Tobacco Documents Online

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Mr. S~muel B. Witt, September 26, 1980 Page one It is important to be aware that there are three types of Industry related ~oking and health research projects in Germany. There are projects funded by the German equivalent of our CTR (Forschungsrat) under the chairmnshtp of Prof. Sc2mmehl in Heidelberg. For these projects the Verband only provides the funding and - largely at our advice and insistence - does not exert the slightest control or influence on the selection, publi- cation, or any other matters relating to the specific pro- jects. This "neutralization" of the influence of the Yerband has been put ck~ in writing as follc~: There is a consensus that this (financing of the projects) is done without any scientific assessments of the research projects by the Industry. Some ten research grants, totaling about DM 1.775.000,-- have been approved on June 9, 1980; most for a period of about one year. Detailed Gernmn language descriptions of the projects are available. However, their discussion does not seem wa~-~nted because ol the mentioned "non-intervention" clause. There are projects which are financed by R.J.Reynolds (~hH in Cologne, and about which I have written previous reports. Incidentally, I anticipate to write a further progress report after my next visit to Germany, which I hope to be in late October or early November of this year. It is stated for the record that these projects are, of course, confidential, except for a "need to know" within PJR and Ed Jacob. There are projects which are"contracted'and which have been handled by the Verband since about 1977. "By definition" these projects have been kept confidential fr~n the old Forschungsrat, and are being kept confidential from the ne~, Forschungsrat. The Yerband has total oontrol over the design of the experiments, the right of the researchers to publish or not to publish, etc. These projects likewise need to be kept confidential to the outside (including Cl~) excepting those having a "need to know" within RJR, Philip Morris, Jacob & Medinger, and Shook/Hardy. ./..

Mr. Samuel B. Witt, III Sept~uLer26, 1980 SMOKING ANDHEALTH~~ IN GERMANY, PaKe continued 3. Continued These are the projects ~here we try - at times successfully and at other times unsuccessfully - to achieve some consensus between Philip Morris and us, i.e. between Bernd Pelz and Dr. Fink or another PM representative in the pertinent Ccmaittee of the Verband ec~rpo~ed of the - or one of the - leading research scientists for each company. (TFA - Tabak Forschungs Ausschuss) Incidentally, I n~y have opened a ~t better line of ceta~nications~ithl~ on such projects, by talking directly toDr. TemOsdene (Alan Rodgman's equivalent at l~) and/or Alex Holt~an. The rest of this report ~ill consist of a discussion of these special projects. These projects are discussed in approximate chronological order of starting dates, except that projects by the same investigators and related subjects have been grouped together. II. I. PROFS. GRIMIER and BRUNE, University Hamburg A~JFL3ED (X)-CARCINOGENESIS OF NIOTFINE. (Mouse skin) The experimental techniques are quite defective; rest importantly, very impure nicotine was used, i.e. nicotine which - at best - con- rained only 7(~ to 8~ real nicotine: A slight increase in carcinogene- sis has allegedly been observed; however, the "statistical signi- ficance" as determined by Peter N. Lee (consultant to the Tobacco Advisory. Council in Great Britain) is at best very limited and, in effect, totally meaningless because of the mentioned experimental deficiencies. The results are not publishable, in my judgment, and it is my understanding that Dr. Adlkofer (now Professor Adikofer) agrees. PROF. MOHR, University Hannover ~ OO-CARCINOGENESIS OF NIOYrINE. (Han~ters) Intratracheal installation of nicotine and carcinogens in hamsters. Project almost completed and being evaluated. Apparently no effect to date. However, this can only be assessed once the results are complete. In my judgment, provided the data are valid and significant, they. sho,~Id be published, even though most researchers are reluctant to publish negative data. Regarding items I. and If. on page two, Prof. Adlkofer is apparently planning more experiments on the alleged eo-emmcinogenesis of nicotine. I am trying to persuade him that this is a scientifical]y meaningless and wasteful endeavor for the following reasons:

Mr. Samuel B. Witt, III September 26, 1980 @dOZING AND HEALT~ RESEAtt~ ~ IN (t~MANY, continued. Page three III. II. Prof. Mohr, Hanuover, continued a) 7his particular problem was started by Dr. IDCK of RosVell Park Institute. tie has presented results alleging a co-carcinogenic effect of nicotine on the carcinogenicity of benzo-a-pyrene (not ~oke). The results, even though presented several years ago, have never been published in a scientific Journa2. In a paper given at the International Cancer Congress in Buenos Aires, Dr. Bock pre- sented some other "positive" results which contradicted his earlier results. I challenged Dr. Bock publicly on these and he was unable to provide a meaningful answer, except to state that his earlier results would be published, which, to date, has turned out not to be true. b) The above described unsuccessful experiments contracted by the Verband. c) The National Cancer Institute has tried, allegecily tmsuccessfully, for three to four years to produce such effects in dogs. I am trying to obtain the pertinent doctwnentation and wil] forward copies to Prof. Adlkofer. PROF. ALT~ta~N, University of Vienna, Austria DETE~IINATICN OF NITROSAMINES IN SIDESTREA~! (Repeating published experiments by Brunnemann and Hoffmann of Dr. Wynder's American Health Foundation. ) The results of Prof. Altman are allegedly the same as those found and reported in the literature by Philip Morris/Switzerland, i .e. the nitrosa- mine level found was less than those reported by Brunnenmnn and Hoff- nmma. However,the 1~! values are not much less. In my judgment, the PM results are defective because of faulty techniques used. (Please see my memoranda of August 27 and September 3, 1980, on which you were copied. ) The Allan project is alm~t cxxnplete, but still in the evaluation stage. No judgment can be made until the data beoome available. , IV. PROF. ALTMAN~ University of Vienna| Austria NITROSAMINE FOP~TI(IN IN HUMANS - URINE. Effects of a meal rich in nitrates and amines, Comparing with and ~ithout ~king. No usable results to date. V. PROF..A~.T~N, University of Vienna~ A~ustria Using same probands a~ in the Schievelbein spermatogenesis study. (Please see below)

Page four ~r'. Samuel B. Witt, III Sept(m~ber 26, 1980 SMOKING AND HEALTH RESF~ I~ IN GERMANY, oontinued VI. VII. VIII. IX. PBDF. ALT~I~N, University of Vienna, Austria EFFECT OFS~DKEONDNAREPAIR~I~L Effects to dateareminor but study not completed, and results re~nain to be evaluated. THESIS, Freie Universit~t Berlin Dr. T. PJ~mer under the direction of Dr. Buckauf. OXIGENUPTAk~BY SMOKERS IN PRESENCEOFCARBONMCh~IKIDEFRf~ ~3KING The earlier literature claimed ecmpensatlon mechanisms, such as m~re hemoglobin, etc. This was not always confirmed in this study. The experimental techniques used in Berlin leave quite a bit to be desired. But, performance in young smokers oompared to young non-smokers was not impaired. However, results are probably not publishable because of questionable techniques and too few subjects. OTKER ND THESIS, Freie Universit~t Berlin Cand.med. Kulb~rsch and Dr. Arntz. ~ OF S%~)KE ON LIPIDS AND LIPOPIKTI~INS IN ~. Comparing gas phase, total ~noke, and sham ~noking. No differences to date, but evaluation not completed. No determination whether or not results are publishable until complete data become available. SCHIEV~V.IN and BOP~,I.I, German Heart Research Center and Technical Universit~ of Munich. SPEP~TOC~%~SIS IN 18 TO 40 YEAR OLD S}.~KERS AND NON-S~OKERS. (Please see also V. above on page three. ) Blind evaluation. Evaluation almost c~plete, but results to date indicate non-~nokers have more anomalies than smokers. Probable ~pletion date of evaluation etc., about December 1980. No judgment can be made until data become available, especially since the number of subjects tested was apparently limited to 18 or 36 men. PROF. HILDEBRANDT, Berlin EFFDL'rS OF SMOKING ON BENZOPYRENE HYDROXZLAS~ IN LIVERS AND LUNC~S 'OF HAMS'rh~S. Results to date show no effects, but project to be aborted because too few animals were used and also the model turned out not to be a good rr~tel. Results almost certainly not publishable.

