utre tobacco chcsrss. Dai.: on, tobacco chcwin2. though incomplete, are of con- siderable 3nterrst ia that they sutecst that tobacco may cot re• quire eombustion to be arcinogenic to maa. bioore et o.i." have reamly demonstrated that tobacco chewing is a sigai6ant fao-1 tor ia aneer of the moutb. Cancer of the oral cavity is esccd- ingly eommon in those eountries where betel nut chewing is an eztcnsive habit. Otr" and KhanolYacs' have satisfactory data showing the extensive betel nut chewing habit among patiena with cancer of the oral aviry. but it is yet to be shown whetber ~ tobacco is essential as an additive to the betel aut ehewing for ~ cancer to ottvr. Scrne otber iriteresting gmokmg habits involve • anccr of the hard palate, which is rather common in i cenain trea of India wbcre eigus arti smoked with the lighted end ia• 115 AP8 001154
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' • ~rI1t:1'G r: rrf.•-T~ufnlr,•n .Crunf.~in~ nrrr? (,'arrrrr • 0 prnldcut Lave 6cru di,ru~...d hy Sr6rt•l. uu•1 .SI- LILrn (:f1). bm• Curdr,d Ilrnl tnirLt b,c ucr•/ tcWtl,l !,C tlm rnlirt• grr:up r.f leAivnl..tn.lil•,l. JlY ILis mt:ut•. U,r p:rlirnl• aillr nnt• particular :•:rse rc co:upand ta!i 16r nlln•r p::lit•nl:. ~I u. fir.t t;) thi.Il')rC uf tvrtlrUl C,prel It' )II1nwiIlp i. Iht• Irtibttp:rl f:n•Inr Ilh:tl ia cml•irlricrl il. I1.•i, papr,r. Il nr.:}• Le :n.un,r.l Ilral1 eat:r•-r tCnr.Ll w,l 6rtailh- nr Lc lltt• rc• sull uf, ulilrl .rnr,!:irte. '1•i,rrvb.rrt cig:n.lb• alnul.• ,• irie fr•r Ihi. alu-l}• tta. r1aG;i.•d thr n.r uT tt:n or n1urC cie;ircllrb a J:/}•. 77.e tlur:llinr, u! •utnking tta: oot Con.QrrvJ yt llri. ptriul. 7b colnfr.lrc Ilit inc•i,b•r.rt• t.f cie.ucllr suwlciue iu ILC tlilfcrr;rt pturin of pnliculw lhr -r:ipltic nrclhud dc•r:ri!•rJ by Sc6r.+ (.".i) i+ wrJ :unl is ph•.rult•J ill Pigure 1. l:.rll poinl ill Ihr gr:tph al,utrs thc annlLcr of p:rlitulr aull Ilit• p:•rct•olnp- 1 L,-~....wera.~N t wnl J ly r•.;.. tNqM r :trr..n 3 1 Otn.r w*w t L w to y a o e• c: r» av .:a N-) W Wo . R.ct.rdt,t..nua.C•^ir ' Flc. l.-A campari•wr of Ihr peeentapr rr tipanlle .molise ill oll r.:irn:s eith lh:t ia p.,fir,.li eillr r+ntrr of terlain .iIH.'fl;e p.-rernta.r of r!uol;rn in Il,t hldrul roup er•n! S•onl palirrdt i. SLS prr ernl anJ is rcprr,rnriJ t-jW thr horitenlnl line. rwe tunt, .l.ow U.r liaul, d tip:i5. t',net. A p•.is1 m, U.r pnl•'a tl,.d 1+C. tul•i.lr tl•rr n,ecre ahu•rr. (i, riSenod;. frcrn Iht e..dINI In it. J+'KCntff..• Of r'r,,r,tte.,uuken. of cig•ut•tlc sniokcrt in thc l;rotlp. The prrccntagr u! .n.aIct•rr in tl,t• tontrol erunp consi..lin; of nll 3.Ir:19 I•.:1it•nl: i-.il.S p,•r nnt anrd is raprrsruled 1'Y :I !••rir.oural linc: TJIr di.l:lncc bt•ttrct•n thc P^I:• : r! ILc hnriaontal lirrr n•prr,cu!stl:rJi!fcr• enr•• lr:;,:ccu 16e pcterl:lap•, c,! snlul:t•rs in rntl: Ldioit•.Il r.:uup auJ 1hc cuntrril: To Jvtcruliue ttL. ILcr thia dif(rrt•nct is alaliait:111L• si".nifir:url, rur•; t. I-:trc lircu dran-tn to ,Irote thc lin.il> uf >i~ .~ ~ro,qt'urlfalit•n!, ri•ptox•nla•,I in Ilit 1'Y n puinl thut fall:oal.itla; lbv..• rnrccx In:ay Lt• s:tid tn dilfcr aipuific.ndl}• ill ils prrc.rdag: uf ci .rn Ilt stnn!:rr., fr.rat t6t Cunlrrnl. 01 ap.rci:d iuItrr.l ill I6r grapir i. Ilrc Fruury or pati-utr Leillt "nlhcr Iaurnrn;" Ilud i., hnnnn u111Ct Ilr:ur llru•c of Illr rr.•pirato.•y and ui+prr rli- /;rttitt ttat•l.7•I,i, l:re. Ic r .nr), ,.f .i;: j4rtit•ur: !sl.l Iti.S pt•r ccr,I ,nu:cra, ttLicL aa. >ieniScxull} loucr lh:m ILC ~1.5 1>Lr eerd fur nll p.rlicnt... •J'hc fiurliu, nf an apparrnl urg,titc turrrlafiun bcltcrt•n mi,.•cl6mvau, c:,n.rr Uro1 ciprcl tr swul;• in;; ca,L. d,mLl ou tL,• t•alirlitt• rd n.ins :,II Ihc• Ir.i• •liruts ni :I cunGul Ju fact. l,alitrt/% trilh t:uiccr und udlll uthcr di..ca•c•s arC uot tornlr:tndJe ill several rt•;prtt.. In the Rr.t plar:, lhrtc is t6a °f r•ol r•n r. 4 et e ou.r .s t..,.., e.~•. .r r Lt~.u.:.:r1.'d+ r D6~ D6~ / s L.. ADt~ 7'u.r•. tY.w.0. tr,t\ t Gaur l.ean O L p 19 •: ::: tJ: JT. .A W ' r:l pS b.nNr .ir::...u n r•.q '!',n. !.-A tun,p:vi..~u cr il.t {„e.•nW,r nr iti ill pntiVul/ eilh Icnwrs eill, 11w.1 ill p.ilirnt. eili, GucSr of tcr::in titr. I':yI.-nalinn if 16e •nnu.: fot f iq. 1. proLr.hlc diffrrtncc iu Il:i• n;r di;lriLl:unn of thc pnlitatl> in Ihe hro „rocp.. J'urthenuorr• onc nnl!l lakc into eoll.•idt•r:dion Il,c fncl that tIri< ho:pilal dnrin; 1J1'.-al not aol)• was a gt•urral ho•pilal Lul n:rs, in adJilion, a c.tuct~r ct•nter. ;It o etnc•ral ho?pilal, fcriiculs from Chirago and thc ritirtit}• t,'crc adwillt~l 10 it with till 1}•pt•a of Intdit•,d nlr-l sr.rgieal eu:Iditions. .Sa n ranct•r eculr r fur thc ti•ct• erans :Idmini:ladinn. )t:r:it•otf tt•i:1: tlr•nors ts~rrc h•far,ta•ll tP lhl. IIO•ilila! fl•..Ir/ narrr ~•rlPrdlli 1,10,• pilalc iu the tntirc ~JiJttt•:t• `incc smol.•ine hahits ulay bc ns.umrd to eur,r iu difft•rrnt p.ut< r•t tJte conoilr}'• onc c:uu:n!, nl Ir.:,t iu Il:is u<c patitnl{ tt•ilh uthcr tlisr:r..t•a :Is a control fur p:l• li~uli tcillr lu:unr. ' it lun}• Ilr eur,tludrd. Ihrn. Ilutt• arrnrJlag to >6l.~l.in ~.in~ hnl,it,.'all jr,dit•nt> trrrd nnl a suilahlt eolilru! fnr eunrlr:rriu;, teillr~lmuat palirn:.•..1 nwrc :ui1aL!t• t•nnlr.•I ;;rnnp fur au,lciu;; palii•nl. tcith Intm•r, id 1!r,v rr•jrir:.l•~n•:un! Jiar+licv Irnct trtnd~l srrrt In,hc mt:t with ^vtLa: lumnta." . -. . ,..:_ r
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0 TIt! 11oLO01c LrrLt:TS oT rolAceo side the oral avity.u•st Ia the B2u distria of India, tobacco is pisccd between the lower gum aod 5p, and a hiEb frcquea.y of anar is repotud in the region of the iana surfiee of the b+m Iip" Also of ioterest in this rnpea is the obsavatioo by FriedeIl and Roscathsl„ that eanar of the bueal mot= is most of= aca at the poiat where thet•e wu the Eratat contact ia tobacco ehe+riag. - T.uts 7 TOTAL lATtENT3 DlSTRJBUTED dY CL.tSS OF 1LINESS AND TTtE OF SMOKIVG (Froa S.donty. D. A.- a eLN) ON4r Uleta Onl OrFar T.teA .up ToRrve avity• rhryfiz cae.. Totakpotints $71 132 3ts dS 613 Pa ant .'bo snol•ed 91S 94.7 921 E9.< 16.E Pcr eent Mbo smoked dguctte=f 6S3 629 $<A 763 72S • t:ewprisa eaaar of the Loor ud sr+of of eoatlL SUM, twcal mo- eroca. palste- and tonal { tiwse vho unoted dptetta only, or dtucsa toretba witE eitan a od/oe pipo. " t7inial data" suggest that in cancer of ibe or+l cavity thera are eontrn'butory factors, such as syphaTstie glossitis and dietsry de8deocies,. Mbich themselves, s,tn of etiolo~ie sigoiHcaaee in.the , development of some of these cancers, pnrticularly those In- volvittg the toogue. Gettsin dtetuy defiaeaeia, apeeially tbose Involtiag iroe, may promote ancer of the tongue and butzal muwsa in the absence of tobacco use, as indicated from the Swedish data,'~" especially in Womea. Pss=t evidence indi- I16 ates t~st tob of the tongut, a lesscr one, the onl avi: among whic~ ofthefaath bea bumedi tanca for labc tinogrs ia t: ESOPFLAGVS Csn=, of ~ eassed, bts i t , borae out in whieh varies : aciuded a.~: more commo: tobacco smo: 104 ms7a w smokcrs and with Ot3es for u toundforI. • factors Cocsit: of the esopbs . sTss, sad diet: ' t'ioaal de5eiet aot adequate.. ame from Su onstrtted bet, Vinsoo't dise
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: .. Tat ltoLOatc Irrac-s or ro.ACCo csble to indca ==, tSooFh F1ory obtsiae3 paplllomss fa al1 of bis ai~als. The fart t5at pap0loWas were obw-ved by F7o7 is ccasidere3 by some iavatigiion as sn.5dcat evideace fot arciaogtaic edau of tbis ttuter:al. However, ags.ia 1•1ot7 e:mpioyed a &sa7Icd tobacco nr. Data oa mia as the esperimeotsl •zrm,t have rxcatly b= tstie.md, aad it Was shown that in otily seven iastaaees had a sqsamans all aacer of the sk:a b~-z induced with vati.ous mm- poccan of diirlled tobacco.u It has ben pointed out, hovsva, tbat.taost of these studia were arried out over too sbort a pcaod of time to be regarded as signiGant" A aambcr of imdies .+ere carried out aposiq mia to ta bacro smoke.' Thae studiq " e:e aeg:ovq eza?t for a s=at , rspaa by EsseabcrE,u who producd a gcater aumber of pul• ao:ary adcaomas thza he found in his control goop. It is of some interest that Eneabe--g"4 did not 5ad aa taaeased auss- ber of such tumon whea the mia wes cxposed to smoke 8om cigsrette pape.•. Pulmonary adeaomss are laiaas of a diReaat type from the rpidermoid aacer that 1s being caeouatcred ia mar In respect to the 's^.s'alstioo stady it must, of course, be raa'L••d that'it is most di5cult, if indeed tot imposiible, to dupliate esposas: to tobacco smoke as it oaurs in man. In 1950, Wynder rr aL" rsponed their iaitisl results on mice painted aith condensed tobacco smoke prepared from eigzrctttt smoked in a maruur simulating human smoking habits. Tbcse dstsbave been svmssuized ia Ftgurt 20, whics' shows a ptoduc- tioz of 44 per c-.nt ciaeen among 91 CAFI mice used in this esperim,eat. These din' clarly prove that tkest is a.mouse cat- . ciwogsa active for epitheGal tissue in tobacco tar. Yrithia the pesidentioas outlined above we may assume the cuciaogea or 120 arc;aog= to time the r..ajor tzcted towuds Mae ele;. c: doetot.hesu^: TOr so .a 0 «.•u; Fast jrou 4 ciaomu proKc or eotardmogr: .rould bc cutia . Caf;3tioIIf C( vc ' COaCepttL'loD a. preseat time oce tsve for tobaao AP8 001159
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! ,. TaL 71OLOGtC zrrzC:s of so:4ceo Ia the u,arc.h for a..mogrs oce of eaarse Erst Cim ta idco- nfy the bown areinoEcu in tbbara tu. 'Ibe Srzt eff on .u d'uscsd tonrds dete:%iaiao tbe preseaa of berzpyrtre b ta;. In spita of a report from RoEo w rscrat studies such as those by Eby," WaDa,n and Commiss cr aLst did aot ideatity bcz- pyrsae ia tobacco =oYe. Mors nc-atly, however, Coopcr ct ', aLss' ideotificd ria nitrsviolet spc: togapby re:y sman szom-a of bezzgysrne ia the aearal tnaloa of tobaao tu. Cooper aad Lladseyv as weD as Leteaine+t have ideatffied bcaayr= in eijaroas paper. It must be emphasixed, bowerr, tst Lefn^.: e's idatibatioa was carried out on eigare :e psper tar that 9ad beea pyrol)ad. These ara condi:ia^s tot foaad'e htmun smot- inb Coamias er alss "smoked" d,nrsttes made of ear•np dgsC reae papa. Bat evea n sueh an ezx.timeat it is mou di.5:.il: to dupl9ate the burnin3 tanditions of the usual dbarer.n. As far as the be ;zpyreae eoatent of d,rarette snoke is oon- el=ed, its eoaantratioo is of morn than aadc3e impoaana. Wrigbt exdmates tFst i{ bensp}:tne is iode:d prneat in dFa- rr..a smol:e it is preseet in a eon=tstioa of less than one part per miliioa.4 A simtla: estimste bss beea made by Liadsoy ~ Prrscat aaicul espesimcnts iadiate that this amount of berzpy rt~te is iasufbcrst to Induce ancer ia the ezperimc:sI aniaaL No one ean prove wbetber this amount of beazpyreae might Iuvc any acZivity ia man, but on the basis of the aaimal data Ws concsatraoon is not likely to have a eatdaogeaic eSea on rua. Arseaic is kaoaa to be present ia tobacco smoYe in qttantities . of about thirty puts pet av'llion; bowever, previous workers,'s ttsia; i much larer eoncentntion of arseniG worn unable to induea any signi6aat number of stin eaacr,s in mia. Human IZ2 APg 00,161 d.tu,t+ ta is trseht: t&-- bmE' the L•s..- Wemu tmidesy5e by c':r-rIc tIIlation rr motn pot: this partic p -aur:. strss, svcY sluds aac eoae from r2p^..'.ne^: etal.nd:: iramicn t:f notcr~cto be'sb arr. rena tu. I: ia diercnt u'bk diHer. In brief. be arcino! simaar to the si3ni6e that tbe t: posstble rn: est, isolsti:. measvres.
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0 j NEOtLAS7IC DISEASES atu tsat tobacco does pisy a role in the development of ancer of the tongue, soor of the mouth, bueeal mucosa, iDd gians, aad a lcsse.r one, if indeed any, in anxr of the pbarynz Cancer of the oral avity appeaa assoeiated with all typa of tobacco use, among which tobacco chewing is of partieulu iatrmt in view of the fact that it involves tobacco eompooents which have not bera burned. This observation may be of considerable impor- taaee for laboratory workers attempting to identify spcGSe ar- r:aogers in tobacro tu. F.SOPHAtiL75 Cancer of the esophagus, like the other types of aaeer d'u- a:ssed, has a sigy5antly greater rate of incidence amoag males, whieb varies from 3 to 10 to 1. It would be even gnater if one excluded eancer of•t5e cervical esophagus, which is relatively more common amoag women. Cravert' found a higher intake of tobacco among pntients with ancer of the esophagus, which was borne out in a more recent study by Sadowsky rt al.N Among 104 males with cancer of the esophagus, 96.0 per cent were smokers and 77.9 per cent smoked einrettes either alone or with otbet fornss of tobaeco. Ibe number of smokers is the same ? as found for lung eancer, but the use of cigarettes Is ius. Among factors considered to play*a role !n the development ot cancer of the.aophagua are alcohol inake, hoctood, spicy food, sypb- ' s7is, and dietary de6deaeies.t=•" With the exaeption of Dutri- tional deficiencies, the evidence found In this respect so far ii not adequate. Among nutritionad factors the most significant data came from Sweden,s• 3t where a elear rel:tionship has been dem- onstrated between cancr of the upper esopbagus and Plummer- Vinson's disease. In this region aneer of the esopbagus oaun 117 •. . . .. . . 1 ~ ^ . .. ~. . '•. . \ .. . . . Ln N W N .P• AP8 001156 w o+ Ln A
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RHc'UJ/ATOfD ARTHRITIS-GUEST ET AL. J ti u, ,1 • . Ytr ^, Irya t EPfNEPHRINE, PREGNENOIONE AND TESTOS- TERONE IN THE TREI.TMENT OF RHEUMATOID ARTHRITIS C. rArwtaa cutsT. LLa• A..r, M. T. . niwArr n, c.rrtstL ae. 1ussnL ~ act, su. r soteroM • rtuoM, Ye. w...a Repuru of the eScttivrneu of cortisone ({endall•, comlxsund L•, or 17-hydroay-11-dehpdrocortieoste- rone) aud of pituitary adreaoeor,icotropic hontwtte (ACTH) in the trttmtent of rheunutoid arthritis utd spoudylitis I have given rise to the hope that rubstances lalown to stimulate mdogenous production or liben- tiott of pituiary adrenornrtlcotropte horntone miRht also be edective in these conditions. Vor s denlonstrated in several different species of antntals that the antounr of active cortical material released into tlu supnrenal Lue eaw t/: c.a.r vein in one minute is many times ,that which alt be 0 r an alntost equal increase in the incdeact of lip ancer, cottlpared u'ith ather sntokers or nonsmokers. It ii somewhat surprising to 6nd that the type of smoking. i. e., cigarets for lung ancer, pipe for lip ar•cer, is the associated factor, rather than ehe actual use of tobacco. Ttu dafa suR;est, althou`h they..do not ctahljsh, a au~eliiton bet+l_ern ciearet and pipe smokine.and caeie-r of ifte'I'titie aud lip, respectively. The statistical association auy, of courle, be due to sonte otlter unidetttified 'ed' conunon factor between these types of sntoung and lung and lip cancer. Cancer is now ten- enlly eonsidered a disease attributable to multiple auutive factors. Anton` these are "irritants." The tenenliution has been advanced' that, although not all irrirauts are arcinorenie, all arcinoeena are irri- TAaee I..~ewp,rriter ul tNe Preprtin •.f Ceur d Cr<ap e.I LiF Crrerr ,~neup ]le/r 3'enautaFert aud Swelrrr, rf 1! Ynri D+resfew p Jhre u Rertevll Pn1 ueWlNt IRJfilYrr, lOJJ•19JF x..f .-- -, e.~traeted frotn both adrestal cortic~s by present metit- ine e . ec a I_ ut~ „ ~ The adtuinistntion of hriae t f d • keaaeGtwe l.r Ip .e.1ut 1er JYInAitIN .f t1tM a.Ye. tTnbewnt7 e/ tN •t.mN JIenM trt... p.a4n .M .w• rlnf wNellae .r NtM .IOw. I YMt1.4 wweat .. r. t•tN..t a1Lr :••n tase w tf7ft of tMe.. Muo tM" n,otm( Wlr e« qye. p p vas oun to x.eewernnws.r t.+ueu ....s cyua ~u. ......... Co sa mr :ei n u u inaeax the amount of cortial material which coldd Ix n.t...stn; ............. aw a U la . tu. us rmrorered fran suprvestal venous blood by severnl ~ytte•..n. ....••... m r u ur s us •++ hundred per eent.'. Her raults surilested tlut epi- T.tata 6.--Ce,n/vri.an e1 tAe Pre/anie.' e1 C.xe of L+np and Lip Ceueer .fuu+9 7hfe 1'euu,eferf rrd S.ufrrs ef, 1! Ynri D.rotien er 31eer of RaJtevll Par} J/rweriel LBitur,191F-191d L.eC.e.raWerer xe.ef lw.w C..n aar Ft Ca.. bu• H JwrtwMarr" .tef: ?t L U « 0 N : aarbn:-............. sa s. at .a a u i ant.rMe: ll /7 tii u YI •ta u u ~ .N ......... r a1p tMten i ............. Cle.t twY" t-.•.•..••.• tm lle u 1/ w tlJ w aia se R 7tr aer 17J alt -aYYWIYa tet.p 1e.utt .A dYnnYt4. N btel t•aN. 1 a1MNMtltr .f tM MMnrd JlanRn tllttna tMYn .M Ya• ttMlrn w.amaa tlr M1eN N.Y. I r't/.w. ~tAt ew7 w tfp" of tMw.i. taau, that is: apabte of inducing chronie reparatiYe hyperplasia, 13erenbfum " has shown also that aa im- aat (croton rain; basic rar fnction) which b non- areinotenic alone may nevertheless inaeue the percentage of tumors produced xhen iu action is cofn- t,tned with that of a areino`en. Thus, some experi- snenal basis eaisu for explaining the apparent e$ett of eipret and pipe smoldng, although the true nature of the association with lung and lip cancer remains to be detenuined.• + • . L(e/ a.ndJw, L: ttna>u ..r Cueie..rat, Atd rtd aet 1p.:u (OeIJ lfM• (e) rdliqtr a. D.: F'UY rlnt'.1 3fwt 6Ne of s.N pMrortLe Nrenanna. ). htt a a.a. af:.1Jd71, /f•G Sale=aardiati the pre(auioa.-E.ey physieisn dauld aid ie taietwrdinE the ptofeuian .asinu- ed-ssiauep 'R of dsote she an dehden ie moral dofaaer a eAuorias-Seetim ; matter III ef the Puxetua a1/rsleu E.ata of dx ' . Mnrian lfadiat A7saiatioa nt:phrute, admututeted In doses approan4me the amounu that ntieht be libetated nornully within dx body, stimu- latu the adrenal cortex diretzly. Long • concluded tlut the action of epinephrine on the adrenal corte:: is indirect ¢nd is dependent on the presence of the anterior pituitary gtuld. Tllorn' hu emphasized the fact that eputephrine is effective in stiniulating the pituiary-adrexal systens in man. He and his collabo- ratoa ` dwx ed , that qanephrine increues • 11 osy- steroid and 11-l.etosterold excretion and lowers the total circulating tosinopht7-cvunt by 50 ~1er eesu or more in normal subjeeu but not in those wnh pituitary or adrenoeortial insufdeieary. Abny and Lara=h' con- firnted the observation that epinephrine consistetttly produces eosiuopeau in nornul penats. Thom' su`- gested us4 03 at;, of epinephrine subautaneously every kc hours in patients with rheunutoid arthritis and referred to improvement trhich ht Ind obtained 'ul rn.~ tlnr ~Yd,id Kf.nier M W Vmnee M.fuwnm. NrywuL aW.rA.FCw:.I l:i'..w7 L'wl l•'YiIM~' N. \~t 1t.aMw.f. \.X. . tu.tr.M it tN Vwn... AeOf.irntim .ne erMiArd .ita tY u.».r.l d tM Yawf ateliel tltrww. Tf...aw.ata rM n.d0d•u. WNiMN y tM .wa.. .n a t`wM .f Jnt "a ~Y/we .N b rt , .etet.anlr was W.i.r ee rMitr d W Yww.n MwwlwnM.:. L I/ ntta. @. a.: ttMtlL L Cl at.u,.\ C. IL ..e TMt.r K. F.: T4 4t.n .e a Nww•r .( t1~ Aen.M C.n.. (327 lnn7-11. t4.r4w.ni.~errw: C..,wN a1 W.f rn.+.rt w.nn,te• nwk N...:~t ~ Ia..w«.r Atetfae: Tnttw.ur a.7.n, rnc fwf 1c..c Lu. Gt:u a{I sa1, I7N. J, V4r% y,: Yhe oVIM .f t:RliOt ttN'~M t} t4'1trYlYY S.wu...~ ). r17wL 1q1J/1, 1fUt ar An..+..1 W rleMrMr! ~ftle Fw.wi. .f qe ArnW Crr. .:O . Mn•t - CL,.wt 31•eif.., arFP. at.i a 7.e. atrA, 1147. J. l'.71. ),i Ot~,r.+W Y a.s.C..1.fO.,,If.N.t :N 1014 .F Nrr..n 0...+t tlr u. a.~r.n.a C.v+. J. rlrrM. i!a 1317, tf.a. ., 6ae, fl M,. H.t a..ta Salta• r tM F..aer .! W N+arl . Cwteb a.0. x.. Y..t Ae4'Nd fatrM, aN7, .. t Tfua a w.t T y~~I e uf rt..nr.: er A/,.e•t ue7, fe~Yide, ttl. Ci.. i; 71...a, h11iNn. 1M. Ta.., C.. W: {.rya T. a.t }ce..4s~r.,,,,t.K F.nya !. 11.: • : Ni0. S. 1t : f~,t~ y. .N ,YUr.~ + Lt .. W e.YU~ .! . p.IwYl/'.4hwlt r'CIA ~ FJIr•r0. I7,rY, x1I pA.IMf J. Jt1e.' t~a137, INe. . r. At.7. T. t_ ne tu.e\ J.R: a.e.ai•. : GnUWie L:.. ~u FMt•.fy L.,.Ytiu. rt,e " a+Tetoe.nu+a Am. ). .. 31wL f t ltl, lI/f. . l TMeR C w: ts et..-rw w trwe\ L.O.: Ws4n, L C.: sl...\~ L u1 F.e.r, tC i:~ t'fa ./ a NrrM M W A/n.J , l'aa. tt7.•NNw.r•~s.aqe/.nnewnr: Gme""e tt w d tb . piM...tY Mew.r.,,my.e.e NHraw.~ r• ~ Anann• ...e . ~~aiAn~ ~ ~ 14r i. IM. '~~..e A..nnn tn tJ W fJ ~ W tn Io 4~
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SaZ srotocrc LrrEt:rs OF roRACeo b a siFiSant ==bcr of wromea ia't3e abseace of tobaco smoldna. In S«cd'ub mea with esopbaEsal cancer, invuiabty a heavy tobaao coasnmption is noted.' As of the prneat, data saust tbat tobaca, particalarly in mm .:.ay play a role in the da.dopmcat of cancer of the esophagus, though fartha dua are aneded. oT}LT7t 7YfFS OF GHtf7t The praLminu7 daa of the Ameria.a Cancer Society u reported by Hammond and Horn"•st have sug;ctted that anctt is genetal may be assoeizted aith tobacro smoling. Their eady data suE;aud to tl:= that this miFht acply to all major anc-.r sites which they bare studied, with the ez_--ptioa of lympboma. More data mcst be obta.acd to make this view ae:.pmblo. Spel cal attcntion should be dimrsd to canCr of the bladder and cancer of the stomach. There are, bowever, to el3sial statistial dua on the former, and the data on eaaar of the itomac5 are r.ilf tratmcntary, tbooth ReiP', recenQy svcscsud on the basis of prelirinary data that a statistially signi5ant relaticn does ezut bcr.roea saokin•, and cancer of the staoach Eperfinental Data The pamary purpose of aa'anirssl ezpe:imeet in aneer =s- seareh3s to elueidats the mechanism of arcieoteacsis so that it mty be applied to t5e 'buman cancer problem. T3e. results of research on animals yain sigaibance if they arc eoosistent with observztioas on bumin beino . A given agent which can iaducs aaeer in a mouse, but for which there is no evidcnea that it induces cancer in m:.n, is primarily of arademie rather than of 113 i i , t t : x pra`^~1 iatcxs: C'+nSC aaG"".= m r tbe cspe,i~al stttdy the mstlaz fzu Dot pam3ie this, to tmEastas= cmr=dybc~mga rrsearc't is not bc luagcaxaia= mt•stlcs, elini;al i diseasa. The sigr.i.' help in idcatify4ng . If toba=* did nos gaa the buman f doa aot pev.c it : oatainly adds to t research thero bas bcrwsea aS= ts aalaal Data cn c sene as an eampl ES?crimeatal ta though unpl r=2 +t oauioaal .rvtke would pasa aitboc producing a iarge n be eonsiderod to bc deu of tobacx tu. by using tsr d'istiUa: atilike those eacou: giua" and Flory "
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~ WtN-DCa ti aL-Erperimenlal Cmeinoma toitd Ciparette Tar 859 8 ~ -1~a we 0 ts MP C..v. ebt.i»d br t8i6 metbed. Tbe a.vyo . ydyod tmt etbaael d,y ie4 bo.e.a. ^e a!r C. vby TrmpentarY ef the tmoks ao dietiaaai.bd trom that ef the mald :..y. smf dcwtv: T.eat7alkt pap eea maetuataa tbtr. .: a.o .. nwla oae io.et.d 'm the nceiriol eaa ef the dpeev4 two muu mrt at :a tnd the dra.tv!'en rmuked de.a m the rbmt boxt poiet a eotteo lk.e Wr-~o apptaa.Dle n» m the tempentan ef the am6ki .v the moton tnm 1.( ss~d mtil the dtanttr wce omnmed to batt lottk. Tbe retb a.a.t.d by seu.tuea ef the ®eke r.opd trnm l0.7 le W C. 6 pe eittrrMte.t e /rin.je..d.-Ouekoadnd6fq•¢CAF, mia(leeH'aal- . Tbe da.ntto e.n f baotm»a. P, bybridr fnm tbe rn.e d/Cbadm.a iabrd ®, yaN. ( tv maln br BALB/C inbred rkain femal, obta7ad f»m tM, .yrna (yeA a inmme 8. J.ck.ce Yemoriol Lbenta7r ot Bu 8.rbar. dea .itb diminibi.! L:e). witb ta epaal dirtnbulioa of mols aad frm.lr, ... Yet !o avb» ww °0.4 Lt i'tt .eelra at yt. llaav%n Gbm W tB tbe mia .en kaered is r.6o4eeb e.p motaieie! 1t larimabeT soo s 1- amb areb. aad .en fd a dkt a! Rorlt4od mmw pe1kL, ,e »parda tL+..n •'6ol»t ^wkmeat aad .otr od bbitum. Tewd tbe md o etnnd at -T C.: ttie e:perimeat, aaim.ly dev.kpiot lsiaoe .ae tetrept.d a»Iutiaer. i efrtu.dieicdl.idoalrlerfat.. elutieos wno mde .p Sobrroupe: 71• CAPt mier .ae ori(inall7 dividwe mtn ta. Tke ebe;or d rs. ° p01I* le. oee rradp af 11! mir. p.leted .itb tebaona I prim.ril7 oa tte fre a;e .oetoae aed a reeaod (nap ef N mrce reetirin! .etleaa inoleoie and el» b.. ~ Pnliminae7 Radin oa eo S.ir mioe ebooed that the :.iat medium fer u: -!R&4 w11`C reo.itite to t.n ooatainiot nicotine. p.KiroL*(7 • :neamtrol<d »lulioec 8eie!oo~oi+u:t of tbe rm.itisiv af iatn1l6.mLponr" ~'b~Otan,.ebet.atb.CAF:troupavtiowbmm! .joad7 wtitb.d: ty" ~ou.>lutiooa, the eoonatntioeo of wbieh .en trodutU7 ia. ne o robtia= fu fr t+~ Tbe t.ned treup .u etarl.d with tri•.eek(r p.iat- .eirbt af t8e J d a rrridu.l tar/aabee »lutioa ecotainin! I port of tu 9.1 pa/r0a epn(ta s d.ateoe. Tke doulv .en trodual(7 ioaeued to did b arj Va, e/,., t red 6nolly ta 1:1 ntie 1e I meotLt: tke lett» do.µp me to 1 pa. tat) er 'Mted a mr of tar/aatoee »lutioa per p+iatiar. 0 bettl» aod atmd i tt+er to oeb palotmg the mtin donal trea ef »eh momo mo®ta of lhere d• + r6aad o( emea beb .itb ta ekctrie elipper. and me e nduoe the e.eprr mbd broblul of the W/aeetune mirture was .ppGed to ' ' t Sditb 2` fi bi bbltb ae.e ateo v oos e.metarrur: ona. rtoa at o( e.naa R wed. br!(naiog at the napo of tbe neek end .arkiat beek. . w tbee. ttarriI rod b tb. tail tqioo m.dL117.ad 6ten11~. TLe ometol eai. of the .ennm rt tb awr. o a ma~um niw d ir.m moatL aMr oaet of pQatiap Db of tbe lot rur.i.• voie of -! mm. 71i ; t.md mice .ad le ef tbe e! tm.i+iet eoetro4 on .eaaeo -1 mm. ead » two m rrpetoted ead ji.ea oa oddittae.l paintiae per .eck a! . maomum of -t eua x trat erotoe naie la ae.tino (Bereobhoa (1() is oeder to et.ao. (:amine the eoateinopafe ptopertia af avtoa r.afa la nh. e+d8 tbe lempenlts j to bb.cce t.n. Soeb rvbpoap roataiaed aa eqoal aumber a tEvmmeupl..iJ 'aelee aod femake. The aetott r.ia tolvlko .ar fouad to erlla»4aralaM1d.^n •rtnmely irti4tial to the tkto rl mie. aad eu»d wida. r/ft at tl.l' C. ead b wd alernttea, Do.aps won nduoed without nlid o(tbit 'n witS a eombm.l T rofitiee. Two mootho I.ter tbao aaima6 wn ebaapd te a e as.d. Tbe bmpar aemt »Iatia of erotee on (Cnlee pil N. Y, i1L ]tatour. fJ.aaamebr pa" :Le, aad &youd, lae, New York City) (a mioe+ol »7 .m 0 to l.000' F. 7L Z Super4 \e. St, Stoadud CSI Ca of Iad). .hkk" aL tbe peael»tiao d IL .Ilb mueh lea Gribua! b the akia, onmed to iodact.e.e» TbernotOo(/ots aka , . ;90' C. Tbe oeerttr d b the Irib moatb af poiatinl a few ef the tar/»etaae md .itb o room trmprs r aatoa/aeetooe wim.L we ptoad an a deairotinited 1:1 r: aetaee »lution, prep.r.d by estnating the aieetjne .itb aprette: CombuGs w aat k7dneklorie oeid. This tnatmeat .u uxd enl7 ;ng to pale thVIVO -I tke aeimal had ae p» alantin! Ie.ion. Si3ea the laioa rotimalet7 tbrnq." Obd o.er, the vbole tu/aMeee solution .ar »apptied. i by tbro rmo.ing tb . ew moet of the aeimt4 .itb 1..;eat .eee kept oe the ,nctioa of tbi tb~ :k tar/aaeteoe »lutiee tbroulboot the esperimeat..lt wst•uti6a »ae. TrmpoV ieaall7neree»r7 to renrt to tbir Iw bce tnatmmt I•: denieotiaissed »lutkor in mder to preur.e the aaimaL out by the F~Jn S.L N u the aafmaat bec.me .eakeoed by old a!e ar d'uea.e, the 1~ Miotintf wen deve..ed by paintint menly the letioa it. ,,dpoiat, eod at kv6 v.eeo aba.ed eod palat.d with ocrtuoa in the wmo .it. Wkee a Imue had bomme a porelr pmd" eaniooma, the tar p.iatiep .en rbpped mmptae(y. Tbe aoirryl .ej tbea aBo.ed to Gee hae ef peiatiep aed w.s a.e:i6eed aey wbea death .ppe.»d mmiomt RESULTS Catsral obar+sanbna.-Tbe whole tar/acetone solution promoted a general thiekening of the skia, but tuely produced lartmg aeeas of complete hair lost. The tu/aoton group showed more hair loa, tdkken+ng, reddenia& and ptoliferation of epi. theGum than the regular tar group. The acetone/ esoton group showed hair loss and thickening and eeabbiag of the s1®, but not to so great a degtee as tbosa aaimalt on tar/auton. The slon of the acetone controls remained soft, pGable, and nor- atal throughout the erperimeat A di$ereace in the rate of hair regrowth was aoted bet.een the e:perimeatal and control groups. Tarted animals regrew hair rapidly be. tween paintings aad required regular shaviag. The tar/croton and aetone/coton animaLs temained , d6auded for loaget periods, showing spotty and sometimes complete hair loss. The acetone cron. trob always kept a short stubble of hair; yet they regrew hair at a much slowu r.te than the aaimaL on tar or on croton oil. H'istologie sections on a separate group of CAFt mice at 10 days showed byperpluia, and byperkeratosis in 75 per cent and disappearance of sebsoeous glands in 100 per cent of the animals painted with the tai/aoetoae solu. tioa.t None of these ehaage.t were observed in ani• mals painted with acetone alone. Little ditficvlty was encountered becaux of drug intosxstion, since, as described above, the animals' taleraace to nicotine was inaeased. In one instance, however, unintentional evaporation of a solution apparently led to aa increased rnn. centration of nicotine and brought about a number of deaths in tbe tar/aoton oil group. At the onset of the painting proccdure, the mice appeared to be tn a partially drugged state and eslu'bited occasion. a16ne tremors following paintings. Thex tremors and stuporous states wete t'areiy observed afta . about 4 months of application, but frequently re- appeared in old age until the dosages were deeteited.. Papi(loma formation.-0f 81 tarred CAFt mice, 59 per aent-•48 •lemales and 44 males-developed papillomas. The earGest appearance wu observed during the 31d week, with a mean time of 56 weeks. Of the papillomas, 8.8 per cent re . The lesions were unifotmly distributed over the painted alea. Tweaty-thfee animals had mote than one papilloma (Table 2; Chart 2). A typical papilloma appeared as a. Brm, low. r Dr. {'ctoru Suatard', pemoal oberr.etioa. . Ap8 001241
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! ~ ~ ~; . ,~.... , ~p br,a s saozs had a _ vaaoas eam- : o : bootr.,, : too short a ~= Lit : to to- : fo: a rt~t --=be: of gW- !--oup. It is of _..:..aSCy a=- ~ ft= diEereat : ~:<7SL'L'::ed . m : ef exx.•se, be cposr3ie, to on rsice m dgzrtnes ; =abits. These ::as a p:iodue. _ tued ia'tbss •szmo•isceu- x. R^ahia the i Ld.~"""„0~°'.9 oY HaOt'LASTIC DIiLASLS cnr~.'sog= to be the saac Soi mousa aad maa. At the prmct time the majo: effort of d'ifferert tsseucb acatrs is bcia6 di- rected ta*•ards isalatng these spccifle fractioat The e?ees of a eomposs,d sho.a to be ar.iaogenic may be dne to the =matioa effer. of seve:zl sabttiuesbold a.bogesis y ............. o 4 s a u to t+ Miw"v r Y«~w M y~4M..• -- w, .. nn c:.+.. ..t.e.,. --- w, .:e rsa~ r.. Fuuu 20 Fust azoa appurua of papi7loau'.oQ a:eiiocsu. (M eu• cbossu prond tixiololicilly.) (Froa Wradcr. t: l., sr aLy) ot eo-ardaogeas. so that ao siagle compoacat of tho.wmpoua.d would be arciaogenic;'oi the effect may be due to miaute con- ectruloni of Ycty active pRinocenS, which upon isolation and coneeatadon a•ou)d give a high pcreentage of caacus At the present time one car.aot say which of these two possibtIities holds tSCe for tobaeq7 tar. 121 I : AP8 00II60
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52324 3665 0 . EXHIBIT 8
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• :LACCo x_a of tobicco iavar::ably a _~e p;seat, data aay a role in the :;g3 further d= ".;.,-cr SoaetJ as ts.ed that aacr :dag Tbeir early : an rrajor anar :s of 1yMpboca. : a.....-- rtabie. Spe- : tbe bladder and : .11aial statistial :: the r'amaca's are on the basis ~_. relatioa doa ::Mtj:7eaDe..KiL- :y:nesis so that it _Tbernvltsoe t eonsiimat v}it3 =•bi:3 can induce : evid:nce that h ~ ratber tbaa of 1 , xLOrLASTtc DtSLASLs pra..^dal iatr.-st 0: the otSer hand, an L.--nt wSic: u kaowa to ause tanzcr a aan and .vbi~ca' is also able to induce wcer h tbe a,xrimctzi.anical gairs iaportsncs, for it eaables us to etudy tbe aecbaaisa and the eaapoaeats of the ageat to a da- gxe not pesstble on the brmaa lereL It is important to tcaliz-a this, to tmderstaad the si;nifiaaee of the animal espcrimtais eotreatly being eoaducsed ia the 5eld of tobaao mearc4. The -rruurh is not being eaaduaCi to provs that saohag csusa long aacer in nsan, a proof which lies eatirely in the fie.ld of rtaristies, clinical cspcrienee and teognpbie d'istribctioo of the d'isease. }3e sigai5aar. of the animal rssearrb is ptimusiy to belp ia identifyisg tpcci5e a.^: aogrs rithin the tobacco.saok : If tobacco did not induce cancer in animals, this would not aeu gue the buman fiadiags. The fae thaz it does induce aac doa not prove it to be a cause of ancxr b man. Ho«exr, it' certarly adds to the evidese-., because in the history of eancer raeu-a' there has beea a a:aia deger. of eieattut relatioaship between r<genu that cause aar.r ia man and in the experimental anfraal Data on coal ars and eertain high•boJing-poiat va= serve u an'wmple. F::perioeatal tobacco resea.-.s' dates back as far as 19004 though tmtrl recently it vas not carried out oa a Ia =e sealr. An ocasional worker would tatYle the problem and then years would pass without any further work. Roffos-:J suaoeded in produeing a large nuaber of lesions on the etn of rabbits which be considered to be cancerous, utint different distillation ptod& vets of tobacco taa His cfiotu wera critidred, bowever, because by usiag tudistlIlates he exposed the tobacco to conditions quite naliYa t3ose eacauntred in bumaasmoting. Furthermore, Su1 giuras1 and Flory,u in attempting to repeat Rofto i work, were 119 APg OOflgB
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• i . , rr !' ' .,r. ( Irnrrr tr.,r•r •.'• :. rr•1 P,•' r.•it T lmn.!. f••nli.l r,r.!y 1:. lu r t'r•tll r• :,nrl •:I prr r, td 1:•. .•lu•rl r: in G•' fru!urr:rr Canr•.•t. (i1•,rr (I•7) .!alr. Ir:n•u•Ilil• •.•rir, rJ p:lli•mr, r.i/lt Iln• Iuui:. Un• il.liri•L:r), arcrr lu'u;}• ,ulnk'•rq dntl :Ihlr•,I :1!I t.rrr inlsrll•:.• \rrrh :dl of Illr•<•• in\•r.:i;a:rrn in dilTerrul „• r• part 111r' in, irltrot•: 14 ,nr•kill_ :n::••r:; 1 li, .t idl r'nln:: r trf Ih: rr,I,ir.r!cn' Il.r, r.'I'6c •° • 1.~~1~ ~•'n+'ll'.I}r•, c:rtur,l Lr r!rt, rr•/iut~tl ttit6- 1•t' !'.•• :i:•: IL• •:,ut!:in~ l::thil. vf n t•nltrul }.neqr. !'r n:,:'Lrr, rri icrrrm. in uma•ing unJ iurrr•,..r Fnluc Ir•••r. u+rd a lhird Inrllrvl uf rauct• of slunl:irn~. flt•; h•)r'rtlotl Iltal in tht• 1 nllctl SL•Ilva li•. •ri;.~rrL'r (ulj>elr:friiol. \s:a Qlirlr-Grnr lilnr, ;, u•I:ch in 1901 n< itl 1:1f1,1 (I::LI l.i!lOn aq ro:n- l+al, d ttr 5.7 Lillion). In ooulr:ISI, !l,r u.c or Cigar. t(rr!iuat 1,}' 1% prr ccnl during Illis inlars•nl (hnrn ,,IC in G.;} I•illioai. \IrX:,lly allril-ula.l ILe r,pnrt,'(l T•11:1•t: 1 t'rlcv t">Cl` 1v T.tICi~6 Tnl• 111• I1":I'- nl' 1'lll' pvul.Lt:Iltnmtrl I•s~ln.si= . tt:Pt ('I:.•.rr tnrrlr•• ln•?u \1c:.ILan?u r~~ rr t rc '\L.'r tirur 1 1'... 1 oc !r•• ~-r. \I,.rr It~.m G .~.rit. Inul tcl.rrlt+l Ilu• d.•cclupnrcut hf lu:m;• hnu•,r• t ltr.•L:,.nl L.. N')Itr.'h lie Ill:lpn<rvl :r, Carc1110111:1• I 1,11n.it I;ll, , 1-*lrrrv (1:') yl•I•JI:•1f tlllllllra r,f Il,l"lLlll 11, :111/1: r lt,•rtl•! In• 1:. or ;,;: r/L!.il.:nl•I iu l) ou: (uf':1: Ini•'r trt'+Ilcd :ril6 I Il;• Ii.l. n„ tarPnrltlr•Ilht•r!r••Inlrli\'crfi.(ilf.rliuunflrrltli•t•r••>r, ~n•1 \ri:6 t:lr rrld:tir•'•! b~'.:Inbl:in~ In!,:Prrr in Iri!o,. I,rl n• li•~: ILI t6•' nlicc, tv:o luumr, srrrr r!iagun,tlf 11,.yo:l. ('i~.:•tnt tnnu,•rr II r•arril..•n::,•. ;r:lrl li(It'cn a: It•1 . \fn,t of Ihr r.,I~LiI. dcer!t~prrl p;pillunr:,, :nr! a C:Inrt'r tlrn~' fCt: "oarrirmrn:,l•,i.l" - :ull u(, n,a Inc:rlr•l b+•:d!}• 6mh t•n:tnrtli\'v ti+•trt• :rtd Il~In• ~ in, fr,r 16r• T111:IIIC I,qt 11u•Y 11:,f Ilnl Itlt'I:I,IJ•r::t':nr•I IunrC big,r, dill urrl has'r t6r p::yn•r:I• of mlrr•Irirlt,l U. I l.a-tu,l r.•,• 1'llc,c Ilnuur. \trrr unl, Ihl•rrfurc, cun•i•IrrvA r.n:.; i -I'v cw:••. Ccr.,. iu Ufr rl•:i 1'Ilc rzprritnt•nt:,l rrirlrnrt• uu 16t• rlinlu:ic tuollral dI • nl!ir•fI1Cl' Of Ir.lq,l'CO in tallrt•r la tllott I,I'.•:I ,ln t••lilari:d iu Lw•mf (?1) cvnclu4.', \a'illl tl..Iw• ~Lno, thr t. i t!rrt:rtcn!Cnl t6at t6v trork ailh ;mim:ll< I::r• nr•I yet t•IcYrt•lI Clenrt'IIt' >IUoKlll'e• frntn xu•picion at an ~ t`' clin!ngic f:rclnr. • I lmbirr 1-f pnlirrds ,ril7r run•rr nr,A ir `1 w~ lllrprc,rul:.orkl6 ,in,.• • in,hJ•it, nfp :it'ta,\\•illla)+:Irlir-,ILtrI\pt ~ Cer\ct•rrcrdc~.•ro!s\itlll6rau.rr d.il•nf I:mli I ~~~ in a Mul::,l ;:'„ult. '_9, W: h:l\'r u•t•d Il.is Inrlltnd. 7'hrir \to:'~ mi!i IrrI :. rca•ic\call !:Ilr'r awl nill 6< ctnnluv.d \\illt ilrc Gndiu;•• itl Ihi• ropnrl• >n:riIOoS ir:rw•, ia rancrr of tLC lung In Ihr• oL::•rctd irt• cr'in Ihc u.,t• nf Cig.lrcllC•, 11uClu~:tn (17) al•rr ror:•!l:tr! :!IC i11Crt;t•C in f•nlmu::ir antl r=nP!c:',••'al C.:I:rcr \sith (11C IltCrt•a9Al IlPlnl!:Iri'~ 6f cigarrllr .ur•tdI;r. \lavy n:llcr tcritcts• accort)ill; l01I:Irl•••r (IS '• t••r::>',irral Ihal IIIC grcah•r iuridt•ncc of c:ut- ! i ) Crr Of t!a• lung qa. Ilnc o Ihr i:rcrva,c in tnln , up lu lpl1. T1t. ll,a.cr rt.•trlrtl Ih,- pr:,rlit'c :t: il-i• t• ~ hi,•or\' ,~ II, f I\'' '•••1 Clcrh t•It ' I ' l l J W e 1 • t} • P 1•. . 10+1r ~ • , • ~ L I Wl:,ia~ llla• of cac!: !cdit•ul al tiulro! :.•!:r.i•• ~ i.. ll W l : , i a sion Irc ulcau., nf :r riw•r: iunuairr =1•na 1: iu 1'::!'o I. In I:IIS. hr:. Il,d!•trd anrl 1)n!gali alunnr.lri:rd S,Itda rcrn:d+, •t•ht•tcd :d nutJoul, ni to .urh fat•• tl di:t^::•,•i•. 1'ht•>r urr:l 11.!rilc nr t <lulisin r o a a r . l f. • r.f l: li ll J i • i l d • i FIn. I - Lr}rri,:.rr.5:r s(.r•!irs.-1 ht•.c clitlir:d anrl sla- rr un lt l ularc., n arh c \cvrr pr•rt ct rrr•J.~n~ i. . li•:ic:,l h,tvc led nu:m• int'cai;.xtorr. Io up- p::..r!: pn -1d.:n t•Kirt•rilucutal!•: hr slwlciu;t t"Trrl of w•nlw nr:•f t:ctrncll nf I••i•,r,•;. It i, o'r: ntrv><:::;• in I!li• •r(+nrl Iu rrcir\e Ir. .! :ni! l)u• c~f:a•il: t•ulal ara!.. c.,ln't•i:.ll}' •intc snrokil:a \\'ilh p.f+:ie u!r•cr nud hr;lrt di•ra•r. '1'L••• rcrl:u. •11.• dala thu, ult::,in•••! a\vrc cn:lrrl aull p!nr,d ~ panch canl= Iv f.:ci!i!alr'an:d.•i: Tilc pl:ur•b r.a'I• ~ul•I•,•L~... act•rr!vvlrarvl!::Ir! I:at:,l!n! In• \Ir. \',•n:iyl •!::.r. • r 1 \G G 0 lillrfo n( Celcrar.+\Jr.:i: ;::; 4111......,r,.l, ..•. +t:p Ia.l.:.•> af Ihc lilcr.dnrr a:rr: git'Cn II\' ' 17' ia l:\ 11 a::.l SIrnl and \\'illil••iul (••',n in l'•I: . I' tvil! :1.'•"a.• hr:acallinn Illc us'rr•c:!1 liu,lir.•;•< : :L,• alc!t nn :I:.inr.d.•• linn. I J lllc :r.n0a rrce:,l• arr rcric\c rvd iu ILi, p.q,r: br , ur Ci~. rr: rl :. rlcr:Lil:,• Ihr :Ir•r•',i.didn of >u"•': n~ ::l:d (.::[C• r. ' I.f I Il ~hualtl L•~ 11• :• rI IIIaI IIIP It.l!1CI11, It: III:• •.Ir'!\,l,ll;l:: p'••:ia M1 Plr1al11lYl Ilo C!At•rI 6r olll\' r!a!:I Ch:! ,:r.r. iuo tuirc. r,d,~. antf r•Ild•it,. . u'rrv tntrl:. nt'••:!\• all I,f a'hvnl \roR• 1~'urt.l 11'.1: 1:rt 1I or olLcr \rar;. 111c p:airnl• r I„•i,,!;:,n•1 in Ir,.rl,•ccu Iar nr ln brh:osu.,lnir):r (•'~1_ arrr:nlulit:r•1 tlu:inel~>.:•:{1'.. . '~ . .~,,•.- . . . . . . ' l)1lrlal\',\'I'hl\> . • \ 6 . ,r r.:cu n1rL:i:it1l nulr a'.iI:gL• r-:rr.anur;l in r.:. ro;:i•t •t!Irralnl.^.uiri,a!: ?L:.ST.' :L'( ,tirrf../r.4 r:r•r•:tn•!.annql:-~iuastu.Ic,nrL ( !" • hal::ll'rl I111' t':Iri nl Lt!.• ,l, Ilti,. (l,r 1'rllrt::) rfrd:4t'OI i.: IIIY t'll•~i:C 1.( :1 rr•p• :111•1 rlVrl\all\'1•S frolll Iilr I:Ir trt.l iU•411r. lt/.I1V v.r11•VIrl1'•1 Ill N I W N ~ W trt tD J
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i SACCO :--ve=^-r== of •- •4a1 caa be .±ss sSaa•n ihat :r~•oaally to s: a ~od•zatinn ...:.ave beea _ssay,70G=. azd thar some : nr by wti_z':L x.-=tur tas aateral J sn:h tae as ~s of tobanen :cdseiy remove . : o: it thougb r. a giwca Slter, ;.:ie properties :c.e.Weaa r.a IdxtiSed a .'e~ hc-a1 NLOtLASTIC DIStASLS MODffICA:.ON OF TOIIA=. TA>: A m044adon of tobaca tar to t=ove or reduc the ar- ebogoie eotapoaeat may be poss:'ole eithrr by gTo"'`~•g mb&= ddit•tcttJ or by modifying its mtnufactun. It is kao.+n, tor ==pk, that d9IIcreat types of tobae.o have t diffe:att aioo• tine eemtret It eould similatly bq as previously mentioaed, that tnbaoxs pvwn in different parts of the world have diSereat ean. catntiors of the carciaogeaic eaaponeeL As was snted for the f>7ter ptobkas, the possibli utr7iution of modifying tobacco tar iue]f mrst await idca~t•Fntion of the aacrx.indudag con:ponent .uh fL at~ One of the gr.atest hopes at haad in the aaeat•toba.;a ptob- !e= is to reduce the exposure of maa to the rssr:aogea by mea:s of ti:e above measures. Eztensive ebemicaf and biologic efforts aost be d•ue`-.ed tnR•:rds this cod. Ia view of the faa that i:mg ea:.cr is already the most ~aunon cause of eaaer deaths in t5aks and that it is expected to continue to iaetease markedly o+e; the aea t.4rec or four deadea, it is most ur•,ent that we dusr oar tuUut attention to this problex. 711s ttrgenry is fur- ther e-p'rasusd by the effea that tobarso has an the deveiop- meat of cancer in other sitet Ia discussing tobacx as a possible cause of certain types of eaacvr in maa, one must suess, of eout:e, that according to our pracat kno.rledge thett is no single yuse. of cancer. Fsperi- aeataittideacl bis sbowa ihit a eurInovoen C6ty Induce asieet a oae s-.al: of animal and not in another 1ad ako that the same type of eaacer aiay be iadueed with entirely difierent types of 125 APB 001164
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C.:r..'IU t:nu. f- This report is bastd on a study of 1,fS33 mafe cancer In tables 4 and S the data are presented to shote the patimts and W5 male nonancer patients. The nncer relative prenlatce of lung and lip cancer amon; non• sites selected were lunr, lip, pluryn•c, tsophaeas, colon. sntokers and atttong citaret• pipe and citar snlol:crs in reaum and a scattered number of other sites. Ttu the patient population. There were re Torc~F;n a•• e oonancer patimts were those with symptoms rtferable as nunr ases of ltnt _anecr antcnE c•earet smokers to the same sites but which proved not to be due to u amottT aity oer yrou`Q -Pape smokers and ciear cancer. Only the users of aearets, pipes and cigars , are considered hert. since the number of patients n•ho T.at 2-Prer.lnrt rf Sroetnr Anes Lalt Ps(jjatr by I used snu8 or c.4en* tobacco u-as neilllplde. Sntokers TJPr af Swelur t.d Dmg,.reir Grenr and cigar smokers beause of this factor alone. Accord• ingly, comparisons should be made of ase•speci6e preva• Imee ntes or of prevalence rates stattdardittd for age mgagin` in more than one form of bmoking entered htto separate analysis for adt such form, so tlut the sttm of smokers is less than the sum of sniokers of adt type. The factor studied was a•hether or not the patient had ever smoked, regardless of whether he was a smoker at the time of admission. Over 80 per cent of all patients were smokers (nble I), Prevalence of sntokers, reeardless of rype, •did stot vary strikingly nzdr:ee past ttte age of 23 (aee the iecompanling figure). Pretalenca of cicaret smokers, however, decreased with ate, and that of pipe anoken and cigar smokers inaeased with ar. Obti• otuly, comparison of groups with differing age tontposi- tion would show different proportions of ciearet. pipe• T..au l.-Prnalrwr .f Smesrrr Ane.p Jblr Ct.rrr r.d Xe"arrr Parir.u by T7re el Sn. eFi.Q t•M.tt.crt.n..v .v•....__ ..... . r.fr.Nrn.tssaT• Tw.t C.M aaTrsn Ct.nn Trn CU.n cauw ................ 1J4 6w.w.f....,•,..... rI rt .............. •.... ._.. W 1.1 tTJ .IJ , . ut ut saJ r„1 tu , ns ril' al:' .• JN. rt.W/Mlwl. - t r MMtw RM+lan arte .M b 1.1#f e Yd a by applying the age-specific rates to a standard popa- ladon, The latter device nv adopted, using the entire series of 1,650 patients as the standard population. The si~t+18ant ohserrations are sutnmarised In tables 1, 2, 3, 4 and S. 'fltete xere more smokers among cancer patients than noneancer patients, because of an escas of citaret and pipe smoken among the former (table 1). This excess aas due entirely to the inerased percentage of eigaret smokers atnong patients with ancer of the lung and the incrased per- ceata~e of pipe solol•ers among patients with attcer of the ltp (nble.2). Thne diffetenees, in ttsrn. Rere oonfined to those .ho lud smoked eigarets or pipes for , r.rwaq. a ss.n. • YfT7M Cf.M rlrw t:nn at tn a.r..•u c.«. S r % r s r s r L,Ynrrtn.e.rN ts M.t .... at _.. taJ .... ttJ .•.. .o-. 0ban.MtRIT.u01 m rU IS YJ aJl S/ {pl t0~ f1i tAatM.h/tn........ u. C3 .S {Lt CP1 u: rw L.1 •.ri 01lffNrr.MR......... 11t r1.i rYl 1L1 001 W rNl rLr 1.01 WrrRwWr.,N tC Ml _.. .ai ~. al _. 'rJ ny_. Otnn f.net t.x..n . a/fl.................. MO /J ail 45.0 4,11 t:J rJt 16J 0.1/ t1rONnn.n......•,,. !t t/J rH lL l1 33.7 r0: N.e ..,~. otMrtwr.w.f....,••.. Zi :r.l CC IL/ LJI e:A .DI n. G^I • Jn nNdatl/d. smokers had no more cancer of the lung than did non• smokers. Lip cancer was significantly increased amoug ~ipe smokers but oot among ci`aret smokers. Caxs of lip cancer n•ere inerased also among cigar smokers. In table 4 persons who smoked more than one qpe oi tobacco are counted in each ateYory in nhle S-only those who smoked but ore type of tobacco are con- sidered The obserntioce in table 4 with respfct to lhn` ancKire the iime v tn fable 5; 1: e onl; ci`iret smakers shote any si`nfiicaitt incrnsa of lune anc.er ot•cr nonsmokeis: For lip aicec, only pipe sntokcrs shotc a sfgaifieant increase over nonsmokers. Ao osftet_site of.ancet,tlut nv included in this sntd•r aas found to be asociated nith any. piniatlar npe ot mtoldtt`. How•ever, not all sifes of cancer n•ere Tant 3.-Prnvlrvtto ef Ciprn a.d Pipe Snakrrt A.«erp 11dr PniarJ bJ Dnrie4 d S"ubi.r end Diar.euir Greep nN.ln{ 1f sfa•ahe enMCTt. utr.weO..r s..t nt m (3) tn a.r.«r c.". >.. a• r x.. r• r Nt•M aoan`n LYen.nrMt" .ttP' tfl u tir . 14 Mt OtMfMNRtfinrltWi41ar1wt rt W. OJt C LJ •OJI wt s«ns.eM ...... :......... Irt v w Oa M su OJt a..r.w..wr .................. rrt Ot AJ wm OJ ..rt rA. a.er,n L/rn.nrnsMt"t.nt~ 1W I rJ N ilt .... .... otrenMRtrrnrtMYS.MteOtIM 111 aa aet ta nJ OJt Ur awnMn. .................. Jt a uJ W n nJ ..r1 al"r.MnMn .................. tA U u U/ aT ItJ esl • Jn n.ww.a to eccl.ud4 the pasibt ltty thac the ~ram perretttage e bC "2Sr yars or more" sntol,'ers in the ancer groups , studied. It is planned to continue attalysis of the was due solely to the grater proportion of older persons records of the Itosuell Park 3(tmorul Institute to pro- in these groups. The fa3hsre to find comparable ditFer• ride data regarding aII t3pa of malignant rumors. eaees in smoken of less than tw mty-fit•e yars' duration ~ltese dan ind_iate that. in, a hosQtts( popuJ{ticn, lwt~ xtvn morq tfun stue u frequenily_ e of such ' taneee qt the n+a be d lash el sti rc ta eh aU t ewmtyfrve yae or km3tr (tsble 3). It should be noted tfut the prenlence rates of sntok• ers in eoltuons 2 sssd 4 of tabk 3 are a=e-standardiaed rates, obtained by applying the sse•spenfie rates for eaeh sub~totsp to the age distribution of the total troup of LtS30 aule patiasts. Since len;th of smoking fs relsted to a=e, thts statistial praecdure w-as neeattry ' ; t y y = ae e x t pe en o smoksrs which tnay be expected in an older populition. ant,a-ft tsose ~bo tiace imaked ci~ara}.foe cnmsy_five Funber study o( farje numbcrs of younger jssnmts tnaS ~a_rs. at"li n_Lmailt otha imo{ ers ot. nonsmttken, ot alter this obscrsation. tomparable a~e Pipe smokets apparently e~pcrience - tn N W to W in ~ .. .. . .. . . . , . . _ . W
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i 1 „ 192 11OLOGIC LfTECTS 0t TOtACCO E Caacc of the lunt. Edlto't•iL Ne,+ EnrL,td l. Adrd., a9:<6S, 1953. 9. C.ax>stsar, l. Broochiil on.'zo-r,r-A pudci:, Danl:k Mcd. 8+tlt. 1:37, 1914. 10. Q.txuutx, I, tlrxuoK,A, and Irxrot, E. Tbc Aaeccau in iaedeaa of earciaocu of the lumj ia Desaark 1931 to 195O. Brft. l. Caua. T t 1. 1931. 11. Cournks, B• T, Coorsr, R. L. wd Laaam A. J. Polyc~i: arboas ia si;arcrte =oke. Brfr J. Cmtec, E:276, 1954. 13. Coopa, tl. Pe:sonal eonmiaaiextiou. . 13. Ccot~t, R L, and LarescT, A. l. Tbe pnercoca of poiyaudeu 6Ydroarboas {o dpectte caoke. Chtnsirrry anE lnd+ur7, 59:12D3, I9l3. _ 13a, Coorss, L L, La+asrt. A. 1. aad WAUta, L E I~e pret • coa of 3:< beazpyrnc ia d;areae =ata. CAemisa7 and Jnduury, 46:141E, 1954. it. Camcz roa Tta IxrmAttotuz OacAxcuTSoxs or MLm'as• Sasxcs uadr the auspixs of the World Health Or_ranca• tioa cad United Natiotu EdnntionaL Sccnti5e and Cyl• • hcal Orps•ruioo. Remmmenduiom adopted by e,5e syco. posiam oe the eademiolo;y of ancsr of the 1uni. Gnar RutarcA, 13:471, 1953. 15. CaAVLa. 1.. F. diruenl Study of aiolory of Esrtr9c and esopha- Fe.al eucaos drt>. J. Cateer, 16:6E, 191i 16. Qnwtx, M. P, KLMruaAY, E L ted KrmtAwAY, N. M. 7he Iaddeaa of wsecr of ibe lung and larynz in urbaa and rural disWcts. Bru. J. Canur, 8:1E1, 1954. 17. RtTS.u, S.I, and Lovati•w. D. S.Ybe risk of developinS 1un= eaaeer and its reluionsliip to taokiap J. Nat, Caneer lnrr, 15:201, 1951. lE.,DATr; M. E.r pou. R, taQ 1Cz•ntAa.t, t+ 1.. Gacc of lual In ielatioa to tobacco. Brli L Cencer, 5:1, 1951. 19. Dots. Il. &onebiai aseiaoaa: Iaddefla and aetiololy. 8rit. M. J, Y:521, $as, 1953. 12t 20. Dcu., R., to L` 2L DorL, R B+ic 22. Dots,1C, o1 tb 23. DuweAZ, 1 24. EsY, I- 7. 2s. FssL+am . tooca I16:5 iSL FtSUtirl: =POFA 1954. 26. Fs.oeT, C. : Rc4a 27. Fur.+es., I c3ewi 2130, : 23. GaLAT $L:. tlu lu; 29. OsMS, 0. E 34 FiAUUOrm, : Du~aa 1316, 1: 31. HAatuorra. E 3L He>;tca. W. Indun.J 31. Hvctoc. W. 7Lomu.' It, IACOSUSOK, F. 19SL. 35. Kovi•mms, . rad:ot, : APS 001167..~ ~ N W N ~ . i
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0 18Z 1IOI.0GfC 27f2CTf 0f TOSACCO Preventive Mearurer and.Otttlook ItsFaniiag tobacco sraol:ag as a far.oria the dewlopmeat of s..^ae bt:.-aa exaas, it rer..uas to be dircvzsed what caa be ds sbot» tsis fr.diaE. Thtec mcuura pttsest thc=cfves. 3d0aYRATION o7 s)d0KIIt0 }tA3ITS Ia riew of the fart t5at aD statissieal szudia bsve sLowa tbz: the risk of dcvdopiag tuag eaaect iactuses proportIoaally to tye amo©t of icbs= smoked, it secnts t:fesr thut modeta5es of smot?ag ~sbits is iadiated. FL'.TRA77oN Durla3 tr_-at yan auay types of fihercd dgue:.tt have bert t:asufscmred. It is thought that ezposura to, let us tty, 70 Gtrf of a m:trrial is aot zs harafui u to 100 Gm and that some fdte:ed eigucttes remove 30 per eaat or itore of tar by rreight It rer vrs m be shoun wfietha tr.aoviag a smsll pcrr~atsge of twe w sTII dccreue the aniaogenie activity of this taiteziil. '17u aamt in this questioa cannot be givea uaa7 such time is we Iaos a•hit the oe:ive asciaoeeaic component of tobacco tar really is. It may be that a givea_ fittet wt7l seletsively remove tbe arci:ogea, or it may be that it on'll remove aoae ot it though it msy tennove some of the tst.l3esefots, whether a given filect is rottcssfut.in removing or nduaag the eareinogenic ptoperties of tobacoo smoke cannot be ascer.aiaed at this time. We can only hope that wbea such components have.beta ideati6ed a filter can be devised to ntffidently remove or reduce humaa ezposure to this eampoaeat 124 i Nt: i I u0Dff1CAT10N 01 A mosri5atica c C:JQgOnk C6QporC diz,ereatly ot by a: eatmpte, that diffcc tine coa=t It coul. tobaceos gmsrs at c~- oesttttioas of the a: filttt probley the p iue]I must a.nit ide, withia it oL'iIAOZ Oae of the r=te« ktaistoteduatsec of tbe above =zasu.: must be d'uee:ad toan aacz~ is alrendy the auks and that it is c ovsz the ata three a. d'ue..-t oui falleu att= tbes emphuited by th meat of eanca in othe In diuussina tobocs caaaz ia taaa, oae mt ptsseat,kmdw.iedge thc as,rsnI evidena bu sb. in oaa suaia of aaimal c type of aaecr suy be AP8 001163 r,
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. / S SMOKING QndHEALTH REPORT OF THE ADVISORY COMMITTEE TO THESURGEON GENERAL OF THE PUBLIC HEALTH SERVICE • U.S DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE Public Health Secvice .
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0 Public Health Service Publication No. 1103 fw n7.1f J. S.Mr1.r.Ma.f Ow....~ Dt C.../....u tK.Li.f Ofs. •.y' . ~ D yu. .G SGWS • triw i1.If
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0 014CC0 _y- S.^st t:•i= to iden- _. i%e E r eSor: vu : of br.~^yTCne in tar. _d:csn-wut5oubY _d Dot Idcatify b=- bzmMr, Coope: el ; ~•e7• r...a11 amotWis. :z.= ur. Cooper and .-USezi berspyrsae in Lelesnit"'s _ prpc tzt that bad :r_ d'ab•~nsaok• - =ad..• of cot•up dra- :: it is ~est dit5ailt ta si cigYSeaes. ;s-ss smoke is eon- a zd ^.Ie imporaae.: ::r' present in en• : of Ieu tban one patt 'e by L.iadsey.•' _s amoumt of be:=?y- : ezxrimeaul nnimaL of - bet%:?yttne miett :'s of the asalmal data u.~.-ogeaie efe.^t on zo =ok,e ia quaatities :, p:nious otirkea0 Se::c, wert: unable to :.-z in miee. Huaan HEOPLAfTtC DIfEAfEs diti," too. 3C'to iadieatt L"it the L'fC^ie C.7nte.^.t Of tobacco is tarlated to the eaaetr ineideaee, as taas>;.:d oa the basis of tbe gcflgraphic d•umbuiion in various par•s of the werid vbce the suse:re wateat of tobara varies signi5cant}y. wo asy ustme that we ue dealitig with a nsr.noge : so far rtideatified. Pteseat work iavo}va L-u5oaatioa of toba--z tu by cbemical cbtomatographiS ion esduaSe, and molemilzr dzs- a7ladon mctbods, in an atir.cpt to obtain fractioas which ue more potent t!,= the total tu. Tbe timeionsumipa fcatu:z in this puticalu sw' eme rests primart7y with the biologic testing pro=dutt. Tbougb there ue several possible saeg ceas- are; sue5 as those iavolving the disappcara: a of sebaccous glaads and possible cbaaga in Ducleoli, the btsie, asx= mnst come from wbetSer a glven frsction will induca ua.= in the exx.•smcaul saicuLu.u Pre:=i:ary obse:ndons by Wynder a cl: s dc=ostratn that the rcaovil of the nicotiae-L:- basic L•aetioa of ihe tu wiII yield a tar frxtioa whle5 is s•.ill a.ti- Dogenie to the mouse. Esperiauau vitb pipe lad eig:.- tar ars being ea..-:Sed out to dcter=ine possible diSe=cs from cga- rtm: tz:..In addition, tobac:y tars obtained &oct tobaeco ervam in differeat puu of the world ue being tei~ed to dcurminc pos, nblo diffesaees in euriaogenie aaivity.n In brief, czperirncatal work has demonstnted dgarctte tar to be easeinogcaie to the e;peri,.~catal antsral in a ty?e of tisrue siaslu to fisac involved In tasb It has beea poiatcd out that the significaace of the obserntio:' does not lie in proviac tbat'the nr does cause anar.In man; but this is the only poivble aei:: of idcntifyin; speci6e cudnoe_etu ia iobaaro tar, isolntioo of which may lead to signilfaat preventive me2ttires. . . . 123 I qp6 001162
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NZOrLAS:IC DtSLASLS be essodatsd c,ta the dcvdopment of o4e; typa of aa~ 4. The sigD;5rsac: of a:.:.-tal data provinE t mouse arcnoa Eca in dSarece saote lies a the fact'that it caables us to idea. t1y a+d isohu spcc•5c arcErogcrs }a iobacx smoke. It can oniy be asrc:med tst the hucaa aad aaimal areiaoteat arz idential. S. Pnvmttive meuwcs irclude modencon of smokinE habitt, production of "eRer..ive" filurs, aad modi6atton'of tobaeco subse~ueat to idearsation of aeeiaoges• :tz Bibliography 1• .Uat. R. Cana: of mouth: Care arainst toba=. Ne. YorF M. J. 102:1. 1915. 2 AMwtax Gurcu Soesn. Penaaal eommuaiadoa. 3. Ncsoa. K L P:idispoo(txrade Fakrorta fix Platteaepithci- k3rz:.."oa ia'bfuad. lfa?r uod Speiuro"tue. ]Eine stuistiscbe Untasadti.:i ata Af&tr•:a1 dea Radiumberaauu. Acra _ , radial. 1E:163• 1937. ~ txsstca, L, HoAC, tN, L.• RuxuttzN, 0, aad AaaAxs, H. K. peeypadoas aad d;arette raokiar, a: faaars in lua= eaa. x..ter. J. Pob. Remlrh• 4J:171, 1954. S. Btosct. A. TbearuiscSe und apaimatalle Uateaucbuatea = Patho;aais und H•utoFeaesis der malimm Gaeh- vulrtt Yirchew7 Arch. Pathof..feat, 16::3?, 1900. 6 CGxntst. J. A. Gsdao4caie alcats prescat ia the atmospEere aad iaddepu of pruaaiy luag tumouro in mta.'Brit..1. Pspa. Parh, 20:121, 1939. 7. Crnaclflnar in Srn Urban.Irrar of the (leftedSrares. Gacs; Mor3iditr $eies. 1950-1952, Rcpors 1-10, Public HeaAh Service, U. S. Depa=eat of HaaS• Fduadoa• aad weuars. 127 . ' ' ' . . . . . ' . ~ • 1 • • . f' ~ Apg 001166
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i THE SURGEON GENERAL'S ADVISORY CObI14iITTEE ON SMOgING APiD HF.ALTH Stanbope Bayne•Jones, M.D., LLD. Walter J. Burdette, M.D., Ph. D. William C. Coe6ran, MA. EmmanueI Farber, M.D., Ph. D. LouiaF. Fiaer, Ph. D. Jacob Furtb, M.D. John B. Hie7cam, M.D. C6arlea LeMaiuue, M.D. Leonard M. Schuman, M.D. Maurice H. Seeren, M.D, Ph. Dti lu
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! 0 Chapter 9 Cancer
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I t I • CANCER BY SITE-~'•oatiaued Lung Gncer--Cootiaued Retto.pecti.e Studin-Coatinued Pap Amount Smoked . . . • . . . . . . . . . . . . 155 Dunrioa of Smokiag. • • • • • • . . . . . . . . . 138 Age Started Smokias . . . . . . . . . . . . . . . 158 Ialulatioa . . . . . . . . . . . . . . . . . . . 1S9 Hiaologic Tne . . • • . . . . . . . . . . 1S9 ReLti.e R3alt Ratioe from Reaoepectire Studia . . . . 160 Ptoepecti.e Studies . . . . . . . . . . . 161 Ezperimental Pulmooary Cuciaogeaeau . . . 165 Attsmpu to Iaduce Luag Cancer with Tobaao and Tobecco Smok. . . . . . . . . . . . . . . . . 165 5ammu7 . . . . . 16S Suacapailit7 of Laag of Labocatoq Aalmall to Caxia. ageaa . . . . . . . . 166 Pol7c7elic Atomatic H7dxoeuboaa . . . . . . . . 166 Puuaea . . . . . . . . . . . . . 166 Pa.a3le Iaduatrial Cae®ogeaa . . . . . . . . . . 166 Summarl . . . . . . . . . . 167 Role of Ceaedc Facton in Caaar of the Luag. .... 167 Summ.r7 . . . . . . . . . . . . . . . . . . . 167 PubobgT.Motpbolog7 . . . . . . . . . . . 167 Re4ooa.hip oi Smoking to H6top.thobgical Changes ia the TraeheobrooehSal Tree . . . . . . . . . . . 167 Seamaq . . . . . . . . . . ... . . . . . . . . 172 Conduaioa . . . . . . . . . . . . . . . 173 T~m g of Lung Tomon ... . . . . . . . . . . . 173 Conduaioaa . . . . . .' 174 E.aluatioa of tbe M.ociation berroea Smoking and Lung Canoer . . . . . . . . . . . . . 175 Iadinct Meuuro of the Ai.odatioa ...... . 17S D'cect Meume of the Ai.oeSatioa . . . . . . . . . 179 Eaabliabmeat of A..odatioa . . . . . . . . . . . 179 Gu.al Signi5naea of the Aa.odatioa ......, 182 The Coasfateae7 of the Mweatioa. . . . . . . . . 182 Tbe Strength of the Aa.odatioa . . . . . , . . . . 183 Tbe Spedfidty of tbe Asaoeiatioa .... 183 Tempocal Relatioo.hip of Aa.odated Variabke . . . 18.5 Cobaeace of A+.oeiatioa . . . . . . . . I85 (1.) Rise in Luag Cancer Mottal}ty . . . . . . . 185 (2.) Sex DiSereatial in MoeuRq . . 185 (3.) Urbac•Rma1 Di&reaoew in l.rmd Caa«t Mot• taliq . . . . . 184 (4.) Sodo•Eoooomk DiSeteatiah in Lang Caaaer Mortality . . . . . . . . . . . . . . 186 (S.) Tb.'Dow•Rnpoaw Relation.hip . . . . . . ... 1.87 (6.) Imcalixation of Gnoa ia-Re4tipa to Type of. Smoking . . . . . . . . . . . . . . . . 188 HLtopathologic E:ideam . . . . . . . . . . . . . . 189 1?3 . . .. - ~ - . . . . . . . cn . , . . . . , . ~ N N W O1 J . r
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0 0 7at stotoctc trrlcTS o? rotAt:co eur:aojcs. S'uas7u data ue avas7able for established hur..aa ar.:..'oEeas. For an afeat to be rt;uded as ar::aogaie to maa. tsercfoss, 'tt does not have to induct ana: in every iastaax, nor is ft prer]uded that the same eancer a'saot be fndueed by aaother aaces-iaducinj sussnace. The fatt that a given aaimal or tttaa does aot develop ancc, even if exposed to a hown aieinoaca, mtut depend upon some meebaaim of internal resistance. Such resistaaee, however, does not deny the fact that in the presence of a ardao;ea the aaee ocurs .itb gsatu frsyucacy than in its abseaca. The apsat in question, thersfore, is not the only cause of the putiadar aneer. Hotsver, If this asent is associamd aith a aajot proportioa of the aaxs and If in its abseare aaar less eotttmonly develops, it bewcta of obvious impor.aace u a link in the developz7ent of the d'ueue and must be regarded u"a" cause. la liae sith these eoasideratioas and %ith evideace prruntrd in prrvious puaFzphs, tobacxo is eoasidered u"a" aa=. iaducag ivbstxacc for ar•ain tJpes of human acoplasr.u Pre. venti-.z masufes, bo•Yvar, ttuy be at hand to remove or u leut reduce these eIIees from tobaca. Summary and Conclusfors 1. Tobam smalin& aad espeaafly eigratte smoLiag, plays i a role ia the causation of lung cancer. Thix statement does not deny the role of other faaon in the developmeat of this disease. • 2. Tobac» use ako sams to incrsase siSaiflantly the risk of devekpmeat of cancer n( the lar)Ttz„ ton3ue, buaai mueosa, foor of the mouth, Etcu, aad esophagus. 3. Tobacco ufe bas so far aof-beea elcarly deaonstnted to 126 i . xic be auocatnd v9th t: 4. The ciEaifiaac j^s ia eiairstte r=l tify sad isoLta apcc oaly be assamed tS fdensial. S. Prevtmive mo: produetioa of `eSec sabs.-qocat to id=ti_' 1.MsLlZCL-cer M. Jc 10=:1 2. .V.asacat+ C.r+cc 7. Axnsou, li 8. P laraiaoa c : Uataasw+ u:. radloi. 16:1 • 4. Suss.o.v, I:••. Ho. CKwpuioez oer. d nK. J. F S. B.asex. A. 73e= ua' Patbos= vMssa YYeh 6. Camtss:u.J. A. C aad iaddnc Fspc. las1L 7. Cancer !llnm in 7 Morbidity SC! Savix U... we]fue. t.n Apg 001165. W
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x:ottA:TIC afsIAsta i 20. Doc:. R, aad Has.. A. 8. The aoruLry of doeors in ruticz ~ i :-7 and ::h•ns m't.:~'-smokia= habin. Brlr. M. J. 1:1lS1, 1954. i 21. Ibtl, R Moruliry fmm lunl eizec anuas nco•cmokct• Brir. J. CmcQ, 7:303, 1953. 22. Dou., I, aad Has. A. 8. A saufy of the aaiolop of cu--.:aoru of the hms. Brir. M. J. 2:1271, 1952. , 23. Duwou, Tf, Iuns eareiaoma in Ioeland. 1dnccr, 2.•215, 1950. ; 24. Esr, L T. Pcrsoaa] oommuaiadoo• 23. Euamtso, J. M. G;uute emoke aad the iaddena of puly momrr?• oeoplasm of the lung in the albino motw- Scicna, 116J61, 19J2. 2Sa• E,auMun, I. M, Ineidena of IunS nunon ia albino mies aposed to smoke of dfareue papc:. Science, 120:1000, 1954. -26. Fiotr. G M. Prrduet;oa of tumon by tabaeca aa Cauc Roemrh• 1:262. 1941. 27. Frmeu, H. L, aad Rouxm&t, L M. Etiolo;ie role of eiewinj sobaez in anee: of the mouth. J.IM.f. 116: 213D, 19t1, 2E. GXUs Buuar, ldoasrnr or Hzurx. Smokia3 aad anca of e5elwy Loodon. Feb. 12. 1954 (mimeo;sapberl report). 2S. Gsat '0. Brooehialksruaom und Tabak: Ursaebea do Lun- Ieakrebsea. Schwri med. Wchnfchr. 81:662, 1951. 30. Hi.uuoxa, L C_, and Hoax, D. Tbe ralationsbip bx.-t%-- hutaan smokins habiu aad, deith taus J.fJtf:(. ISS: 1336, 19St. 31. Huotoxa, E, C. Unpublished data• . i 32. Ffvuta, W. C. Luas ancst and the lobam smokia; babis• i lwdut._ A/.A. Sur._ 23~17_ 195C . 33. Hvtrt' W. G Occvparionaf 7umon and .tfGrd D'urasrt. Tbomu, Sprias6eld, IB. 1942. 31, J.cassor, F. CarGaoma of hypophuynx..fae rrdioL 3S:I. .1931. 35. Koviu>tsis. M: Smoking aad pulaoouy arcinoma: .(csa : rcdief, 39:253, 1953. 129 . AP$ 001~68
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• Cr4vCER BY SITFr-~'•oatiaued Stomach Canoer-Coatdaued P.,t. Cucino6eaeiia . . . . . . . . . . . . . . . . . . . 228 E.elnatloa of the E.ideaae . . . . . . . . . . . . . . 2Z8 Conduaioa . . . . . . . . . • . . . . . . . . . 229 SUMMARIFS AND CONCLUSIONS . . . . . . . . . , . 229 Luoa . . . . . . . . . . . . . . . . . . . . . . . . 2~'~9 Or.l Caaeer . . . . : . . . . . . . . . . . . . . . . . .233 Lar7az . . . . . . . . . . . . . . . . . ... . . . . . 233 E.opha;us . . . . . . . . . . . . . . . . . . . . 234 Urio.qB4dder . . . . . . . . . . . . . . . . . . . . 234 Stomarb . . . . . . . . . . . . . . . . . . . . . 23S R EFERE NCES . . . . . . . . . . . . . . . . . . . . . . 235 Figures • 1. Mortality from eanorr (all ute.), U.S. Death Re6i.tracoa Axa of 1900.1900-1960 . . . . . . . . . . . . . . . 2. Ase-adjwted mortality rates for nacrr-dl sites, in 17 co®triee, 1958-1959 . . . . . . . . . . . . . . . . 3A. -1{e.adjurted mortality nces for cancer of rix ritea in six 128 L"9 130 38. Age-adjusted mortality rates fdr cancer of six dtee in ds, edeoted coaatria-femaka . . . . . . . . . . . . . 131 .decsad comztri e. maka . . . . . . . . . . . . 4. Comparieoa of ap-adjaeud mortality rates bT ks. United Sutea, 1959-1961, with iaddeaee rates from State re;ia triee of New Yort aad Cooaeeticot . . . . . . . . 5. Tread. ia a6e.adja.ted mortality rates for aacer by sez- all sites and rapir.tory system in the Uaited Statea, 1930-1960 . . . . . . . . . . . . . . . .' 6. Tread& in a6e-adjneted mortality rates foe selected cancer utes by .e: in the United States, 1930-1960 ...... 7. A;aadjmted mortalit7 rates for eaaem of the lung and brooehue by birth cohort and age at death Wr maJee. United Suta, 1914, 1930-1932, 1939-1941, 19d9-1950, 1959-1961 . . . . . . . . .. . . . . . . . .. . . 8. A;e.adja.ted mortality racea for eaaxr of the lan; aad broaeh,u by birth cohort and age at death for female., United Statee, 1914. 1930-1932. 1939-1941, 1949-1950, 19$9-1961 . . . .',+ ., . . , . . . .:. . . . . .. 9. Ctade male death rate for lung eaawr ie 1950 aad par capita eoa.amptioa of d=arettes in 1930 in .arious aouatriee .. 10. Peroeatase oIpenaaf who ha,e ae:er rmoked, by wa and am Uaited Statee. 19SS . . . . . . . . . . . . . . . 132 136 137 138 139 , 176 178 12S
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• aa rator.oalC Erracss or ToSAeco 36. Xr+L M. G, and R•a, K V. S, P~cb1em of aaeer. lnd:an X. Ge&. 72:6T7, 1937. 37. Tawmofsu. V. R, aad Svxs4sai, B. Caaar ia f•elaaoa to oaaja: 3 ao*• types es 1^'•a..(rek lath. 40:361. 1945. 32. K7turor.tu, V. R. On1 aaoa in Boaabay, India: Rerie.• ot 1.000 oonseatire aua• C.anra Rurerrh, 4:313, 19+4, 39. Kr.rat, F. K E+ioioib Kattiaacfu P1'ue aa Podtlade 146 pozmartai Niekol'ko Poa.azot K Modolopeksj D'us• oe.u'!ce PI'ueaej Rakaviny. 8rarlrl. Lsh LrrtY, 33:321, 1933. 40. Ko'tar, P. FaLL H. L. M.asa. P, and Taoua, M. Aivmatic bydroearboas, 1• Pmcea in the Los Aapeles amo:pbe:•a aad the areiao=eairitry of ataospiu:ie ezmeo• AreA. ladasr• NYt. 9:153, 1951. 41. LvsKn+s. D. V. Penoaal corarroaicuion• 12, Luroi, A„ and K>'`~+.wav, L L Expe:imeaul produaioa ot eaaccr by uxnic &u. X.1, 2:1107, 19~r. 43. Lzwt. M. L. Gotsncr, H., and Gtxuuicor, P, R. Caa•.~ aad tobaeco amokiaj: A prcTiminur roport 1.(.lt.f, 143:336. 1950. 44. Ltvfx. M. L Tbe oesuneace ot fua; noce:.ia man. ACT.f, lntcrnac, Union etainrr Cenur, 9:531. 1953. 45. Ltvtx, SL L, Kxssz, I_ C., and Got.asrstv, H. S;•phla aad easeC: Reported rypbllit prcvaleatt amoat.7.'+61 eaacer piticnts. New York Sfau 1. Med. 4Z:1737, 19i.. 453- Lmasa7, A. J. Pcmoal cu=uaiatioa• 46. IaKaua IL L aad Dotmve. C. 8. Caacer ttudia ia Mam- • chasevt 2. }labits, eharutesistia, and nriroameot ot iadiYiduah witb aod .'itbout aaeer. Nr+. Enriand J. Ue4 I9d:4E1, 191E. 47, McCommu, R. B, Gor<cox. K• C. T, aad Jo:cu, T. Oaupa- . tioasi and personal taaoa in tbe aetiolog of tars:iaom of tDe lua=. l:aAenr, "1:63t, 1952. 4E. Mu.u, C. A.. and. PoxTTx M. M. Toburo-spokins babiu in aa Aar.i= dty. 1. Nat. Crneer fnat, 13:11E3, 1953. 130 , i AP8 00.1169 49, Mooxz, ca_ 1: 34 Mi.z:u A, SI.Ou,Ll e:ic SIa R=, A St R~ox, the uo. 33. ROtra l. aac 54. Rorro, A m,ed. S4 Rorro, . T.b, 55. Reno, .4 Taba S6, S•wow=r, CSIIC lun;. 57. Stoxr. R Tobas aC.C SE• Sstms, 4/. Itsti c avs S9. Suoaiu, K .( as. 1 60. VrrLL Su; Uaite:• ia;to~ 61. W,uza. R Caneer
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N10PLASTIC DSSEASLS : ~ 49• 1•SooK G• 1:, Baxz:xnv~ L L• aad Pr.ctst: = C• in:actal aacer aad the usc af dcwiaS tabaca.l. drr Gciat• Soc, 1:497, 1933, i :+ of ' S0 MursutF.liTohakmutbaucSuadL~jcawrei~omZtsclu, 1Gebrloneh. 49:57, 1939. 1=L ~ 51. Ouc, L M• Oral naca ia bael aut cbevsa in Tnnawtt: Its esfolon', pat3olojy, and crcu.•-uat• lancrr, ::375, 1933. :21. 1 S1s. Rea, A. 1: Pasoaal eocuauaicuion. 57 R:oaox, R. H-, and 1Caotorr, H. A wnsideratioe of some of 3ac I tbo tbeocia ts:uive to the aiolorv aad iaeideaz of 1am3 aace:. Trsv Rep. BIaL bfed.10:76, 1952. a re $3. Rorm, A. H. Durc3 Tabak beim P.aaincbea eatwickdta Car• cSaom Zudv. Krebt/orrch 33:321 1931 I , - . $4. Rorro. A• H• Da Tabak aL krebsazauetada A jem• Druuatr med• Wdwchr. 63:1267, 1937. Y of S4a. Rorao, A. li. Krcbsauuceada Bca:pyrcn, jrabaea azY 0 • _?.f, ! +:issa• ! I :c: of !•frd_ _: =a ! • .::u ia ,! 59:3. I I Tabalteez• Zuchr• Krrb:lor~ch. {9:Sdj, 1939• SS. Rono, A. H. Krebsecrra,rade F:nhcit der v ulucdco ct TaDaktecc Dryuchr med. H'chnxhr_ 65:963, 1939. 56. S.~.roKitr, D. A. GtLLLUt, A. G., a.nd Coarnttz, J. Tba w• tiuieal auocation barcra sa:olinj aad arr:xcu of t~sc Junj. J• Nu. Cencrr lnu.. 13: S'_37, 1953• 57. SooLu, R, SAru L A., HA r.LAP-, G. P. and Dot•oorr, S Tobara aaokiaj as an aiolocic fanor in disrum L•Csa• oc. Canto Rarorch, 10:49, 1950. S1: S.wrzu, W. F, Cooru, N. S. and tV».vu• E L BSolojial tar of fracdons; derived from cjarenc ataoke coodra- aaus Proc. Am..f. Canur RurucJ,, 1:11, 1951. 59. St:cn:xA• K• Observations oa aoimals painted with tobaeco tas• Am. l. Cancer, Eb:41, 1940. 60. VrtAt• StAtima• Special RrPoru: Caocec motsaliry ia the 13aited Statea. Natioail OSSa of Vital 'Statis:ie3, WaaD• iaStoa D. C~ 1950. VoL 32, p. 46. 61. R'u.tv. R. E the beaxprteae con:ent of towa air. BNt. J. Canco, 61:8, 1952. I ~ N AP8 001170 w N ~ W 01 q.