Mr. Samuel B. Witt, III September 26, 1980 SMOKING $,ND HEALTH ~ ~ IN ~, continued Page five XI. XII. XIII. .PROF. BASSENGE, University of Freiburg DIR/~3T AND INDIKECr ~ OF NI(X)TINE C~ THE HFAK'F AND CIRCI/LATORY SYSH~M IN (~J~. To determine whether or not nicotine acts via the catecholsmine mechanism only, ors/so through other mutes. Work project intended to offset scme "unfavorable" results by Prof. SC~T/TLER (University of Heidelberg), based on inadequate dosages alleging also a non-catecholmninemechanism. No data available to date. PROF. STOEB~, Institute for Aerobiology, Schnmllenberg/Germany (in collaboration withProf. Mob.r, University orB ann over) DEVELOP MECHANISMS YOR GENERATING AEROSOLS . This is a %echnological' project designed to develop the appropriate techniques to generate "valid" aemsols of pure nicotine and nicotine blended with other substances. This project w~s only started in Feb~_mry of 1980 and no results are available. I ~mopposed to this project for the following reasons: a) Using pure nicotine in lieu of smoke is meaningless because ~oke is a highly complex substrate and any effects of nicotine alone are drastically changed by the presence of other ~oke components. For example, some effects of nicotine are offset by carbon monoxide and vice versa. b) Other reasons have been given under I. and II. above. DR. NI~TH (former]y Director of Research of R~fI~), Head of a chemical consudtin~ laboratory in Har~urg. CARBOLIN~S SUCH AS HARMANE AND NORHAP~IANE IN MAINSTREAM AND S ID~%i S%~E. The resu/ts to date allegedly confirm earlier data by Philip Morris (Poindexter) but show much lower levels of both. These ocmpounds have allegedly been found to be mutagenic or carcinogenic. Prof. Adlkofer wants to publish the data; I am opposed to such publication; Bernd Pelz independently has voted against publication during the last meeting of the TFA and will do so again in the next meeting. Philip Morris is joining us in that determination. DR. SCHIEVEII~V, IN, Gern~n Heart Research Center, }.kmich SCHIEV~F, IN CC~,~ENSATION Sil/DY. (Please see also IX. above, page four.) This project ~s in the late planning stage. It is aimed at determining ~¢nether s~okers who s~tch frem old style, full strength and full flavor

Mr. Samuel B. Witt, III September 26, 1980 SMOKING &ND HEALTH ~ ~ IN GE~N, continued Page six Xl%T. DR. ~CHIEV~I~,IN, continued cigarettes to lo~ 'tar', low niootine cigarettes, "c~mpensate" totally or in part by changing their puffing, inhalation, and other ~nokingpatterns to come close to their former nicotine intake. I am adamantly opposed to this project on genera] principles, and also because with the research protocol made available to date, the results are not likely to provide a meaningful answer, even within the "intent" of Prof. Adlkofer. As regards this project, Prof. Adlkofer is able to largely bypass the opinions of the TFA and its me~bers, because he has been able to obtain, what he interprets to be a 'blanket approval' of that project, several months back,, from a meeting of the Executive Committee (Vorstand) of the Verband, composed of the chief execu- tives of the madder firms (GeorgRosenbauer), or, in s~me cases, their delegates. For this project the TFAhas set up a special sub-comnittee in which BerndPelz is presenting our interests, but in which Philip Morris declined to participate. It is symptomatic that several years back the Verbandwas~adamantly bent on proving that there was no compensation, and they even have published a review of the literaturewhich - if one is charitable - can only be charac- terized as on-sided. They have shifted gears since and their current intent is to "prove" that there is c~,pensation. At the time of writing I have just received, due to Bernd's diligence, by special courier, the follow-up to the protocol. In characteristic fashion, after having procrastinated for menths forms_king the partial protoco] available, I>rof. Adlkofer - on the follow-up - insists on a comnent ~Hthin three days. I have studied the voluminous docuTents over the weekend, and discussed them withBernd by telephone (Sunday). The ful] study and the pre]iminar] study are '~atergated"with reference to purpose and grantor, not only as far as the probands are concerne~ (which is probably necessary), but even as regards at least one of the University professors serving as consultant. The study is represented robe dealingwith fat metabolism and its alleged effect on cardio- vascular parameters. A total of 25 to 27 different anthroprcmetric bio-physical and bio-chemical measurements will be taken. 27 of these ~Hll be determined one time, 25 of these t~ times, and six of these three tim~s, yielding about 95 (laboratory) data per proband. In addition, about 500psychological, lifestyle, and related questions will he asked, about 40 of which deal with s,Dking. The about 30 questions dealing with "eating" are, in my judgment, inadequate for a fat metaboli~n study. This would - in my Judgment - be apparent even to a reasonably perceptive proband. The data collected could possibly have some usefulness for a,current and later prospective, study to ooapare ~kers, ex-smokers, and non-~okers. That would, however, require not limiting, as is the present intent (see above) the study on]y to persons certain to be ~,okers, but also to probands and controls which are currently non-~nokers and ex-s~nokers. However,

Mr. Samuel B. Witt, III Septa~ber 26, 1980 SMOKING AND HZALTH RESEARCH l~ IN GERMANY, continued Page seven XIV. DR. SCHIEVE.I~EIN, continued before I am willing to oonTnit myself to a definitive Judgment on this, I would like to see some of the data of a preliminary study, provided it includes non-smokers and ex-smokers. When defining the purpose of the study, Prof. Adlkofer has e~pressed himself as follows: "It is again noted that the question of compensation can not be directly elucidated with the planned study. The study may, however, give strong suggestions about such mechanisms, ~ahichwill go beyond what is known to date." And further on: "It is clear that the procedure described will not yield a sampling of s~nokerswhich is representative either for Munich or for C~rmany as a whole. It should, however, be possible for the interpretation of the results, to make reference to available statistical data. Mr. Heller (one of the statisticians on the project - FGC) ~dll assess the usability of published data." (Note: in other~rds, Mr. Heller will investigate the applicability of the data ~fter the (preliminary?) study has been started. - FGC) To the best of my recollection, the blanket approval of the Vorstand certainly did not anticipate a study where already in advance the usefulness of the results, even if they should turn out to be statistically "significant", will be extremely questionable. (I have asked Wilfried to send me a copy of the minutes of the Vorstandmeetimgs, and also ~ked Georgwhat his understanding of the intent of the Vorstandwas.) Further~re, the follow-up protocol contains s~ne very questionable or downright erroneous facets (e.g. it is the intent of the study robe limited to probands certain to be current smokers. However, one of ~he questions is "Are you an ex-m~oker?" and another question is "I have never smoked in my life?"), which Bernd Pelz has brought to the atten- tion of Prof. Adlkofer. The study will deal with well over 500parameters. It is one of the most elementary priniples of statistics that the larger the number of parameters tobe m-~ked, the larger mustbe the number of probands in- vestigated. The nt~ber needed for a large nimbler of questions is further increased considerably if the different parameters can be anticipated to sho~. a great variability. Such a very great variability can be expecte~ with the psychological and other social science questions robe asked, as well as with the expected variability of the over 25 biological values to be measured. Even for a preliminary study, especially when a great variability of answers is anticipated, the number of probands should at least be equal to the nt~vber of parameters if same reasonably meaningful. data are wanted. This would mean over 500 probands for the preliminary study, but to the best of my information only about 150 are planned. (Mr. Beller, i.e. one of the t~o statisticians of the study, allegedly

Mr. Samuel B. Witt, III Sept~-,-ber 26, 1980 ~KEING AND HEALTH RESEARCH ~ IN GEB~NY, continued Page eight XIV. DR. SCHIEV~EIN, continued also has some apprehensions regarding the nt~nbers problem. ) Fortunately, the full study will be preceded by a preliminary study. It is my ,strong advice that the Vorstand again be approached whether they really approve a study with such limited anticipated results. Furthermore, I ~Duld like for us to reserve ourselves a veto for supporting or not supporting, financially or otherwise, the full study, which is certain to be costly. This can only be d~ne after somebody with a good statistical background can give us cc~petent advice what the minin~ nt~ber of probands ~K)uld have to be, to obtain meaningful data (even within the limited purpose of the study). This opinion will, to a large extent, have to be based on the varia- bility of the questions resulting from the preliminary study. mC/ks cc: H.C.R. l~]. H.C. W.D. B.F.P. P.l~L S. T.},~.F. Frank G. Colby