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0 . 884 Cancer Raseorch We postulated that tobacco tars have only a weak cucinogenic activity and thus would eshibit a long latent period. Therefore, we started with 8-14•week old mice. Our resiilta clearly indkute that if all the mice bad died during the fu~st Year of painting or if we had stopped the eiperimcat at that time, the data would have been much lest significant. For the same reason. we used a higher dosage schedule than had been used by previous investigaton.. Subsequent studies may show that aa additional increase in dosage may furtber ao• celerate tumor formation. Preliminary studies indicated some dtffietilties with the tu solution that contained nicotine. This problem could be overcome, however, with the de- sensitization procedure employed. The basic factors of the method, therefore, were to collect the tar in a manner simulating human smoking habits, toIlse the whole tar obtained, and to apply it in relatively large quantitita and for a long time. This approach may be in part respon• sible for the greater production of cancer in this investigation compared to that of previous studies. The possibility remains that the CAFs strain of mice may be paRicularly susceptible to the carn cinogeaic effect of cigarette tan. Effed of crofon oil.-Subgroups were painted with croton oil to determine whether tumor for• mation could be speeded up. as had been indicated . by Berenblum (1). The CtAFs mice received croton oil in mineral oil once a week starting with the 7th moath after the painting with tobacoo tars was begun. Because of a high mortality during the 14th and 14th months, in this group, the crotonoil effect on tumor,formation cannot be properly evaluated erom tbi~ esperiment, although within the period of observation no acceleration of cancer formation was noted. Tobaa'o anw meGlqld~dant)srett.-s+lthoug h~dant)srett.-s+lthough tSis study eptabl'ubes condensed cigarette smoke as a carciaogea for mouse epidermis, its activity is less potent than that of inethylcholanthrene. dfeth lcholanthreae of oourx is a.ery potent Y earcinogen, nther tbaa a esude substaatt in which sigaitieaat degree. Therofare, in view oI the W+• '~y one•half the I l d h data we suspect th+t •duction of broncs i d uuted, tave an umaa aa ma suspected carcmogcat may be .s.lthough crude tobacco tar is less potent as a tobacco coatains,specific careinogen(s). ~ t Oae carcinoma carcinogen than methylcholanthrene for mouse Which fraction°ot the tar is carcinogenic 6 n'4 *<as aad another o: epidermis on the basis of the number of cancers yet kaown. RoHo (31) claimed to have idenwi•J ~7geaention. induced and the length of the latent period, the benspyrene in tobacco tar, but this could oot 1' ii Control mice ; fact remains that over {0 per cent of the aaimal+ confumcd by Hint and his co•worken tll. ao'1 }ved ao skin lesioc painted with tar from cigarette smoke developed more recently that subtt6nee could not be deteri.~1. ; t>ag. 33. per cent Eb ' d t~ 0 carcinomas, whereas no lesions were observed in the control animals. Animal eernu Auman'dola-.~~m ~do not necessarily confirm or deav_}uman datt, aT• tSough bistorsea y much of our presen un er• standing of carciaogenesis is based on corol4ry studies between clinical and laboratory nsea+c5. The studies on ooal tars from Pott to YanuLgica and Ichikiwa and to Cook. Hieger, aad Eennanc serve u a classicaf example. In coal tar iavenip_ tiona experimental data confirmed the cLaird data. and thus added import wu given to both. A rimilu relationship now esats in the tobacco tar field. Here, too, a clinical association belwem mmoking and cancer seems established. It has bm shown that a condensate of this smoke may induce epidermoid cancer of the skin ia the experimental aaimal. The ampected human carcinogen has tbus beea proved to be a carcinogen for a labontory animal The most far•teacfiing effect of this obxrvatioo. perhaps, does not lie in its immediate relationsh;p to humaa carcinogenesis, but, rather, in that the proven susceptibility of animals furnishes us witb a working tool which may enable us to identify wd isolate the carcinogenic ageat(s) within the tan. It is an interesting and perhaps significant Grt that with the CAFs mice it was necessary to have an e:posure to the tar for approssmately one•hall of the life span of the animals (average 71 Reel•s'•. This agrees roughly with the previous finding ~~1 Wynder and Graham (40) that the matmum in• eidence of broncbiogenic carcinoma in the hum.n occurs after 30-33 years of smoking-about o0o- balf of the human life span. Tobaeeo as a ransaoprn.-It appean surprisimt R carcinogen. is p ydies by DaH and aenio content ot )Eac'ca tends to plsc vic element Heat, r ttiog agents have on in the ptoduc oted that clinical e =jsr•smokiag. pipe•: ; u possible factor the respiratory an• The actual carcinc remain to be i emieal and biologic tion are urentl: ideatify definite cz ving them, or at le tobacco, proper pr d. Such studies m. ?luman aad anima, rthe development c against cancer. St?LILtRY ! t. A cigarette tar c woking maehine w habits. The result x and applied to ~ eofi0mg.oft L• Control mice V t Of 81 tarred c that, in view of the detailed work carried on with .S,aomas. The first coal tsrs and its derivatives, relatively little wort ~k, and the meaa has been done with tobacco tars. Beeause tec.ot ~ clinical data have placed inaeasing emphasis on ; l Of 81 tarred mi< tobacco as a human eatciaogen, it is our hope that '%~ically proved ear anetir more investigators may approach the tobem (a observed in the netir problem ~ of appeanace w Although aeveral huadmd chemical aad tt months, 58 per c cal agents have been found to induce cancer m ani• faae weeks constitu mat+, each one of thex ageats seems to have aa Hte span of C.' specific carcinogenic action. Chronic traumak u• b{61y with the fac ritation as such does not induce esncer to ee.+ :=+n about S0-S3 ~ y ~per cent in the by. Waller (S8). Aa ezsmiaat5oa by study did not re~•eal a,. this i d i b , e a acco lar u to spectroxopic evidence of the known eartin~ 6?x it-The group of m aromatic hydroearbons. krsenie. in .ccep ''tion to the tar.. rJ. Ibr. Dn+sa+lc^me°"'°li°'' . ~"0t be properly e N W ~ ~ N A AP8 001244 ~^ •z•,,.:;.~r•'s..1:; . .
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52324 3683 Exhibit 9 0
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~ ~ SG ('rrnrrr L,rlut.• onr, a: is imlir•r1eJ ily tLr fnrl Il:,tt lhr at'rr~er aw of Ihr rmdrul /ucu te:m :IG.(I7 1'Cari. trl::l,:r II,••:,rcr:,~ra;,rnflL•:raurcrprlicnl:ua, ~7.° I 'rar... )l )r•rru. uufvrlul..dr Ilcll Ilir ram:lr!C• nLl•• .li!Tt•rcnr'o.. in Iht .uni,iu, hal.il, of ILr htu 41r•up• pu,n• , I•r In'upr:!t'rt'alu:d,rl hcc.ur•r of alr il:•nf:~rirnt ,t:•li,liral n1uJt••i: of lhr Jala. ' In tllt• prr.rc: It•nrt:, thc .n/op nf !.dirni> e•il6 t:auCrr of l6c li;r•!id nnl hast• an clrrar•J pt•rt•c•nt- e;C of pipc >•lunl ;•r.,. nur y Iorc In'rrt•Ulaer of crea• rvltc slnnker<.'CL,• rrnllicl in lht' fiudiugc Jto nnl ncr0~lrilv lurau llurl Ihrre i•:In trror iu t•i/hcr Ihr tcork uf I:rndcr- or in tlwl al the hrt•M•nt alI1L'ur,. 1'a.lliorl: in snw!cing cun• at Jificrcnl liuws uud amone Jiflcrnd ;tnops of pr•ople. If srnoking ia'rn •etiolov e factot iu eancc'rn l6e t•arialiuns in the srnol:in; 6nLil, trill l,c n'llt'clt•J by ehang.-s in Iha ty'pc or lhc il.cirlrurt• of Conrrr. Fur atr p•rtict, ls a! -ll:lt'u C•linic iu 1b2n, pipc.•mr,ltin; mao, • Ir,tt•C Isicn a sieniGc::nl cliuh;!k factor in rancrr of tllc lip. For tbe palit•cts of 1linrs Vclcc,n. 1lnapital i.l 1G4:-ia, r81ft•jtlre to BtIllllehl, rallier Ihan slnnlc• Ing, •11,ilrart'll lo b(- tLe tnajnr rtiningic faclnr in llt) eara'llloal.l. ' Iloffnl.vi (17) studicJ the suloking 1c•rhil: of •nccr paliculk iu 5.111 Pr•inqsco. ISuIT„1u, aml Iloslou. IIv founJ Ihal lhc prrcrntage of hcatty snrokrrs tt•ns 07, mmnu; ?i palirnt4 with tancrr of tlhc lung, ir amcmt; S: tt'ith lan'uSc:ll c:mcrr, end iS anlone 1'G with cancrr of Ihe lip. 791csr pt•r• •crnt::ert rnaj- bt• cowparrJ e-illl 43.6 h.avy smok• -e:; in 1.4 1G malc patients tcilh all hunors and j':.w ' in S9T mcn tcilh ehrunie di<rasr..lecordin; t o lhtse 6gures, l,c failctl lo nhtuin any drGnitC cnrrelalirn bcltetrn slnokin; and eanrw•r of Ihe rrspirr(tlr;• tract. IIc minilrnacd• hon•et'er, this nrFalive find• ine antl ctllribuIrrl it to lht•sulallsizc of thcgroupr, to the pc+o: bi+lnrit•s of Ihc zuml:ing hahils, an4 to the prr>tvta• of ol6cr CI iningic fsclora. Ouc al.~u luo tn con.citlrr ll:c .uilahiiit•r of the eonlrnl goup ia Considcrine the si;;nifieauee of lbC n,atit•c finJ• in.,t. Slrikine n•.uh: p1:1hc eorrc•latiou of Ian; e:nlrer ar I.•ntaS;iu;; nerr oblainctl hg )Iiillrr (•!rJ), who r / I ilqa•Ilultl,f• :Irn1 u:r. r!t I,• .. i,. Ibv c'lini~.,! • Ilu• lo Ir•: ~ rrl.tliuqal,'1, 1,. 'I'iu• cl,arm• . >Illi, i u,i.,•tl to a ••l,cl tLr t••.,•. , Lrct:,r, a, Ih, 1t i 1111'~!ID:f 1•f L,.J;, 1 , unr:r.rr,evr 1•.Ill ~: I+ nrlilir>:Ir,d p„i, . 1 11414-16a cuulJ 1.•. Thc srroml .1. , d•s tuntn.! and :: t•ndan• f:rrtun :,, tl:i, uorh il n.r• l +r:aly.i. o: L,d enu:•! I„• u•, - n,.ItrVl ,:rl.! f!:1:" irl.:u„1 raucrr r•.: a•'•i ..rrd tht• snlnkin~ hahila of s/t urr•ri n•ilh t•an• ticd ct•itlcnes• tL.lt a torrrlaliml i> eer of llie h/ng x•illl 80 unrnuJ in.liritluals in lhe niCcanl 1 thir,i un•I'iu,i. slnat' a"e Fruups as.111e ll:tiirnl...'1'he sroup of pa- lt'illi.. (::4) mummnrixrF t.cl! 1Lc cn:.r!u•Enu, th.: nr1 r.Iali,•:: tirnt< hnd p rt•Inlit4!y rerc hig-h pcrrrclaec'uf • nlny Lc dtauil fmm a:!ali.lir.d au,!t in t i. <LIt,. •:d .ludh•: iu •!.'i• ht•ary .mul:vn (:d1,ll aa tunlpnnd to 10.3) antl a mt•nP: "Cc•rulr.rri•na uf I!a• <r.wkiar ha!•i!• uf ci,. . t• •li_.ilnr. 'I'Lr r. currr.y,lndiugl; 1oa• li,•tcrulagt Of unu;nwl,rrs l'a, enmirarrJ 141 IG.:f). J Lr:n rsrilokrr tcax Jr• 'YI •1{ nlll• 1CI,(t IINiI al It•nsl i cif::lr5, Sli rig:l• rrtlrr, ur °li gul. of 11i1u' Inhar•ro. (iurliu. I. IrJ \l ii:!rr It• t•Intctlulr lh:d auukin„ i. ;ul inqw•r. 14411 r.ln.r n! ranrrr ut Il,r• tun". C:•,•,•ul Iy, 11'y'n:lcr:md Cralbnu (:I11; rr!•r•rierl to T-<rarrlr a cnncrr mar•lin;, ia \Jt'1;;1 !,it a cvu:p•Iri••m a/ tllc suwl.iuo Lal,il. 4 ?w! m:dr !u lirol s tri:l, t•:ultcr uf ll,r )nn;; aud of .1nll ruuln•1 ilnlis•i•hcJ,. T11r•y funlnl a rrl•,lirrly hig!i prrcrl,l.r;•a u! Irracy t•i~a. rcllC nnlol.t•r., (D.7.3 :r, c(nnp.:r,J br ;rl- prr rrlrt lhrn,rgliun!) an•I n luu• prrrrld:r:r ar Ir•naunLt-n ((1.,; 4% rnwp:lrcd In 11). a Irrat•y• Ci;;.rrcl!C +•ul4k:Y nas rlrfint.l :1< mlt uiw Icnl auu'r•? at IC,r..l :'U ci.-:,n•l tct a J:ry fr,t?U y r:rr,. 11'y•arirr alt•1 Ciral,-,uu. Iikc 1f iillrr, fnnud a rlrfir.ila• Ji!Tcrrna' in t!:t sluo!:• iug hnLil.• of palicula n'ith llulrnwlic c:nlccr::nJ d. Crnli rol Incn. S euml.rricon of llsc n•aAt, of Ihc di:.r.;cul iu. t•raligalurs tLo+ci tl:al .l(ullvr. lCyI:IIt: „r.d Gra- Ilam, aud the Iresenl anl6or.:p, cr ia lLr fln•lul;; that cancer of lhr lun;; is ai,oriatrtl tt'iUl heart• sumking. .jn inciJ••utal ul,screatiun lhat nr••r lit Jrricrd (rum t!:r culnlc:ri:vn i. !I,r Ji:`rn•ncc in t!,•..uw!,. inz 6:,hils uf 16r• rmrirnl Fruup< of liir t•srinrn• slu(lic9. For ccaulp!c, nUUauol.rr> i:: Il,: coldro! groups u crr °-1.i (1lrodcr•).9.} {\l u:cn. 1101' y'i,• drr auJ Cral:am), and •?:L9 prr crr.! {T,rr,(,l study). The ub>cn;d tIi15•rrnrrs art' ut•: surpri<. sincr ILcy t•rty indir::tt• th:lt )tr„•!.ino lr.,!r,l. tan ily di!ictt•nl In,r.ililic, mul at tiuiv:. 9iic fiuding strc••c, ll,r nrcJ for dclcra:i:,in :h: ;Il:n!:Ine 11:1bi15 of a Fui1BI,Ir• rolllrof g.nll:ir. Thc ta'nrk r•f 11twL•r,• and U,c o:!:rr< ii,riic'atr<m furtl:rrlnorc, lhal it ia not rnoo_h lo r•:c a Con!r,f Fmup for con,pa~i,nu u'ial tht• c:rn-r: p.rli,ul>. I: is also nCCa,ary to cLrc!: t•::ro:c!ly thr cun!n•! brorlp to sce lhat it is a suilalde our N'r thc ticular factor ttadcr inreslipation. ij san:G•irrg an r:iolrwlt frn':ar irr ra::rn!-Protu Ihia shldr and lraln llle u'ntla of ,lliili:r arJ 1Cpa• Jcr and Cralcun, it tn:rr I,r c•nlx•h:dr•t!!:~l t!r•rc i• n po.itice a•r.Ki:,/inn nr Mr.r!.tti:tn r! c.u,rr: of tttc lung a1sJ in;. The corrvl:lti•m ia niGc:ml. bul i, i: Liolr~ical.' si,n!lira:::'1 A sl.::,• lical study c•tnnnt 1••r,re t:L•:Ihrr tl:ctc i• a caa•,- alsrl-t'Ilod hcltlr••11 Isc,r f:,i!or+. .11 brsl. 111c sI./ti-!iral atudy C:tsl pntci,!r t•ir: mn,tan• li/ti, uf lun;; taurt•r tcith tl:...r ld i'vul:v! rz••• • Illilicrl hy cardnl (ur.l.lrua ~n,ur•L•fura:.lrrlia.lhr w:r.:n •u" rt•,ulh nf ru,ntiug' I•ul. r.u;::. •• tit'r. Ih,-r r,,r.nnl a!i••nl t•.:IuCi:,llt• iu 11,e t'y'••, uf >u........ r• 11, ') hr alatidi: al liluliu;> an• lhrn r:•!} t•in Ir,•• 52324 3603
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tbe bcnzo(elpTrene concentndon oi •ariow tobacco and smoke prepan• tione is only ru8cient to account for a.ery small part of the carcinogenicity of thex materials One hypothes:r ruggeta that promoting agenb present in tobaao and tobacco uaoke, such aa.arfoua phenofr• enhance the potency of the carcinogenic hydrocarbons so u to account for the biological activity of the tobacco produexs Further, possible synergism between low levels of the rereral known carcinogens in the tobacco condensates and extractt may alfo enhance the carcinogenic potency. Other Moterrn4 o/ Po.raible Importance in Corcinogenrcitr pESTICiDES paticida currently used in the huabandry of tobaeco in the United States include DDT, TDE, aidria, diddrin, endrin, ehlord me, heptaehlor, malathion and occaaionally parathion (we CLaptet 6). The firat two are used mote commonly than the others neater the time for harvesting. TDE has been detected in tobacco and its smoke (242), and endtia hu been extracted from tobacco on the market (34, 35). Aldria and dieldrin have been found to increase the incidence of hepatomar in mice of the C3HeB/Fe strain (68). Aldria Ia metabolued to dieldrin, and the e8ed may be due only to the latter er some subsequent metabolite. DDT has been shown to induce bepatomu in troat (153) and rats (253). The powible role of these compounds in coatributing to the potential carcinogenicity of tobacco smoke is not known (aee also Chaptet 6, eeetioa oa Pesicides). 01 cACCONES The laetooes have been auggested ie contributors to the etrainogenic e$ccsa of tobacco. Att.eatioa wu focused on tbae compounds by the dir ca.ery (74q 74A, 291, 29Z. 362) that Q•propioladane used u a aterilant and preservative, is carcinogenic for mies Coumar'vt, a L)adone, has been used u a common 9a.oriag in tobacco. Hydroxy- aad metboxpcoumariae are cooatitueatx of the led itaelf and are carried o.er ia the smoke. Also the ytactanq A•le.antenolide, is present in both tobaaro and smoke (354). The following lactonen (not auggated to be present In tobacco) have beein found to be carcinogenic for animals: p•laaooa (patulin, peoic)'llie acid, methyl protoaaemonin) and E•lactona (para.orbic acid lactooe and aAatoxina). RADIOACTIVE COMPONENYS Potassium 40, a,8•emitter, has been reported to be a source of radioactivity in cigatette smoke. The amounta of this activity taken into the lung, even by the heavy smoker, are minute when eompated with the daily uptake of K 40 from the diet. Furthermore this material is highly soluble and it is rapidly eliminated from the lung tissue thereby pre.enting any local build•up f 300a1. The a•p.rticle activity dua to the radium and thodum content of tobacco amoke, even for the besvy smoker, fe (eaa than one pertxat.of the atmoepheric radoo and thoron inhaled daify by aqy Individual (347a). A recent but still uapubliabed report holds that Po 210 Is the major soutx of radioactivity in cigarette tmols Tbe amounts caku}ated to be absorbed are high enough to merit furthv uudy u a pooible factor in earcinogenaia (282i). No data 145
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Contents • pap CANCER MORBIDITY A!v'D tifORTALITY . . . . . . . 127 Souron of Informatiou . . . . . . . . . . . . . . . 121 Sei Ratio . . . . . . . . . . . . . . . . . . 133 Geo6r.phic Yariatioa . . . . . . . . . . . . . . . . . 133 Urban.Rural Credienta . . . . . . . . . . . . . . . . . 133 Income Clua . . . . . . . . . . . . . . . . . 133 otccpatioa . . . . . . . . . . . . . . . . . . . . . . 134 Ethnic Groep . . . . . . . . . . . . . . . . . . . 134 Treada . . . . . . . . . . . . 135 A6eSpcd6c Morulity Fcom Lm; Caaar . 136 Effects of C3an;a in Lung Cancer Diaaaoeu oo T'mu Trenda . . . . . . . . . . . . . . . . . . . . . . . 139 CARCLYOGENESLS . . . . . . . . . . . . . . . . . . . 141 Fuadameetal Problems in Greiooseoeaia in Re4tiora to Iadoction of Ncopl.stie Chan6ee m Maa b7 Tobacco Smo6 . . . . . . . . . . . . . . . . . . . . . 141 'Ibre,bold . . . . . . . . . . . 143 Cu®o6enidt7of Tobawo and Tobaooo Swuke m AnimaL. . 143 Si® . . . . . . . . . . . . . . . . . . . ... 143 Sabecuaeoa+ T'usue . 144 Mech,aaiam of tbe CardaoSeaidty of Tobaora Smoka Coadeeuce . ........ . ...... . . 144 Other Mate:iab of Powble Importaaae in Carccwgea. iciT7 ' Pandde.. . . . . • . . . . . . . . . . . 145 145 Lactoaer . . . . . . . . . . . . . . . . . . 145 Radioacai.e Compooeat . . . . . . . . . . . . . . . 145 Sommaq . . . . . . . . . . . . . : . . . 146 Carcino6cacaia m Maa . . . . . . . . . . . . 146 Polye7die Aromatu H7droearboaa . . . . . . . . . . 146 Iodmtdal Prodxta . . . . . . . . . . . . . . . . . 147 Soot . . . . . . . . . . . . . . . . . . . 147 Coal Tar aad Pirch . . . . . . . . . ... . . . . . . 147 Minanl oile . . . . . . . . . . . . . . . . . . . 147 S omaa:7 . . . . . . . . . . . . . . . . . . . . . 148 CANfCER BY SITE . . . . . . . . . . . . . . . . . . . 148 Lpu; Caaoer. . . . ... . , .- .' . .. . . . . .. . 149 8lrioried . . . .. . . . . . . . : . . . . 149 Retroepe~sr.e Stndia. . . . : . . . . . . . . . . 150 Matbodobsie Yariablee . . . . . . . . . . . . . 151 Form of Tob.ooo U.e. . . . . . . . . . . . . . 15S 122
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52324 3686 EXHIBIT 10
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/ndustriol ProduC.t • • SOOT Carrcer of the serotnat in ebimney sweeps subjected to prolonged mas~ive ezposure to soot was a commoa 5adfng in the eighteenth «ntury (279). As many u one in every ten men eagaged in this occupation developed cm• «rt (204). Sporadlc eua of cancer of the skin at other sita such u the face (60), the ear, and the penis (264), were also described. The neo• plasaa usually oeeursed in men between 18 and 47 yean of age (213), possibly reAeetiag the early a6e at which boys catered this oaupation. Whether there is an increase in cancer in persons nov working in industries involving exposure to "carbon black" is being debated (108). Tlu c6emi• cal end physical propertiea of "arboo black" vay widely (109, 110). As early as 1922, Passey (266) -found that aacer of the skin could be produced experimentally by eztracts of sootL More recently, Falk et al. (111) showed that polyeyelie hydrocarbons in the "earboa blsek" were presat ia proeesud rabber, end rubber eareW were found to be earciao• gmic for the skin of mica Also Falk aad Steiner (109,110) found furaaee• type black rich in pyrene, Auorantbeae, banro(a)pytene, berao(e)pyreae, anthaathreae. benro(d, h, i)peryleae, and coroaene in partiela having an average diameter of 80 mp or larger. Tbese compounds were not prvent in channel blacks which have smaller particle si:e. The amoum of beuo• (a)pyreae eztracted from different wota.aria from none to 2 mg. per gm. (307). COAL TAl{ AND PITCH Butlia (SO) in 1892 described anoei of the skin as an oceupationai haud in the coal tar industry. The distillation of eotl tar yielda mciy di$ereat organic compounds with a residue of pitch containiag polyeyelie aromatic hydrourbons (300). Heary (166) reported that up to 1945, 2.229 of 3,753 cases of industrial skin uneer•rtudied were aruibuted to espoeure to ter and pitch, the rrmunder to mineral oils. The latent period for in- duedon of thia ppe of anar is estimated to be 15 to 25 yars. Mod reports about this type ot eaacer'ha:e come from England (166), but they have also appeared from other countries (44, 73. 231, 310). Somet (32) reported an interesting case of pulmonary cancer in a workman erpoxd to hot tar containing three percent benso(a) pyteaa. He estimated that 320 rg. of the arcinogeaic hydrocuboa could have been inhaled hourly. Car• cinogeniciry of both ueoeote oil and antbracene oil for the skin of workmen bas been documented (18. 39, 259). MINFRAL OIIS " ~ So-Called par.lrtn cancer is not aused by pareffia but by exposure to Impurities in oils used ia the process of puri6ation (165, 203). Recent work (321) b.u eoafirmed tbe vfew tbat refined pvafea wax doa not eontaia polydydic .rom.6e bydrocatbona'aod that it Ie not arcinogea)c: The duqer (neideatal to exposure to mineral oils hu been decreased by atraetion of arcinogeoie hydrocarbons with sulfutie acid (164,). Bioasaay of nuaetal oils indicates that their content of careinogens varies with their 147
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Illustration r.,e 1. E:amplea of cormal md abnormal broacbisl epitheliam . 168-9 of the oral ca.ity . ... 198 10A. Sammnry of results of tatroepacti.e studies of smoking aad detailad titea of the oral earit7 by qPe of etookm8 ... 201 11. Oirtlice of mtroepecti.e etndiee of tobaecro use and eYacer ef the t.rynz . . . . . . 206 ~ 12. Summar7 of inetbods used in tettwpecti.e itudiee of tobaooo uee and eaneer of the aopha`ue. .. ... i I 214 13. Summaq of results of rasro.peeti.e studies of tobacco uee and uxer of the teopha8va . . . . . . . . . . . . . 216 14. Summ+try of methods used In retrospective ttudies of smoking aad eaaaer of the bladda . . 220 15. SummerT of reeults of tetsa.pbcti.e stadiee of smoking aad eaaoa ofthe bladder . . . . . . . . 221 1SA. Summary of tesalta of teuuspeoti.e etndlee of dsuette dmakiriS aad eanus of the bladder Itt taales .: .'R24 16. Summaty of inetbods veed Ia 'tecoepeeti.e etudies of +mokin; and eenoer of the stomach .. 226 17. Summary of results of retrospective studiee of smoking and esnoa al the itomaah . . . . . . . . . . . . . . 227 L all uudia . . . . . . . . . . 149 2. Outline of methods used in retrospective stndis of smoking ic telatioo to lua8 eanaer . . . . . . . . . . 152 3. Croup eh.racterietiu m tenrwpecti.e studies on lung cancer and tobaooo u.e . . . . . . . . . . . . 1s6 4. Relatire risks of lung eanrsr for smoken from retrospective etudiee . . . . . . . . . 161 S. Mortality ratioe for lung cancer by .mok9aa status, " of .mokio{, tad amount smoked, from se.ea proepecti.e studies . . . . 164 6. Percent of alidee with selected laioaa, by &mokina status and peeemce of lung eaneer .. 168 7. Chan;a in bronchial epitheiium in matut ed triads of mala ooe4moken .ad smokers of digereat typee of tobaceo .. 171 8. Reladon between WHO and $rVjber8 daaiScatiooi of bm; tumors . . . . .' . . , 174 9. MactalitT ratioe for eaaexr of the lung by smoking elw and by type of tumor, US. Veter.ae Study .... ... 17S 10. outliae of retroepeeti.e rtudiee of tobacco aae and eanoer List of Tables I. Pspected Lad ob.er.ed deaths and mor..liq ratioe of cur• rcat smokers of d;.rettee only for alected uneer eitri, all eitn. and all causes of death: eaeh pro.pecti.e study and 126
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0 CdNCER BY SLTF.-C,oatinoed Luag Caaoer-Coatmued P•n Coardt+roooal Pi7potbrai. .............. 190 Gweae Con.iderasion. . . . . . . . . . . . . . 190 Epidemialo6ioal Coosidcrations . • . . . . . . . . . 192 (1.) Lua; Canar Storu)Sq . . . . . . . . . . . 192 (2.) Tobaooo T.rs . . . • . • . . . . . . 192 (3.) Pipe and Ci;u Smo7cia8 . . . . . . . • • • . 192 (4.) E:-CIgantte Smoken . . • 192 UcSer Etiolo6ie Faeson and Coalnnadio{ Variable. ,,. 193 (1.) Occapational Huuds . 193 (2.) Ucbaniueioa.ladoresliuooo,and Air Polluoon. 194 (3.) Pn.ioa. Ra.pinmq lnfeation. . . • • . . . . 195 (4.) Qthet Facton . . . . . . . . . • • • . . 196 Cocdvrioaa . . . . . . . . . . . . . . . . . . • 196 Oral Gaar. . . . . . . . . . . . . . . . . . 196 Epidemiolopeal E.ideaoe . . . . . . . . . . . . . . . 196 Cardao6eme.iw . • . . . . . . . . • • • . . . . . 202 Patho{0b7 . . . . . . . . . . . . . . . . . . • . . 203 E.alnation . . . . . . . . . . . • . . . . . . . . . 203 Condoaiow. . . . . . . . • . . . . . . . . . • . . 204 E ' emiale LLr Caaar 20S pal E.idrsu . . . . . . . . . . . . . . • 205 Ratro.pecsi.e Stndle. . . . • . . . . . . . • . . . 205 Pro.pecti.e Smd3c. . . • . . . . • . . . • • • . . 209 CLI'claoraftis ...•. ........... 210 Patboio67 . . '. . . . . . . . . . . . 210 E.a)utioa oI the E.idmce . . . . . . . . . . . . . . 210 T•mta Tnada . . . . . . . . . . . . . 210 Sai 1?i8eaeotiai ia Mortalit7 . . . . . . . . . . . . 211 Laeafiation ot Ledons . . . . . . . . . . . . . . 211 Condo.ioa . . . . . . . . . . . . . . . . . . . . 212. E.opha`eal Caaar . . . . . . . . . . . . . . . . 212 Epidemiolopd E.idmm . . . . . . . . . . . . . 212 Retrapecri.e Studies . . . . . . . . . . . . . ... 212 Psv.poesi.a Studins . . . . . • . . . . . . . . 217 Car®oaenew 217 E.daarioa oi E.ideaoe . . . . . . . . . . . . . . . 217 Condu.ion . . . . . . . . . . . . . . . . . 218 Uriau7 Bladda Canoex . . . . . . . . . . . . . . . . 218 E pidamiologal E.ideaea . . . . . . . . . . . . . . . 218 Raawpmed.e Stndiee . . . . . . . . . . . . . . . 218 Pmapeeti.e Seodia . . . . . . . . . . . . . . . 222 E.a)~ 223 o( tbs E.idcaos . . . . . . . . . . . . . . 223 Coedudoa . . . . : . . . ... . . . 22S • Stooseh Canaa'. . . . . . . . . . . ... . . . . . 22S Epidemioioped E.ideaoe . . . . . . . . . . . . . . 22S Reanepeai.. Scndie. . . . . . . . . . . . . . 22S Pewpecri.e Studies .. . . . . . . : . . . . . . . . 228 124
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i 136 FAISS A`ID hfISLEADOit3 ADVE&TIBL'Ia STATEMERT OF DR. JOHR E. HELLER, DIRECTOB, 14ATIORAL CAFCEB IRSTITUTE Dr. HEiI.aR. I do not, bir. Chairman. I am prepared to answer any particular questions Tou or the members of the committee may hare and provide any additional information you or others may wish. Mr. Chairman, I am, like Dr. I3urnev, a career medical officer in the Commissioned Corps of the I'ublic Iiealth Service. I have been in the Public Health Service approximately 26 years. During that time my activities have been primarily in the field of preventive medicine and public health. During the war I wns Chief of the Venereal Diseases Dirision, which played a very active role in a very active program. In 1948 I was appointed Director of the National Cancer Institute and have serred in that cnpacity since, u to the present. I am also an Assistant Surgeotl GeneralPin the Public Health Service and have been primarily interested in medical research ndministra- tion. Mr. Chnirman, I might amplify, for the information of the coni- mittee, one point which Dr. Iiurnev mentioned; namely, the proshea tive study nmonp reterans of Norlil War I, upon which no report hns been mnde. This stud,r, in my judgment, is a very importnnt one nnd one which should elncidnte many narles of this problem genernll~•. Mr. PLAPI\CF.R. This is still a statistical study? Dr. HELLr.R. It is a statistical study; that is conrct. It is prospec• tivo in the sense that we tnka n h oup of people and follow them to find what hnpper.s to them from the standpoint of health. There were approximstely 2!10.n00 mcn of World War I who had national serrice life insurance. Questionnaires were furnished them through tho cooperation of the Veterans' Administrntion. Part of the questionnaire incorporated smoking habits of this rroup. The questionnaire hnd other fentures, such as occnrntion and other elements which probnbly shonld be of uEefulneca and vnlue in con- sideration oftheirllealth history. The reason that recipients of national service life insurance were included is that when they die, someone claims the insurnnce. We have knowledge of the death fairly promptly. Frequently they die iri veterans' facilities and frequently post mortem ezaminntions are peiformed. We, therefore, have a fairly accurate medical hnok• grottnd upon which to append an analysis of these cases. These individuals, of course, at this age group are dying at an almost predictable rate, something on the order oP perhaps 5,000 per year,Rrth an increasing mcrnment each year: This study has been progressing now about 3 years, or 3.plus years. We have made some preliminary checks and the data which are de- rived from this study would seem, in general, to parallel other prn- spectire studies for men of th is age gronp. The importance of this study is that these individuals are spread orqr the United Stntes fieographtonlly nnd represent a eariet}• of or cupations. Of the 290,000, some 260,000 answered the questionnaires and we have now about 220,000 whom we are studying because their questionnaires are complete and otherwise statistically significant. .•. We hope'to make a prelimihary report on.th6"se data, these studies, probably next spring. This should give us considerable insight into I
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terian Hospital (New York City) (32'•), and the Massachusetts General Hospital (Boston) (54), now fmd many more lung einwn than in the past. (n the Massachusetts General Hospita). for esample, only 17 cases of 6ron• cyogeoie car,etnoma, 11 males and 6 females, were diagnosed in 5,300 tutoptia from 1892 to 1929 (autopsy rate of 33 percent), compared to 172 eases, 140 maln and 32 females. in 5,000 autopsia from 1956 to 1961 (autopsy nte of 68pereent). This American experience is consisteat .rith that tepormd abroad where rirtnally all patients dying in certain hospital services have beea subjected to autopsy for many yeus. Steiner (328) summarized several such series and Corn6dd et a1 (62) returned to the original sources and found the collective evidence to affirm a rise in the peraeot of lung eaneers foand at aeeiopay from 1900 on. The Copenhagea Tuberculosis Station data, reviewed by C)emmexa et aL (56), present an unusual apportnnity for evaluating the effect of improre- ntmt in diagnosis on the dme ttmd. In the Copenhagen mbercu)osis referral sariee, used e>Yenairdy by local pbysiaians, where diagnostie standards and proeedoro ineludiag systemade bronc3oaeopy remained.irtually unchanged between 1941 and 1950, the loag cancer prevalence rate among male examinees ineremaed at a rate comparable to that recorded by the Danish eancer regiatry for the total male popu)adoo. 71e tising tnend for lung cancer during the past 15 years thus is well doeomected. Tba inrreeasing frequeoq of lung cancer found at necropey from 1930 ooward, while of itself not deeisi.e, when eonsidaed in the light of ixent events reported by cancer registers, would support the conclusion that the rix in lun; cao«s did aot begin ia the 1940 deude, but wu a eontinuation of a trend begun earlier.. ' CARCINOCENESIS Tobacco and tobacco smoke contain a complex mirnue of hundreds of di8erent chemical components among which am (a) numeroue polyeyclic aromaria Aydro=bbna and (b) inor;mue compounds. Many of dtae com• pounda hare beea shown to be carcinogenic in aaimaIt For information on other components of tobamo and tobaeeo smoke oee C5ap0er, 6. Before considering the biological evidence available for the careinogenie effect of these components of tobacco and tobacco smoke, it may be helpful to review briedy some basic prindpla of aueiaogeaa(a. Fdrrn,tatEmu. Paoat.Eau m CutcacocENESn ax •RELtTtott To INDOCTTON OF NEOPt_ISSIC CHANOE7 M IVIAN HT ToBACCo SMOLL Cu+ninogenoie Is a eomp)es prooeea. Many fadors ate involyed. Some ara relatcd to the hoet, otbas to tha agenta.. The hoit facton indude geaede, sttala, and organ differences In sensitivity to given agenta; hormonal and other facton which modify sensitivity of eells; and nutritional state (1?3). The cbaratter of the a;ents involved in e.rdnogeneds varies gre.tly. Some agenta by themselves uuee irrerersible alterations in cells which may 141 :~..~r~. . , f W J ln
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r TALSE AND artst.EAaera Anvas`rX3ara 137 the problems generally of amoldng and health, among ot.her things. It mav give us some additional insight as to the types of individuals who die from whatever diseases, as correlated with their smoking habits. This study, gentlemen, is another, but probably the best prospective etudy, and one upon which we are depending to give ns additronal information to enable us to understand better and more intelligently the entire problem so that additional programs might be implemented, if necessary. Dr. Burney has indicated the statement he pr4sented on July 12, .ch ich reflects the best ,'ud fiment thnt we of the 'ational Cancer Iasti- tute and others of the Public Health Service are capable of rendering. We believe thnt this problem of smoking, particularly excessive cifiarette smoking, is one which needs to be brought to the attention of the American public as being a health hazard, the magnitude of which we are not completely prepared to state at this time. Previous testimony before this group would indicate that it is enough, certainly, to direct our attention to the problem, and for us as health people to undertake every action that we know to take in order to find out more about the problem leading toward possible remedial action. Mr. Chairman, I believe that is about all I have to comment upon at thif particular time, since my rols was that of being in a position to assist in answering questions, or present any additional information which }ou or your committee members may wish.fo have. Mr. I3r.A•rxrs. Thank you, Dr. Heller. Doctor, did you give this statistical study which you have under- taken with the veterans of the First World War-there is a larger group than Dr. Hammond hns in his statiatical groupint,*s. His Ivas about 186,000 and yours is ahnut 260,0(X). Dr. HF.r.LEx. hir. Chairinan, that is correct. Dr. Hammond said it was somethinglike 186,000 or 188,000. Our studies from a statistical npoint will consist of better than 220;000, although we have re- Xved replies from 260,000. However, we had to eliminate some as being not desirable to include in the study because of insufficient information or data which otherwise would render them statistically invalid, so that our study will represent 220,000, but is pretty well dist ributed over the United States. The Cancer Society prospective study is an excellent stud,r. and reflects a statistical sample of 9 States involving 394 counties. I wouldn't say this isn't statistically valid. I believe that it is. Our study in which vice are very much interested, and which we believe will be significant, is a larger national study and comprises the entire• country, and we believe that its real significance will be the additional number of post mortem examinations we will have which will com- p1etely define•the diagnosis which is made. However, the Cancer Society study did have a very good sample of post mortem examina- tions to indicate that correct iapnoses were being made and, there- fore, could be established as being statisticall, valid. Mr..Br.nrinx. You feel that these statistical studies do have-merit, and are positive in their findings? The reason I ask that question i.s that it was mdicated..by some of the medical witnesses last *eek that Dr. Hammond's study was merely a.statistidal study, and geve.na ee946-0T---70
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appear to have been published on the uptake by the tobacco plant of radio• active constituents from fallout (e.g. Strontiun 90 and Caium 137). Swnntarr Condensates of tobacco ttaoEe ate carcinogenic when tested by appliea tion to the akin of mice and of rabbits, by sttbcutaoeous iojectioo in rata, and by painting the bronchial epithe6um of dogi 7be amount of known carcinogew in agarece smoke is too small to account for their earcino- genie actlvity. Promodag agents have also been fouod in tobacco tmoke but tbe biological action of mixtures of the known carcinogens and promoten over a long period of time is not underuood. CMCL`tOGEPtESt3 tN D'1A.Y Despite the many tmoertaindea in the appiiestioe to man of reseurlt results in animab, the animal dau serve a purpose in indicating potential urcinogeaieiq. T3e greseeat eottaistaoey Is observed in rapea to those groups of ehemiul eompounds which are cueinogeaie in many speciet. Several of the poiyeyelie aromatic 67droearbotu preeeent in tobaao smoka fall into this category in tlut they are carcinogenic for most .aimal species tated. Since the rapotue of most human tirum to ezogenow factors is similar qaalltati.dy to tbat observed in esper.menal animaL it ia highly probable titrt the tissuea of man ara abe au.oeptible to the caicinogenic aaion of some of the same polyereJie arotnatie h7drocarboas. The resuka of exposing huttuns to pan pol7cyd3c aromatie hydrocarbons or to oatusal products mntainiag such eompoonds ha.e beea re+iewed by 1a11t et aL (108). Polyeydic dromatie Rydrocarbona Cancer induetion in maa by the appliea>ioc of "pure" polyeryelia aro- matic hydrocarbons hu not been reportad, laar (188) reported an epi• tbelial tumor oo his left forearm that appeared three months after termination of an experiment in whicb mice were painted with 025 peroent beaso(a) pfrme in beasede. Cotrlnl and Manone (63Y applied 1.0 peroent bc=(a)p7=e In betuene to the ddn of 26 .oluttteas in daily doea and observed the eequeatial development of erytbems, pigmeatatiett, desqnama• tion, and nrrecee. Tbe ehanga were more pronounced in older than in fatmger .oltmtoetL After 120 applications, the experiment was tamirtated , and the laioas re;rearad witbin throe mootltt &hoads et al. (286) de~ tcribed aimilar elsangee in hemen skin painted with the same eueittegctt. 1100 teeersible thaat;es were aimrlar to the fttitial ehangn in the tldo of mea who altimudI developed in.asis e.ncers followiog iadasetisl e:- ponue to euaiaogena. Cancer of the skin of tbe Fngers has aot_ beaa ta , ported in dsaetta emoists despite the'iatettse dixoloradon so oftea aeca at this site (212). Howe+er, spontaneous caacet of the afda of the bttgeta fe .e:7 rats 146 I
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* to repeat Roffo'a work, obtained negative rattltJ. wherau Flory (14) in a rimilu iaree-acale ezperi• ment obtaiaed papilloma.t and several lesions which he designated as "earciaomatoid%" in rabbit aarr after appQcation of a tobacco diitt7late (44, S0). Rn9o also used rtt; as experimental animals. He implanted pills of tobacco tar into rat bladders and noted cancer•like growths alttr B montba (29). ASa'.ally (45) appGed a water•aoluble product of aigarette smoke to the mucous membt+ne of the orsl e..ity and to the tongue and afon of rats All animals were lott within 4 months due to the toric- ity of the material, and no signi5cant ch.ngea were noted. MATSRLtLS A-*7D 3fETS0fS Tbe method of study employed in this in•etliration u pie- .eated in eome det.ilbeuun tbe .arriu6 naults J diduent worken ma7 b. a releetien a( didenat methods uwd. Ie this SMOKW(, APPARATUS ili~fllll~ .. _~.:e a • S4aeI4a IaY a • CC+CCMI14 rL1SK a•rM 6-o•+Ct•+SSCTMaha e -C6TTnM flLtta r • TI4ta 6 -YaC W Y Cast 1: Schematie dn.ing of tmokint tppantur rlud7 the Ittidint principle in mlk"6 the lobaae t.n .aa to.imulate bum.e amokin/ bebita J Sloarly and u pnctiat(y an poacible. It was felt that ae' change in temptntun or the nmonl of say (nctian (nm the ameke might Jtet the tQeR of the resulting tan. Therefore. a wed a rrnoka toadea+ate obtained fnm smoking eipnttu intermittentl7, aad" uah7te moet other ia.rtipton, .e did aet t.mon the aicetine from the tan in the Initial pbum of the erpaimmt fobaoto t4ei-A popular braand J domestie ti6anttee wu ared. Stnnl:np appeJue: Tbe lobatco tan wan tollicted in the folWinl mannn. Sitty dPanttea .en placed in a baltery J atau rmokine artor (A) tontainia f separate kolden for tea ci ntter eaeh and.G66ted .ilh 6 multiple jet pr bumer (t hart 1). Tbe emokin6 sems wen rotated aad changed la the eipMtee burned deen, keeping the appan,tu Slled with 60 eipntter at Jl times Jtn the eri6ioalla.diat. The arme .en plaardia peuiUea on Itan eaadelabn-hln teceiven an each of the two rmokinl aaila. 7hese tecai+eri'tete iointed pad too• netted to e wriere of tbrve l.000 mLTWr tlaeka (B) and aoa• neetin6 tubee an each unit. A'ntvum was eeeated b7'a emall elecaially drivts sb pump (G) (1J ev..ft• d'uplAftment J . ene air per pinutr at a vaeuum of 17 in. of mceeury).At lbd eteoud inttr.ab Mopea.hut valve. 6eued to a tbret r.p.m. } honepo•er motor (F), was tutomatrcJly opened for a t• tetoed period. allowiaa the .acuum from the air pump to be applied to tbe[entieneiat 6ulrr and ultimately to the burnfn6 et;' an.ta The toadeasin6 Euke .en eoelord in ienyl.d etaiole. Rnl taeir filled with u per emt etkaael end dn +n (D) to Inwa the tempentun to tppntimat.l7 -10'C. Tka rmake that faitd to eoodeare iaride tbe mnled tanb them Pe.d oa to a third task outside wA anit and Sn. talated with u ubcrtn jacket Tbe two oaitr met at a mmmee ou+t. J.acuumf at wkieh point a mltoe EJt,+ (E) .u placed in the Wte to protect the motaea fnm tu cona7eo. Tbo smoking time per eyartte seented fnm r+ e. / minata or from fs to 7: putTs per eNetts m a nta of tbn i..cnnd paZ per minute. Tbe ry' uettr tew butad dows te approamat.l7 a t-tJ~. lm/tk. Aa the rmoke moderwd. a dark browa wietom Bqud formed and edba.d to the Ilau appusttm .ilb dminuhelr density to the third ret of Lulu. Aller SO eaMU s.n amehed" a11 J the tat contained in the Ilar.an ebcee I}+ tettoa Eltu .ar wubed tl.aa with appnamatel7 700 n. -1 anetme•b7 d'umaatGnt aad corking the repante t4uea; pi.os. Tbia tu+ntone mietan was tk.a rtaed at -Y C. ie /lwitoppeeed battles antil m.da up into rolutiona . Prrp*aeion oJta»/oe eppiitanoti-Selutionr .en mede q ftult moatltl7 from SO eaMU J eiaarettea Tke ekoin af w- taee u a solvent for tbese tan wu based primaril7 oa tke len that aatoot wu knoWa to be noneutinotenic end etr btm euoe it .u found to be the but diaolcine medium fx t1: rubtana. The tar+eetcnq mistvr .u pound into Il6mL pornlw enperalla6 d'ubea which had bwa pnwioudr •wirhd: Qw. .en platad ia aa exhaust hood coatainin6 a ntatint fu 10 r houn.nd ..n then le(t oevni6ht-Ta ateeaee .dtbt el lAe reaidtul tu obtained ia this manaer wu 9.1 tm/t0o cipnttn An equi.al.at .olume of acetooe wae edded to each tmM d n* eidtul tat .ad this mirtm. (i oe= aatone to I 6m. Url c+. plaeed ia 1t7-O1. Pyrea tlwtnppend batUn and rtond n -f C. until wd. St3ea ared. small smouou of thrr ali.ttnni wen npouted into etbet bettlm to redun tke enpem lien of the aeetene at much u port3la EaPrri'nrnmt eo.dieieae.-Teeta tor the amount of nnem applwd on the rmoking ei6uette wen made at tkne Npe •! burning. Le., at the rlut of bvmiap at midpoiat. tnd et Mt rtaa., fa the 6nt rta6e the ma6eitude J the .atvom at tti atart of the pu11 was rent it Inm.aeed to a macmum.dv.! -/ mm. ei .ater and thaa fell te ae atets{e J-1 mm Th:. nlus was found to rNeb a maaimvm of -t mm. eod ee arm ye o( -6 mt6.la tbe recoad eta6.. and a marimam J-1.. with aa a.enp of -4 mm. im the butt eta6e. Temperatures a( the bmnin/86aretU a AUtbe tempentm' rtudi.e .en m.da with bvo eee.taatta tbermenupfin eas weldtd hot junetiou. \o. 14 pup duplu 6We+naleud ^n with a eombined reaistaxe of 1.4 oban/et at tLl-C. rd e \o. fd pu6o duplex mumel larulalad .ire with e nmbbd a- titt.M. J!f ahmr/ft at l1.1• C. wen vud. 'ike tempn' tuee .en registered oe a tutpended Pelvanomelee Prnu' ometerlyye null bslaan, nbbnted fnm 0 to ROOO' f• r-' burning tip tempenturj deponded ea the peoctntnt el etu thermocouple into the aembuttun aooe. TLe taulU of m trs' penttur reediep ranged fnm 716 to 6pP' C. Tte a+rnR I the 60 tempsrstun nadinp .u CSa' C. htb a toom ttm}Te' tunJre.YC. ~ tte Cemka~'. . Combuilioa tempenturv of tha ti6ue .: tempelstuw nn obtained by inrntid/ 93 Inp `°' eouplu up thnuPh the mouth aed apPnsiwteli ~ne'e°" ten of the length of the Si6ateette aad by then tmetin{v eiaatettt to the point wben the hot iunetioo of, the tMa' eouple would pau through the eombuitioa taoa Teao^e'r Tempentun studio wen eattid out by the M rt Ent'v,taia6 Co.. St. Louu. Sto o tunr ap to 66B C...en a n+adin(. however, was r6i Tcmpentutee J t!e c bvninl ti4arette: Tweet• .aeeapla .en inr.rt.d ; um. and the dlarvttet . %ate. Ne sppreaab4 rise rctiad uatil the ct6sntte umpe+ataro of the mokr lni.u[d wL-Que bu b bomo6eseom P, hrbride utia males by 0.4L8/C tM Odcoe H. lseksea 36 lfaiae)..itb ao eyusl d'ut auted at 6-11 wnk.t o( a All the mic. .ere koa. udm.L mek• and wen fe emlled oat Iupple_eeC a: d tke erperimea t, snime b ad Placed in i6di.idual t: Subproupt: Tbe C.1F, :w troupt• u. oae 6rau-, an ie eeetane and a aecoa. doae. Pnliminuy rtudie tiimaL .en ren.itive to tr ateneeotntd wlutioes. i aim to tobaoro tart, we he, thne solutions, the NatSC ryard. ~t+rted group s 7 J saetene. Tke dm I;1 ud finall7 to 1:1 n: xenred 40 m.e of lu/sae Prior to <eth painting t rm ebaeed 01 trter h.u etunted bwWul af tLe t hrbaved ana wit! a tio.. 4n ud. bePinninr at the wd to the tJl te¢oa met 0611 we shaved sod pe araa• Secee months afler oru4 i 4rnd min and 14 of t: an relr.p ted and liwea 1 rr emt erotoo reefa in a ~trmiae the teateino6ea. im te tobaam tus E84 u f eula snd females. The seetnmel7 Irritating to • ad alanlina. (bulq 'ditien. Tw6 moetht lat, 4lremt.olutioa Jaotao 46ee. aed Ri7nud. Iee tot Superla \o. 34, Sta tWh muth leu irtiutiar. +nte~ G the 1ltb month of pa r'3otoa/aCelCOe animatt eStetnoe rolution• pnp.; ~)wmat bydeoehlorio ar rea the animal bad aanpe 'ruhd etu. the .bele t. 6ma mat of the aaim "Lle tar/antoae eelutfon 'sEaiullT nta•ntar7 to r i dnit:otiaiud .nlutiou, s u the animaU beeame eP•latiop wen drne..r AP8 001240
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i • 105. 132. 139. 263. 296. 297, 338. 371, 373, 3ffi, 333). Wyuder et aL (382) appiied a SO percent soludon of cigarette smoke condensate in acetone three timea weekly to the shaved baek3 of mia so dtat each received about 10 gm, yeariy. The animals were usually punted for 1S mootlts More than S gm. annually was required for the induction of epidermoid carainoma and more than 3 gm, for the induGion of papillomss (372, 373). Siaa the areinogenie potency ot a smoke condensate can be altered by varying eoodi. tions of pyrolysG, the manner of preparation of the tar is of importance 1392). Thia may be one reason for the negadve reports (154, 262, 267, 268) encountered in the literature. Extracv of tobaeco usually have weaker carcinogenic activity than do the eondensates of cgateete ratoko (93. 340). Gdlhorn (126) and Roe et al (290, 293) have reported that wodeaeaea of dgamte smoke ba.e eocarciaogenic or promoting properties. It was found that the appiieadoa of a mimue of bearo(a)pyrene plus condensate of cigarette smoke to the akin of mia resulted 1a the'produdion of many neoplasms, whereas the sama wnceotraden of bemo (a) pyrone alone failed to elicit tumora. CeJlbora (126) fouad that the tobacco mmoka eondeasata ap• peared to accelerate the traneformadoa of papt7lomas to careiaomaa. Anti. careinogena have also been reported in condeasates of cigarette amoke (107). Nicodne is not usually considered a c+teinogen oa the baaia of aaimal etperimentt (346, 391). Remoeal of nicotine or otbar alkaioids did not diminisit the earcinogeairity of condensates of smoke for the skin of mice. The indueuon of pulmonar7 adenomaa in mice by aretitm (120) and of skin tumors in tnjee by ultravioiet radiadon (121) are not altered by the ' admin'utrat9oa of nicotine or some of its oudadoa ptodaeta.. Subcuianeous Tis,uu Druekroy (92) found that oigaretse smoke condensates or alcoholic oz• tracts of cigarette tobacco tegulariy induced sareomu in rats at the site of subcutaneous injecdona. The material was injected oaa weekly for 58 weeks, the total doee administered being 3.2 gm. The animals were followed, t)ureafter, until death. Approrimately 20 percent of the animals in each aperimseat developed the neoplaamL Drnckxy also carried out similat e:• periments with be=o( a) pyrene and found that the amount of this polyeyclic aromatic hydrocarbon in smoke croadensate or tobacco e=aett cannot account for more than a few peroent of the activity of the tobacco products This same discrepaney between the quantity of benro(a) pyrene In smoke eon• densata and the carcinogenic potency of the condensates has been reported by several iaveadgaton using the moux skin teat (92, 93, 126, 37Z, 390). Medranirm o/ tke Carcinogenicitr o/ Tobaeco Satoke Condenaate Tobacco emoke oontains many arciaogeaie polycyd3e aromatic bydro• arbotu (Table 2, Cbapter 6). 13easo(.)Pyteae Lt praeat ia much tager conermtruiona than is any other aroinogenia polycytiiehydrocatboa. The inability to account for the carcinogenicity of the'tobaceo produers, eseept to a very minor degree, by the amount of beaw(aipytene present was unantieipated Both Drvejtrey (92) and Wyndet (372) empitasued that 144
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0 Fda•,4E AND MIBLLADL':G - ADVS8TI8L'IG 141 Dr. Bvaxar. I am not sure too many of us read too much of the fine yrint on anything when we buy it, as far as that is concerned. Also, think there is a litf.le difference between taking a medicine for a periodic ailment as contrasted to the matter of smoking, which most of us enjoy and Which we do routinely. I enjoy emoking myself, al. though I smoke a pipe and have for about 15 years. I think there is a little bit of difference, Mr. Chairman, between labeling pills or other medicines, which we take occasionally for something, as contrasted to this. I would question whether too many people would read the fine print. 3ir. Br.Ar.vrs. Doctor, getting back to the main thing that concerns me, Dr. Little, speaking m op sition, more or less, on behalf of the tobacco industry-and we willphave to gct his exact quote, but, in es- sence, he said there was not only no evidencg proving there was any substance in the cigarette, or in the smoke of a cigarette, that would induce or tend to induce cancer, but neither was there anything in the smoke of the cigarette which might be considered harmful to the body. That iu his general position. Then he followed up in answer to my question, "Then why the fil- tersi" He said he doesn't know; he is not interested in filters, and regards them as a thing so inconsequential that they are of no concern at all. That is his position. He is a scientist, a medical man, an adviser to the tobacco industry. What we ara trying to find out, and we hope to do it before the week is over, is: ~iVhy the filters? If we accept your statement, that there is a rather substantial significance to the statistical relationship between heavy smoking and prolonged smoking, and thehigh incidence of deaths in lung cancer, if that is true, then how effective are the fil- tersl How effective are the filters? IYhat do they filter4 What do they remove, and how much do they removei What I am trying to get to, Doctor, What is thd rtsponsibilitT that falls u.pon those of us now representing the Government-you in the eaecutive agencies, we in the legislattve branch, in protecting the health of the peo le and discharging our responsibilities in protect- inq the health ofpthe people, in this case from false or misleading advertising, that encourages them to smoke filter-tip cigarettes, that gives them some notion that they are being in some way protected or that something is being filtered. What is our responsibility, or is there any Federal responsibility there T Mr. Bmtxxz. May I refer that to Dr. Heller, Mr. Chairman4 Mr. Btarxra. Dr. Heller. Dr. HrsrxR. Mr. Chairman, as indicated in Dr. Burney's opening statement, we have not ourselves undertaken any definitive research in filttrs. It has been our viewpoint that there is a desirability. in elucidating the fundamental problems in this question of excessive smoking and lung cancer, which by no means depreciates the possible Vtance of filters. e do not know what in the tars cause, or represent one of the can4es, in the producing of lung cancer. Filters, for the. most part, are made up of cellulose acetate, and, as I am informed the tightness of the filter is the "gimmick" involved in filtering out the. smoke. .. Obviously, since the tars; or the condensates'from' the smoke contaia the material believed te be carcinogenic, anything that filters or strains
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0 FALSE AND MISLEADING ADVERTISING (Filter-Tin Cigarettes) TIIFSDdY, J4LY.23, 1957 HOUSE OF REPRESF_qT.%ITVEs, LZOAL ANO DIONLTAR7APFADt6 SCRco![]IITTEE oF TEE CAu"'''^'''T' OY GovER\ SIE?1T OPERATIONS, T7aahington,D.C. The subcommittee met,~pursuant to recess, at 10 a. in., in room 100, George Washington Inn, Hon. John sl. Blatnik (chairman) presiding. Present: Representatives Blntnik, Mrs. Griffiths, Mender, and htin- ehall. Also present: Jerome S. Plapinp r, subcommittee counsel; Curtis E: Johnson, staff director; and Elizabeth D. Heater, clerk. Dir. &...M . The subcommittee on Legal and bionctary Affairs of the House Committee on Government Operations n ill continue with public henrings on the role of Federal Govenmient agencies in the effective administration and enforcement of la.v and reo lntions per- taining to false and misleading advertising. T71is morning we have for the first time the Government witnessms, we have our two top medical authorities. We welcome.you, Dr. Burney and Dr. Heller. We h'ave Dr. LeRoy Burney, the Surgeon General of the Public Health Service, Department of Heallth, Eduont.ion, and Welfare, and Dr. John R. Heller, Director of the National Cancer Institute. The first two hearings held on Thursday and Friday of last week, Doctor, we heard witnesses, pro and con, from the professional world, the object being not togo into the medical problem wit.h a view of try- ing to make a medical determination. That is neither within the com- petence of the committee nor within its legal jurisdiction. However, we do feel it is essential and vital tlmt we have, althou gh in somewhat summary.and general terms, a complete statement on the pros and cons of the problem of the effect on the health of the public. To do that more correctly, and in better perspective we felt we should have a background of the latest available medical opinion on the subject, and agn' lnst that we can get the true relative proportions of the nature of the problem and whether or not there is a Federal responsibility for you men in the executive offices, and for us in Con- gress in the legislative field, to do something about it. We will first hear Surgeon General LeRoy B. Burnav. nr. Fiurnep, we welcome you this mornin~. Will you please give us s brief lntroduction which•I am stlre is Rel] known to most of u°, but for the record a brief summary statement of Sour bnckground and your recorf d'of experience, and then proceed with your statement. tST
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FAL'4E AND NtLSLE.1Di\G ADVERT1Sf\C 5.55 neponr<lbllttY to bring health facts to the attentlon of the henlth professions and the publ lc. "lo June 1p34, units of the Public Iiealth Service Jolaed with two private roluntary health orcanlzatioas to establish a scientific study group to appraise the available data on PmokloR and health. We hare now reviewed the report e( this rEude Rrnvlr and other rttrnt data, lnrludlnx the rewrrt of llr. F3. C. Hnmmond and Dr. Daniel Horn oo June G to the American Medleai Association in New Tork. ••In the light of there etudlee, !t Ia clear that there Is an IncreaslnA And con• sistent body of crldence that excewalve cigarette smoking 1s one of the causative factora In lung cancer. ••The study rroup, appralittng 28 Independent st;tdlcs, reported that lung canrer occnra much more frequently amonv, c:'arette amokenr thao among nonemokerrr, And thrre la a dlmt rrlr;t:cuaolp between the Inctdence of lung cancer and the amnunt rnrn~::. •17t1s ftnding sc•as retnforcrd by the more recent report to the nylrr.. linmmnnd nnd Horn. ••Jtuny Independent studies thus have confirmed beyond reasonable douht that there la n high degree of stntlstlcal as.ociatlon between lung cancer and heavy end prolonged clrsnrette emoking. '•Surh evtdem•r. nf (VIarNP. hl lnrael,r rpldnalolnRlrnl In nntnre. It ehmtld be noted, however, that many importaat public health adrancee in the past hare been derelnprd upon the bnale of etntl.tlcal or epldemtologfcnl Informntlon. The ttndy group ntso reported that In laboratory studies on animals at least flre Indeprndent Inrestlcntora bnre produced mallt'nancles by tobacco smoke con• den.ntca. It al.o reported that biological ehnnzes similar to tho.u which take plnre In the goneaa of cnntrr have been nharrni In the lunga of heavy aumkern. Thu<, rnnie Inturratnry and htnlorlcnl data provide contrthotory eridence to .upl•irt the concept thnt excessive r.nmktnc t.r one of the causative factors In the Inrr.nanc Inrldentw nf Innt' cancer. "At the enmO time. It la clenr that heavy And prolonRe&clearette emoktna le not the only cnure of lung cancer. Lun¢ cnncer occura amonR nonsmokers, And the Inrldenco nf lung cnnrnr nmong rartous population groups does not alwaya cnlnrfde with the amount of cigarette emoklnc. "The prrcir+4' nature of the factors In heary and prnlnnced cigarette smoklnR which can cause :unr; cancer Is not known. The Puhile Health Service supporta the rernumrcndntlon of the study group that more research ly needed to Identlf,r, Lnlnto nnd try to rlindnntr the fnrtnrs In extrnntre rttarette Fmokin2 which can cnn.~ cnnrer. "Tho Rervltw'nl.o aupports the recommendnttnn that more research Is needed lntn thr role of air pollution And other fectorsyp•btch may also be •cnuaes of lung cnncer in man. "Tn help olseeminate the facta, the Public Health Service ts sending copies of thlA rtatement, the study group report And the report of I)r.. HanmionA and Ilnrn tn Rtnte health ntllcera and to the Amrrlcnn Uedlcal Ati.oclntion n•Ith'the reqne.t that they crmador diatribntinn copies to local henttb otRcers, medtcal eoetetlen And other health groups. "1t'hlle there are naturally t1lRerencrt of opinion In interpreting the dnta on lung cancer And clgar!tte amoking, the Public IIenlth Service feels the weight of the evidence la lnereaaingly polntlor in one dlrectlon: that excessive smoking Is one of the causative factnrs In lung caocer. "The Servlee notr•a that the etudy group found thnt more stuft Is needed to determine the mennlna; imd significance of nny etatlrtlcal as.•ociatlon between rmnking And heart dlren.e. The study group reported there is no convincing hlnlnt;(cnl or citnical evitlence to date to indicnte thnt smoking per ae la one of the causative fnctor. In heart dlnea.e. Although the report by Drs. Hammond and Horn hu. since provided addltlonal data nn thla subject. the Service feels thul wuro xtnll+tlrnl ruul hinlnl;lrrd r1nht 1.4 ncrrled tn rxtnAllxh it detlnltP MpItlon on this matter." ~
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0 142 FALSE A.~TD M1SLEADIING ADVERTISniQ these tars would prevent this material from Rettinfi down into the bronchi, or the tubes of the lungs. Now, the original filters, I believe, were found to filter out some- where in the area of 40 to 80 percent of the smoke. I am informed that the company thnt oriXtnnG-d this filter found tltnt the cifiarette was not as acceptable to individuals as they would hope because some• thing was wron^ with the taste. Thcy missed something. Therefore, as I understand it, there wns a loosening tip of the filters; the mauu• facture was so adapted that smoke could get through more freely, and tars nnd smoke condensates would go through. I am informed at present that filters will eliminate something on the order of 15 to 'd0 percent of tho smoke and, therefore, a prol wr• tionate amount of tar. It has also been stntcd, ns you hare heard from prerions ~riti~c~=es, that in order to compensate for the possible loss of taste and the loss of effectiveness of cigarettes, that some different types of tobacco were introduced, and in some instances, that result was an increase in amounts of tar as compared with that originally obtained in nnn- fil ter cigarettes. I do not know whether or not this is true. We have not done this work in our own laboratories, but I believe the work has been done by responsible individuals ttnder cirrumstances which would lead one to heliere the work is good. We do not know, Mr. Chnirman, that any filter can selectively sort out that component or components in the tars which are responsible As I related earlier, there mn7 be n promoting factor involved which along with the tars is responsible, or partiall,v responsible, for Iun~ cancer in certain indi~•idunls. 'fherefore? a^ far as my knowledfie goes, I~ronld say that the important thing is to find ont what is in the tobacco to chemicall}• characterize those constituents which we be- liere to be incriminnted. If it is possible to filter them out, I titinl• it is perfectl•v nccertnble and proper. I do not know what is inrolred from the adrerttsmg viewpoint, where filters are concerned. I do not know the claims of companies for the virtnes of filters, whether it prnrides a cooler smoke and that sort of thin fi. But I do know that we are intent, as scientists, upon obtaining the funtlamental hasic information concerningthose thing's which cause or tend to cause lung cancers. Then the proper preventive steps can be tnken, and we hope soon. We have no desire whatecer to ,oin the antitobacco leatpue. As far as we are concerned, if people enjoy cmnking, nnd can do it with little or no haznrc~, that is perfectly fine. 11'e do feel, however, that as long as there is xn agent which is pos- siblv causing lung cancer, or is one of the causative factots2 we should undertake.studies nnd to nssist in supporting studies Rhtch will be directed toward finding out these compounds, or :he compoundd in- vol red in this process. Mr. Chairman, I mm not sure sour question can be completci,r, directly, and lhoroughl}• nns~~•cred, butt that represents a rtnsonable attempt on our part. Mr. Br.AT.nx. You irould; then, recommend ittrther research on the part of; the Government to find out more abotit.whitt sub.stnnces 'in the cigntrtts cause cancer,.end perhaps how that sttbstance may be t•rnored or rednced to protect the peoplel
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r µreinogeanis or lower the threshold to a kaown eueinogent. There is al.w some riidence for the presence of amicarciaogeaic aubuancca in tobacco utd tobacco amoke (107). Thruhofd In any aumtmeat of eareinogeaieity, dosage tequira special considera. doa. ne smallest concentraboo of benzo(a) pyrene known to induca carci• noma when dissolved in aeetone and applied to the skin of taice three times weekly is 0.001 percent (380). Subcutaneous eaneer follows injeetioa of only 0.00195 mg. of benso(a)pltsae in 025 ml. triaprylia. Whether there is a threshold for effedi.e dosage of a urcinoganie agent is contro• aisial at the prexat tima Ibe erideace for the ezisteace of a tbteehold has been summarized by Brva (43). When pulmonary tumon were in• duced in mice with dibenuntbraeene and ur than by Heuon et al. (172, 232), a linear respotue was demomtrated at higher doses bat a curvilinear rc tpoox appeared at lower doses At attemcly low dosage, the possible effect of the agent beeame obscured by the incidence of spontaneous pulmonary tumors. In the eax of induetioa of cancer by foni:iag radiation, it has been claimed that there is no threshold (210). It is conceivable that there is no threshold for certain neoplume, whems thera may be one for others. Neither the available epidemiologie nor the erperimeaul dau }re adequate to fix a safe dosage of chemital cateiaogey bdow which thete will be no response in man (43, 172, 210, 232). 0 CutaNocE*ttcrrr OF ToB.cco arm Toe.tcco Sxoze tx A.vtxat, There fs evidence from numerous laboratories (31, 42, 92, 93, 105, 132, 139, 263, 294 297, 338, 372, 373, 382, 383) that tobacco smake condensates and atncv of tobacco are carcinogenic for x.eral animal speeies. Several laboratories obtained negadre results (154, 262, 267, 268). 9he aatura of the teet qstem (e aitieal in smdie on earcinogenie activity of such eompla mt^^r•- The tdati.dl high w.aptibility of mouse skin to euciaogeaie hydrocarbons has made it a favorite tea objed (6. n8). A second test s7stem also used ia the (nducrion of pulmonary adenomu in miea 'ILis will be detailed In the section on F3perimenul $u)mona=y Gr• cinogeoaia. A third srtem which has been used lea f:equmtly ie the iaduetioa of subeutaaeam aucoaw in the rat whose eonneeti.e ti.uues have beea found to be atteaptible to tbe catcinogm(e .etioa of many differeat ehemieala as well aa of compla materials. Another trs4 which has beea used in eome etudin and oaa be read within ft.e days after painting the skin of mice with t cueinogm, consists of determining the number of seb.eeoas glands and the thieknes of the epidermis (342a). However, the reliabilitT of this proeedure aa a bio-aasay for eudnogenes(s is open to quesdon. Skin Many ia.eatSgytora have a6o,wn that the application of tobacco tar to the skin of mice and rabbits induces pap(Uomas and carcinomas (31, d2. 92, 93, t1{-/27 64~It .. •^:1•"..-w..~ 143 i
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0 FAL3E AND INiISLEAMG ADVEg17ST,jG . 135 time, cre esptvssed our beli,tf that heavy and prolonged cigarette smodmp is not the only cause of lung cancer. Three major investigations on the relation between smoldng and lang cancer are now in proqmss by the Public Health Service statl. The first is a lurf,+e study in collaboration with the Yeterans'.admin- istr.ttion of the smoking habits of 220,000 veterans of World War 1. The second is a national retrocpective analysis of lun; cancer in women, and its relation to smokin~. The third is a national survey on the relation of occupntion and lifetime residence, as well as smok• in;;, to hin- canrrr. The method for this study has been tested in Prnnsylvnnia nnd found to be feasible. Since 19:-i2, the Public Health Service has not undertaken in its own fnr,ilities direct labornto~y studies on tobacco. Close linison with the :lmcricnn Canrer Society and ninny other individual investi- pltnrs has led to the jtul;ment that such studies nre being pursued ~rUh suff cient resources, nnd that additional expansion is not required. Research «ork nn tobacco proQact, and on filters nt ptrseut is being supported by a number of intlustrial concerns. A number of requests for „ruits nlsn have been made to the American Cancer Soctety. Intofar as cigarette filtets are concerned, research data available to the Public I-[enlth Sen'ice are in5u/ficieat to wnrtnut a conclusion at this time. 3fMiilicnrion of ci;:cu•ettes so tluat their harmful elTects would be reduced is of nln•iou, importance to public health.. It has been pro- pnse~l, thrmcticallv, that. such modifications couid be achieved in thire ways: (1) l,~• changiug the tobacco leai a:ul other initial con• stituents of the cimarette, (2) by reducing the teniperature of the hnrniu„ cirnrette, and (;) by the removal of certain constituents frnm tho smoke. The hist. method, of filtntion, preferably should remove harmful mnterials from the smoke and retain those materials that provide smoking plcnsure. . It is apparent that further research, both on the general question of tobnceo and its relationship to lung cdncer, and on the qucstion of filtration or other means of modifymg cinarettes, is needed. ThE Public 1lenlth Sen•ice is prepared, ol course, to play its part in this resentrh, of importancn to inditstry, to our economy, nnd to the health needs of the pPonle of the \ ation. Thaiik you, a(r. Chairmnn \fr.Rrararx. Thankyou,Dr.Burney. Dr. Burney, Dr. Heller's testimony will tie in and give tac scien- tific details to support the general statement you have mnde? Dr.BraxsY. Yes,str. Mr. BWTxIK. I suggest you proceed rileht on with the statement and then we can come bark Rith our que,t.ions. Dr. Rrntvtr. Thnt icill be fine,.Mr. (;liairmmt. Mr. Rr.nTxtx. Dr. Heller, we welcome you to the committee this morning. Would you give ns for the record a short biographical background of your professional backprnund experience and then proceed! Do yon hnve a Rt•itten.stntemPnt, Doctor? . ~
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9 0 134 FALSE t-ND \tI3LF.ADI\C ADVERTISI.\C STdTEXBAT OF SVRt3. OBR. LeROY B. BD•HREY, pUBLIC HEALTH SERVICE, DEPdRTMEHT OF HEdLTH, EDUCATION, AND WEL. FARE Dr. BcR~t:v. Thank you, 1fr. (,hairtmm, and montbets of the sub- committee. I was appointed Surgeon General nbnnt 1 year ago. My previous experience has been almo6t entircly in the United Stntes Publ ic Health Service. I have been a career officer in the Commis:iouer Corps for 36 years, coming into the 1'ublic Health Service in 1932, although I in- tcrned in the service in 1930. Following that I had n 3ectt• at Johns Ito )kins lini~•et~itv in the Sehool of IIygiene nnd 1'ublic I[enlth, :wd t~ten ciunc into tlte Iegu- lar corps of the Service. I serred in various assi,"nntents ,iuce then in the Public Health Service, and n•as detailed to Im.liwut as n State health commissioner of that State for Jye:us. I came b;ick to Washington in 1954, as nn assistant surgeon fiencral, deputy chief of the Iinreau of State Serv- ices, nnd, as 1 sat•, last.lugntst was appointed by Ptvsident T;isenhower as the Surtieon Genetal. With your permic5ion..llr. Chnirronn, I would like to read this very brief statement, and will certainly be very pIeasrd,togethor with Di•. 1Teller, who is much mnre of mt espclt iu tliis nt•rn tllan I am, to nn- swer any questions which memlkr; of the cmnmittcc might have. The. 1'ublir, TTrnlth Frt•virr, 1)r,intiinrnt of HcaTfh, 1•alttcation, nnd 11'e!f;tre, has particilrile l aclive'v in re-out.•1i em lim~ r.u c~•r :ince the establishment of the National Z:nn~•er Inctituta in 1:1.3T. This par- ticipntion has included nseardt at lLr ln.,t;tutc:;. !!t•ant-;npportea rn- senrch, in institutions outside the Federal Gavernment, and close ail- ministrativo and informntionnl liai>nn «•ith nr.-anizxtion, and with investigators concerned with the problem. [-ll to 1953, emph:i.is %vns placed un labot;itnry~ im•c%,tit;,dions nn flte Feuettc and other fnctur, in lnng hmtnrs of nslct' and other nnimals, Ihc !tistngenesis of lung tumors, and cnrironnuntal carrinogcncsis in- cluding.the search for carcinngens in atmospheric dusts and in tobacco. A recent selected bibliograph,v of cnntributions by the.stnt[ lists oser i;i titles. Since 1952, the emphasis has turned townrd ehidcminlo;;ical inve,t.i- gat.ions. One such retrospectivr stndti• by the statT nn smoking and cancer was publishM , in l~.~y. ln~ttlier one, supported in pIn't by a grant, was pltbllShP(1 in t05}. A national survey of tobacco-smoking habits in the United Ctntes was c:nndttcted with the I3nrenti of the Census and published in 195G. Ur. PtartvoEx. Mny we have a copy of that for the record, pleaseT Dr. Rt'R\F.T. I will t1e happq to sul)llly you Nrlth a cV17y. (See appendix, exhibit T, it. !°1.) Dr. I;tmxsy. Several t:tnttAiral amtl,•sr-s of nvailable data on the subjertt were also prerarctL In light of these and other tttuli~-. the Public I~enlth Serriee statcd on Jnly 12 (see nppcniiix, exhibit 8, p.':i54) that it is clearthere is nn inrrenaing and consistent body of evidence that excessive cigarette Smilkinp Is.nne of the cnnsntire fnctnrv in Iunl,• cnncer. At the r.ame
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0 0 140 , 1•ALSE AND 1fISLEADL'7a ADVERTI8LY0 .. try of Health, whereas in this country the States are sovereign in mat- ters of health, and we have certain interstate responsibilities, but are• not the directors or administrators of State and local health depart. ments; so, there is that difference. In other words, when the British Ministry of Health prepares post- ers and sends them out to their district health officers, they are sendinZthose out to their own employees over whom they have administration. We have never in any of our public health programs, whether it is the Salk program or the fluoridation pro•ramJ prepared that type of post- er, and so forth, to send to the States for distribution. 1Ve have some- times helped them in the preparation of material, but they, in turn, do their printing and put their own byline on it and that sort of thing. Mr. BLAr.Ix. tiVould, perhaps, labeling on the package containing the articles iteelf help! For eaam le, I notice rather innocuous sub• stances, such as "low salt content,'Pin articles purchased for saltless diet, and I believe the bottle or the product is required to be labeled with a complete description saying there is a salt content of a certain fi^nire. With regard to beer, tlie,, indicate 3.2 percent alcohol. NoR, why are they compelled to label the contents of small amounts of things that are not really harm.full Do you think there is any validity to the rerommendation that, perhaps, you ought to have a label on a cigarette package saying the total content does not exceed 17 millifirams of tar, or so much nicotirie? Would that help in passinr on information to tlie people'! lf it. is a filter-tip cigarette, slFould it contain a label saying, "This filter removes 10 percent of the tars, or removes 20 or 30 percent," so the people have some idea of how mnch protection or how much filtration they are getting from the filteiied cignrette? Would something like that, do you think, be a sound sug - gestion? Dr. BcnvEr. We, as Fou know, do not have responsibility for label- ing, and that sort of thing, but if the Federal Trade Commission-in answer to your question, my thought would be, and Dr. Heller is ablr, to add or subtract to this-~'e do not have sufficient evidence at this time in the identification of the agent. and the relationship of that agent to, perhaps, cofactors, whether it is air pollution or what else it might be, as the causative factor in this. In other wordst even though I am firmly convinced that we were right in making this statement at this time, and in letting the public know that, in our opinion, we believe there is a relationship between excessive and prolonged cigarette smok- ing, I do not believe that we would be on firm ground In'recommending• such a warning sign at this time until we have much more specific information. Mr. Pr.ArixoEa. This *ouldn't be a warning, Doctor; this idould merely be a statement that "this ciparette contains blank milligrams of tar and blank milligrams of nicotine." What would be your objec- tion there i Dr. &*nvzz. I, personally, n•ouldn't see any nbjection to tbat, Mr. BUrxlx. I notice alon the same line, Doctor, many medicines for the common cold; many o~them will have a label on them.sayingt "You take 1 tablet every 4 hnurs, not• to exceed 6 in any 36•hottrpbriod. • That is jnst an eaatriple. "One every 4 hotirs; not to exceed 6 m every 36 hoiirs." Sap ou had a pack which said, t'Not to exceed.l8 or 15 in any 24-honr riod," as a thresholdT • How will t}~e.people get. thoxn facts unless v. u have them printed on the package 4.
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0 . lud to the productioa of canter; othcn promote the carcinogenic proccea (21, 33). The former are ealled initietorr. the latter promooerr. Some aubatanees, such as ureman, eaa be both. Several dasw of chemiul+ are kaowa to be capable of inducia; cancers (143). The chemical propertia, the phyaical state of a aJstanee, and the vehicle in which the substance is iotroduced into the body pn inAueace the cusinogeaie potency of eaviroomeatal agents, e.g., insertion of a plutie membrane into tlu uea can cause a cancer (2, 261, 347), but a fine powder of the a.me plauic has eot done a(257). Carciaogeaa vary with rapect to organ a6mity and mccbanism of inducing a ncoplastic change. There is mounting evidmce that .iruxa may also play an important role in the induction of tumors (137, 140, 345). It follows from tbex coa+identioes that failure to produce caaeer in a given te.4 by a given materi.l, does not rule out the cardnogeaic capacity of the same material in another apecies or in the same speda when applied under different circvmataaas. Convenely, induction of cancer by a com• pound in one aperies does not prove that the tat compound would be carcinogenic in anotber species sader timiLr eita+"s+•"c-- 13erdore, teata for carcieogenirity in aeima, can provida only supporting evidence for the eareiaogenldty of a given compound or material in man. Neverthe• less, any agent that can produce cancer In aa aaimal u suspected of being e.reieogsate in mao aLo. ?he types of cancers produced by the polyeyclic aromatic hydrocarbons and othQ eudnogeaa depead on the tiaaa with which they make coetaet Cucinogmeaiu ua be iaisiated by a rapid aiagk event, beet eumplified by tFe carcinogenic effeer of a apliaaecond expoeare to ioaiua; radiatioos (e.g, from atomic detonation) (40, 351). More often, howe.er, it appears to be characterized by a slow mu15•wme proxw, preceded by wn+ped& tiawe ehaagea, as ezemplifled by eaacen arisiag in burns. Evidence ia pred atated in another section of this Report that caacer of the lung in rigarme .moken, as well as e:perimeasal cancer iadueed by preanmed cueinogetu in smoke, is preceded by distinct histologic dterztions which can progreaa to the dndopmrat of "caacer in .itn." 'lbeee aeed oot proceed to the formation of invuive eanear, and may regrw following removal of the ttimulua. . The c3ancter of "precaaeeroua" change varies in d,iHereat organa, e g. in the bladder it is manifestnd by the formation of "heaign" papillomu; in the oral cavity, by the formation of white patches of thickened aquamoua epithelium-leukopWda-a aoa-eeeplutie reversible eh.aga Ihe evolved cancer fa also subject to further ehaages Often, rapidly growing variants develop, a proasa termed proaresaion (119). Almost every species that baa bem adeqnatrly'tested hu proved to be auaceptible to the eSect of ee:taia polycydic aromatie hydroarboea idettti• fied In cigarette amok.e and deaignated as caniuogenie oa the basis of tean in rodeats 73erefon, one can reasonably poatulate that the same peiy cyclie hydraearbeoe may, ala, be. carcinogenic In one or more tissues of mm +vith wbich they come Io conUct. Experimental studiea have demonatrated the presence of wbatanca in tobacco and smoke which themselves are not carcinogenie, but can promote 142
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0 150 FALSE AVb aIISLEADL\C ADVER:I6L\a elements, is in these tars, as we have indicated previously. The tars apparently give the tasts the individual gets from smoking a cigarette. Mr. DfuDEa. Rather than in the nicotine ( Dr. Has.LEa. That is right. So far as we know, nicotine itself is not involved, even remotely, as one of the causative factors in lung cancer, as far as we know. 3fr.1IEADtat. The nicotine is tastless 1 Dr. HELTXH. It is tasteless, and produces a physiological action, both of which are associatzd with the taste, and they are indlstin;,nlish- able, as far as the individual is concerned. If he doesn't get the slight stimulation from nicotine, then the cigarette doesn't quite satisfy him. But the same token, as I understand it, when the tars are removed he doesn't quite get the same taste, and it is, therefore, not what he is accustomed to. The third factor involved, as I understand it, is the psychological factor, which is doing something with the hands, or seeing the smoke curl up, or otherwise the satisfaction that one gets in release of his nervous tencion. by merelv holding a cigarette. Considerable work hns been done by psychologists as well as physi- oloti sts as to what really constitutes plensure in smoking, and I br• liere that represents n consensus. DGIch more work needs to be done on the effect of nicotine, ns far as the possible deleterious effect on the human body is concerned. We have reason to believe, for example- and I, certainly, am not expert in this field-that the action of nicotine does not have n beneficial effect upon certain cariliovascular discase• such n5 a disease cnlled Bnerger'c dlsease, or endarteritis ohliternns. It is the technical name, in which the terminal arteries nre can- •stricted by the disease, and there seems to be a fiirther constriction by the action of nicotine and, therefore. wcrsens the disen.-n. Now, this has not been elucidated, anil I do not claim that this is a pnrticulnr factor in cigarette smoking, but it needs to be elucidated, and much more work needs to be done. But physicinns generally will advise individuals with coronary heart disense not to smoke, or to moderate their smoking, and this is true in other similar cardio- vascnlar diseases. Nicotine probnbly has a much more direct action in caidiovascular diseases. Again, I repeat as far as my knoRledge;.roes, nicotine is not involved in htng cancer except as it promotes the pleasure in smoking that the indiFidnal might have and, therefore, he is less likely to smoke mod- erntely if he is accustomed to the effects of nicotine. Mr. )t1EApEn. In othe,r.words, I take.it that your research activities are'reflected primarily toward the identification of elements in the ' tars, and their effect upon possible cancerous conditionst Dr. Hetr.r.a. I would say generally, Mr.. Mender, that is. correct. We by no means ignore the possibility of such things as arsenic on the tobacco when it is growin fi, the constituents of the paper in which ciQaretta9 nre wrapped, the waxy coating of the leaves which nr.• Wynder undoubtedly mentioned in his testimony, might be removed by hot hexane before the tobacco is processed for cigarette making. . ,We believe as a very practical measure that the most, direct ap, 'proach is -toRard these tars and particularly the neutral fraction; which, cotnprises only about 2 percent of.the total tars; nevertheless, we are not eliminating oi• ignoring any bf the other possible factors involved. In fact, ~re pride ourselves thnt we keep an open mind, and
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• ruas errD i,rsst.r,.+ncva eavzx=12NG 153 more money to spend," and I would expect that the same policy would be followed tbiayear. Mrs. GRirmxe. May I ask when did you first make a::etermina- tion that there was a relationship between lung cancer and ezoessive smoking1 Dr. IlaszR. It was brought to our attention in 1950 by the work primarily of Dr. Evart Graham and Dr. Wynder. However, part of that time in our own laboratories as early as 1939, some investigations had gone forward which were inconclusive, in attempting to establish a possible relationship between smoking and the production of lung cancer in animsls. Not until 1950 did it come to our attention that there was a real problem involved. We recognized at that time that there was probably a statistical correlation. Subsequent studies were made in this country and abroad and in 1954, an official viewpoint was es~ressed by the Surgeon General of the Public Health Service-I don t think there was an otficial docu- ment put forth as has been, here, but• simply a statement to the press and others that we believed there was a statistlcal correlation between excessive smoking and the occurrence of lung cancer, but we did not believe that there was a cause-and-eiiect relationship, as expressed at thistime. Subsequent studies, and particularly laboratory studies, have brought us additional information, and the increasing weight of evi- dence caused us to recommend to the Surgeon General thnt we believed there was a desirability of calling to the attention of the public the information which ha~ been derived from work, not only at the Na- tional Cancer Institnte but• in the world in fieneral. Mrs. CRn-fzrsis. When did you suggest thatl Dr. HES.LER. Just recently. Mrs.GRrkrrrta. Withintholast60days4 Dr. Hrzr.r.n. Within the last 6weeks, I would say. Mrs. GRrr1-rrxs. Is this the first written statement that has ever been iscned by the Public Health Service, or have there been others! Dr. HULER. In this regard the Surgeon General issued a statement on July 12, concernin the attitude of the Public Health Service. which I believe is the first written one that has been so formalized by the Surgeon General. • Mrs.'GRir-s-mle. May I ask yon, hnd other countries made these de- terminations ahead of 6e United States? Dr. H>z.r.ER. Yes. Britain in about 1954 came forth with an official statement by the ,liinistry of Health thnt there was at that time a• statistical correlation, and they believed it to be a cause-and-etFect rela- tionship. Dtrs. GRrfirrxF. Have you already sent this information to the health departments in various Statest Dr. Bc*Rxrr. Yes, ma'am. This statement was given Friday, July 12 and the mnterinl went ont, I believe, the following Monday. Mrs. GmFzrns. Have you notified the Federal trade Commission? Th. Hsrd,F.R. Yes, . TtrSf tiRl}'FITIIF. And hnve vnu. nntified the Departnient of Juttice? • ' T)r: Hr.1.LF.R. I hnve notified officially the Federal Trade Commission. I have riot officially notified the Ikpnrtment of Jnctice. . 4494O-ST-11 J
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JJJ FAI-SE AND N.IISLEAD_[\G ADVERTISLYG 0 0 proof of smoking being a direct eausative factor in the inducement of lnng" cancer. Dr. Hr.r.LF.R. Mr. Chairman, I believe that statistical studies are «'nrth while in the hands of good statisticians, in the hands of conipe. tent people, n•ho interpret the stndies. The}• are tools in the hands of the pnblic health administrator and epidemiologists, and Lave proved oaceedingly valuable in the assessment and management and control of other diseases, such as polio, syphilis, tuberculosls, and other di.enses which for the most part nre fairly well nn<ler control. We therefore believe that Such statistical studies are extremely Vslunble and extremely significant, and it is our bPlief that on the basis of the stndies which have been presented, and of which you have information from testimony of nthers, these studies reflcct a situation of n'hich.re r.tuit take corniza» ce, and which cnnsidered in connection with labnrntol;v studies, brou~ht about the statement the Surgeon General made on.Itily 1?,1~:~7. Mr. RUMlt, 1)actnr, ns head of n very important Government health agency dealing directly anil almost exclusively with cmtcer, its origin, nature, and h:Ksihle 4ctnr, what wmtld be ynur officinl rccum- men<lntimi, -,'our oflicial thinking, on tobacco as aFource of c:tncer- indncin~ ~nli~t:tnces? Dr. lfer.r.en. Mr. Chairmnn, it is nur belief, on the bnsis of the in. fnrm:ttirn, which is arnil:tl:le to ns -apd we have indicated a ntotmting evidence that when cit:arette tobacco is burned (p1'rnlt•sis is the Nr•lutical n:ume) at abnut R(W Centigrade, we believe tltere is n chemi- 4•al ch;tnre in ccttain ht•drncnrbnnc in tnbacco o•hich llrn:luces ccrtain :ancer-enusing compotmds. We do not know n•hich of these coni- l:nund is the culprit. We do not know whether it is a combinntinn of these compounds, but we believe f ru!u the best knowledge that we have ::t this time that the cancer-cnusinp; l:roperties or nFents are in the tar fniction in smoke cnnclensates. There is reason to believe that theqe :ur. some of the higher polyclic, tnarro rin~*ed, 1»•drncarbons, which are rery complicated hydrocarbons, and about which we need to 1,-non' more. 1t l:t~-ont nntch research is going on in several parts of the ~~'nr)d, :ut~l in our own country, on these very important and very comhli- cated chemicals, and we hope that they can be chemicnlly chnracter- ized, thev can be identified more hrecisely, and their role or possible role'in the production of factors in the causation of lunti cancer can b: mora precisely defined. It. may be that there are combinations of such compoandc, it. may be that some promoting factor which interacts with another substance or compound is responsible. Thece are some of the things, '%[r. Chairman. that we believe mnst be established before we can precisely put onr finger upon nll of the com;+oundg. S1 e do believe, hoaever, thnt ttt this ''nncture ennn~h is known and enmtgh has been demonstrated from inboratory and from epidem- iologic invectia,ttiona that• we, as Federal health officials, shonid direct. to the public information concerning these compounds and relyy upon the laboratory, rely upon dther investigators thronfihout the country, and, in fact, throughout the a'orld, for attditionnl information in order. thet Re may be betterr prepared to know what are the next steps that might be taken. , " ~
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144 FALBE AND JdtSLEADLNG.ADVEg-,LqL`G. There are 4 or 5 individuals in this country who have been working in this area, and we can expect in the future that additional good work will originate from these areas. I would say, Mr. Chairman, and members of the committee, that one of the very hopeful things about this problem is the willingness of the investiga tors throughout the world to share quickly their in• formation with us, and we in turn share with them. They recognize that this is a problem which is international in scope. As a matter of fact, the incidence of lung cancer in England is greater than in this country, and it is similarly true of certain other countries in Europe. Norway, for example, I am informed, has much less lung cancer, as has Sweden and Iceland practically no lung cancer at all. At• tempts are being made to correlate the smoking habits of the popu- lation of these countries with the occurrence ofgung cancer, to deter• mine if there are factors there of which we have no knowledoe in this country. We believe that the pooling of information which we get from in- veatigators throughout the world who are proceeding along lines which are believed by our scientists general]y to be proper and productive, and we believe the immediate availability of these data will enable us to move much faster in meeting this problem from a preventive medi- cine standpoint. Mr. BLAx:rra. I have this last question: Doctor, just what is being done in America, then, to protect the people or inform them on the possible dangers from eacessive smoking or just-smokinmt Dr. HEt.zra. There are several things being done, D~r. Chairman. One, as Dr. Burney point?d out, officially, there have been furnished to State health authorities for transmission down to local health de• partments in some three thousand-odd counties, information indicat- ing our official concern over thisproblem. 5imilarly, the American Dfedtcal Association, the spokesman for or- ganized medicine, will pass this information down to local individuals. Newspapers, radio, TV, and other media have done an excellent job covering this problemt and a very objective ,'ob. This is an eaceed- ingly valCable way of informing the public. There has been an inter• pr,,tation of the scientific literature by us, insofar as possible, by other interested agencies and gi r,jp% and there have been many discussions and additional discussions of planning in the future, of ways which are dignified and proper, that would not be productive of a scare to the public, and yet be consistent with the facts that we have. We wish to proceed in an orderly, dignified, and proper manner in order to present the facts as they become available to us, to the public. Mr. BtArxrs. Have all those things been done to help inform or help protect the public from the possible dangers of smoking? Again I come back to what puzzles me most and that is that no one seems to know anything about the filters. The scientists representing industry, their own people-don t know. We are spending, we will find out, literally millions of dollars to promote that one filter, and I will ven- ture to say, sight unseen, and I am open to correction-this is just a statement and I shall seek that information, I venture to sav that in our country as a whole, more is being "nt just to promote the smokn ing of filter-tipped cigarettes than is being done to find either the ciiuse : of cancer, or how much that filtrntion protects. I ean't understand why such a large ezpenditure is being carried out with no purpose.
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l0L FAI3E A2.'D MISLEADL'7Q ADVERTI$LYa The Chair wishes to announce that the hearings will continue to. morrow when we hope we will finally get some informstion on filters. I have never seen anything that has been advertised so extensively and p+-rsistently, and at great expense, about which I finally discover I lotow so little about. The witnesses tomorrow will be Mr. Irving Dfichelson of the special projects division, the head of the Consumera Union. Dr. Walter Wolman, director of the caemical laborator7, American Medical Association, and Dr. C. S. Itimball, executive vice president of the Foster D. Snell, Inc., the research agency in New York which made the laboratory tests and the report for The Reader's Dib st, which is reported in their articles of thss July and the comir.t,* i<<llP M An~~ust. So until 10 o'clock tomorrow morninq, the hearings are ndjourned. (Whereupon, at 12:15 p. m., the subcommittse adjourned to re- convene at 10 a. m., Wednesday, July 24, 1J57.) V O~
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• geographic origin (3i8). Animal te•+b show that the eareinogenicity of mineral oil increaaes ar the temperaturs of dirtillation increases or when cracking is iauituted for the formation of new compounda. A.ariery of carcinogenic eompounda has been f+olated itom different fractioat. Some fractione presumably frce from betuo(a)pyrene have neverthdex been found to be carcinogenic. Coal tar contaitu 0.3 to 0.8 percent beaao(a). pyreae, soot 0.03 percent. and American rhale oil 0.003 to 0.004 percent (S1). St1NMRY T3ere u abundant evidence that cancer of the skin an be induced 'm man by iodu+trial exposure to soots, coal tat and pitch, and minenl oilr. All of these contain vuioui polyeyclie uomatie hydrocarbons proven to be carcinogenic in many species of aimala. Some of theae hydroearbono an alao present in tobacco smoke. It is reatooable to assume that theae can be eueinogeaic for man also. CANCER BY SITE Tbe seven proape<tive studies dexsibed and aummarired in f3aptet 8 provide a natural point of depamtre for eoeaidering the relative riaka, for smokers and ooo.mokria, of cancer at apedfie aites The consolidated Yndinga (Table 1) identify eight sites as diry4yiag blgba risks of anar among ugarette amoken, who in recent deeadn ba.e beea the predominant eonwmera of tobacco. 'I3ex eiteu'are lung, larytu4 oral avit7.aopbagvs, urinary b4dder, kidney, atomaclL and prortate. The mortality ratia for cigactte amokera oia-*eir ooo-ccookaa range ia dacedin; ordet from nady 11 to 1 for cancer of the lung and brnnchoa to 13 to 1 for proeutic cancc. For five of these aitee-lung, laryay oral cavity, ewphagua, aad uriuary bl.dder--eigareae ®okerv ha.e a wbarandally higher cancer risk than eoa-mtoken. TLe..maller aoaa riaka among dg.retta emoken for adeer of the rtomach, proatate, and kidney deaerre commeat. The protpective studies are not in complete accord as to an aa.oeiation witlh amokieg hisnry for cancer of the proetate and hidney, and in some of the studies which wera conducted with other objecti.a in mind, the relatiooshipe of proetatic and rsnal anoer with smoking history represent Ineidental findings. No other evidence can be adduced in evaluating and interpreting the prowtic and reaal mortality tatio., since the e$ecta were not large eaough to drew the attmtioo of in.ati. gaton. For the.a reuoaa, cancer of the proetata aod kfdney will not be dta. etta.ed fanher at this time. TbL decision doea not imply a conclusion that the 6ndinga mort be attif.aa, but rather that jedgneat oa tbeae sites should be auqxaded until moesdatabecome a.ailabla . 13e aae for ooeaidaritig eaneer of t)as atomaeb in more detasl Is eot much straoger thaa for proatate and kidney, but the cottaiateac7 among the proe. pocti.e ttudiea i. beuer. Io,additioq the uadia report a rttooga awociadoe of amoking history with stomach ular. Clinieal imprexione of this reladoe. 148 r W T I 00 N
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CHICACO. ILLINOIS CCRYEMf. IaSe. rf AN[MC.Y }ttlCIL AYOCYTCM NOVEN . iBER 28. 1959 CAUSATION; PREVENTION, AND CONTROL OF'ACCIDENTAL POISONING Harold Jacobxiner, NLD., New York © HERE has been an increasing awareness Ic recent years of the importance of acci• denial chemical poisonings as a cause of death and•disabilih•. N1ore children under- 5 years Of age died lasryear 'in Neu• York City from accidental' chemibal pbisonings than fiom diph•' theria. poliomyelitis, rheumatic fever, scarlet, fever. and other streptncoccic infections combined. Four• teen hundred fiftv deaths ~s~ere , reported in the l.'nited States last year frum puisonincs by agents other than poison gases and spoiled food. Over 466 orthese deaths u•erc in children under 5 years of ace.' The :darntinc inc•rc, s• in huth fatal and nnn• r.r.l ....... ...... . . i . . . , . . OF THE American Medical Association Published Under the Auspices of the Bodrd of Trustees The New York Ioison Control Center, es•' tobBshedinf953, occwnuloadd reportr en. 23,062 incidentk Of poisonink until the end : of.195! Amony tYte. 17,069 petienrs under'. . . the epe of 20 there,rere 70 deoths, and S/ .. of the deaths in this group were caused by lead poisoning. In this age group ospirin ac• counredfor 15.7%, o/rheeoses.butthedota elro onerted to /he frequency with which tranquilizers are no++ lound in the home. Nearly oil the reoorted. ineidentr were ore•
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0 0 FALSE A.\D W$LEADOG ADVERTS6LNG 143 Dr. FIY.LLl:R. By Government, Mr. Chairman, by others who are intere,ted, and by Government support of research, which as you know is one of our traditional roles. 3lt•. BLn•rxlx. Hon• much is the Federal Government spending, it- Qelf. either directly or through grnnts to other independent research grou;tIs, or universities in the form of grants for this cancer re• Sen rcl l I Dr. I'I}:LLF.n. \Ir. Chairman, I am unable to give you that figure. If ~•uu will allo~~• me to, I«•ill insert it in the record. ~Ir. PL.,rl.ar:R. ltay we hure that by year, Dr. Hellert Dr. HEf.Lr.R. Yes. \Ir.PL.%ri\(;RR. \favn•ehavethenamesofthegranteesP I)r.IIsLLY:R. Yes. 11'ould you like it for the last 5-yenr period? Mr. Pr..%riar.r.R. That would be fine if it is not too much trouble. ~See appendix, exhibit 10, }). G72.) Dr. BonN-Er. These would include other causative ab nts that might produce cancer or lung cancer. Mr. BLar:nx. Are other governments concerned nbout excessive smoking as a possible cause or source of cancer i Could you nnnle the governments, give us a brief idea of what they are doing? Dr. HELrsR. Yes, Mr. Chairman. We have knowledge of studies on the part of individuals in nine different countries, such countries as England, Finland, Sweden, the Netherlands, France, and Italy. Four governments now have put out a national statement concerning their alarm, or I should say prrsenting information to the public con- ceraing this question, and their alarm over the causative factors in- colved in excessive smoking. These four countries are Great Britain, Sweden, the Netherlands, and our own. Great Britain, I believe, was the first to come out in about 1954 with a statement. Only recentlyy the Medical Research Council of Britain, a very distinguished and authoritatice body, has come out with a more definitive attitude toward this entire question, nnd this has resulted in the action on the part of the Ministry of Health to which you referred earlier. The Netherlands has put out an official statement saying they believe that eacessive cigarette smoking should be brought to the attention of the public and individuals should be guided accordingly. Sweden has put ont a similar declaration. To the best of my knowl- edge, no other countries have come out with an official document, or a statement which reflects of8cial attitude. The work that is being done,llfr. Chairman, in other parts of the world to some extent parallels that going on in this country: They have approached the problem of the constituents of tobacco tars in a slightly different manner. In France, for example, Dr. Latarjet and his associates in Paris have been primarily concerned with how much benzpyrene may be formed from the burnin~ of cigarette paper. Now,lir. Rand, and his associates in Cleveland, in this country, have been similarly preoccupied. The group in En fil.and had been concerned with air pollution, with the correlation between ezcessive smoking and individuals subjected to heavy pollutants in the atmosphere. They also hade been working .' on 3,4-benzpvrene in tobacco tnrs: Their resu,lts, in general, confirm that. of Dr. Wynder and his associates in this country, and also those of Arthur D. Little in Boston.
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52324 3717 EXHIBIT 11 . .
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0 FALSD AND AIISLEADL*7G ADVERTISLYG 145 Here we have great difficulty in a congressional committee to find out why there are filters. If we don't know, how many people don't lmowP Dr. Little told us right here last Thursday, on the matter of filters, he said it was a matter of no interest to him. It might be of no interest to him, and lie might have good reasons for saying that, but we would like to know where we can find this out. Could you advise us, Doctor? I know it is a little out of the field of your medical research. Dr. HECtiEa. Mr. Chairman, this, of course, comes completely into the field of developmental, industrial research. lYe know that physi- cally the filter simply removes certain constituents of the smoke. Now, whether or not it can do a complete job, we hope it cnn, if our tlans continue to hold up as they have. Whether or not there are tter filters that. can be made, whether or not industry proposes to undertnke additional work on filters, we do no', know. I do know that individuals such as Dr. Wynder and others, some of whom are not known to me, are working on this problem. They are fitted by traininh, by interest, to undertake this sort of research and Re are keenly interested in it I, personally, Mr. Chairman, propose to go into this much more exhaustively and completely than we luire in the past. May I repeat again it has been our gelief that it is eminently desir- able for us to elucidate the basic mechanism involved here and not necessarily introduce another variable. If we kneR all of the con- stituents, tf we could identify the particular tar or tars, then we could turn to such factors as filteis, or washing of tobacco to remove wax before the cigarette is made, or whatever the remedial measures that should be instituted might be. But, since we do not know those things, we believe that it is desirable to find out all we possibly can about these other factors and then see where filters fit. After all, filters nre merely mechanical strnineis and. as far as mi • knowledge goes, there is no chemicall nct.ion involved. Therefore, it is derelopmental research. Mr. BcaTxzx. Doctor, does the Federal Trade Commission seek medical information firom either you or, perhaps, from the Surgeon General in their analyses and evaluation of the propriety and correct- ness of cigarette smoking? Could you give us some idea on that? Dr. HrLLra. Yes, Mr. Chairman. The Chief of the Division of Consultation of the Federal Trade Commission has been in constant toach with me concErning this item. Hee is rery anxious to know what the Sur~ eon General's attitude is, what the SurReon General's pronouncements nre: I have been in touch with him. We have kept him informed. He has been, indeed, most cooperative and helpfiil and since this problem came to his and our attention, has indicated a desire to work cloqely with us, and to be guided by the medical facts which are developed and the medical opm!ons which may be derived from the scientific endeavo.rs generally. I can.only,indicate our extreme pleasure at cooperntion with this agencl• of .the Federal Government•. Atr: B.r.At^rtx. Thank you very muah. Mr. ]tieader 1.
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0 FAISS A.vn `dlaLCd,DLVG ADVtxTI8l:ra 161 Dr. HIUxR. Taking the country as a whole, sir and speaking of individuals whom I respect and who are responsible indrviduals, I would say the majority of them concur in this viewpoint. Tbere are certain individuals, like Dr. Berkson at the 3fayo Clinic, and others around the country, who do not agree. They agree, perhaps, with Dr. Little's viewpoint. This is characteristic of science In~general, where there is a difference of opinion on many subjects. However, when one anaIYzes it to the utmost, there is not as much difference as one might think on the surface. Mr. 3fIwBS1A[,r.. Can you give us a ratio among the private surgeons and cancer experts as to what the ratio would be'i • Dr. HcLLtR. It Ncould be purely a t;uess on my part. bir. TfIVBt[ALL. 14-hnt is your best guessl Dr. HELLLR. My best guess is that 75 percent of the physicians or scientists who have knowledge and some competence in •this area would concur with this formula. Mr. PLarlxoEn. Dr. Heller, in an article that appeared in the July 19 issue of the New York Times, there is a reference to the fact that a Dr. Smith stated that the National Cancer Institute, after protests from chemical compnnies, had abandoned a study aimed at determin• ing the extent to which chemicals might cause cancer. Would you care to comment on that, plense? Dr. HFLLER. Yes, sir. I am aware of that testimony. That is not a correct statement of action by the National Cancer Institute. The Public Health Service has not stopped any field onlaboratory inveati- ~ation into cancer at the request of any individuals on the outside. Such projects as have been terminated have been terminated because theT logically had completed their course, or because we found it was fruitless, or for other reasons. Iwoiild say this is either a misunder- standing on the part of the individual or individuals who made the statement, and not founded upon fact. And we, in,fnct, have increased our studies in environmental cancer over a period of years. Mr. BLATVIR;. In conclusion, we are certainly pleased and relieved to hear that our top medical agencies in the Government are workin~e so closely and intimately on this important problem. ~Vithout trying to self-evaluate, would it be proper or correct to say that our Govern- ment officials, those of 3•ou in the top, executive positions, and those of us in the legislative* are doing about what is being done in other countries in Europe concerned with the problem of health and smoking, Doctor4 Dr. BoRxEZ. I believe we are Mr. Chairman. lir: RL.kranx: In terms of research dyid in terms of keeping the people informed, and in trrms.of keeping t.he.Government agencies mformed ? Dr. BIIRA'f7: I think we are. We are doing more than many coun- tries are doing, as Dr. HellPr mentioned, and I would also point oat that in addition to specific research on this particular area we have to recognize that some of the resenrch in cnncer, whiclt is not directly aimed nt this field, may have a bearing in giving some answer to this problem. Mr. RLATNTX. Well, thank you very much. 1Ve appreciate your 'excelleht *cooperation, and your splendid assistnnce, and commend you for your straight-forward and forthright statements.
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. • F.1L.SE AND \IISLEADL\G ADCERTtsL\G 13y .1[r. Jiur.%ntc How would you reach the public to disseminate in- fnm.iation, especially when you have the competition of this terrific ad~•nrtisinF enconrngmg nll penp'e to smoke? If you are fat, smoke and you will reduce. If you are weak and lethargic, smoke and it Kill PeP you up and yon can keep nP R'ith the athletes. I~r. t1F.LL}:R. ~j'ith your peI•ntission, Dr. Burney can speak on that. 1)r. Rtrns}s. Thank you, Dr. Heller. Mr. BL.wra-tx. I)r. Burney, please. J1r. Bux.ec. I don't know, .l[r. Chninnaut tlutt we are competent to ,ui~Ncer ti.at liarticulnr question. We Rre prminrilv a Federal health agoncy; nnturnll~•, n•e have a responsibility in health education, in in- fortuing the 1» tblic ns to health facts whic.h influence their own indi- ,•idu:il health needs. That is the r;ason we felt a responsibility to put this statement out at this time. as Dr. Heller said, Nre felt thnt, as a result of the resenrch n,• had done, and tltnt otltets hnd done, at this time there was increasing and cnn=istent evidence that this excessive and prolonged cigarette smok- ing was one of the cnus,ltice factots. Now we, ns yron know, hare sent out this statement. together R'ith the b.IC~ up informntinn to the Stnte nnd Territorial health officers, nnd to the -1mericnn Medical Assnciation, surpesting they pass that infor• mati.on on to theit' Stnte me(lical societies and local medicnl societies ;uui local hPnlth departments. lre reco"nize that this may not be sufi'icient. On the other hand, the f,u•t>• hnve been fnrnished to the public through the press, ns a resnlt of this etntemrnt. together with the facts brought ont in your hearings, and the State nnd Territorial health officers have definite responsibili- ties relative to public informntion and henltll edncntion. Iwnuld a.-ree with Dr. Hcller thnt mtr position nt this time, I think, rrl:ititi•e to this whole matter, is that there is a lot thnt is unknown in this area. Itt is a cnntrm•crstal nren in which some well-known sci- entists have opinions which differ front some of the otherpeople whom yrnt have heard tn these henrinrs. Our position is that we have informed the public through the excel- lent coverage of the press, radio, and TV. We have informed the ofdc.ial health agencies in the States who are responsible for this area, and we bare informed the American Medical Association, recognizing thar. many people will go to their own ph sicians for advice. We belicre that is as far as we should go at this time until and when we have additional information. If, for example, next spring we have some definite findings coming from this survey, then I think we have an obligation and responsibility to nt^ke those facts known, nnd nny additional information that may come out. 'Mr. I;i.ATTIIt. Doctor, the British, Re understnnd, are circulating ~aters thronh local health authorities. samples of which are included in the .hdy 26 issue of U. S. News & World Report, accompanying your interview, Dr. Heller, on 'he truth about smoking and cancer. iSee appendix, exhibit A, p. 5G8.) Would thnt be a proper function of the Goce.rnnient. in view of the concern expressed hcre as to the seriotts- ness of smo.kinF! . , . . Dr. Rvarrr.z. I don't believe.so, Mr. Chitirman. In the first place, The British Ministrs of Health is s cetltrnlized.ori,*nnizatioh: 'In:otlter words, the-district henlth departmenta are really branches of the Minis-
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• • FALS!': AKD \tt&t.EADtNC ADVEATISL\U 147 impelled to, after much study, and sce believe that we resPectfully disagree with Dr. Little in this matter. Jfr. biranea. I believe you do say, after saying that excessive ciptrette smoking is one of the causative factors in lung cancer-your next sentence says: At the eame time we expressed our belief that beavy and prolonged cigarette moking rs aot tbe onty cau3e of tuag cancer. Let me see if this isn't a reconciliation of what apparently is a conflict between the position you take, niid Dr. Wynder, and Dr. Hammond, and so on, with that of Dr. Little. He asserts that there has been no lobic,tl demonstration of a causa- tive agent in the tobacco or in cimtrette smoking which produces cancer, and I believe that is conced4by all of the rest of the scientists who testified. He takes the position that the statistical association, while it might show the direction in which to conduct research, might be misleading and, as lie said, cause one to clrase one fox instead of looking for some other foxcs, and mi ght retard the discovery of the logical relationship between cause and effect in smoking and cancer, because it might discourage exploration of other avenues, if people are satisfied that they have the culprit already identified. So it seems to me that there isn't really any too great disagreement on basic scientific attitude between Dr. Little and the other scientists who have testified-simPly, perhaps, a greater question of causation on his part than on the part of the other scientists. Would yon nrree with that? Dr. Hr.r.r.r.n. Partially, Mr. lieader. I would say fundamentally itt is n difference in interpretation. May I say, Mr. Meader, and members of the committee, that gen- erally in cancer causation there is a belief that there are certain products within the body-endocenous products-which may be re- sponsihle for cancer. It may be hormones, it tnay be an anatomical anomalv, such as polyps, ~rhich we know in certain cases usually proceed on to cancer, or there may he exogenous factors, or things brought from the outside in contact with the body, or inhaled or in- geste.d. What we say lrere is that we believe there is an exogenous product which is brott.ht into the body, :or in contact Rith sttsceptible Part.s of the body, which may interact with an endopenous factor or other exo- ,genotts factors. Dr. Little does not quite interpret these products in the tars as being exogenous factors. We are led to the inescapable cnnr,lusion that we believe there is a causative factor, but we are unable to identify that particular factor. 11rc hope that it can be identified and then we can proceed much ntore effectively. Therefore, truly as, sctentistst we are all seeking. the facts, and. there is always a difference in interpretation. I certainly give Dr. Little every respect nnd admiration for differences which he may have. But we believe that this subject is so important-and as protectors of the public health in general, or at least in our particular roles as protectots-t)tat ire feel compelled, nevertheless, to indicate our inter- pretatibn.' This represents n•consensus after lon4 nnd careful study of ouc.medical staff fieople who ai-e workin~ tvith.rt for the most part, and with others with tvhom we have talko~ The adcice comes from the outside and represents a body off opinion, and not just simply in- '
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154 FAIBD AND MISLEADL`70' ADODRTSBLY4 0 Mn. Gxzrsraa. Did you consider doing thatf Would that be part , of your~ j'ob 1 Dr. Ha.z.Ex. Ordinarily, it would not be a part, Dira Griffitha. However, the Federal Trade Commission is directly concerned, and have been in touch w;th us quite closely as I have indicated to the ' chairman. Mrs. Gxu=e. Have they asked you what you hava found 4 Do you know of any official inquiry that the Federal Trade Commission ever made of you concerning lung cancer and smokingP Dr. Hrs.t.rn. Oh, yes. Mrs. Ga=us. How long ago Y Dr. HEr.r.rn. Mr. Grandey, the Chief of the Division of Consulta. tion, I believe it is called, of the Federal Trade Commission, and several ' of his associates, visited me several months ago, 3 or 4 months ago, and we discussed at length this qroRinF problem. I indicated we were studying this problem throu gh a smoking and study group-which gave a report last June-and that probably we would recommend some action to the Surgeon General, but we were not completely sure of what it would consist. We have been in telephone conversation with them since then. Mrs. Garrmxs: They have never asked you to check filters or asked your advice on filters P -Dr. Hr.t.Ea. No, only in a very general fashion. Mrs. GarFTrrHS. Do you know if they are checking filters? Dr. HEU.Ea. I do not know. Mrs. Garrnnrs. Would you consider it a wise expenditure of pnblic funds to put this information that you have given us in every school in the country 4 Dr. HEta.f:n. As a part of a general health-information program, if the Stnte health authorities npprove of it, yes. Not as an official action on our part; as Dr. Burney indicated, the health authorities are soverei fin. Mrs. Gar?tras. Why don't you think It is a wise official action i Dr. HELLr.x. Because,~e nerally, we as a Federal ngency do not indicate the way that healtlt departments should npproach their par- ticular problems. Dirs. Gea'rrras. But it has nothing to do with your conclusions4 Dr. HEZ.r,Ex Oh, no. Alrs. Gatrrn•ns. So if the Congress suggested this, actually you would feel it would be wise to warn children, would youf Dr. HrJS.in. I would say if the State health authorities, in view of their knowledge of their problems, and the sittiations with `d`hiCh they are confronted, believe that this information warrants a conclusion in such a program as they wish to make, then I think that is thQir determination. :1frs. Gar=a. Have you or any official of the Public Health Service, ever appeared on a television program and announced your . findines! Dr. Hr.Lr.r.n. In this particular regard4 Mrs. Gatt-r-trirs. Yes.. Dr. Hu.tsx. I have not. ' llfrs. Gnrrr-crsts. On anp others4 Do you sometimes warri thepublic - of vnrious dangetst. Is that one of the means that the Public Health . Service has traditionally used since television has come into use4
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0 ! 140 FALSE A.\D SfISLEADNG ADV£RTISING bfr. DfaaDER. As the chnirman mentioned, we had Dr. Little before the committee Inst Nreek. I don't know whetheryon are familiar with his testimony originally girelt before this committee. Dr. Htt.m. 2 es, I am. Mr. bfEAD£rt. Iwoltld like to refer to a few passages from his testi- mony. On l>nge2 of his prcpared statementhe said: Atter So cenr. of resParch ou the origin nnd nature of cnncer. I have the Frcat• est rest+ect for Its ciRor, versatility, and complexity. I therefore sincerely nnd deeply deplore premnture nod overampliaed rnncluFlons nnd tnttn.1lce publlclty. Then on pa,-e 6 of his statement lie refers to the study of Dr. Ilnm- mond nnd cays : A{16siflte nssodatlon Is clalmed by the Amerlcaa Cancer Society throuFh the Aammond•Ilorn Study of 1057 betn•eel, escesslve smoking and death from cancer of the lung. And then he lists a whole lot of other organs of the body and diseases that are associated with excessive smoking. On pa;e i he makes this comment:" It Is a dldh-udt It nnt !m(u+salble aclvntitic Aymnntlc feut tn InmeAw n cuu e- andeffcct relntlonshlp In lhl.r overall ndmnre of lmmnn aliment+. ecpeclnlly wtth a atriklncly Incrensed life apnn of our population, and Inereased nationnl tobacco consumption staring us ia the face. Then on pa ;e 64 of the committee's trnnscript, Dr. Little testified: To establish a canse•and-effect relationship on statisttcal associatlon without the experimental evidence is not safe. It cannot be doae. You may get an indl- cntlon of something to look for. but to eay that the case Is aolshed, the evidence Is all ln, and that you can satisfy eTpertnuental scientists, all of them, that 1q not possihle becauee too tnnny of us have aeeo too roany stntistlcnl rclarlmiships whlch have not belped the cause-and-effect relationship. In the statement presented to the committee this morning, I quote from page 1-I b less the statement is in the name of Dr. Burney, the l ast pnragraph : There is an increas:ng and cous(stent body of evldeace that excessive clgnrette smoking Is one of the causative factors In lung cancer. Now it strikes me the comments I have quoted from Dr. Little and the comment I have just now quoted frorn your prepared statement seem to be in conflict. You say there is a causative relationship that is established by the evidence and Dr. Little says it is dangerous to take the statistical associations and from them deduce a cause-and-effect relationship. ' I.ronlct like,ypur cemment,onwlaat appears to be a cmflict.. Dr: HrLr.nt. Certainly,.ltfr. ltieader. ' Dr. Little is a distingrutshed nnd beloved scientist of the Nation. I think, perhaps, you ry ay be aware of his accomplishments in the field of genetics. Dr. Little is indeed a very fine gentleman, both as a man and as a scientist. But there are differences in interpreta- tion among scientists as perhaps you are well aware. Dr. Little is sincerely of the opinion that these data do not warrant the inferences which we have indicated. We do belinre. however, Mr. Meader, that while Dr. Little is en- titled to his interpretation and we respect himr still we feel on tlie. basis of our background, our knowlediee, our esperience, and our infotmntion, tlutt our stand is a properr one for us to take. We feel I
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reisa AND nuszra=a eDvzaTsMa . 155 Dr. BoR.qzr. I don't believe we have ever asked, Mrs. Griffiths, to appear on any particular program, whether it is on polio vaccine, or anything else, but occasionally we' are asked by a certain moderator of a program, radio or TV, to appear and discuss it. Mrs. GRg•f-trxs. If you consider this a peril, and the Federal Gov- ernment controls the airways, would you consider it a legitimate use of those airways for the Public Health Service on a public-service program t.o announce their findingsY Dr. BuRVEr. I would be very pleased to present my statement on either TV or a radio activity. Dfrs. GRn'FrrHS. Then I am going to ask for you to have some time. Have any States requested irformation on this probleml Dr. BIIRNE7. I cannot answer that specifically, I am sorry. I can 8nd out for you. It '•ust happens that the executive committee on the State and Terri-i torial health authorities was meeting with us the day before the state- ment was coming out-it had nothing to do with the statement; Re: did inform them that day of our statement coming out the follovring: day, and Dr. Heller gave them the background which he has given you all here this morning, and told them we were sending this material to them. But, as far as I know, we have not.received any specific requests . Dr. HEU.ER. I don't believe we have. Mrs. GRa=s. When you were considering the relationship be- tween lung cancer and smoking, what contrary evidence did you con- sider 9 Dr. Hr.r.tFv. The fact that there was no proved connection between the chemicals involved, and their ability to produce cancer in man; the fact that prospective studies were preliminary, and as yet not de- fined. as precisely as Dr. Hammond has defined it. Lack of knowl-• edge of the processes of the pathology involved in lung tissue, which, only in the last year or so hns come to tlie public attention; I would say in general these rn.present the basis for our hesitancy before com- ing out-the fact that these particular factors were not elucidated properly to our satisfaction. Subsequently we believe that happened. Mrs. GRrrnTss. Thank you. Mr. Br.nrxrx. Dfa Minshall. Mr. MnTsaeri. Mr. Chairman, at the outset I should like to ask unanimous consent of the committee to make part of the record a very excellent and concise article that appeared in the New York Times, Sunday, July 21,1957, by Willinin Di. Blair entitled "Hnge Tobacco• IndustryAa m on Defensive." I think it ~as some background in- fotmation that would be of very much assistance tc this committee. Mr. Btarr-rx. Without objection, it is so ordered. (See appendix, exhibit 11, p. 579.) Mr. Mrtisxas.r. Dr. Heller, you mid you were familiar with Dr. L'•ittle's testimony that he gave before this committee. Dr. HEU.ta:. In general, sir. Tir. Miriaq,u,z. Would you gSve us an opinion of his testimony-not as to whether or not you disagree with it, but of his fin'dings 4 Dr. Har.r.ER. S1'ell, Mr. Congressman, I would say that Dr. Little's• testimony reflects the attitude ot a scientist ts'ho has been preoccupied with-=
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EXHIBIT 12 52324 3728
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52324 3732 EXHIBIT 14 0 0
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• l.`Kf FALBE AND SII67.LADL*IO ADVERTIBL'fa Mr. bf.rxesau~ Did you happen to eee the New York Times article that appeared in last Sunda s paper, where they stated that they are using all kinds of stems an roots in the tobacco that they•put in the ci~srettesnow4 Dr. Hrsaaa. I did not happen to see that one, sir. I have heard that statement made by others, but I did not see this particular report. Mr. MrxeErAts.. Doctor, you also mentioned some statements put out by the health departments of fore3gn countries-=sir. Chairman, I think it would be also advisable if we had those statements put into the record. Dr. Hznnzx. I will supply them, sir. Mr. Br.A•r.*r>g, Without objection, it is so ordered. (See appendix, exhibit 13, p. 5D3.) Mr. Mtasnera,. I have no further questions, Mr. Chairman. Mr. Bwrxrx. After a 3•day hearing we have come to this point: First, we have from the layman's point of view a rather comprehen- sive picture of the extent, statistically, of lung cancer, and its high statistical relationship with heavy, prolonged smolcing. The medical witnesses representing more or less the point of view of the tobacco industry, say there is no direct evides.o to show any causativo factor in smoking that would cause cancer. Nor, as Dr. Little said, is there anything that he knew of in the smoke or in the ci fiarette that was harmful to the bodye We have other testimony, and these two witnesses this morning state that there is something which justifies deep concern on the part of both official and private apencies and bodies, protecting the people from pos- sible medical harm from excessive smoking. Last year, in 1956, a study group on smoking and health was or- gani7ed including four organizations: The ?.merican Cancer Society, the American Heart Association, and the National Cancer Institute, and the National Heart Institute. Dr. Heller, were you involved in the forming of this joint Study Group on Smoking and Health! Dr. Htta.at, I was, sir. Mr. Bwrx>R. In their report the statement is made- the aam total of sclentiffc evidence establlsbes beyond reasonable doubt that cfgarette amokln; ta a ausative factor In the rapldly lncreasing Incidence of haman epidermold carcinoma of the lang. Does that statement hold as of this moment, Doctor 1 Dr. HuxEa. Yes. Mr. Brsrxss. Is it correct, Dr. Bnrney, to say that is the basis, the combined collective judgment of these professional people who work in the field of cancer and heart disease, studying the smoking and health, that that would be the basis for this statement, the policy made by yourself, on behal f of your department 4 . Dr. Bvxxtr. That was the major factor, Mr. Chairmaa. In addi- tion, there was the report of,Dr. Hammond and Dr. Horn; also the additional laboratory biological data that Dr. Heller discussed, the h,vperplasia, the changes that occur in the cilia, and the bronchiohes, the stndy group appraisal of existing evidence and their comments-these oonstituted the major evidence upon whi; we based our conclusions. ' Mr. Br.iTmx. In the conclusions of this joint Study Group on Smoking and Health it says: '
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152 PAhgE A.\D lIIS'LEADIIG ADVERTISLVG Mr. rfz.DER. Are you financing any chemical research into the composition of the smuke in tobacco? Dr. HELLaR. Yes, Mr. Meader. We have financed Dr. Wynder and Dr. Graham, who died last March, from lung cancxr, incidentally. Their initial work was financed by us and partially so continuing. We have financed work of the French investigators in 3,4-benz- pyrene. Some work has gone on in onr laboratory in this regard bnt we don't have individuals particularly interested in this field. We have financed some of the work at Sloan-Kettering. Of course Mr. Rand and his associates in Cleveland are independently financed, as is Arthur D. Little, of Boston, independently financed, and a group in Boston, I believe. There are only 4 or 5workers immediately in this field, as far as my knowledge goes. There may be others of whom I do not have knoRled fie. We believe excellent work is going on and probably enough work is going on to give definitive results without blanketing the country with this sort of research. These investigators have to go through a very carefnl and quite complicated approach which, of course, re- quires considerable study and considerable knowledge. Mr. MEADF:R. Mr. Chatrmnn, I didn't mean to monopolize so much oC the time, but perhaps, since I made a personal reference to Dr. Little being president of the University of Michigan when Igrad- uated in 1tt•27, I might also mention that my brother, Ralph, has been associated with Dr. Heller in the Cancer Institute.' Mr. IiL.%T-,Ix- On the question of expenditures, Doctor. I recall quite well there was a special interest in medical research %vhen ap- propriations were made by this Congress. The President asked the Congress for $46,902,000 for the National Cancer Institute for this coming fiscal year of 19158. Congress ttpped that by almost $10 million. Ttie Congress voted'$56,402,000 for this pcriod. A'ow for this first quarter of fiscal year 1958, could you tell us at this time, or supply for the record upon checking up, whether the National Cancer Instttute is spending one-fourth of the funds which the Presi- dent asked for, which is $46 million-plus, or are you spending one- fourth of the funds which Congress appropriated which is over $56 million? In other words, are you spending a larger figure or a smaller figure? Dr. HELLER. Mr. Chairman, as of yesterday, to the best of my knowl- edMe, the apportionnient had not.come.down.from the Public He.alth Service and the Bureau of the Budget, so I cannot answer that accu- rately at this time. I will be pleased to supply that for the record as of today or Rs of whatever day the apportionments are made. - (Dr. !Ieller advised the subcommittee that the first quarter appor- tionment totalled $35,258,000,) Perhaps Dr. Burnev might have some additional information. Dr. BIIRYEY. I assume we will do the same as we did last year, Mr. Chairman. In other words, we received quite a sizable incrense lastt vear and there wns no ceiling put on the amount of funds; and the In• stitute, through their adoisory counsels and study'sectttaries were " tbld ihtit "A'e have this amnunt of funds and if we have the projects to go ahe.ad and slrend the money. We hope that the samc quality of review and appraical of project will continue, even though you have 0
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0 0 156 TAIBF. AND MIFLLADI:PG ADYTR?7SL'lo Mr. Mr:resett. Dr. Little is not a doctor of inedicine} Dr. Huun. That is right, he is a doctor of philosophy and particu- larly noted for his work in Fenetics and as an educator. I would say that Dr. Lutle's viewpoint is one of a vory well-in- formed scientist who is interested in the basic components of research. He, by his own admission, wns not interested in filters or the develop- mental research that is inherentin a discussion of this problem. Dr. Little's testimony in general-at least the impression I received from it, was that he simply did not believe that the epidemroloqic and statistical evidence submitted was suflicient to allow an interpretation of a causative factor being involved in tobacco smoke. I think we agree certainly with Dr. Little that more research needs to be done. We disagree fundamentally in the interpretative aspects. I will not take exception to Dr. Little's basic attitude, I think he is entitled to that. I differ with respect to his basic interpretation. Mr. Mirrsa+u.. The question was also asked you, Dr. Heller, as to how soon you thought some definite findings mrght be made known to the publio-whether it was just a manner of speaking but you said something about next spring. Dr. HEr.r.za. I was referring primarily to the report which we hope to-make of this very large prospective study among veterans. Now, as to what pronouncements might be made in the future would be dependent upon what findings emanate from the laboratories, or from the work of other investigators, and I do not know how to predict just when that might be. I can predict, because we believe that the initial reports will come• oat next spring on this prospective study which is a very important one, in our opinion. Mr. DizxsHAtt. Your studies thns far Rre the results of analyzing the statistics of the World War I veterans. Am I correct that yoc said those studies thus far parallel the reports and statistics as b ven before this committee by Dr. Wynder? Dr. Hi;r.Ltn. Primarilv by Dr. Hammond. ?vir. Miveruu.a. Dr. Hammond, yes. Pardon me. Dr. HELix.x. The fragmentary reports dipped into the stream of information. Mr. Mivsx.ua,. What do you mean by fragmentary? Dr. Hsrsta. Well, in the sense that they take out a little piece of data and look at it, and see which way it seems to be going. This dip- pinq into portions which they have examined seems to be consistent' .cith results reported previously. The idea was, as we processed these data, to ascertain that they were consistent with existing ideas or findinga which previously had been reported. Now, obviously, one is unwise to make a dogmatic statement that this is going to be the same as any other statement. We are waiting until all the statements are analyzed, statistically interpreted, a dn studied by people who make it their business to interpret properly, and put into a practical usaqe the results of such. studies. Mr: Msxaxua.. $ave you at any t.ime conferred with the chemists or the doctors, other than Dr. Little, thnt represent. the tobacco in- dustry} Dr. Hrr,tsa. I know most of the members of the•tobacco industr, research committee. I have attended a social finthering or so of this
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0 eatne.out. FAIfiE AND liIBLSADL7G ADVSRTLSnYG 157 group. I know most of themper~onally and we have discussed it in very general terms I called Dr. Little >'or ezample, before Dr. $ur- ney s statement came out, to keep our haison. We are good friends and we have alwa; a enjoyed pleasant relationships which I hope will continue. I do not know of the work of the investigators who are suprarted by the tobacco industrq~ research grants. Mr. Marsaara.. You, of course, have discussed, the general effects of ianoking and cancer with these people representing the tobacco indus- try; haveyounotf Dr. Haszn. Yes, sir. Mr. Msxartars. Have you ever discussed the relative merits or de- merifs of various kinds of filters that they have used I Dr. Hsra.En. To; I have not. The times at which I have discus^ed the problem with them, filters have not been introduced into the cors- versation, and,'as a matter of fact, there seems to be a lack of knowl- edge, generally, of the results. Mr. Mnxeswt.. Well, the cigarette companies are making fantastic claims and have over the past several years as to what these filters do. Are you familiar with their laboratory tests 4 Dr. Hmaa. No. sir. - Mr. Dirxaaer.z Do you know that they do have laboratory tests4 Dr. HEr.r.mt. We understand that tobacco companies have their own research laboratories. We do not not know the-results of any work which they have done. Mr. kiIxesars. Have you ever requested that information from these research laboratories of the various companiest Dr. Haaxa. No. sir; we have not requested it. Mr. Dfivsu.ua.. Don't you thing that Rould be a good idea Y Dr. Herssn. I think it probably would. From pasteaperience with industrial laboratories, they traditionally or conventionally do not,give out the results. Mr. Mcxsaet.r.. Tnis is a different matter. This is in the interests of medical science. Like a gasoline company constantly sample tests ; the quality of its gasoline it puts in its service stations, and I am sure the tobacco people do the same thing n•ith their tobacco as well as the ~ filters. They test their filters periodically, do they noti ~ Dr. Asrs.rn. Yes • I presume they do, ~ Mr. bir.reuAi.r.. ?Aave you ever discussed that matter with the ~ tobacco people at all.a Dr. IiFSS.Ex. No; I have not, sir. Mr.llinrsmil. Where did you get the information that the filters were 40 to 50 percent effective when they first came out4 Dr. Hums. Primarily from the work of Dr. W~ynderand hisgcoup and also from the work-reported in the Reader s Dige.~., of shich ]< 4 had some knowledge before it came out---done by Snell & Associates I, which isbelieved to be good work. ; Mr. Murs•s.u.u. From your knowled~e of reading these various pnb- , lioations, and talking with Dr. Wyndbr; are these $Iters, ds effective '! today as they were when theycame out i i Dr. HEcs:m The information I have from these discussions:is that these filters are not as effective today as they were when they first
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• 0 FA2,iE A.\D AtISLEADL\C .ADVER'I'I8L"IC 149 into something, and no resulte nre obtained. If $2 million had been slwnt for ctuicer resenrch certainly, one would expect some results to come out of that. PrItbl.• some resttlts.•are coming out of these studies. I just don't happen to know of them. I«ould not be too critical of the results of research of $2.2 million worth of cancer research, on the basis of our experience in the Na• tional Cancer Institute over a period of yeutx, in which much more *thnn $2.5 million has been spent. Truly, I would cett,tinly accept the pn,position thnt any prant•gr.•ing group Itns a right to expect reports of progress and infot•tnation as to the direction of the research, the arcmnplialtments of research. attitudes of the investigntn • ns to alierf~ef" ey cc ~ :n'i~rr~t[it'r17+1tCtrnt , tfnrrg-- 1e:epect that i9 a•ltnt Dr. 11'vndet• is referrin~ to, as well. \fr. ~fFtint:R. Now, Dr. Neller, there ~~•ns a comment on page 2 of Dr. Burney's stntement, the lnst pnragraph: lfoditlcntlon of ciprettea eo thnt thelr bnrmful effects would be reduced 11 uf obctoue fmtwrtance to publie Eenlth- and I think it similar attitude toward this question is expressed by Dr. 11'ynder and, perhnps, by other witnesses; that there isn't anr desire or any hope that tobacco smoking is going to be wiped out, (ont that tLe ,unt shnuld he to identify rhe Dnrntftil agents in tobacco and see if they cannot be eliminated, and, thus, the bntl effects of smoking roiild he reduced. Thnt leads me to this qucs-tiou, wlticlt I ltnven't• heard nxhlnined in nnr record vo f,tr: .iust. what are the effects of•ci-arette smoking ,rr the elentents in cigarette stnoking on the humnn Cody, the stimu- lating effect, how does it operute, and is it possible that Arhatever pleasnrnhle efferts derivrd from smoking can be separnted from the Ir,trmful efiectsi In other words, that getx back to this question of the filters that filtered out ro much of the smoke that nobcdv wanted tn smoke filter ciaarettes any more, and now the'manufactitrets ap- p:trently have put in cheaper tobncco with more tare and rf)me of these elements that are suspected of being hsrmful. As a result, people V t n kick out of the filter cigarettes, but they ara getting as much nf the harmful elements as they were before. Now can you.asa result of your research explain the operation of the elements in ct arette smoke upon body, processes, and what element stimulates, an~throafih what means there is a stimulation T Dr. HELLER. Yes, Mr. Meader. My understanding is this: There seem to be three constttuents, or major constituents, in cigarette smok- ing from which the individual derives the so-called pleasure..of smok- ing. 'One is the effect of the nicotine on the individual. Now, nicotine is a very complex drug which has a complicated action on the human body from the standpoint.of physiology. It brings about increased pulse rate, stimulation of what is called the parasympathetic nervous system, and involuntary nervous s7stem, a stimulation of saliva, and a vety complex train of physiological action which varits somewhat frompetson to person, but, in general, can be predicted. The second is in the tars, themselves. This is a mass of many hydrocarbons which haven't been completely identified chemically, although b or 6 of them hace been very de6nitel y• established as being present in tobacco tats. We happen to believe that the carcinogenic, or the cancer-prodn.cing ..
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0 FALSD A-\b d3ISLEADL\G ADVE:RTr$r!rG 151 that we are alert to every possibility in research which may be quite important in this entire question. Mr. DlrenEx I believe you agreed to give the chairman a list of your cancer grants over a 5-year period. Could you give us an ap- prozimation of the specific research on this problem of the relation- ship between smoking and cancer, in proportion to the total cancer research progrnm P How much of devoted to this particular prob- lem 1 Dr. HES.r.ER. From our work, or that of the Nation generally? Dfrf hfrADEa. I refer to yourgrants. Dr. Hrs.r.ER. It would be completely a guess. We do not support ann awful lot of work, Mr. Afeader, and fre- quently work may be omg on in this direction in connectior. with certain other grants wgich we are supporting, of which we may not be aware until they report on it. I would say that several hundred. thousand dollars are now utilized in support of this type of research, as of the momenE. Mr. DfEADER. Probably not as much as the $2.2 million that the tobacco industry is spendingl Dr. HELLEn. I would say not, Dfr. Dieader. We may be supporting is much as a half million dollars, depending upon the definition of what constitutes research in this area. :1ir. Mr.iDEn. Could you describe sa that a layman could understand it, some of the svenues that you are exploring in this particular field? Dr. HEU.ER. Yes. In addition to the epidemiological investigations with which you are, I think, reasonably familiar-tbe veterans' study and the study tho cancer society is carrying on-we have engaged in studies to deter- mine the smoking habits of a cross cectimi of the population. Mr. Mn+DEn I was thinking more in terms of the purely scientific rather than the statistical research. Dr. HEU.ER. i11l right, sir. In the purely scientific approach which the,lnborntory scientist can work at, we have been quite interested in finding out what are the earliest changes which occur in tlte epithelium or the lining of the bronchioles of the lunl,~s. Two or three studies with which you may be familiar, as referred' to b~ Drs. Wynder nnd Hammond, have indicated that since cancer of tl'e lung occurs at a certain predictable rate, there would be reason to believe that early changes which precede the actual cancer lesion might be obserred.at autopsy. : These studies havo indicated that thece are verY early change.c, indicated by a diminution in tho activity of.the little cilia which propel waste material outward in the bronchial paasagges: in the nose and other parts of the bronchial system. There are varying degrees of change of this tissue, proceeding to the actual changes in some of the basic cells, and to what is called carcinoma-in- situ, or the very earliest stage of cancer that is clinically demonstrable before it becomes clinically recoFnizable. That is a very important approach, from our viewpoint, inasmuch as it enables us.to know, , or at ]east partially to know, 'how long it takes from, the time th:gt exogenous fnctois ate applied to a sensitive epithelial or mucous membrane,-unt.il a fnllfledfied carcinoma'"of the epidermo"id:type is- produced.
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r~~r..ua..V l.~.uu...]...V 0 in this, I think now that I might not stop smoking, but might' not smoke so much. I wouldn't swear to that, because I get a lot of pleasure out of smoking and, even though the threat is there, I might stilt continue. Mr. PL\rINOER. We have some evidence along that line from Dr. Hammond that I might turn over to~ you. Dr. Rigd~on, the head of the department of patholo~*_at the IIniversity of Te:as, mentioned in his testimony that in the United Stntes Public Health Service-- there le a wide rarleHon with recard to the role of cll[nrettea and cancera. Yon have certaln one. who eny it just can't occur, and others say lt might be bat !t hasn't been provea, so you bare a split In there from people who are now In that orgnnlratlon. Now, I would assnme that on any issue there is divergence of opinion-and I have been professionally trained to believe tltnt there is such a thing as a 5•to-4 decision in the Supreme CourG-but how wide is thA vnriation of opinion within the Public Health Service or within the Nationnl Cancer Institutet Dr. i3vx.a. I believe Dr. Helter should answer that, but I should s,1y it n•as my undelstnndinfi when we prepared this position that the consensus of t.lte scientists nt the Nntional Cancer Institute were firmly behind this particular position. Dr. Hl:r.t.rR. Thnt is true. Mr. Chairmnn, there nre ronny scientists in the Cnncer Institute, and man }• differences of optnion, scientists being scientists. However, I would disaggree with Dr. Rigpdon that there is a wide variation in nt.tit.ude. Even a part.icular scientist who believes that nir pohrtion is much more of a fnctor, for example, than smoking, snvs, howEver, thnt there is no doubt thnt smoking is incriminated in this: process and it is simply a matter of derree. There ntr others who nre of the opinion that there might be such lung-cancer increases ns has been stated, but that, through better dintrnotis, it is coming to the nt.tention of the media'ti profession and the people. We llnve bettar doctors, we nrc dagnosing more quickly, and so forth. However, I would say thnt the consensus tn tlte Cnncer Institute-I can't. sPenk for the entire Public Health Service, but oprtainlv in the Cancer Institute and in the National Inst.ittttes of HenIt.ll-tha coneensus is reflected in the statement which the Sttr."on General hnc promulgated. Mr. Pr.Artxal:n. Does that menn 51 Vercent, or is it. orerrnhplmingP Dr. HELLFR. An overwhelming majority. I would say with the exception of only 1 or 2 who do not agree completely with this oieR- ~int, but the over~shelming rnnjority of the scientists in the. National Iastitute of Health agree. . Mr. PLnrr.rar.R. With regard to the 1 or 2, what happens to their rPSenrch that may have been going off in one direction or another ae a resnlt of this pronouncement of Government policy I Dr. Iir.r.r.Fe. The go right along, sir. It is not stoppcd. Mr. MINPItALL. ~on have mentioned what they do with it in the National Cancer Institute. Have you had the opportunity to discuss this with, for example, the Mayo Clinic, or any other private institutionci . . .. Dr. Ha1.1.r.x.. With individuals.of the Ochsner Clinic, and the Mayo Frfmp, nnd so forth: I have discussed'it with individunls. . M.r..Ml.rerrAr,1.. And what ivas their feeling4
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e.uaLA.Nu J31aLC~DI\G ADYERTlBLtiG 0 dividualpetsonnl opinions which mny be correct but, therefore, might be considered only personnl opinions. This representa a body of opinion. Dr. Loaxsr. .llr. Mender, may I supplement this just brieA,i•- 11'e Rould nll like to have the idenl situation in any public-heulth problem, to know the causative factor before we !~roceed to invoke preventire mensurcc, bnt it luw been our experience throughout the 1,,0 years of thn existence of the Public Health Service that many scri<,uv public•henlth problcms h;ire been solved very largely before the final causutire ngent or its method of spread has t)een determined. In pellnRra, for example. we tlidn't know what the final diecm•- part was tFint prevented pelln ra before certain remedial me;isures n•ere carried ou. We ilicht't ~now the snme nbout mnlaria, alwut I•e11ow fever, and a mtmLer of things. We did have, hoKerer, slntis• ticnl and epidemioln;:ical informatton which pointed up certnill far• tors, and upon whirli a•e could proceed to eliminnte malnrin, }•ellua- feYer, and peilugru before we could identify the specific cause. We would like to tiruit until we hnve the specific ngent, and be ;Ojlc to identify it, and isolate it, before ire pick nny approach. Uo the other hand, it has not l~cen our experience in pnblic•heulth work tluat that has either been possible or has been a responsible course to follfjsc. Mr. 1fe.sDt:n. Thn n k ruu. ,Dr. Heller, Dr. Little nlso tokl us about the $2.2 million that tlic tobacco industry has supplied for research in this field. Are you familinr with the Frants mnde under Dr. Little's supervision, aml Rliat progress has been mnde as a result of ezpenditures of the tah,iocn in- dustry in research in this tield ? Dr. HrLtsn. I hara seen n list of the firnntees and the titles of nce grants. In general, those grants nre bnsic, fundamental studies in what R'e call cnrcino;:eneAist thnt is, those thingswhich cause cnnf-er. To the best of my recollection nnd knowledge, there nre no studies in progress Rhirh nrn related directly to such things as filters or other applied-research components. I do know that the recipients of these grants are reputable scientists who nre also recipients of grants from the Public Health Service, nnd from other grant-giving bodies. The work they do we cnn expect to be good work, and certainly, the re• search which is being conducted ttnder thn auspices of the tobacco industry research committee can be classed ns good research. I do not know of any outstanding results which have come from these studies. Perhaps it is a little enrly, inasmnch as they have onl•r been in operation,perhnp~ a couple of yenra So that, while m} in- fornmtion is not tletailed, in general, I think that represents the situation ?Ifr.lltr%nr-n: nr.lI'vndercommente.d thntifhehad spentS2million on his cancer re.search; and had so little to show for it, he would ce• ceive some very severe criticicm from his superiors. Mr. Br•AT.sIR. His superinra wouldn't be very happy about it. Dr. Hnt.tn. I don't quite agree wit.h thnt,Mr. i<feader. I have been following cancer research, and hn.ve been responsible, for cancer research, fienerally, fnr, a 1onG time. It is a long, slnw. laborious, henrthreakin^, frnstrntina experienc.e: 'Research, generitlly, in what- ever field, medical. research, indnstrinl research, or what hnve,yoit. is expensive and time consumtng. It is frequent that mitch money Oes
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9 1n.yr. ~1u AuDLtu1YLIV AYVJI3AL".Y 1J7 The study group coneSudee that the amoking of tobacco, partlcats-r1y Sn the form of dgarettes, ls an important health haurd. Tbe tmpitcations of this state- ment are cJear la terms of the need for thorough conslderattoa of appropriate cootrol measures on the part of officlal and voluntary agencies that are con- cerned with the health of the peopla Would you say that statement sets forth the latest thing and the latest area of agreement on this important subjecti Dr. Bvartar. We believe, Mr. Clwirman, that in that report we had this responsibility to express an opinion and make these facts known to the public, and our interpretation of the facts. I would like to say again, however, that we do not believe the final answers have been secured and that there is a limit to what a responsi- ble, official Federal sgenc7 can or should do before they have all avail- y I thak we have stopped at a certain able information. That is wh i point, using our particular judgment, and that until such time as we hava much more definitive information, we should not go all out on a campaign and put stickers on cigarettes and certain other things. Dfaybe our udgment is scrong in that, but I think ~ce have gone as far as we shoul~d go at the present time. As new information comes out, as a result of what Dr. Heller is doing, or other things, we will make those facts known to the public and to our counterparts in the States. Mr. PLAPINOER. But you said in your published statement "it is confirmed beyond a reasonable doubt °' It seems to me you are now sapng, "on the one hand," but, "on the other hand:' But you have .sald in the first instance Omt "it is confirmed beyond a reasonable dottbt that there is a high deffree of statistical association between lun ; cancer nnd heavy nnd proqonged cib rette smoking." That is an unequivocn1 statement, Dr. Burney.~ Dr. Bu:u~rEZ. That is right ~Ye believe that, and Dr. Heller's group agrees with that. Mr. Pl.tirrxaER. You are not prepared at this time to do more than make this information available to State saencies coneerned with health. Having made this pronouncement, appaielltly that ends the public information-education phase, or is that a premature conclu- stonl Dr. BuRNtr. I would suspect this subject will be discussed this fall when the Surgeon General has his annual conference with the State and Territorial health of6c-trs. I would also suspect at the same time that we will discuss accident prevention in children, which is one of the very serious causes of death. This is not the only health hazardk and we certainly have some very definite information on those indications, and so there are other health problems that State hes lth officers must consider. But, at the present ttme~yes, sir; I would say this is as far as I would intend to go, and whic my seientific , roup have recommended. I ir. PrrtrtN~c.r.ii. How about informntion in your own installations, such as the public-health hospitals, and among Federal Government employeesl Dr. BmtNEZ. This information has been pretty widely dispensed, as Dr. Heller mentioned. , The press hits given, I would say, very cotn- plete and very factual'reporting on this. I would also say that we are gettin~ into an area ltere where individ- ual likes many times overcome ones fears and prejudices. ; I have smoked a pipe for. 15 years. If pipes were more seriously implicated
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tGt. t't..y. tJ LCNG C.tSCER-BCRNEY tlii 123 1 ue btulog;c•ally aclf•prutective, and biologtcalh this is correlated with robustness in meeting mortal sttess from disease generall,v. 3. Smoking increases the 'rate of living' (Pearl). nnd smokers at a given age are. biolugic.lle, at an ,+ge older than their chronologic age. As a result. smokers (in particular, hea.v smokers) are subject tn the death rate of nonsmokers nr relatively light >mokers who are chrunolocically nlder: . . ' Little " speaking for the sc:entific advison- hnard of the tobacco industn research commtttee, +puestinned "the existence of suwcient definitive Hcmmond and Horn 160 r Imr c 12J a ~ ~ 100 ~ ~ 80 0 0 c 401- 201- 0t 3.4 Less than one pack per day 57.6 ^n,ups would be expected to di&er in cancer inci• dence. ..' He quoted a study ++f the smoking habits of identical and fraterttal nvins in support ,,f his thesis. firnuke•" after an extensive statistical study of deaths =-:im lung cancer in England. concluded th.+t the initial development of cancer of the lung• ur some predisposing condition. nccurs many •vears befnre the overt d'uease. probabl • during the -teen" a;es, and that the cancer of r!te lung now •een may have been at least p,:rtly determined ciuring these Ynunger years. He be!ie•:ed that exriv Qoll and Hill One or more pocks per day 157.1 60.5 Never Still Ex- Still Ex- Smoked Smoking smoker Smoking smoker L 103 ~ ~ ~ ~ ~ ~ ~ 7 0 Never Smoked Still Ex- Smoking smoker~ I Fig. I-Aae!adfusted 1ue9 eoncer death ntes(or smokert, enmaken (persons who hed tinn up smoking tot l0 yean or more wheo' interviewed), and oonrmokers, by stud,r,•• cvidenqe to establish is simple ratise•and-effect ex• planation of the complex problem of lung cancer.' He also said. 'Many experiments on inhalation of . cigarette smoke in animals have failed to produce a single cancer similar to the most prevalent type nf lung cancer in humans." Fisher'r questioned whether the genetic factor tan be dismissed. -There can therefore be little doubt that the genut3Pe exercises a considerable influence on smoking'and on the particularr habft Jf smoking.adopted . .': genotypically di$erent in the present century there was an "explosive increase in bronchocarcinogenetic furces " He did not attempt to identify these forces but suggested that they were environmental. such as motorcar exhaust or radiatioss. He believed that smoking cannot be considered an etiological factor in the initial stages of the cancer, if the disease does commence as early as he has suggested..'On.the nther hand,' he said, 'iC would not be entirely unreasonable to sup se that bronohial or pul•t monary. shangei;' p uced by othe:. Factor3 them- t
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52324 3731 Exhibit 13 , ~ ~
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• 0 t'ol. Cl, No. IJ LC]C CANCER-BCRSEY chuserts and the United States, the mor.ality in men was more than five times that in svomen.'= This difference is not easily explained. There may be a true sex difference in susceptibility to dte causes of increase in lung cancer, but the data are not conclusive." Studies of apparent differences in smoking habits also have not accounted adequately for the varia- tion in death rates between men and womea. But there is conclusive evidence " that nonsmoking women have about the same lung cancer death rate as nonsmoking men; that among .vomen the environmental factors contributing to the rise in lung cancer (fiy 5)." There are also noncarcino• genic pollutants which are imtants and may a$ect the body's defense mechanism against inhaled carcinogens." Socioeconomic Stntus.-Some investiaators " have found that low suciuecunomic groups have an in- creased incidence of lung cancer. However. the low income ;,rnup. by ecunomic necessip•. is apt to live near industrial centers where the air is more hea%ily cvntaminated with pollutants and ai:borne carcinogens than it is in peripheral resi- deatial qreas. It is also true that the low suciu• ecdnumic group. as a whole, receit-es less adequata medical care and lives in a less hvaienic envirnn• ment than the more furtunate pomnn of socieny. Thus, it is di(iicult to measure any direct effect nf socioeconomic factors alone. Lower 1lortaiity in tt'omen.-Until 1926 itm; cancer death rates among men and women in \(usachusetts" (and, presumably. in the rest of the United States), were approximately equal. Ao lung cancer rapidly increased, its distribution be- nveen the sexes changed. In 1936, in both >lassa- light smoker carries a risk of hing cancer twice r. I~ry.-~rr~.wet ~~ .. ~ m e ae Fig. S.-Seleeted ensircnmentel Qeton-trends for United Slates, 1p6a-1YS7 (adapted frooi Hammond1el. that of the nonsmoker; and for the woman smoking more than one pack a day, the hazard is 6ve times greatu. Physical Factors-fiy(e and Cigar Smoking.- Hammond and Horn" have shown that a person •' who smokei cigarette; his almos~ three times the risk of dying from lung cancet as the pipe smoker 179i183] tfic. 6) and seven times that of the cigar smoker. It ts possible that this relatively favorable status of pipe or cigar smokers may be due to the more adverse ph,vsical characteristics of cigarette smoke. Cigarettes burn at considerably higher tempera- tures than pipes or cigars." Undoubtedly, too, deep ~~s. nr Gpnne Clpw.w Sw.f' Ur W. .~do+.r pdr Fia. 6.-Age-ediusted lung uneer death ntes by type of smot(na (data hcm Hammond and Horn'), inhalation of smoke is associated almost entirely with cigarette smoking." Othen" maintain that the lower death rates of persons who do not smoke ' cigarettes ezclusively merely reflect their less ea- tensive use of cigarettes. A Concept of Pathogenesis of Lung Cancer The association between the use of tobacco and buccai and lung cancer has been supported largely by statistical evidence until relatively recently. This in itself has seemed conclusive to many in- vestigators, although the mechanism of cancer growth in the lung has never been demonstrated. If the smoking hypothesis is valid, it should be possible to show a sequence of events, started by cigarette smoke, which leads to the development of lung cancer. The same course could be initiated by the inhalation of carcinogens from polluted air. Several recent investigations lend support to such a concept of pathogenesis. It should be noted that this conceptis theoreritaL.for the-full course.from . causative agent to 6nal tumor is not known in man. Furthermore, the statistical and experimental ase sociation between smoking and lung cancer applies essentially to the epidermoid type. The incidence of adenocarcinoma and undifferentiated carcinoma of the lung has changed little." Carcinogenic Subrtanees: It hu long been known that certain polycyclic hydrocarbons are carcino- . genic for animals and man. Those present in the tobacco leaf are fragmented 'at the burning tem- . perature of the cigarette into incomplete combus- tioti products and arp included in the tar portion . of the smoke. \Pynderi' has shosdn that cigarette
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. THE JOURNAL OF THE American Medical Association Published fi nder the Auspices of the Board o/ Trustees VOL. 171, NO. 15 CHICACO, ILLINOIS Ce.cucwr• 1939• ar AuZme.a slcemu. Assocattes RELATIONSHIP OF NOXIOUS GASES TO CaRCINO.NiA RAILROAD WORKERS Isadore Kaplan, M.D., Baltimore © HIS study is presented in order to com• pare primary lung cancer deaths in railroad workers with those in the "non• railroader" public. It analyzes. the lung cancer rate of the railroad emplovees from the standpoint of occupational exposures to noxious gases and air pollutants. Lung Cancer as an Occupational Hazard Lung cancer has been recognized for many years as an occupational hazard. The earliest reported case, related to radioactive substances, was in 1579.' Farber; in his book "Lung Ceutcer," said that, in 1935, Lange found that between 60 and i0.°e of all miners at Schneeberg (Sa.com•) died of broncho• genic carcinoma due to exposure to pitchblende in the ore. Heuper.' head of the environmental section of the National. Cancer Institute, mentioned that the total number of Schneeberg miners who died from cancer of.the lung between 1879 and 1939 was approximately 400, while the number of Juachims• • thal (Czechoslovakia) miners who fell victim to this disease reached 225 between 1926 and 1943. Jlaehle and Gregorius' stated that, of 193 deaths In chromate workers, 66 were from cancer, most• ly of the lungs. In addition to the uranium and chromate listed above, aisenie, nickel, asbestos, coil tar fumes, and ben•llium havee frome tlme to . time been stupected is'lung carcinogens.'Todiy; entironmental and.e.tperimental studies are being , DECEMBER 12, 1959 OF THE LUNG IN . The medical records of 6,506 deaths among railroad workers included 818 deaths from mclignant disease of various orgons, and 154 of the deaths were ascribed to pri• mory carcinoma of the lung and/or bronchus. The 15/ deaths were classified according to the oniount of exposure to exhaust fumes from diesel engines involved in the de• cedent's octucl day's work. The group of workers regularly exposed to diesel exhaust, especially engineers and firemen, proved not to have ony higher rate of bronchopulmonary carcinoma than did the nonaperating groups, which included clerks and janitors. Paro• doaically, the highest rote was in the clerical group,, which also contained a higher per• tenlage of urban as distinguished from ruraf " residents. The place of residence was more significant than the lype of work. The cases of branchopulmonary carcinoma here stud• ied ell occvrred in men eren though about l'/. of the employees in the deportment con• cerned were women. conducted to ascertain the possible, role of air pol. lution by'no:dou•s fumes as a carcinogenic factor in the production of lung cancer in human beings. ; ?f.dinl and 5urtint DLener, eahimen and Ohio n.dru.d Cumeanri 97/2039
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i;u 1830 CC\'C CS\CEIt-RCn\EY c.:nt.r :,r.u!c 411 nmr•, tll.Lt -t dle nulbmri{,c•r.. pipe .m,,:m•C !c.l, ••,Hriated wrth Iwl; c.mcrr tn ., le,ser degree tlun a.u cigarette smukm•;. Hammmld nnd //om.-Hammvnd .nd Hum ' ll,n e bren cunductm•_ t longitudinal stud.' uf 15-:53 Ivl.•;re men .1_ed 50 to 69. .~nalyses Svtth regard T.ceu L-Cnnrrr Drar6 Rater' per :00.OM tt'Ltre Nen• uy Soerined Srrer rind Selected 1'earr. t970•i9i6 • .,1 .. . _. •.. .. rrr :~r r .,I ... rn: U:i leeea:v ... n: . 11 . !n; 1,C u• 1':t nreru~n . . .. •i .. ., , .r .. .. I t.ar.~~rrerr.rn:t Creon.o n 1) 11 t} )1 )9 f ' rr t . ....... . I '.Seruqunnl m ~nr rens, ,urr• 11'n ni1t mrlr oneal.non,° i to ltmg cancer in this +ge group at the end of 44 months support the findings of Doll and Hill. The 3?,4'9^_ men who never smoked had an age-adjusted death rate from all types of lung cancer of 12.3 per 100.000 man-years. On the other hand the 63:'i3' men who gave a history of smoking cigarettes es• clusively showed an ageadjusted death rate from this cancer of 1?7.?, a ratio of 10 to 1. This studv of Hammond and Horn is of particuhlr interest since the reports of the individual deaths due to lung cancer were carefully checked and in most cases verified by microscopic diagnosis. The tumor deaths proved by tissue section constituted what the authors called the "tvelt•estahlislsed cases." on which further detailed studies were made. Adenncarcinoma of the lung was excluded from this goup and treated separately because of the small number of cases (•Z°_) and also because of the general feeling that sdenucsrcinoma may r e , HL . nn rto 1rat tq0 1ns Fig. t.-Tnnd in a{e+diusted c.ncar dath ntes among White mea for specifled sita end ,rears, 1910•1956.a' be less assisciated with smoking than are other fortru. Table 2 summarizes much of the Hammond and Horn study. Within the group of 'well•established atses' the ifference in death rates between the nonsmoker Ind the heavy imqker was striking. the ratio being I c.)t_4.. %-. T1. 1939 64 tn 1. Fur thn•e uftu h,ql prc•vumh Inid.cd 6;.lrettve but It,¢I >tnpped the dmal• rate n',usigmfic:mtly reduced. .md. is the penl•d Svithnut smokin•; kn, hened. the death rate became pro. 2ressteelv luner, ,tlthough it never reached the r,tte uf those n'hu had never smoked (fig.:3). Dorn.-The Darn study popstlation' consisted of Ii9,000 C. S• government life insurance policy holders. At the end of two and une•h,df years of this mntinuing study there h,ul been 7>1S^_ dwlths in the grnup. The increased piupurtion uf deaths from arty cause amung the smokers as compared with the nonsmokers was greatest for cancer of the lung. The de:rth rate frum this malign,utcy among regular smokers of cigarettes was about 10 times that in the nonsmoking group. Re~ular cigarette smokers who had stopped smokin¢ cig,trettes be• fnre the sntdv he'tan in 14i4 had ., ?t,,.cr murtality than those scho cvotinued tr, stnuko: au!cc,'er, this rate ,vu.a still ~31F' :rr,tter tIr,:r fr•" -~r.lur~,ken. o s 10 . M~.i.er M or.a. Is Fie• ^-.-\umber of deaths from lunj cnrcrr in imnken for each death in nensmoken, by study." Criticism of the Smokin_ H~porGcsis.-\ot nll investigators are in agreement with the canclusinns reached by these researchers. Berksnn'° noted that the data of Hammond and Horn and of Doll and Hill point not only to an association between smoking and lung cancer but also to a,.ide variety of diseases never presumed to have the same etiuln,; as cancer. He suggestc that some other explanation must be sou-lst, stat• ing, '1, The observed usstsciations are 'spuriutts; that B.'they have no bioloqic,tl signifiiance, but" are the result of the interplay of various subtle and c.)mplic:rted birtses.' The definitive v,sriahles, name- l,v a history of smuking and tlse cause of death, are.. as nhservations, subject to considerable error, and the samples, not having been obtained (or ubtain- able) by scientific sampling methods. are 'se• ' lected.' . . . '3• The observed assrxiutiorts huvt+ a amstitu• tional basis. Persoos'who are nottsowtkers, ur rela. tively light smokers, ue t:he kind s)f peuple whu I I
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Vol. I:I. \o. I] SPECIAL ARTICLE SMOKING AND LUNG CANCER A STATE?tEST OF TtIE PCHLIC HEALTH SERVICE Leroy E. Burney, \F:D., washington, D. C. 0 The Public Health Service is deeply cunecrned svith the inae:uing death rate frnm lung cancer in the Coited States and in other parts of the svorld. Cancer of the lung is increasing more rapidly and causing more deaths than any nther form of cancer in the adult male population. In the United States, the death tate from lung cancer among white men (age-adjusted) a'as 1& per 100.000 lxtpulatiun in 1930; by 1936, the rate had risen to :31.0.' and more then 19.000 persons died of lung cancer in that year (8g. 1, table 1). A rising death rate of this magnitude arrests the attention of evern• phy- sician. private practitioner and public health oi&- ter alike. Many investigators hjve indicted ci:arette smok- ing as respunsible in large part for the increasing lung cancer death rate. Others have denied this, Wying that increased volumes of automobile ex- baust fumes and industrial vapors polluting the air are largely responsible for the causatiori of lung c•.mcer.' The pnssibility that there are other factors .zt unknown has also been suggested. Two years ugo I made the following statement: .. The Public Health Service feels the sdeight of the evidence is increasingly pointing in one direction: that excessive smoking is one of the causative Factors in Itmg cancer: ' Our belief then was b:ued on reports that had been accumulatin¢ for more than 30 years. Since 1937, additional studies. some from our own staff. have contributed to review in this paper I wish new infurmation , , . the data io those publications the Public Health Service has felt to be of particular value and to give our interpretation of the material presented. ~ The Smoking Hypothesis j: In the'tr classic study in '1928, Lombard and Doeritig' ooted an association between heavy smoking ind bucral cancer. Later, examination of time trends in mortality showed that the death rate from lung rancer wu r`apidly increasing. This im- t' mediately raised the question of a possible asso- ciatioo of smoking with bronchial malignancy. ~. - lfany studies' in different countries shots'ed a ~ higher proportion of smokers in.lung cancer groups th'ao in cvntrol gruups.. SuRrw Cmml. Cnn.J Su,M robik HtaI,Y $.n.n. Lombard anr! Sne.-irc)j.-The latest papet' in the Massachusetts studies ou )un; cancer and smokin¢ deserves particular mention. The documenting of each case is unusually thorough, covering a svide range of faaors. An extensive series of cnntrols was subjected to the same scrutiny. In a series of patients known to have died of lung cancer. four variables showed significant correlation and asso- ciation: frequent or chronic respvatory conditions. heavy cigarette smoking, heavy consumption of .doohol, and outdoor work. Of these four variables• heavy cigarette smoking had by far the strongest relationship to lung cancer. "About four-fsfths of the persotu with lung cancer were heavy cigarette smokers (more tban 9,125 packages),... about ooe• third had frequent or chronic respiratory condi- tions, about one-lifth were engaged in outdoor occupations. and about one-seventh were users of alcohol in excessive amounts." However, there was criticism of the retrospective (historical) method, on which this paper and the earlier ones w4re basetL as being subject to un- avoidable bias. The following three studies, recently published, were designed therefore with a pro- spective (continuing) approach. Doll aod Hill- reported from England. Hammond and Horn• for the American Cancer Society, and Durn' from tho National Cancer Institute of the Public Health Service (fig. 2 and 3). Doll and UifL-The Doll and Hill study' is a cuntinuing analysis of aQ.701 British physicians. Among male physicians ' T years of age and over, in the initial four and ane-half years of observa- tion, 1,Tj4 deaths have oecurred, including 64 from lung cancer. Deaths fiom lung cancer increased steadily utith increasing amounts smoked; for nun- smokers the age-adjusted death rate was T per IO0,1I00 of this population; for light smokers, 47; ftrc moderate smokers, 86; and for heavy smokers (more thu 2S cigarettes daily), 166. Giving up smoking reduced the susceptibility of a smoker to subsequent development of lung cancer. The de- crease w•as greatest in those who had given up the habit'for a derade•ot more. Those who continued tu smoke more than 2s cigarettes daily from. the beginning of the study had' a mortality from lung :7, "E: EE%+G•c.TED ;Y ;t1pYRIGn i LAW (TIILE 1.7 U.S. Ct7t7Ea
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0 9 VVT rnl..1r• n..v .•n..lr..~a.\r nutr.itlt.Zt.w Fa111R1T H.1 tFnr rrtro~r in r. n•. Frleny. Jnir 1:. In3TI 1'vtTral STATla IICYARTV/:NT 01' II/:M.T11, F:u(•CATWY, A1n WFLP.tRr. !'rm.tr lir.\I•TI! CCR1'tl?: Wnlhlnctnn _'3, 11. C. Thr ihllrlfr liraIth 8rrt'irr rldd Nal)q• therr 1.4 Inrrenaug rrldenrr that rx• rrsslrr rlcnrr•ttr .Inuklnl; Lr nnn Id fhr Rlt•tnrn trhlrh t•nn rn» ~r lunR rnnrrr, Thr xtnlrment h}• Snrcwnl (:rnrnll Lerny F:. Hurnry mnrti8rll xnmet\'hut Ihr prnN vl.ons ulflvlnl lml+ltiun tnkrn hr tthp I'nhltr 1lenllh `!erelce lit 1!1:.1 nn lhr• .pp•.llnn rd r•Irn rrrtr +mnklnlr nnlt Innl; l•nu1K'r. ,1t lhnt jilne. lilo Service uutrd thvrr t\'nR >•ume eTldrnrr nf it Mtntistlral niz+urlntbm brtn'rrn rlRnrvflr amnkInK nud IunR rnnrer hut Irft ulx-n tbe qnr+tlun uf e•hrtbrr Ihrrr u'm n rml+rand rftrrt rrlntl ttvldp. lu t.•dn•r'.r nhllrutent, Itr• Itnrur;r anhl wn1;T Indela•ndrnt >lndlrm hnrr ,r.n. Ilrmnl hrcnnll ren!mmhle 4on11: thnt thrre Is n hlwh drarrr uf .tntivtlrnl urmK!• ntlon heHvn•n lnna rnnrrr nnd henrp nnd pnd.mcr•d ricnrettr Rmnklnrr. .11thouch thia esldeore I+ +11U lnrccl}• etntlatlrnl lit ntttiu'r, tlr. Hurne;• >;nid• snmr Inbr.rntar}• .rtndir:c nlxn support the cvacept <d R rnurr nnd effect rt!nt!nn• shlp. Itr. hurnry natnl thnt nuu~T luqturtnnt publlr henlth nrh•nnro>, hnre Men dP celuped un Ille bnsl+ lit stnlistirul nr epldeulinlna lvnl Infarmntinu. ('nl:ira nt thr Hnrrr.m (Irnrnll'+ +Intrntrnt. fnCrthor with Rupplnurntnn• tintR, will lie uutdrm•nllnbtr to 8hltt henlth nfllrer+nnll nthrr. lit the hrldth hrnfraelnni na A further arp In brinltlnlr the mnttrr of +mnkInR nnll lttna rnor.•r tu pubtir nttrntlun. Pr. Rurnrysnld It I+rlrnr thnt rlcnrettr:•nlnklnc I:r nut thr only rnnsntlro furtnr lit Inuc ruurl•a Further, hr suld, thr prn•Ime :nr•tnrv b1.rtRnmtle Rmnklnc which rnn rlnl.r lnnc rnnrrr Ilrr nut knotcn. Ilr!uld nu•rr rrerarrh Lv nerdnl to hlrnfffc nnd try tn rlfmtnntr thr!e fnrtnr+. lIr nl.n rnllyd fur mnre re+rnrrh Into ufhrr pruhnb!e ran.rt lit IunR runrrr, In• rlnlllne nlr l+dluflon. The 1'nltrd Ktntee nnn• hn+mnre !hnn =:•dkMt denthd enrh ernr fmm lunc rnnrer. Hntr nlnny of theme per!nn.r were henT}• rit;:trettr Rtnnker.r 1:• wd knu\t•h. -11• tnt;rther, drnthv ftum rnurrr tunkr, up nbunt'..'IU,tXkl of Illr l./i mllllun totnl deaths In the I'nltrd 'Stntr% enrh •rrnr. . :he lhlhllr Fienlth MrrThr l+!unl thr !tntrlneut tlfter t'IrW11IPtI1IL 114 review nf ' thr rrp.,rt nf n audy ;:ruup nn qtnokiol; nnll hl•nlth. Thr atudy t:mhp wits esulh• Ihhrd 1ymlr n/:o lu nl+pntkr nenilaldr !c•ienrldr erirlrnrr nnd Y6rnmmrnA farthrr nn•drd rr>aarch. Ilr. F. M. NtronK• of the t:utaerxilc of R't+rnuxln \lnilrnl Srhnnl. wnn thnlrnlen nt thr>'errn-rnnn stndy trrnnp, a•hirh n'R+nrennlsed Jnintlv I;r the 1'nhilr tlenlth ~rrYirr'n \Rlirlnnl ('nnrrr In+tltute :nul \nllunnl Ilrnrt lnstltute, nnd thr ellitm• tnry pri\'llte ort;lullzntinnv, the Auwrlrlm Cmlrwr Sru•Irf,r Rnd t11c •lturriruu llrnrt •\s+urhl t l un. . The rrport of the studp i;rnnp n'as mnde publit• In \ew York nn Jtnrrh 23, nnd n•nR pnhllshrd In full !n the dune i I!+ue ot Science. Itr. Ihunr;\• Kntd the I'uldlr 1Tralth G•rt'ir•e, In nulklne It.+ fir: t furrnal pnbllr atntement nn oimrrkinR Inlrl health >•inrr 11131. ld!n tr.nk Infn Rrvrmnt uthrr rrr*nt rlnrn• Inrludina the rrlarrt hl><t numth hs Ilr. Fl. t'. Ilnnmalnd and itr, Uuniel Hora nf fhr.lmrrlrotu ('nnn•r K•a•Irty tn thr :Unerlrnll Itrdlrnl .1>;srN•Intlnn lit \rtr 1'nrk. •11 t hnul;h I hrrr a rr lul t lt r:d h snmr di Rrrru<v~ r[ npi n inn I n in t rrprrl Inr thr dntn nn IIUnC r:nurr nnrl riRnrt'ttr ~moklo¢, I/r. ItnnS r}• snld• thr 1'alillr I7rldlh !4t•rrkr fn•Ix the n•ril;ht nf Ihr erldrnn• ir lnrrrnninffy fwdntln¢ lit unr• dinN•tinn: lllnt Ihrrr In nn nxvurinlian hrtwryn rxrrwler nmoklntr and Itw¢ rnnr•rr. Ilo Itnrttr}• .nid tho Pnhtlr Itrnlth SrrYir•r vfntrmrnt ItnR hren t!im•nti'eti n•Ith the r•xerutirrr+•lundtlrr rrf fhr Suur nud Trrritnri:A llrnllh tltllrrrx' ,t.x.-rlallnu. Thr trxt nf U•dn}''+ 1'nLlir• Ilrallh ~rn ir r~Inlrmrut folluwx: •'STATRNF.NT nl' \I'Rn, I:i:N*, Ll:nnY F. Ilt•It\r.Y OP TII1: PI'nLiC IikA6T11 S/:llt'tl'G ..I/Y•RUtT?16\T N• lL:.11•T1t, F:InT.\TInS,-ANP IlS F.%/•/:eelt'/: ('t1:AU/:TrC mIW:11n A\I• II/LV.TIt ' ' ••Ttte I'uhlic 1Tr.llth Serclrr IR, nf( cnnrsr, ennccrnetl'n'Ith hrnnri fnrtnr+ which +nhstnntlall~' af1'rrti the hedlth nf the Atuerlrnn penplr. The Service nlln hna n
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IJ8%1a3a LCNC C.\NCER-BCRNEY /..t.>t..1.. %. .•. ]7. 1939 . selves encuur.l','e a deatre to ,muke." There mav be secondary agents responsible in the "6nal efflores- cence" ui the disease in later years. Hrrd.:n. '.dso in England. noted that deata rates from :uberculusis and lung cancer seem bound together as 4 constant. As one has gone down the T.aLt ].-Sumcrr of Deatlu and Ale-Stardardild Drath Rcrtt' (rom L.nq Cancer bV Smo4mr Habrtrl Dran. rc.n.r,un• LL•MJ C.v. IE`ma• iOe.tOroa- .1Ereo- .ulC..r• e.m0omu oruCOn. L anouae 9.mn pn R.u ~o. Nr„r ,marfJ . IS 1:/ t ~ ~ f It: 1 nr<rncea oe1r ~.~.... ... Clr.n oalr ......~.~ ..- 1. n.t r .............. a: t7 .. rIDM oeIr u itf.n.aJalOn......... A Sr : nr.nlro md amu .... ul !f 1 l0/ ClQrtnn onlr .......... !fY Pf:.: Ir.: TOnI ................... ua •in :sS :. Cvrnat Dfdr C:bretu Smoalotl ?erfr rmo.ea ..,...... ... I. l:A f Len IE.a S o.r. .. rl C .: 11 5.1 DRY .................. N 1073 b 1.: Date ..... ............~ D' =,: n :~ Deeb .................. : :: R.u ~e. auf r.l r Ii 11.1 Il.r I 1 .a t.r 'yl r ..1 /./ 0 C D I: ~ 1s,0 It r.l u.: SS a r.r ] I I {l.l s ).r :aA I 1.I 1410 / t 114 rII] 0 ... • d.0 fnll oU IM.rM m.a....r• •OmLr.Vrn1 ro tM .f~nbme.O. tlaa at the.altf N.If DoD11lalua E/ IM t'C/tFl }f.n-.• aI • Dag lrom 9.mmnen .e4 Rnn!• : abtcn nt ne.nrtr •mctme nmr. other has risen, so that the 'probabilit,v that a person should die of either respiratory tuberculosis or C.L: (cancer of the lung) remains sensibly con- stant in the population.' He believes that it is the antibiotic therapy of tuberculosis 'resulting in the reduction of the combined mortality of males and females due to pneumonia and tuberculosis of the lung, which is responsible for bringing to the fore a disease which has its roots, partly at least, in the genetical make•up of man.' Supparring Opinions.-On the other hand, two groups of equally prominent authorities have come to an opposite conclusion. In June. 1956, the Amer• ican Cancer Society, the American Heart Associa• tion, the National Cancer lnstitute, and the National Heart Institute, by joint action. organized the Study Group on Smoking and Health to review the effects of tobacco smoking on health and to recommend further needed research. After'stz twodav con• ferences, exhaustive examination of tile literatute. and discussion with scientists representing spe• cialized areas of research concerned with the subject, the Study Group made this official state• ment ": "The sum total of scientific evidence es- tablishes beyond reasonable doubt that cigarette smoking is a rausative factor In the rapidly in• creasing incidence of human epidermoid carcinoma of the lung." The second group, the British Medical Rqsearch Couhcil, i'n' 1957. published the. follotvfng conclu- sfons.'•.'1: A.v.ery great increase has oceurred'dur in; the pa.t _i .ears in the death rate from lung cancer in Great Brit,tin and other cnuncies. 3. A relsncel,v small number of the total cases can be Ittrlbuted to specific industrial hazards. 3. A pro• portion of cases, the exact extent of which cannot ,vet be de6ned. may be due to atmospheric pollu- tion. 4. Evidence from many investigations in dif• ferent rnunaies indicates that a major part of the increase is associated with tobacco smoking, par- ticularly in the form of cigarettes. In the opinion of the CounciL the most reasonable interpretation of this evidence is that the relationship is one of direct cause and effect. 5. The ident7Scation of several carcinogenic substances in tobacco smoke provides a ratiunal basis for such a causal rela- tionship.' Other Factors Since carcinoma of the lung is a d'uesse that also occurs in nonsmokers, it is evident that factors other than tobacco contribute to its etiology. The major exogenous factors are air pollution and occu- pational exposure to carcinogens. The latter ac- eounts for only a small percentage of lung cancer deaths. Air Potfution.-Air pollution may be the "urban factoi which would help ecplain the higher death rate from lung cancer in vrban as compared with rural areas (6g. 4)." The major sources of air pol• Itltiun are exhaust products of gasoline and diesel engines, incomplete combustion products of petro- leum and coal, many asphalt and bituminous prod• ucts used in conswction and road paving, and certain industrial effluents. The carcinogenic sub- n.r 0.2 ~ ~so 1 C •..r e.s :;:~'' . ..r / a' ca.r '.csla s^A.r.w atil p.m0• q.e00•AADD Fis• 4•-Agerdimted lung cancer death rates for tiga• rettt smoken and non/moken-urban•fufal tompariaan Ibat<d on data ttom Hammond and Horne). stances contained in these pollutants include polyc}elic aromatic h•vdrorubons such as 8,4 benz• pyrene, 7.4 benz6uqranthene• some alipTlatic oaides, and various laorganic compouods.1e \Vith the ex- ception of coal a0 sources of airn pollution have inaqased in,n recent yeari and. therefore could be
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0 I 9: i Ln . N AP5 024 0843 w N ~ ~ • W ~ ~
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LUNG CA]•CER-ROaBISS 0 To discover •xhat physicians think about smok- ing and lung cancer, staff inembers of the Cancer Control Program haye spent several hundred hours in d:scussions with groups of physicians, and have par'cipated in numerous corderencas and meet- ings in various parts of the United States. These dis:ussioes have brought out one important fact that s::.-.s to bold true throughout the country: there are too many differences between medical research and medical practice to permit either to speak for the other. At the same time, these dif- ferences have led to cenain confusions. Differences Between Investi;ator and Pract9doner. R'hat are these differences? Given any medical problem, differences between medical practitioners and medical investigators begin with their objec- tives. The primary objective of the investigator is to acquire knowledge which is universally valid and serves all mankind. For his work to terminate in knowledge, the investigator is obligated to a rigorous application of scientific methodology, to a protocol that requires reproducibility of results by others under similar conditions, and to a proc• ess of eliminating variables untif only those that can be controlled and tested and verified remala. Finally, in searching for universall•v applicable truths, time is not of the essence. The investigator resists any attempts to saddle him w•ith deadlines and time limits. The primary objective of the practitioner, on the other hand, is to maintain the health of his patients, or, if,he is a practitioner of public health, the health of a specific population. But neither the individual patient nor the specific pop- ulation can be examined under laboratory eondi- tions. This means that the practitioner must ac- cept'all the variables that cossse to him in the person of his patient, and deal with them the best that he can. Indeed, his patients often present him with so many variables'that lie can seldom be sure of what be achieves. And finally, for the practitioner, time is of the esseace: his objective is to preserve and protect the individual before the pathological process is irreversible. Nowhere is the importance of the individual better demon• ttrated than in the doctor-patient relationship. Perhaps Ihe cardinal difference between medi- cal practitioners and medical investigators can be 132 illuse:ated in this way: In the June lI, 1960 issue of the JA,NIA, an article appeared on "The Errors of Medical Studies," by Dr. George L. Saiger. In this ar,icle• Dr. Saiger points out tha: "every c!inical trial involves some ethical prob• lems." He goes on to say: "Failure to recognize this problem or to devise means to cope with it is the most serious error that can be committed in a medical study. A typical example concerns the advisability of withhoidieg treatment when it may possibly be of value." Th: practitioner, fortunately, does not has t to worry about errors that might adversely i• fect a controlled study. It is inconceivable that the practitioner would ever think it "advisable" to withhold any treatment that, in his judgmeat, might possibly be of value to his patient. The practitioner "plays the percentagei' to win any contest for health waged by his patient. Implication of Differences Bens•een Pnctitioner and Investigator One of the significant implications of the dif• ferences between medical praetice and medical investigation is that, while the investigator must strive for total knowledge and conclusive proof, the practitioner must take the knowledge at hand and apply what seems best for his patient while ! there is still time. The practitioner cao ignora nothing that will increase the likelihood that h's patient will live a longer or healthier or less pain- ful life. Like Plato's "courageous man," the prac• titioner cannot wait until human knowledge is complete before he acts: he must always act from a basis of available knowledge. Suppose that carefully controlled studies of a drug show that some patients with specific conditions could bene• fit by this drug. Suppose further that this drug is ; the besf ai•ailable. Then; even though it may nat work 100 percent of the time or may not be fully, understood, the practitioner will use that drug. This does not mean that medical practitioners or public health officers can have scientific stand• ards lower than the medical investigator's. The praetitioner's conscience, his professional educao tion, his professiorial sociery; hif specialty, Ias hospital, and other memben of his profession eon- standy impeLhim•to improve his knowledge and ~ ' MINNESOTA MrnICISE r_ise his of :hc hc pressure z:ds of usm ftc all times Thrc The r er makc these fo st^_ndarc ties, we I ) To First, insist, t foundec alone; knows : and nes his gre: the scic 2) Tc Seco: ways a vantage tor-pan energet ;• he beli is not ter of f centagt i Com of the localiz If ther is onk thu c: ooma - :, rome. ,Wly • fet paCea s-y go Epr
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THE JOURNAL OF THE American Medical Association Publshed Under ehe Auspices of the Board of Trvstees VOL. 1T:, NO. 9 CHICACO, ILLINOIS Corrucxr. 1960. ar Aarcuc•:r ?Qot<.L Aaaaurro:r FEBRUARY _7, 1960 tiEUROSURGICAL TREATMENT OF SPOYTaNEOUS INTRACRAVLAL HEMORRHAGE DIPORT.INCE OF DIFFERENTIAL DLJLCN'OSIS LY "CEREBRAL APOPLESY" AXD EVALUATION OF LONC-TERM POSTOPERATIVE RESULTS Michael Scott, M.D., Philadelphia EREBROVASCULAR disease is the third most common cause of death in the United States. In 1956 there were 177,545 re- ported deaths from vascular diseases of the central nervous svstem.' This is over four times the number of persons that died from motor vehicle accidents and six times the death rate from diabetes during that year.' It is estimated that there are over 1.600,000 victims of cerebravasculnr disease in the United States todav.s The justified pessimism which existed 20 years ago concerning the success of medical or surgical therapy in cerebrovascular disease has been modi- fied during the past 10 years by reports of an in- creasing number of patients whose lives have been saved and in whom neurological d'tsabilitv has been lessened by more accurate diagnosis, selective medi-. cal and neurosurgical therapy, and use of rehabiUta- tion measures. The relativelv recent acceptance of cerebral angiography as an, important aid in the differential diagnosis of "stroke problems" has re- vealed an unsuspected incidence of congenital cerebral berry aneurysms, arteriovenous malforma- tions, and occlusive disease of the arteries of the neck and brain as causes for this condition.a Although this paper.does not primarily deql.with cerebrovascular occlusive disease, the recent popxl- larization of the use of anticongulants. in strol:e- . , problems makes it the'duty of writers on this subject to stress the erucial importance of di&erentiation of The appropriateness of anficoagulonts in treatment of real or apparent cerebral opo~ pleay depends on the differential diagnosis between hemorrhage and occlusion. Becavse Fecenf animal experiments show that enfice• agulants increase bleeding into infarcts pro• duced by occluding blood vessels, the author questians the use of anticoagulants in any primary cerebral vascular accident. A fellow. up study was made in 30 pafients in whom certain indicorions had led to e tplorotory trephinetion and ultimately to verification of the diagnosis of hemorrhage. In two patients the hemorrhage was into a tumor. Nine others died. in the lloxpital,, and 19 who, were dis- charged from the hospital oher operofian were available for follow-up study. The his- tory fory of a hypertensive woman aged 25 years is given in detail to illustrate the clinical course of a hemorrhage into the internal capsule and the resumption of occupational activity after operation despite residual parolyses. Hemor• rhages into the infernal capsule were more serious than hemorrhages into the temporal fobe, but in both sifvations fi.es were tared ' by prompt-nevroturgical intervention. . . Frmn th. Dep+nment of \eurwur9ery, T.m91e Veiraruer >ladlol Cenur. acad b<rare ihe Srauon on S.rvmu and Uenul DLeun at the 10etL Aenwl ?Iretint nt th. )une 9. 1959. Aroenean llediM Auoeiaion. Atunr/e Gtr, 63/889
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Kenneth M. Ludaerer, M.D. November 1988 BSbltorraohy of Seeondary Sources 9 Ackerk.^e:ht, Ervin B., A Short 8lstory of Medittne (Nev Yorkc Ronald Press, 1968). Allen, Garland I., L:!e Sefences in the Tventieth Ctntu •(Nev York: John Yfley, 1975). Berkav(t:. Edward D., 'The Federal Government and the Eaer=enee of Rehabilitation Medicine,' The Bistorian, 430 330-545, 1981. Berlln, Nathaniel I., 'The Conquest of Caneer,' Persoeetives in Biolo . ar.d Medicine, 22: 500-518, 1f79. Boas, Ernest P., The Unseen Pla e: Chronic Disease (Nev York: J. J. _ Autustin, 194 ). Burnham, John C., 'Vill Medical Ristory Join the Aaeriesn Mainstream!• Revievr in American Bistory, 6: 43-49, 1978. Castislioni, Arturo, A 8isto af Mediefne. Tranal. E. B. Kruabhaar, 2nd ad. (New York: A. Knop , 19S ). . Coleman, Villiam R., Biolo in the NSneteenth Centu : Problems of Forz, Funetion, and Transforaation (N.v Tork: JoM YS ey, ). Coven, David L., Medicine and 8ealtb in Nev Jersey: A BSstorY (Princeton, N.J.: D. Van Nostrand Coapany, Inc., 1964). Diehl, Harold S., Tobaceo and Tour 8ealth: The Ssokin Controvers (N.v York: McGraw Bi , 1969). Fee, Ellsabeth, Disease and Diseove A Bisto ot the Johns Bo kins School of 8 fene and Pub it Bea th 191 - (Ba elttorts 2ha Joens Bopkins University Press, 1 _ , Fishbein, Morris, •Blstory of Cancer Ouaekary,' Perspectives in Blolory and Medicine, Vol. $t 1]9-156, Vinter 1965. Friedun, tanneth Michael, Publle Polie and the Seokin -Bealth Controvers (L+sinBton, Mass.: --Lexintton oaks/ . C. Buth 6 Co., 1 ). Fritsehler, A. h.e, Saokin and PolltSes. Polit akla and the Federal Government, Sccoa edition.( ~ evood C L s, N. ,t Prentiee-Ba , Garrison, FSeldinB B., An Introduction to the Cisto of Medieine, 4th ad. (Philadelphla: V. I. Saueders, 19 9). APS 024 0409
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Vol. IT2, so. 9 :41:967 CORRESPO\DENCE STATISTICS AND TOBACCO To the Ediror:-I am shocked by your editorial on smoking and lung cancer. Could you define the kind of evidence which you «,ould accept as show• ing a re!ationship between cigarette smoking and lung canccr' D.cvlo D. Rurs;Ers, NLD. Department of Preventive Medicine Harvard Universitv Medical School Boston 15. See the following cotnmunication.-Eo. To the Editor: In Txe Jocel;.kL, \ov. ?8, 1959, pa,e 1S'?9, appeared a statement' of the surgeon general of the U. S. Public Health Service, Dr. L. E. Bur- ney, on smoking and lung cancer, which has been widely interpreted in the editorial press as an authoritative pronouncement of the Public Health Service and as a definitive opinion on the scientific issues involved in that controversial subject. I beg to present some reasons for doubting each of these evaluations. In general, the article is characterized by an imprecision of language and thought that renders inaccurate almost every important point it deals with. In particular, it contains some frank errors of omission and commission which are misleading with regard to the basic questions at issue. On page 1&30 it is stated.'Berlson ... noted that the data of Hammond and Hom and of Doll and Hill point not only to an association between smoking and lung cancer but also to a wide variety of diseases never presumed to have the same etiology as can• cer." The reference is to a commttnication' that was written shortly after the publication of the two reports with which it deals and before any statistics from the large prospective study being conducted by Dom for the Publtc Health Service were issued. I`did'not merely note the presence of an "association" ' of smoking with a wide variety of diseases. I em• phasizedd that only about 14% of the "excess.deatlu" reflected In the higher death rate of smokers com• pared to nonsmokers were due to lung cancer, while S6". were due to causes other than lung cancer. Fairly soon after the publication of some statistics from Dums study, I presented an anal,v- sis' disclosing similar findings in Dorn's data, which showed only 1?.7`% of ehe excess deaths to be due to lung cancer, 9K'd,ue to other caricer, apd i&.3s, due to other causes. Burne,vs. artide deals meagerly with Dorns re• ports and mentions only some findings with'respect to lung cancer. Takerctogetherwith the omission of reference to my second report, this presentation can easily mislead the reader to believe that my quoted observations, referring to the studies of Doll and Hill and of Hammond and Horn, do not apply to the study of Dorn, when, in fact, the opposite is true. Similarly, his summarv of the report of Hammond and Hom mentions only some data on the relation of smoking to deaths from lung cancer in face of the fact that the report' itself says, :•1 total of 7,316 deaths occurred among regular cigarette smokers, an excess of ?,665. ... Coronary disease accounted for 51.2 per cent... , lung cancer . . . for .13.5 per cent, and cancer of other sites likewise 13.5 per cent. . . . The most important finding of this study was the high degree of association between cigarette smoking and total death rate." The finding of associations of smoking with all classes of disease, not only or even chiefly with lung cancer, is of central importance for an interpreta• tion of the biological significance, if any, of these statistical studies,' and Burney's presentation, which obscures them, could leave an impression of. mis• representatioo. On page 1S33 an argument for smoking as a cause of lung cancer is advanced on the basis of the lower mortality from lung cancer among women, which appears to have made a strong favorable impression on some editors.' Here it is stated that 'nonsmoking women have about the same lung cancer death rate as nonsmoking men,' n•hich, almost certainly, is not true. The death rate fur men is greater than that for women, not only for cancer of the lung but for cancer of almost every urgan that is comparable in the two sexes and for virtually every noncancerous disease also.' The higher general mortality of the male than the fe• male is characteristic of the entire animal kingdom: it is usualh• related, b,v biologists' to the presense of hvo X chromosomes lo the cell of the female and only one in the male, not to smoking: One would not Iason•, reading this portion of the surgeon gen• eral's statement, that a special study' devoted to the sex ratios of mortality from lung cancer had been published, with conclusions different from his, for it is not mentioned in his text or references. On page 1834 one reads, "In the study of Leucis• tenberger and co•workers :.. mice were exposed to, etgirette'smoke ahd examined after'var}ing peri- ods, the longest being• t00 days. In.most animals the bronchial.epithetlum showed.inAammation'and simple and- atypical basal cell hyperplasia. Passey . stated, however; 'Our failure during the p:tst five',ve'ars [recorded in previous publicationsJ to in~ '
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• 10 15. Ernst L. Wynder, "Tobacco as a Cause of Lung Cancer: Some Reflections," American Journal of idemioloev, 146:687-94. 1997. 16.. Richard Doll, "Uncovering the Effects of Smoking: Historical Perspective," Statistical Methods in Medical Research, 7:87-117, 1998. ! 7. Conversation with Sir Richard Doll, British Journal of Addiction. 86:365-77, 1991.
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t'ol. t:t. So. 13 LCNG CANCER-.BURyEf 1tU1835 Future Possibilities for Prevention There can be no doubt that a sicnincant prupor- nun of the increase in lung cancer is.real. This rise has not been caused solely by improve.^.lents in diaenostic techniques. better reporting on death ctriificates. or an increase of older persons in the pnpulation." If we accept as valid the sequence of patholo=:cal changes given above, the preventirm of lun: cancrr. tn e lnr^,e estent. becomes possible. This will be accomplished if carcinngenic sub• stances from any source can be kept nut of the .lir inhaled into the lun:s. Use of Filtrr Tips.-Filter tip cigarettes. which Accounted fur 1.3^r of the market in 1952. nmv constitute apprnximatelv 30"r." This suggests that both the public and the manufacturers are con• cerned that some avoidable toxic agent may be contained in the tobacco smoke. Because the public has widely accepted filtered cigarettes. it is neces- sary to esamine the effectiveness of the filtration. Present knowledCe" indicates that is not possi. ble to filter, selectively, specific components such as carcinogens.3ince the evidence from both human and animal studies shows that the risk of developing cancers is related to the amount of ex- posure to tar, the problem is to design a filter that will permit the minimum Bosv of whole tobacco smoke to pass. consistent with smoking satisfaction. The filters presently in use do not eliminate, but merely reduce, the tar. It is questionable wlsetiur- from a health point of view, any so-called minimum exposure to such a hazard should bf accepted. Table 3 gives the status of filters today, as found in two recent independent studies." In both studies cigarettes were smoked to a standard butt length, at a standud rate, volume, and duration of puff. Any reduction in tar content of the smoke is ac- complished only if the consumer does not smoke more than formerly and if the manufacturers do not alter the tobacco selection, cut, or packing to counteract any deficiency in taste caused by the filter. It has been shown also that, whereas the major portion of carcinogenic substances is present in the tu, others may be found'in the paper of the cigarette or in the tobacco% additives usedP' . 'Tobacco Treatrrient.-The possibility exisu, in theory at leut, of treating the tobacco before it is . packed into cigarettes so as to eliminate the hazard of cancer. Io practice, however, this has not been demonstrated. ' Air FAtrorion.-\tost investigators agree that air pollutants probably contribute to the elevated lung cancer death rate. Cancer•produc.ing agents uein the air we breathe. Carscer can be produced in animals, with use of concentrates of urban smog.' The cancer death'rate in the largest cities.is'twice as high as that in nonurban areas. The.nase is not yet proved, but the weight of evidence grows Iseavier as research progresses. It should be posssble to reduce the amount of noslous material being discharged into the atmos• phore by industry and by internal combustion en• gines." Must of the major cities in this countrv have well-established smoke-control programs. ln- dustr,v has done much already to institute better methods of combustion in manufacturing processes and to develop menns of extr:rcting pollutants from smoke and vapors before they are discharged into the air. Automobile makers now have devices in the laboratory stage that show promise of control. ling the exhaust pollutants produced by the new fuels and the modem high-compression automobile engine. Further study and effort are required, but muked reduction in the future of carcinogenic air contamination is technically and practicallv feasible. Chnn_e in Anokina.-Approzimateh• 60% of the men and '30`7 of the women in the ltnited States over 16 yean of age smoke cigarettes.'e Slightly higher incidences are found in the United l,ing- dom. Recently two persons on the staff cf the Public Health Service contributed to a review of the im- portant studies in this field, including, among other papers, those-listed above as critical of the smoking Tn.Li J.-Com/wruon of "7ar- from FiGer4ip and Regutur Ciaaretter Smoked Cnder Standard Conditione° "TU" Ouc.ieM. ]te. 1.010 oll'ie.rene rater Yoaalrer Nrs,n.rlAmm.~ ......................... S:rrnnoar smerneGr loue W mm .. ............................ 9/lnnnoLr s rs er.od., \1nC rL Inm .. ............................ r.OeaQ N I, lr1\CaU hvptrthesis. The group of statisticians and epidemi- olugists rtporting this study'• recognized that there are areas sahere more research is necessary' and that 'no single cause accounts for all lung cancer." However, they concluded that "the mag- nitude of the excess lung cancer risk among dga- rette smokers is so great that the results cannot be interpreted as arising from an indirect usocia• tion of cigarette smoking with some other agent or cltaracteristie." If dgarette smoke carries eusaao- gens, control of smoking, no matter how difficult it may be, becomes a major factor in prevention :of.bronchial cucinoma• ..... Cooclusiods It is a statutory responsibility of the Public Health Service to inform members of the medical profession and the public on all• matters relating to important public health issues. The relationship between smoking and lung cancer constitutes such an luue and falls within this responsibility of the Public Health Service. The Public Health Service believes that the fol- lowing statements are justified by studies to date. 1;. The weight:of qtidenc,e at presesit implicates smoking as the principal etiological factor in the' increased incidence of lung canc•er. ?. Cigai•ette t ~1t ,V k~ -a N tT
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Kenneth M. Ludmerer February 1999 Additional Biblio¢raohv George D. Lundberg, "!n the AMA. Policy Follows Science: A Case History of Tobacco." Journal of the American Medical Association, 253: 30001-0003. 1985. History of Cancer Control Project, A History of Cancer Control in the United States 1946-1971 (Washington, D.C.: Department of Health, Education, and 3. Welfare, DHEW Publication No. (NIH) 79-1517). Laurence B. McCollough and Frank A. Chervenak, review of Benedectin and Binh Defects, New En¢land Journal of Medicine, 336: 231 v2, 1997. 4. George J. Annas, "Tobacco Litigation as Cancer Litigation: Dealing with the Devil," New England Journal of Medicine, 336: 304-08, 1997. 5. Experimental links between tobacco and lung cancer (editorial). Br. Med. J. 1:1050-51. 1958. 6. Wald NJ, Idle M, Boreham J. Bailey A: Inhaling and lung cancer: An anomaly 7. explained. Br. Med. J. 187:1273-75. 1983. Brownlee KA: A review of "Smoking and Health." J. Am. Stat. Assoc. 60:722- • 39, 1965. 8. The cigarette as co-carcinogen (editorial). Lancet i:85-86. 196•'_. 9. The world is an addict (editorial). Lancet ii:1019-20. 1970. 10. Fisher RA: Smoking, the Cancer Controversy: Some Attempts to Assess the I 1. Evidence. Edinburgh. Oliver and Boyd. 1959. Cornfield J, Haenszel W. Hammond ED, Lilienfeld AM,. Shimkin MB. Wynder 12. EL: Smoking and lung cancer: Recent evidence and a discussion of some questions. JNCI 22:173-203. 1959. Fisher RA: Cigarettes. cancer and statistics. Centennial Review 2:151-66, 1958. 13. Fisher RA: Dangers of cigarette smoking (letter). Br. Med. J. 2:297-98, 1957. 14. Fisher RA:. Cancer and smoking (l.etter). Nature 182;596, 1958.
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Grob. Gerald N.. 'The Social History of Mediclneand Disease !n Aaerica, froolass and Possibllities•' Journal et Soclal 8tstoty, 10: ]91-409, 19'7. 8srden. Victoria A., Inventins the NIB (Baltiaore: The Johns Bopkins Universtty Press• 1986). Hudson, Robert P., Disease and Its Control. The Shaoin of Modern Thou hc (Vestport. Conn.: Greenvood Press• 1983). Kevles. Daniel J., In the Naae mf Eu enics: 6enetics and 'the Uses of 8usan Bere?it ,(Nev orx: red A. Knopt, 19 ). Kuhn, Thamas S., The Stracture of Seientlftc Revolutlons (Chicago: University o C1:SCa8o ress• 1 6). Larson, P.S., Haag, 8.5., and Silvette, 8.• Tobacco: Exoerimental and Clinleal Studies. A Comorehensive Account e the Vor d Literature (Salttaore: The VS lams 6 Yi kins Company, 1961).Holses• Frederic Lavrence. Claude Bernard and Anlaal Chenlstry: TAe Emer tnce of a Scientist (Caabr3aje, Mi.rL : t(ar'/ard Univerrlty Press, . 9 a). Leavitt• Judith V. and Numbers, Ronald L., Sickness and Health in Aser! a (Madison: The University of Viscons.in lress, 1978). • Litton, Robert Jay, The Nazi Doctors: Medical Killing and the Psycholoty of Genocide (Nev Tora: Dasie Dooas, 1986). Ludaerer, Kenneth K., Genetics and American SoeSet t. A Hirtorical Appraisal (Daltiaore: The Jonns Hopkins University Prats, ~). Ludme:er. Kenneth M., Learnin To Beal: The Develo ment of American Medical Education (Nsv York: asie ooks, ). Ludmerer, Kenneth M., 'The Medical Schools of Nev Tork and the National Enterprise of Hioaediul Research, 1850-198f,' Hulletin of the Nev York Academy of Medicine, 641 216-236, 1988. Ludmerer, Kannetb K., 'Methodolo8ical Issues in the History of Mediclnet Aehisvemsnts and Cha11en8a,' Proceedina of the American Philosophical Secis , Sa•presa. Malor, Ralph H., A Histo of Mediclne; 2 vols. (SprinBfield. Ill.: C.C. Thomas, 19Sa . Neuber8er, Maurine 1.. Sabks Screent Tobaceo and the Public Uelfare , (EnSlevood Cliffs, N. .t Prentiee-Ha , 1963). Numbers, Ronald L. and Varner, John Harley, 'The Maturation of American Science,• in Nathan ReinBold and Mark Rothenbar=, eds., Scientifi Colonialisu A Crots-Cultural Com erison (Vashin8ton, D• . Smithsonian nsHtutton rus, ). AP5 '024..0410.
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Medical Practice and LUNG CANCER ; LEWIS C. ROBBL`S, \I.D. Wasbiagtoo. D. C. ~ T:•.e cr-cr :rovices e• e.ccellent cnelvsis of ~ tr! ::avc•r!ny scrr:mc;ng "smoking" and ~' ~ .:'.y :_..._. ._. ...e ;:r::r:cing chysicicn. He :iiiclcl ccsluon i.n iT.. . .... c~r ~~ ...: qenercl :rcelficner who ~ . :ed<: '~re :n cdvisi-g his pasienrs. - i Three decades ago, the death rate from lung cancer began to increase at a phenomenal rate, and continues to do so. Medical investigators, principally in the held of epidemiology but in other fields as well, began to look for reasons behind this increase. In the early part of the 1950's, medical sci9pce had,excluded what appeared to be the non-essential variables, and had found ' one factor strongly associated with Inng cancer: cigarette smoking. In the years following the early pnpers, other studies confirmed their findings, and made num- erous explorations into the unknown aspects of Chief. Caneer Cor,trol Pro, am. Bureau of State krvices. Public Healsh Service. U. S. Depanment of Health. Education, and WeUare. • ~ Presented at Atathodist . Hospital. St. Louis Park: Minnesota. Nov. 19, 1960, symppsium on "Cancer ' Prouation in Orfiee Practica' ~ . FtaRUear: 1962 . ~ . . ~ _ . _ the smoking and lung cancer relationship. These studies, mostly upon the chemistry and physiology of, smoking, reinforced the association first un- earthed by the careful application of epidemiologi- cal principles. But from she first hint of a relationship be- tween smoking and lung cancer there was eqn-' trovers,v, add the contrdversy continues. Why? To a practitioner of preventive medicine, the findings of the epidemiologists appear to offer a possibility for preventing a very important acd a therapeutically recalcitrant disease. Many mcdi- eal practitioners looking (or opportunities in pre- ventive medicine feel the same way; yet most practitioners have seemed reluctant to take a po- sition.against cig:.rette smoking ih the face of ap.- parent contradic:ions in the evidence. ' . . . . . , . Ut
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14J 183a 34 . Hilding. A. C.. On Ciguene Smoking, BrooBud Cue:noma and Cibap• Acnon: Accumulatson of Cigarette T+r upon AniBcully Produced Deuluted Islandr in Ra wntory Epnheliuns, Ann Otol. Rhin. l Laryng. eS:116- U0 (Sfuch) 1936. 35. Auerbach, 0., and others: Changes in Bronebial EpitheBum in Relation to Smoking and Cancer of Lung: Report of Progress. New England J. Med. 75Hs97-104 (14n.171 1957. 36. Rockry, E. E.; $uschner, )I.; Fosik. t 1., and \laver, E.: Effect of Tobacco Tu on Bronchial \lucosa of Dogs, Cancer I1ri6('NC] (?ta>+June) 1958. 37. Leuchtenberger. C.; Leuchtenberger. R.; and Doolan. P. F.: Correlated Histological. Cytological, and Cytochemtnl Stud, of Tnchcobrunchsal Tree and Luags of \tict Exposed tn Cigarette Smoke: Bronchitis with Atypical Epithelial Clunges in Mice E.cposed to Cigarette Smoke, Cacter glt 490-306 (\las•-June) 1958. . 38, Paasey, R. D.: Cigarette Smoke aad Canaer of Luag, Bntish Empire Cancer Gmpaign, Annual Report no. 36. 1958, part =, pp. 4849. 39. Eoprowska, 1., and Bogaa, J.: C>topathologie Study of Tobacco Tar-induced Lesions of UtenoeCenu of Mouse, ). \at. Cancer Inst. 2.1t1-19 (July) 1959. 40. Horn, D.: Trends in Lung Cancer Statistics, in Pto• (eedings of the Third \ational Cancer Conference, Pbiladel- phia, J. B. Lippincott Co., 1937, pp. 457-161. 0 Cigarettes-Two-Part Report, pan 4, Coosumer Ae- pons 2Js628-876, 193g. 41 (a) U. 5. House a: Represenatlves. Committee an Covemment Operationsr S,ocammittee: Hearings .,, FaLe and Misleading Advertising (Filtn-tip Cigarettes), 85th Congress !st Session, Washington. D. C., U. 5. Covernment Printing Office, 1957, p. 793. (b) Aefereoce 41. 43. (a) Miller, L. Js., and Slonahaa, J•: Cigarette Isdus- try Changes Its \tind, Aeaders Digest 72s,13i1 (July) 1938. (b) Refumtt 41. 44. Cardoa. 5. L; Alvord, E. T.; Rand. H. J•; and Hitch- cock. R: 3.4 Benapyrene in Smoka of Ciguette Paper. Tobacco and Cigarenest Brit. J. Cancer 10t485-497 (Sept.) 1957. 45. Proceedings of the `ational Conference on a'v PoUu- tion, November 18-20, 1958. Public Health Service pub6ca• tion no. 63/, 1l'u6ingtoa, D. C., IJ. S. Covesament Ptinting Office, 1939, pp. 47-64. 46. Hammond. E. C.; Lung Cancer Death Rates in Ent- land aod tt'ales Compared with Those ia U. $, A., Bnt. M. 1.2s649-6Si (Sept. 13) 1958. 47. (a) National Office of Vital Statistia: Cancer 11or- tality for Selected Sites. By Age, Sea, and Race: United States, 19J0-45, Vital Ststlstits-Spet:lal Reports. vol. 31. no. 7(July 19) 1950. (b) Vital Statistirs of the United States, \oL e_, 1950, tt'ubin`to4 D, C.. U. S. Coveroment Printing O(dce, 1953. (c) Referencs 24. 48. (a) Doll and HBI.e (6) Hammond and Hortt.' fe) 49. (a) Doll and HiLLr, (b) Hammond and Hom.' V IRUSES AS CAUSES OF DISEASE IN MAY•-A recent count indicates that there are more than 50 diHerent diseases of man which are known or believed to be induced by viruses. Although this is an impressive nttmber, it it greatly overshadowed by the di8erent virtsses that can be recovered from human beings, a number that now stands at more than 150. Of these agents, some 30 are Imowe to . be asi0cisted with respitatory diseases, and' a tisajority of the remainder may lnifiate infections in the respiratory tract, the outstanding portal of entry for viruses.-Frank L. HonfaU Jr.: The J. Bums Amberson Lecnve,, The American Retrkm, SeptertSber, 1959. tn tJ W N ,P W J tJ V t'ol. 171, Ya 13 LUNC CASCER-BURNEY =. \attonal OSce of Vi:al Suosucs: Viral Statistics of the L'ctad State.s: lfortality Dsn, 1956, voL :.,1t'ashin;ton. D. C., U. S. Cove••ament Prinring OSce. 1958. 23. 11'ynder, E. L, and Wright. C.; Study of Tnbacco Cera:noreneos: The Pnmary Fractsoas, Cancer 10:?36..°.1 f Sluci-.\prdl 1937. V. Cam&Id, J., and others: Smoking and Lung Gncer: Recent Es:dence and Dncu,non of Sonie Quesuons, J. \'at. Cancer :m:. 22:17-r2nJ , J., n, / 1939. 15Sdm,c.a. \IBPe:wnjl commumcaunn m the au "r..or. _6. (n'Kre,ber;. L.: Si;nienntt of Histolopul Typing in S:ud, of Epidemiolog;of Pnm.r.Epitheual Lsmg Tumors: Study of 466 Cats. Bnt. 1. Cancer Bt199-208 (Junei 1931. (bi Hamn,ond and Horn." 27. (a) ttlyder. E. L.. t:nph. P.; and Ltgler, H.: Stud9 of Tobacco Caruougtnau: Dose-Response Studies. Cancer tOd193-12DO (Nos.•Dec.) 1937. (b) \tynder. E. 1.., and ?lann, J.: Study of Tob.cco Carcinogenesu: Filtered Cigs- rettn. ibid. 10d301-1:03 (\ov: Dec.) 1937. (c/ ri'ynder. E. L.; Cottlieb, S.; and t1'right, C.: Study of Tobacco Cucinogenuis: DiEerent Tobaceo Tyyea, ibid. 10tL'06- 1C09 ( Soc.-Dee. ) 195. (d) U'vnder, E. L.; Oraham, E. A.; and Croninter. A. B.: Eayerimental Production of Careinoma with Cigarette Tar, Cancer Aes. 1aa83;r864 (Dec.) 193J. (rl Eapeamtental Production of Cardnoma with Cigarette Tat: Tests with Different \louse Snuns, ibid. 1-a443-N8 (Aug.) 1933. (1) 1Vyoder and R'right.e' '?8. ( a ) Eagelbreth-Holm, J•, +nd Ahlmann. J•: Production of Grctooma sn ST/Eh Mice with Cigarette Tu. Acta path et mictobiol. scandinav. 41s367-?7:, 1937. (b) Orris. L, and others: Cueinogeoiciry for Mouse Slia and Aromauc Hydrocarbon Content of Cigarette-smoke Condensates. 1• M1at. Caacer Inrt. 21s3S-361 (Sept.) 1958. (c) Parsey, R. D.: Cucinogenicity of Cigarette Tan, British Empire Caneer Campasgn, Aneual Report no. 33, 1937, pp. 63-06. ,_9. Cooper, R. L., and Lindsev, A. J.: 3.4 Benxpyrene and Other Polycyclic Hydrocarbons in Cigarette Smoke, Bnt J. Caneer Bs104-J09 (June) 1935. 30. (a) Cdlhom, A.: Carcinogenic Acti.ity of Cigarette Tobacco Tu, Cancet Ra. 18sS10.517 (June) 1958. (b) Van 7uuren, B. L.: Idenu6ntion of Some Polynuclear Aromatic Hydrocubons in Cigarette Smoke Condensate. J. \at Cancer lrut. 21s1-16 (July) 1958. (e) Polyouclear Aromatic Hydrocarbons in Cigarette Smoke Condensate. ibid. 21 16141-WO ( Oa. ) 1958. 31. Mellon, R. C.: Hlioka, J.: and Stoholsli. A.: In civo Cellular Localixatioo of Fluore.eent SlateruL Derived from Cigarette Smoke, abstncted, Proc. Am. ,1. Cane<r Res. 2s 17°-133 (April) 1956. 32. Robertson, 0. H.: Phagocytosis of Foreign Material in Lung, Physiol. Rev.21s11R-1J9 (Jaa) 1941. 33. Mac1Jin, C. C.: Induction of Bronchial Cancer by Lotal Massing of f:artlaogea Concentrate in Outdrifting Mucus. J. Thoracic Surg. iJt:JB-2N.(Feb.) 1956;.cqrrea tion81sJ74(>Iarch)1958. • ' . '
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• • 3 010, Peter D. and t.eikiad. Morris C., •soae Landearks in the t(story of r.snrer Researeh,• Internatlonal Patholo . International Acade. 36-3 , 19 6. , Patholo . 31 Psttetson, Ja^es T., The Dread Disease: Cancer and Modern Asertean Culture (CSa~ridte, Mass.: tlarvaid UniversttyPress, 1987), : Medicine Under the Nazis (Casbrldte. Mass.: Proctor. Aebert. Racial flrties,ne1 Harvard University Pres B). Rather, t. J.. the Genesls ot Caneer: A Ste. !n the 81sto of Ideas . (Saltloore: onns soptins, 19 B). Rattint, Rieaard A., Cancet CrusCda: the Sto et the National Cance: Aet of 1971 (Princeton: Pr:nceton University Press, 1 ). Reverby, Susan and Rosner, David, ads., Health Care !n America (Philadelphia: Teaple University Press. 1979). Robinson, Victor, The Story of Medicine (Nov York: Tudor Publishing Co., Rosen. Georte. A History of Public Health (Nov Torkt M. D. Publ3cations, 1958). Ros.n, G.orta, Preventive Medicine !n the Un1t~d States. 1900-1975. Trends and Interpretations (Nev York: rod st, 19). Rosenkrants, Barbara C., Public Health uid the Stau. Chan[int Vievs ;n. Massachusetu, 1862-~6 (Cambridge, Masa.: arvar -0niversi~y ~as. ). Ross, Valter. Crusadet The Otfieial History at the Aserican Cancer Society (Nov York: Arbor Housa, 1 ). Shi.kln, Michael 8.. As Mese Servet. Six Essa s on a onal Involvesent 1930 to ( asP.hrsinston, D.C.t Vlth the Nationa Cancer nstitu[e, u0 ic Hu tA ervice, 1 ). . Shfatkln, Michael I., Contra to Nature (VUhinBton, D.C.: U.S. Department of Health, Educat an, 6. are, 1971). Shiakin, Michael I., Science and Cancer (Vashington, D.C.t U.S. Departsent of Public lealth and ewatt Services. 3d rev. ed., 1980). Shryeck, 8,iehard 8., American Medical Research Past and Present (Nov Torkt Co..envulth lun , ). Shryock, Richard IJ., the Develo .ent of Modern Medicine (Madison: University of Visconsin Press, 1 i reprint o 1 6 ed tlon . S1Herist, Henry E., Civiliratlon and Diseate (Chicage: University of Chica;o Press, 19761 reprint o 96 ed. by Cornell University Press). AP5 02• 0411 0
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i 142,968 CDRRESPOYDE\CE J.A.M.A., Feb. :7, 1960 duce lung tumours in mice, rats, and hamsters bY exposure to strong concentrations of cigarette smoke is a striking negative result.'"The impression one gets from these passages is that the results of Leuchtenberger and associates contradict, or at least mitigate, those of Passey, who obtained nega- tive results in attempts to produce lung cancer experimentally by exposure to smoking. The report of Leuchtenberger and co-workers'° referred to in the passage is an early, preliminary one. A later report of this work was given by Leuchtenberger and others at the International Cancer Congress in London, in July, 19a5. The summary of this report " reads as follows. 1. There is a development of a bronchitis associated with a gradual change of the normal resting epithelium to an in8smmatory, pro6fenting, and dysplastle one ("carcir.oma in situ' multifocal). No incosice carcinomu. :. When exposure to cigarette smoke is stopped for over 3 months, the normal appeannce of the bronchi uggest reversibility of bronchitis and dysplasia. 3. The cytochemical alterations in the bronchial epit.he• liurn also show a-gndual development. . . The eyto- chemical alterations ue also reversible when exposure to ciguette smoke is stopped. This later report of Leuchtenberger and others is, in content and in tone, virtually the same as Passey's, not in contrast to it. An even less explicable lapse is Bumeds failure to cite the experiments performed in the Public Health Seriice itself, in the laboratory of the pathologist, Dr. H. L. Stewart, in which adminis• tration of cigarette smoke to mice failed to produce lung cancer." So it is found that, in these parts of his text, Burney refers to a report of Leuchtenberger and co•workers in an equivocal way with respect to the experimental production of lung cancer by smoking, while omitting reference to a later report by the same author and others which is emphatf- cally clear as to the failure to produce such can- cers, and he omits entirely any reference to ex- periments with similar negative results performed in the U. S. Public Health Seryice laboratories. The article' is presented as a'statement of the Public Health Service. 1Vhen I read this I was sur- prised, for the following reasons. Several weeks before the article appeared, I had presented a paper10 related to the present subject at a biomet• rics seminar of the Public Health Service in Be- thesda, Md. The paper was technical and intended to demonstrate mathematically that some statistical methods which had been used in the analysis of the prospective studies of smoking and lung cancer werelmsound, with consequent misinterpretation of the data iq these studies..The talk was well ai- tended, and I assumq the audience. contained aa fairly large proportion of the biometriciatSs in the Public Health Service: I did not sense, during my talk or during the discussion that followed, any disagreement with the tenor of my remarks. I recall clearly that when I said, 'Ne should not be engag- ing in fine semantic efforts to demonstrate that the extremely compiicated statistical evidence proves the validity of the theory that initiated these studies. Instead, we should set up investigations in large variety to End out what they mean; there was spontaneous applause, from what seemed to be the entire audience. I spent considerable time with Dr. Dorrs and with some veteran experimental workers of the Public Health Service and have corresponded with others. I cannot speak didactically of their views, but I can say that they seemed in general agree- ment with mine, as regards the tentative character of the evidence. Surely, I had the impression that Dom believes that much more work in phannacol- ogy, pathology, and other associated sciences must be done before anything definite can be said with regard to the explanation of the statistical Endings. Certainly, the word "cause" does not appear in any of his writings on the subject, and he has recently expressed himself elaborately on the complexities of interpreting statistical results for their etiological significance.t' In these circumstances, xnd recalling the insumciency of Burne,v's reporting of Dom s statistics, I cannot believe that Dom reviewed or edited the statement of the surgeon general before its publication, nor can I believe that Stewart did, ' considering that his own work was not cited, leav ing aside other inaccuracies that I cannot believe him to have approved. Dr. Dom is chief of biomet• . rics of the National Institutes of Health and the director of its main statistical study on smoking and lung cancer. Dr. Stewart is chief of pathology and a renowned worker in the field of experimental cancer. If neither of these scientists of the Public Health Service previewed the surgeon general's article before publication, not to speak of the fail- ure to consult many other experts in related fields on its staff, how can this article be properly desig- nated a statement of the Public Health Service? There is an aspect of deficiency of the surgeon generaTs statement that is of even more serious im- port than those just d-ssctused. If the Public Health , Service believes that tobacco smoke contains chem- ical carcinogens which cause lung cancer, then the first task of its responsible scientists is to isolate these substances in 'pure culture' and to identify their chemical structure. This is the first step re• quired by Koch's postulates for demonstration of a causative agent of a disease. It is furthermore the first step to be taken in order td usee the discovery for amelioration of the.d-uease. Since.Pasteur,.the isotation of a specific cause 'of a tiisease has been followed immediately, by experimedts •to produce aa immunizing'agent: The'Public Health Service has had appropriated for Its use in a siqgle year . about 7.00 million.dollars; aboµt 350. million dollarS has been for the N.ational Institutes of Health; in• '
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LCN*O CANCER -ROBBrN*s studies. T6ey felt that thc:e was the st:ong pos- sibility that cancer patients thought they w'ere suppesed to say they smoked cigarettes. Follow- ing upoa this criticism, three prospective studies were ur.de^aken. Together, these studies followed almost a half million people wbose smoking his- tory had been established. As the people under study be,an to develop lung cancer or to die of the disease, one thing was clear, and there was remarkable agreement among the three studies: about 10 times more lung cancer appeared during the study period among the cigarette smokers than among the nonsmokers. If smoking was so highly associated with lung cancer, then surely there must be a reason. Nfedi- ca1 science accelerated its search for the etiological agent or agentslhat might be responsible. Scien- tists established beyond doubt the paralytic ef- fect of cigarette smoke upon the bronchial cilia, and oP,ered an hypothesis (10) that cancer patho- cenesis could be explained by the slowness with which damaged cilia removed mucus, with its col- lection of insoluble tar particles, from the lungs. . In a comprehensive study of histologic sections of smokers' and nonsmokers' bronchi taken at autopsy, Auerbach (11, 12) showed a significantly higher percentage of cellular chantcs, thought to be premalignant, among smokers than among nonsmokers. At the same time, other scientists were isolating chemical substances that proved carcinogenic when applied to the skin of animals. Still, there were medical scientists critical of these findings by their fellow workers. No one agent had yet been isolated as the cause of lung cancer in man; no one agent had been shown, under controlled conditions, to result in cancer, and, in its absence, not result in cancer of the lun,. Nor has this been shown today. Further, some scientists believe that it may never be pos- sible to demonstrate conclusively that specific in- gredients of cigarette smoke "cause" lung cancer. Their belief is based on two main contentions: first, the "incubation" period of lung.cancer may be as long as' 2'0 to 40 yetrs; arid iecond, it ' appears impossible to carry oitt a controlled study, usina. human beings, which would permit the .elimination of unessential variables. 1J4 Laekinc definite proof, as that t:rm may be understood in the biological sciences, there can be no wondcr that there are many different be- lieft about the relationship of smoking to lung cancer. At one extreme, Joseph Berkson states that, •'In my opinion, all available relevant facts considered, it seems very doubtful that smoking causes cancer of the lung." (13 ) At the other end of the spectrum, the Joint Report of the Study Group on Smoking and Health concluded that: "The sum total of scientific evidence establishes beyond reasonable doubt that cigarette smokinc is a causative factor in the rapidly inreasing incidence of human epidermoid carcinoma of the lung:" (14) This presents a problem (or the prac:itioner: How is he to operate in a scientific manner in the presence of such a wide range of opinion? Does it rftean that he must stay out of the situ- ation, insofar as his patiem is concerned, until all the questions are completely resolved? If knowledge has to be conclusive then, just how con- clusive must it be ~efore the physician may apply it in his ow•n practice? Finally, considering the differences in objectives of investigators and prac- titioners, and the dceree to which each can con- trol his variables, just how relevant to the prac- titioner and to his patient now are the questions that should and do occupy the attention of mcdi- eal investi¢atnrs? Positions Taken by Practitioners Those facts about smoking and lung cancer that are undisputed. the continuing exploration of pathogenesis, and the interpretations that have given rise to so much debate have all been weighed and considered and acted upon by a num- ber of phbsiciani, collectively and indk•idually,. Many national'voluntary organizations, health ag-, encies, special study groups. and other medical groups speaking eollectively have made /wblic statements committing them to a position that finds against cigarette smoking, and that asserts the opportunity in this regard for the practice of preventive medicine. The position of some phj•sicians may bc rath= ered frotn a rcport by Snesireft and Lombar,d'ori the smokinp habits of more than 4,000 Massa-. s chusetts phj'sicians: 115) Between 1954 and • \tINgCCOTA Atf.DICINE I95S sicia: per.- I ;eon spca:• lar , acen. said'. safe, can ' inC:' Dr publi invcs sibili~ w•oul. cuar solcc In mar} smok cigar titior ph-vsi ings toda• hcrr on 1 finds tag¢s of tt
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1a0;966 FOREICY LETTERS J..a.M.A., Feb.:C, 1960 case in e4derip brcnchitics •vith advanced disease. Englishwoman and three men from Chana. Jor- The absence of recurrent winter invalidism and dan, and Siam resper,ivel,v, There u•as no English consequent loss of time from work was a notice- male applicant. The dif6culty experienced in recent able advantage of continuous ant:biotic therapy, years, at a small hospital some 10 miles from Lon- as shown by the comparison of days lost by treated don, of getting a caucasoid male house surgeon or as compared with untreated patients. It was con- resident surgical officer is now becoming more c!uded that the best time to start treatment is in common in London. Such a lack of homebred, or the autumn. The occurrence of an acute exacerba- even Canadian, South African, or \e v Zealand, tion of bronchitis in those patients receiving the applicants is a new phenomenon and augurs ill for iner: ca:)su!es led to their withdrawal from the the future. The reason for this situation may be tr'al. sought in the cavalier treatment of medical depu- The de, ee of purulence of the sputum aas tations to the Ministry of Health and in the psv- found to be a useful guide to the efficacy of anti- chological and financial pin-pricks and general bintic treatment, since there was gcod correlation atmosphere of denigration to which the medical between it, the clinical state of the patient, and the profession has of late been subjected. In medicine presence of Hemophilus in8uenzae and Diplococcus there is often a family tradition, but physicians no pneumoniae in the sputum. The dose of antibiotic longer urge their sons or daughters to enter the was adjusted so that the sputum remained mucoid. profession. This was about ?50 mg. four times a day. Looseness of the stools was troublesome in about 33 0 of the Midwives Dying Out.-Matemity trork in Great patients, but in none was it associated n•ith a sig- Britain is largely in the hands of midwives. A mid- nificrant change in the intestinal flora. Additional wife, after four years' training, can now start at confirmation of the role of H. infiuenzae in chron- $1,610 a year (31 dollars a week). A district mid- ic bronchitis t;as the demonstration of high anti- wife who has the responsibility of life and death in bodv titers in the serums of patients who reoularly her hands and is on duty 144 hours a week incluc6 harbored this organism in their sputums. It was ing Christmas and other holidays, must often live suggested that H. influenzae has the invasive prop- in the most austere circumstances. Income tic, erties which lead to the inflammatorv destruction of superannuation, and insurance all must be paid but bronchopulmonary tissue demonsc:able in chronic of her inadequate salary. This niggardly manner bronchitis. Bronchoscopic aspirates yielded H. in- of treating the women who bring 750,000 babies a fluenrae in most patients with purulent sptttum, year into the world Is having the inevitable result. Some of the strains of Staphylococcus aureus iso- Fewer persons are becoming midwives. lated during and after treatment were resistant to In 1959 only 16,•(-15 midwives is-ere registered as the antibiotics used, but this did not constitute a practicing, or nearl,v 500 less than in 195S. The real danger. Cross disturbance of normal surface number of district midwives was 7,790, or nearly flora of the respiratory and intestinal tracts was not 200 less than in 1958. About 3,000 midwives quali- observed. It was found practicable to treat the pa- fied last year, but 3,500 left Britain. Kenya and tients on an outpatient or domiciliary basis, which New Guinea offered posts at 62 dollars a week; had the advantage of lower cost than hospital treat- Vancouver offered 3-17 dollars a month for a-10-hour ment. To avoid the dangers of superinfection with week; and Newfoundland offered 53 dollars weekly antibiotic-resistant and often highly virulent micro- plus full maintenance. In Britain there are 1.000 organisms it was recommended that if esacerba- closed beds in hospitals due to the shortage of tions should arise the patient is better treated at midwives. home rather than in the hospital. One serious eon- sideration was the cost of such antibiotie.treatment. ., Television i:eck.-A cohdition kasotvn'as "teleefsion which is about 180 dollars for six months, or 7 neck" may follow watching television from a chair dollars a week, if the patient is treated by his own of the tvrong height, according to the Lancet of doctor. This compares favorably with the cost of Dec. 26. The author tvarns that to sit endlessly hospitalization, which is nearly 62 dollars a week in watching TV brings a risk of illness, including a good teaching hospital, and the additional charge heart trouble, but the hazard is small and should on the state for sickness benefit and the financial not be exaggerated. Simple syncope is not unusual loss to Industrv. when surgical procedures art shown, and true angina pectoris may.be provoked by some pro- Shortage. of Surgeons.-A London consultant ' grams. Prolonged iinmobility in an awkward pus- po,inted out in the Daily 7eleg/aph of Dec. 16 2hat , ture entails a risk' of. venous .thrombosis. One. on Dec. 4 at a Luit London hospital of good repu- . medical writer cecommends that vie+yers move frorim , . tation, there were four applfcants'for a post of '. their chairs at least once an hour. Flickering of the house surgeon to three surgeons ivit}i general and set has been lTown to initiate a fit in a susceptible special surgical interests. The applicants were one epileptic. ' t.Ni
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A Siterist. Benry E.. The Great Ooctors. A Sio ra hical 8isto at Medicine - l:oe tnf Aneient Yo[ t0 th. Tventietn Centu (Garden lty, N. .. Douo eeaY & oapany, 1 ). Slrerist. Benry E., 'The 8lstorical Development of the Pathology and Therapy of Cancer,• Bulletin of the Nfv York Aaadesv of Medleine. B: 6t2.633, 1932. Singer, Charles and Undervood, E. Ashvorth. A Short 8lstorv of Medicine. 2nd ed. (Nov York: Oxford University Press, 1 Skinner, Villia Iverson, Tobacco and Bealth: The Other Side of the Coin (Nov York: Vanta`e Press. ). Sobel, Robert, The Satisf . The C! arette in American Lite (Garden City, N.Y.: Anthor Prus/Doub eday, 1 ). Steinfeld. Jesse L., •Seokin8 and Lung Cancer. A Milestone ln Avareness," JAMA, 253: 2995-2991, 1983. Stern, Bernhard J., Social Factors in Mediesl Progress (Nev York: Coluobia University Press, 19~ Stevart, Ronald B.. Tra edies from Drv theraPfes (Sprin=flald, Ill.: - Charles C. Tho.as, 19 Striekland. Stephen P., Polities. Science, and Dread Disease (Caabridge: Barvard University Press, 1 ). taylor, Peter, The Soake Rlnx. Tobacco. Money, and Internatlonal Pollties' revisad and expanded edltlon (Nev York: Ner Aaerican Llbrary (Nentor Sook), 1983). Troyer, Ronald J. and Markl., Gerald L, CS arettes: The Sattle Over Seokin (Nev Srunsvick, N.J.: Rutgers Unlvetsiry ress, 1 ). Vhelan. Elizabeth M.. A S.okln Gunt Bov the Tobacco Indust Gets Ava vith Murder (Philadelphla: Georse P. tl ey Co., 4). Vhlte, Larry C., Nerchants of Deatht The Aaerieuf Tobaeee Indust (Nov York: Beaeh ree 8ooks/ 1 Saa Morrov 6 Co0., Vhiteside, Tho.as, Se111n Deatb. Ci rette Adve tisin and Public 8ealth (Nov York: Llverl8bt, ). ' Vinter, RutA, The Scientific Cue ainst S.okin (Nov Iorkt Crovn Publlshers, e., ). Vood, Francis Cartjor, •Fundaaental Research in Cane.r,• lulletin of the Nev - York Academy of Medicine, 9: 633-667, 1932. Yankaver, Alfred, "Tha Aseriean Journal of Public Bealth, 1937-1973,' in Charles E. Rosenberr, ed., B.4Sn and 8iste t Esss s for Geoe e Rosen (Nov Yorks Selmce Sistory Pub ioat ons, 1 9). APS 024 0<12 0
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LUVG CANCER-ROBBMS • t9, the authors note, the percentage of phy- ,ar,s smoking only cigarettes decreased by 25 percent. In 1959, too, Dr. Leroy E. Bumey, then Sur- geon Geaenl of the Public Health Service, and speaking for ;he Service, reached a position simi- far to ot`er medical orgar,izations and hea)t't as:ncies regarding the ha¢ard of smokin;. He said: "Unless the use of tobacco can be made safe, the individual person's risk of lung cancer can best be rcdur.d by the climination of smok- ing." (10) Dr. Burncv s final conclusion was made as a public health practitioner and not as a medical investigator. Were he speaking from the respon- sibility of a medical investigator, the conclusion would have dealt with the adequacies or ir,ade• quaeies of researci designs, and with the unre• solved questions that need answering. Instcad, the statemea was a prac:itioner's sum- mary. The statement concluded that the non- smoker smoker has an advantage when compared to the •garene smoker,in risk of lung cancer. As prac• dtioners of preventive medicine, every practicing i; physician has the responsibility to search new find- 'r ings and hard won research for advantages while : today's patients may still benefit. In this search. he may well find high priority advantages, based on valid scientific evidence. If the practitioner rinds some authorities who doubt such advan- tages, will not the practitioner give the benefit of the doubt to his patients? Conclusion ,Medical practitioners and medical investigators alike have had the opportunity in the past few Itcrcreoces I. Griswold, M. H., Wilder. C. S., Cutler. S. J•, and Polack, E. S.: Cancer in Connectieut 1935-1951. Hanford. Conn., Connecticut State Department of Health. 1935. tVan Duuten. Benjamin U The PoFSaucteac Aro• . maric Hqdrocarbons in .CigarcllcSmoke Conden• Na. Cancer Inn. 21:6:3•630, 1958. , ' Hildlne; tt, C.: On.Ci;arcue SnloAin;, Bronchial 13avAnv, 1962 . years to weigh the evidence that (a) condensates from cigarette smoke contain chemicals which are carcinogenic to animals, (b) cigarette smoke injures the bronchial epithelium, and (c) smokers are at a higher risk of lung cancer than are non- smokers. None, or very few, deny the validity of this esideoce. For the medical investigator, however, the evi- dence still does not add up to conclusive proof that cigarette smoke causes lung cancer. And his major problem is to define the conditions under which iuch proof might be forthcomine. The prac- titioner, on the other hand, has a different prob- lem and a different responsibility. His concern is for the individual patient-not as an entity in a controlled study, but as a human being whose life he wants to protect. The long "incu- bation period" of lung cancer in man may be an insurmountable obstacle to the medical inv-s- tieator; but for many practitioners it appears to be a possible opportunity to prevent the occur- rence of a prognostieally poor disease, whose damage is irreversible. The investigator can af- ford to suspend judgment until he has conclusive proof; the practitioner must practice. Given the evidence on animal carcinogenicity, injury to the bronchial epithelium, and the risk of lung cancer from smoking, the medical prac- titioner may well ask: ••What valid objections can there be to my wanting to prevent lung can- cer from occurring in my patient?" "What is more important than the health of my patient?" The practitioner may also ask, when he is told to suspend judgment on smoking and lung can- cer: "Are they telling me this because they seek to improve the quality of medical investigation, or do they seek to improve medical practice?" Carcinoma and Ciliary Action. If. Eeperimental Study on the Filtering Action of Cow's Lunp, the Deposition of Tar in the Bronchial Tree and Re- moval by Ciliary Action. New Enalaod J. Med• 251:1/57-1160, 1956 4. Rakieten. N.. Rakieten. At. L Fcldman.•D. and ,-Boykin. M. J., Jr.: Mammalian Ciliated Respie- - tory Epithelium. Studies withPanicular Reference to. Effects of Menthol, Nicotine and Smokp of • Mentholated and Nonmentholated Cigarettes• A.M.A. Arch Otolaryne. 56:494-503. 1952. '!3S
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16?;2304 ' >IEDIC.{L FIL>tREV1Elc5 1.•1•>t.A., Dec. 1:, l9S9 • results in increased plasma titers of erytkropoiet'n. This finding probably explains the polycythemia- producing effect of cobalt. While it has not yet been completely purified, this hormone is apparently a glycoprotein. it is relatively beat and acid stable but is inactivated by proteolytic enzymes. There is evidence indicating that in the experi• men,tal animal erythropoietin is formed in the kid• ney. Such an origin for erythropoietin may serve to explain the anemias associated with renal disease and the polyc,vthemia sometimes present in conjunc• tion with hypernephroma. There have been no re- ports of the use of erythropoietin in the treatment of anemias im mnn. SJfOKINC AND LUNG CANCER A summary of pertinent data relating to smoking and lung cancer appeared in THE Jot x.At., Yov. 28, pages 1&?9 to 1837. Written by Dr. Leroy E. Burney, surgeon general of the Public Health Service, the report documents the major researches and identifies the Public Health Service with those MEDICAL FIL1'I REVIEWS Circulation of the Blood: 16 mm., color, sound, showin-. time 7 minutes. Produced in 1958 by Churchill R'exler Film Productions, Los Angeles. Procurable on loan or pureha,e from American Heart Association Fihn Library, 267 ll•. ?.ith St., New York 1. This film, by means of diagrammatic drawings. shows how the heart works and ecplains the struc• ture of the arteries and how their expansion and contraction controls the flow of blood. Animated diagrams trace the circulation of the blood through the body. This is a stylized, accurate, and attractive presentation of the activity of the normal human heart. The animated diagrams are augmented by a few actual views of the movement of blood in capillaries, arterioles, and venules, and the anima• tion and'narmtion are escelletit. The'film'is highly recommended for adult lay groups and also for supplementary material in college and high school classes in biology, physiology, and health education. Physical Fsamination of the Newborn: The Art and the Findinps 16 mm., tolor, sound, showina time 33 minutes. Prepued by >tiry' B. olney, M.D., San Francisco. Produced In 1959 by Medieal Ant Productions. San Francisco for and procur,able on loan from Pfizer laboratories, 610 Flushing Ave.; Brookhsi 6, N. T:' P:tit'1 oE. thism film demonstrates the steps of a complete rout.ine examination as it is perfoimed on a baby a fns',hours old. Part 2 shows special examination techniques and'some of thq.more,com- who consider that the evidence to date implicates smoking as the principal etiological factor in the increase in lung cancer. A number of authorities who have examined the same evidence cited by Dr. Burney do not agree with his conclusions. Al. though the studies reveal a relationship between cigarette smoking and cancer that seems more than coincidental, they do not explain why, even when smoking patterns are the same, case rates are higher among men than among women and among urban than among rural populations. \either the proponents nor the opponents of the smoking theory have sufficient evidence to warrant the assump. tion of an all-or-none authoritative position. Until definitive studies are forthcomin;, the -physician can fulfill his responsibility by wntching the situa- tion closely, keeping courant of the facts, and ad• vising his patients on the basis of his appraisal of those facts. The Public Health Service can best meet its obligations by collecting and d'useminatg in; data from all sources and making known to the health and medical professions its own evaluations of such data. J. H. T. mon abnormal findings as well as"normal findings which can be mistaken for anomalies. One of the best parts of this film is the last sequence. in which the pediatrician visits the mother «ith the newborn infant and demonstrates to her many of the points in the physiology of nea•born infants which might possibly disturb her. This is a very good illustration of ptttting a mother at ease t~ith her newborn baby. This film is an excellent demonstration of physical examination of newborn infants and it is hi;hl,v recommended for obstetricians, pediatri• cians, general practitioners, and house officers. iaF % 7 . 1~~ 21 r4a' >. ::r? ~ . ~s The Thiench Wiring For Massive Rectal Prolapse: 16 mnt., •~ color, sound, showing time 15 minutes. Prepared in 1956 by t+• and procurable on loan from Robert Turell• >l.D, :S E. S9rd St., New York 38. i This film demonstrates the technique of inserting ~ 'r 7hiersch %iiie for the tontrol of rectal prolapsc. The author's indications for using this procedure, 4' ns u•ell as his program of preoperative and posG oper,ttive cire, are described. Photographs demon• :~ strate the condition of patients before and after the operation and roentgenograms are shown of .uF the wires in place after surgery. Some of the eom• ;.~ plications of this operation,are described; however, ~ a rather common one, fecal impaction, has been Sg omitted. The teehnical details are well presented; ~u bur one must look at. the indications fof this pro- . ~ cedtire with a very critical eye. The phottigrhphy is good and the film will be of interest to proc• _.Ft tolo,ists. •
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140. 1814 LL'\C CAYCER-8CR\'EY \'ov. :9, laS9 t.sr prcduces cutaneous papillomas and carcinomas %vhen applied for prolonged periods to the skins uf laborator,, animals. Continnation of'hese studies has been reported from other laboratories." There is little doubt that benzpyrene and other carcino- ;enic hydrocarbons found in soot are responsible for the classic human example of occupational c_ncer. Pott's epidermoid carcinoma of the scrotum in chimnev sweeps. Cooper" in 1955 Srst demon- strated the presence of 3.4 benzp.rene in cigarette smoke. Be.^.zpyrene is probably not the only car• cmogen irrvolved." Absorption by CelLv.-MeL'ors " demonstrated that cells can absorb carcinogenic substances. When he genth scraped human squamous epithelial cells from the buccal mucosa and placed them in million• fold dilutions of cigarette tars, these same cells be• came'stained' b,v the products of cigarette tars and fluoresced characteristically when examined with the fluorescent microscope. The Flow of lfucus and Ciliary •ictlon.-Robert- sun " has reported on the phagocytic action of histiocytes extruded into the lumen of the alveolus. \tacklin " noted that the alveolus is the point at which inhaled smoke comes into intimate contact with the rich capillary bed of the lung. The phago- cytes apnear to move out of the alveoli, along with a t:rin, mucoid coating, until the ciliated areas of the sub•bronchioles are reached. By the propelling force of ciliary action the mucous blanket, laden with foreign particles such as insoluble tobacro tars, moves slowly toward the trachea. From the relatively great total area of the alveolar regions the mucous stream follows a steadily narrowing path to the h lu regions where, by comparison, the cross•sectional area of the large bronchi is very small. During this passage the mucous blanket apparently becomes thickened and less fluid. Thus• the mucus is funneled and concentrated, along with its adherent tars, into the hilar areu, where there are additional mechanical reasons for stasis. Concentration.-Occurring normally in the hilar bronchi are the numerous apertures of emerging bronchioles and patchy islands of nonciliated epithelium. Hilding" produced deciliated areas by injuring the bronchial mucosa and showed that the flow of the mucous blanket hesitetes at these deciliated areas. In his study of the bronchi uf freshly killed calves both India ink and, again, smoke were introduced into the mucous stream and observed for var}ing periods. When foreign material stntck either the normally nonciliated regions or the areas of-iajured cilia, the particles collected on the'upstreani side and lagged behind. remaining in contact with the bronchial epithelium for prolonged periods before being swept on. There is no report as yet of i similar study in man Airtopsy Studies.-Auerbach and. co•workers " reasoned that lungs of smokers should reveal''both. destructive lesions and precursors of malignant change in the epithelium of the tracheobronc: ial tree. Their conclusions are based on some ?5,000 sections from autopsies of 117 patients in whom the authors found changes they described as basal cell h}perplasia, stratification, squamous metapla- sia, and carcinoma in situ. The cellular changes showed a statistically significant, increasing grada- tion. Si.eteen nonsmokers had the fewest abnormal- ities. A higher percentage of abnormal slides were noted in the 20 patients who had smoked less than one package of cigarettes a day. Still more aqpical were the findings in 47 patients who had'smoked more than one package a day. Thirtvfour patients dying of bronchial cancer (all smokers) showed the greatest number of areas of cellular aberration. The Concept of Pathogettesis.-Tars eontainin; benzpyrene and probably other carcinogens present in cigarette smoke (or contaminated air) are ab- sorbed by the cells of the respiratory tract. espe- cially in the alveoli. Here these foreign particles are picked up by phagocytes and transported toward the trachea in the mucous blanket of the bronchi. En toute, concentration occurs where the cilla of the bronchial mucosa are injured or absent. and the motion of the mucous blanket is stopped for appreciable lengths of time. During this period the carcinogens contained in 'tar' particles and in - the mucus are afforded prolonged contact with the • ttnderlving bronchial cells, which react by malig- • nant ch.nge. Experimental Proof.-Eaperimental proof of this concept, to date, has not been supplied. The uilti- mate experiment would produce in laboratory ani• mals, by the same type of exposure that occurs in humans, the same type of terminal tumor, prefer- ably through• the same sequence of preliminary changes as has been postulated above. Rockey and his assodates °' applied tobacco 'tar' directly to the bronchial mucosa of dogs and found that within three to six weeks the tar•treated sur- faces became granular and later developed wart- like elevations. In the study of Leucbtenberger and co-workers s' mice were exposed to cigarette smoke and examined after varying periods, the longest being =00 daps, In most animals the bron- chiaf tpitheliuai showed tuflammation and simplE . and at}-sical basal teU hyperplasia. Passey " stated. huwever, 'pur failure during the past five years (recorded in previous publirstionsj to induce lung tumuurs in mice, nts, and hamsters by exposure to strong concentrations of cigarette smoke is a snil•- ing negative result.' The findings of such e.iperiments, in toto, are incooclustve, Whether this. is dut to inherent di6- culties of the expepimentaf inetbods employed " or to the problem of adequat; control," dr whether this, represents a true negative is not apparent at present.
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Vut. l"=, \o. 9 CDRRESPO\DENCE cluding 65 milliun dollars for the National Cancer Institute, with about 20 million dollars allocated specificall,v for research in chemotherapy. How much of these considerable funds has been spent or allocated for carrying out the 5rst steps to be taken to realize the discoverv of an important cause of lung cancer? So far as'I can learn, none at all. Sn far as I know, the only experiment on smoking in re!ation to lung c.tncer published from the Public Health Service is the negative ezperiment" that I cited above, and no work of this nature is in prog- ress now. As I have repeatedly pointed out, the prospective studies show more excess deaths among the smokers from other causes than from lung cancer, and these other causes are distributed among all classes of disease, If the statistical results are not spurious but re9ect some real biological effect, this points to a generalized, not a local, effect. I have presented a plan's for an experimental epidemiologic study to explore this lead. Why has not the Public Health Service set up this experiment, or some modification of it? Sir Ronald Fisher, who has been critical of the analysis of the English data on smoking and lung cancer," early remarked, 'The question seems to be a serious one; when is serious investigation goin; to begin?" His question is timely even now. JOSEPH BERl:50N. M.D., D.Sc. \layo Clinic Rochester. Minn. References 1. Burney, L. E.: Smoking .ad Lung C.mczr: Statement of Public Health Sen•ice. J. .i. \I. A. 171t1S?9-1837 ( \ov. ?8) 1959. 2. Berkson, J.: Smoking and Lung Cancer: Sonte Obser- vations on Two Recent Repurts, J. Am. Stat. A. •ias?8-J8 (\Lvch) 1958. 3. (a) Berkwn. J.: Steti.tical Inveatigainn of Smokim; and Cancer of Lung, Proc. Staff Meet. \la,vo Clin. :I4t306-?2ia (April 15) 1939. (b) Berkson, J.: Stetistieal lnve.atigatiun of Smoking and Cancer of Lung, J. Phamt. Belgique, no. 1 tod 2, Jan: Feb.. 1939, pp. 3-1a. 4. Huntmond, E. C., ard Horn, D.: Smoking and Death R.nes=Report on Fon,v.Foi,r Months of Follow-up of . 187,783 Men: It. Death R•stes by Cnttse, J• A. \I. A. 16etrMa-1J08 (Slart:h 15) 1938. S. (a) Laurence, t\'. L.: &.ienee in Review: Controveny on Lung Cancer Plues np Again over Statistin, \tw York Times, Dec. 6, 1959, p. E 11. (b) Berkson.°` (e) Berkaon-" 6. On Hitting Nail, editnnal. 1\',t+hington Post, Dec. 6. 1959• p. E 4. T. \ational OfBce of Vital Stati,tia: Mortality from Each Cause by Color and Sex: United St.ttes, 1957, Vital Statlstit,s-Speatal Reports. Stta35-6?• Feb. 4, 1959. '. • 8. (a) Jennings, H. S.: Cenetics. New York, 1V. 1V.. Norton & Company, Inc.r1935. (b) Crew, F..4.E.: Sea Ratio, \ature 1JOr1-t4-i33 (Sept. 11) 1937. ' ' ' 9. l:ircho6, H.; and Rigdon• R. H•: Gncet of . LunS- Se.e Ratio: Reviesd of Problem, Tesas Rep: $ial. 4kled. ' 1709-48. 1959.' . ' . . , . .. . . . .. . UJi 969 10. Lcuchtrnherger. C.. La.chtenberger, R.. utd Doohn, P. F.: Correlated HietologicaL Cytological, +nd Cytociem- ical Study of Tracheobronchial Tree and Lung.. of Mice Expo.ed to Cigarene Smokt: Bronchitis with Atypical Epirheli.tt Changes in Mice Esposed to.Ci;.trette Smoke. Cancer 11:490-306 (Ma,v.June) 1938. 11. Leuchtenberger, C.; Leuchtenberger, R.: Zebrun. R'.: and Shaffer• P.: CorreLted Hi.tological, C>tologiciI• and Cytochemical Study of Sequence of Events in Bronchi.d Epithelium from Mice E.epored to Cig:rette Smoke, Act.s Cnio intemat, contra CGnemm 1:.:6T3•639. 1939. 11. Loranz. E.t Stewart, H. L.; Danitl. J. H.: and Vebon, C. V„ Effects of Brenthing Tobacco Smoke on Strain A\fice, Cancer Res. 1s1?3 (Feb.) 194.). 13. Berkson, J.: \Ieasure of Cnmpeting ?lorulity Risk>: 1t'itlt Especial Reference to Study of Smokin, and Lung Cancer, unpublished data. 14. Dom, H. F.: Same Problem.c Ari.in; in Proopective and Retrospective Studies of Etiology of Diuase, New England J. Med. Ytt1:3i1-3T9 (Sept. 17 ) 1959. 13. (a) Berkson.' (b) Berkson.° (c) Berkscn." 16. Fisher• R. A.: Smoking: The Cancrr Contmcrny, Edinburgh, Oliver & Boyd, Ltd.. 1959. ELI LILLY MEDICAL RESEARCH FELLOWSHIP (SOUTH AFRICA) To the Editor:-The attention of medical prac•tition- ers registered in South Africa• who maI' at present be in the United States, is drawn to the facC that applications mav now be submitted for the •1960 award of the Eli Lill}• Medical Research Fellowship. The fellowship is given for the purpose of medical research and is not intended for postgraduate clini- cal stud)•. The net value of the fellowship is S300 per month for 12 months, plus return travel- ing expenses to the point of study in the United States of America. Further details can be obtained from me. The closing date for applications is April 30, 1960. H. A. SH.tP1Ao• M.D. Honorary Chairman: Selection Committee Eli Lilly Medicttl Resesrch Fellowship P. 0. Box 1010 Johannesburg. Union of Sottth Africa FAT CO,\TE\T OF SEMEN To the Etfitar:-In my busy practice, I Bnd.myself several weeks behind in reading THE JoMVAt., and it was only last night that I had an opportunity to review the Aug. 1, 1959, issue. I would like to know where the scientist who prepared the answer to the question on page 1756 of this issue obtained the calnric values for fat given. Seiv.. York City. . I regret to state that the person who prep:ued the reply has been given another assignment and is not available for'comment.-Eo.
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LLNC C.wCER-ROBBNS r.ise is standards of mcdical prac:ice. The work of the health orTteer, too, is constan.ly exposed to ?ressures urging him to meet the exacting stand- ards of public health. His wrork is open to criti- cism frct fel!ow scientists and practitioners at all timcs. Three Responsibilities of the Practitioner The manifold responsibilities of the practition- :r make it necessary for him to take account of these forces and pressures moving him to higher standards of practice. Among these responsibili- ties, we may take note of three. 1) To be scientific. First, as the AMA Princip'.es of Nfedical Ethics insist, he must "practice a method of healing founded on a scientific basis." But it is not science alone; it is science-in-relatioo-to-patients. He knows that scientific knowledge is not complete and nevec will be complete. In L':is regard, one of his erntest problems is how to practice when the scientific evidence is not conclusive. 2) To search for advantages for his patients. Second, as we have seen, the practitioner al- r ways'attempts to give his patient whatever ad- vantages he can. Nothing characterizes the doe tor-patieot relauonship more than the eonstan6 energetic application by the practitioner of what he believes to be good for his patient. To do so , is not often easy; in many instances. it is a mat- ter of playing the percentages. Sometimes the per- i"antages are large; sometimes small. For example, °,a Connecticut study (1) has shown that if cancer of the cervix is found and treated while still localized, 5-year survivals are about 65 percent. ,It there is regional involvement, 5-year survival ts only about 33 percent. On the other hand, it ;td'u cancer cann be discovered at Stage 0, carci- ooma in situ, theoretieally 100 percent of the women would survive at least S years. Thus, ` al pry diagnosis of cancer of the cervix, now pos• iible through a routine Pap smear, will place his Patient in a group having a statistical advantage in 5-year survival. The practitioner believes it to be good practice to search for such advantages for Ns patients. 3) To praciice promptly and adequately. tThe third responsibility of the practitioneris !a apply his knowledge .in time and adequately. Uav.ar, 1962 ' So much importance has been attached to time in the treatment of cancer that early aeatment needs no defense, The American Cancer Sociery has said that "treatment delayed may be treat- ment denied." Adequacy refers to the completeness with which any medical procedure is eartied through: not the excision of part of a cancer, but all of it; not the recommendation to a chronic alcoholic to have a few drinks, but to have no drinks. L;.t us now consider the differences between medical practice and medical investigation more specifically as they affect attitudes and action on the issue of smoking and lung cancer. The Basic Evidence Against the Cigarette From all the studies on smoking and lung can- cer, we may point to three key facts over which there seems to be no disagreement. First, there are chemicals in cigarette smoke that will experimentally produce skin canc:r in animals. Various reports list the number of these animal carcinogens from 5 to 18. (2) One of the carcinogens, benzpyrene, was the first human carcinogen to be so identified: it was the cause of scrotal cancer ir. chimney sweeps, as discovered by Potts in England. Second. Cigarette smoke injures the bronchial epithelium. Cigarette smoke produces partial pa- ralysis and injury to the cilia in the bronchial epithelium. (3, 4, 5, 6) Third. Mortality from lung cancer is higher in cigarette smokers than it is in nonsmokers. (7, 8, 9) Infeipretation of the Evidence Although these three key taets are undisputed, their meaning is. not. Here, tha differences be- tween medical investigation and medical prac- tice enter in. The medical investigators, for ex- ample, who made the first 9 studies of lung can- cer cases, found a higher percentage of lung can- cer cer patients admitting a smoking history than could be expected in the „general population. Other medical investigators looked ai these Gnd- ings- unearthed by their fellow investigaton and quickly criticiied them for being ;retrospective 133
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IL`.1816 LC\'C C.t\CER-BCRNEY J..1Jt.A.. .\,... 15. 1939 i I :mF)kin, p.:r••tcal.triv is .tssurieted with nn increased chance if developing lun; c>nter. 3. Stoppin¢ r';a- rette smoking even after lon; eqrusure is beneficill. 4. \u method of treuing tubaeeo or filtering dte smuke has been demonstrated to be effective in mueri.dlv reducing or eliminating the hazard of lun; cancer, S. The nonsmoker has a lower inc:• dence of lun; cancer than the smoker in all con• trolled studies. tvhecher anal.zed in ter:ns of rural .:re,ts• urban regiuns, industrial occupations, or ses. 6. Persons who have never smoked at all (cig:trettes, cigars, or pipe) have the best chance of escapin, lung cancer. T. Unless the use of tobacco can be made safe, the individual person's risk of lung can- cer can best be redttced bv the elimination of imoking. Referrtnces 1. \~tmnal OfHce of 1'it.J Statistics: Vital Statistics of the L'n¢ed States: >lortality D.ua, ol. ?, tt'ashington, D. C.. C. S. Cn.'emn:ent Printing OfRce. 1945. 1948. 1947. 1948. 1919. 1930. 1951, 1932. 1933, 1934, 1933, and 1938. :. Hueper. et', C.: Environmental Causes of Lung Cancer. Pub. Health Rep. 71t94•98 (Jan.) 1936. 3. Burney, L. E.: Statement. July 12. 1937, Ca. Bulletin of Cancer Progress 6t4•1 (March-April) 1938• 4. Lombard, H., andDoering, C. R.: Cancer Studies in ?las<achu.etn: H+bits. Ch.uatten,t¢v And En,iromnent of Indwiduals tt'ith and tC;rhout Cancer, New EngLnd J. \Ied, N18ra81-4gT (.lpril-'0) 19-°8. 3. (at Bresiow, L.: Hoaglin. L.: Rasmunen• C.: And .{bram>, H. K.: Oca:pations And Cigarette Smoking a. Fac- ton in Lung Caneer,.Un. J. Pub. Health 4js1T1•1B1 ( Feb.) 1954. (b) Doll, R.. and Hill. A. B.: Sn:dr of .{euology of Careinoma of Lung, Brit. ?I. J. 2r13T1•1?96 (Dec. 13) 1952. (c) F:oulumres, M•: Smoking and Pulmonan' Car• cinoma. .{cta ndioL :114!33-160 ( \(areh) 1951 (d) Levin. M. L.: Etiology of Lung Cancer: Present Status. New York J. Med. 3•Id69•-T (11.uch 15) 1954. (e) McConnell. R. B.; Cordon. K. C. T.: and Jones, T.: Occupational and Personal Factors in AetioloCy of Carcinoma of Lung. Lancet ss631•636 (Oct. 4) 1952, (j) 11i8s. C. A., and Porter. ?(. \I.: Tobacco Smoking Habits And Cancer of Mouth and Respiratory System, Cancer Res. Irst339-34'? (Sept.) I9.30. ig) 1luller, F. H.: Ltbakmiobrauch Lind Lungeneareinom, Ztschr. f. f:rebsfonch• ersr37-83. I939. (h) Sadowsky, D. A.; Cilliam. A. C.: and CornBeld, J.: Statittical Assaoia- tion Between Smoking And Caninoma of Lung. J. \et. Cancer Inst. M1?37•1:58 (APrill 1053. (7) Schairer. E., and Schoniger, E.: Lungenkrebs und Ubal.•erbnuch, Zeseht. L Krebsfonelt. 3Jr?6l•?B9. 1943. (i1 Schrek, R.: Baker, L• A•: Ballard, C. P.; and Dolgoff. S.: Tabasco s:nnking as EtioloPa Factor in Disease: Cancer, Cancer R<s. t or~9•58,( Jao.l,1950. (4) Stoqks, P.. And Campbell. J. \I.: . Lund Cancer Death'Ratn Among \on•.ntokert usdPik .md CigaretteSmoken: ~Evahsation in Relason to Air Pol• (ution by Bentpyrene and Other Substances. Brit• \I. J. 2s9?3-9!9 (Oct. lS) 1953. fml Wassink. W. F.: Etiologic F.uron if Puhunn:uy Cancer. Y.derl. tiid.ehr. v. genee.k. n2s1T3:•3T16 (Nov. 13) 1949. (n) R'atsueu \V. L. andConte, .l J.: Lung CancR And Smoking, Arn. J. Surg• RMt 447456 ( Feb. ) 1955. I o 1 tvynder. E. L-: Brvss, 1. J.: Corn- Reld, I.; and O'Donnell, eV, E.; Lung Cancer in Women: Study of Envtronmental Faetors. New England J. )led 2tsd11t•1131 (Dee.' 13)1936• (A1 trynder, E. L., And Crsham, E. A.: Tobacco Smoking as Pos.ib4 EtiobOc Fac• tor cn Bronehiogenie Carcimrma: Study of 684 Proved Cases. J. A.,31. A. .g1Bt3?9J36 I\IaY "-TI 1931)..(tll 1lyrder, - E. L., And Com6eld, J.: Cancer of Lune iri Physitians: . New Engl.nd. J. Sled. 24ur4-1144i (March 1E) 1951. t1.. 5h:n. k:n. \I. B.. And \4neel. \'.: Reco• •Fnn,e stud,' nt Lnni; C.ncer :n l1'umen. J. Yat. Cancer ln.t. 21:SJ3-Sa_ t\u,'.I 193S. (sl Seh..:trtr, D., and Ovnm.. P. F.: L'enquete (nneaue ur I'dtiolog:e du cancer brunciw•puhmnaur: rule du tsbac. )emame hup• Paru :g:le A330-i6a3 (Oct. 30) 193T• (t) Segt, \I., And othen: Ep:demt• nlogmal Study on Cancer in JaPaa Cann Ulr Supplement (Apnll 193T. lul Stocb, P.: Report on Caneer in North A'ales And Liverpool Reg:on: Bntish Empire Cancer Cam. D•ugn: Aanual Rcpurt No. i3 (mpplement to Psre Il), 1957. rcl )h9s. C. A.. And Porter. ?t. ?I.: Tobacco Snmking, )lotor Ekhaust Fuine,, And Central Air Pollution in Relation to LunC Cancer Inc:dence. Cancer Re,. 17t981•990 (\or.) 195T. 6. Lombard. H. L.. and Sr.e;ued, L. S.: Epidenmologtcai Smdy of Lung Cancer, Cancer 12s406413 (\farch-Apnl) 1959. .L DDoll. R., And HilL A. B.: Lung Canc<r And Other Causer of Death in Re4tion to Smoking: Second Report on )lonality'af British Doctors, Brit. >I. J. 2:I0T1•1081 (\ov. 10) 1938. S. H•unmond. E. C., and Hom, D.: (a) Smoking and Death Ratn-Report on 44 Months of Follow-up of 18LT83 \len: Total Mortality. J„{, )1, A. ltsNr1139•ll"? (\larch S) 1958. (b) Smoking And Death Raten-Report on 44 Months oi Follow-up of 187.7,33 )(en: Death Rates by Cause, ibid. IrsBQ']94•1308 (\larch 13) 1938. 9. Dom. H. F.; Tobacce Consumption and Mortality from Canar and Other D(oesses, Pub. Health Rep. 7Is381•393 (July) 1939. 10. BerCson, J.: Smoking and Lung.Cancer: Some Ob•.en'ation on Two Rettn,r Reports, J. Am. Stat..1. S:WS-38, 1958. l1. Little. C. C.: Statement, July l?, 1937, Ca. Bulletin .d Cancer Progre». 1112 I\lar. :{Pnl) 1938. L. Fi,her, R. A.; Lung Cancer And Cigarettes? Letter to the Editor. Nature 189t108 1 July 12) 1935. 13. Broeke, C. 0. S. B.: Incidence of Cancer of Lung 19.7-'-1936, Brit. 1. Cancer 12s481-i91 (Dee.l 1938. 11. Herdan, C.: Incre'ase in Mortality Due to Cancer of Lung ia Light of Di.tpbution of Dis<ase Among Different Social CL»<s and Occupations. Brit. J. Cancer 1Y:499•306 IDec.) 1958. IS. Joint•Repott of Study Croup on Smoking and Health. Science l2 Sd P39• I 1.i3 (June T) 1951. 16. Tobacco $moking And Cancer of Lung. Statement of British Medical Re.eueh Counctl Brit. ?I. J• Is1323-13?I (June 29) 1951. I17. (a) Eotlo. P.: Role of Atmospheric Pollution in Pathogenesis of Pulesonary Cancer: Review, Cancer Rn. 1 MdT3-a93 ( June 1 1956. (b) HaensseL tV., and Slumkin. tl. B.: Smoking Panerns And Epidemiology of Lung Cancer in United States: Are They Compatible? J. \ae. Caucer In.t. INt141T•1N1 (June) 1956. (e) Hammond, E. C.: Smoking and Cancer: Consideration of Some Stattsneal Mpects (Ab- tracx!, J. ,4u, Sratisticiane :1. 31412, 1936. Id) Hutper. U'. C.:, Quea Imo En.irnnmemal C+uss of Cancer nf Lung, tl. S.Publia Hsalth SvtvSde utonngdph rq 76, Washingfon::' D. C., U. S. Coremnsent Prfnting pt8n, 1953. 18.Cotin. P.d E.perimental Tumor Produetioe •ith Air Pollutants, in Proceedings of National Conferenee,on Air PnButlon. Sa.'ember 18-30, 1938, tS'a,hingtnn, D. C, C. S. Covemment Printing OIBee, Public Health Senice publia• twn no. 63i, 1939. 19. Hatmnond, E. C.: Smoking and Death Rate-Riddle in Cause and Edect. Am. SciemfstJ6s331•33•1, 1938. ''4. (a) Cleosmetea J. and Nielaen, A.: Social Di.anbu• tiuo of Cancer in Copenhagen. 1943 td 1947. Brit. J. Cancer •7af59-,ISI (June) 1931. (61 Cohart. E. \I.: Sotioceonomie D'istributldn of Cancer of Lung 3ss New Haren, Gnoer Yt • 41:6•119 ( \ov.•Dec. ) -I9S5. . !t: Lpmbard, H. L.: Inqrtase in Lung Cantti in \la,s.r . chmetts, Cancw trt66TS0 (July-Aug.) i958. l W J N O~
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