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f,~,DRANDLN R.J.Reynol~s'lbba~,c3 Company From: Frank 6. Colby and Oskar Stuhl ~ November 8, 1982 To: Mr. Samuel B. Witt, III Mr. Peter J. van Every RE: TRIP REPORT ON VISIT TO OF IkIRT-~mbH, September 2~ to ~tober 6, 1982 ~e visits to the gr~tees were entirely s~cess~, ~d all our objectives were met. ~ent objectives £or ea~ preset project ~d £o~co~g proposals are tenably on target. In ~e £ollo~g re- re~rt, the visits are disused separately for ea~ ~tee ~ s~e detail. For 1983, it ~y ~ssibly be adv~tageo~ to ~eck ~ on so~ of ~e projects so~t ~re Sr~uently. ~e trip w~, however, ve~ strenuo~, s~ce ~ere were ~et~gs ~d/or travel eve~ ~y, ~cl~g .~turdays ~d S~ys. ~ ~T- ~H ~temal meet~gs on i~83, b~get~g ~d gener~ ~licies, etc., co~d not be held co~letely be~e of co~et~g priorities. ~e atten~ce at the Pors~gsrat Titisee ~et~gs was ~val~ble, not only for the re~o~ ~ted out also pe~tted ~ to contr~t Pors~gsrat resear~ ~d ~T-~H re- search, the latter berg co~aratively £~cially ve~ ~est. In our option, ~st of ~T-~H spo~ored research is not only of higher caliber, but also more val~ble £rom ~ Ind~t~ ~t of view. ~is is so ~ spite of the fact t~t &e ~T-~H ~ded resear~ers are totally ~dependent whi~ the Porsch~gsrat are t~, theoreti~lly, even though ~ practice they seem directed. ~ofessor ~ria Blo~e ~iversit)" of Heidelber~ ~ofessor Bloke is one of Ge~y's for~ost epid~ologists. She h~ ~'o projects ~de~'ay. ~e first project on ~ich ~ta collection is co~leted is entitled "Psychosocial Factors ~d S~k~g as ~sks of L~g It is also recalled that several ~nths ago ~ofessor Blo~e pub- lished a paper endors~g the "controversy" concept of the alleged re- lations~p between smok~g ~d l~g c~cer. ~is paper was ~itten co~letel)" ~dependently from her ~T-~H research contract, at the t~, a ve~ gratify~g but total sunrise to ration w~ first given at ~ ~rt~t over

-2- then appeared in a widely read ~erman medical journal. Coming back to project number one, Professor Blohmke and her asso- ciates have evaluated part of the data and prepared a manuscript for publication in a scientific journal. These data deal with the responses to a detailed psychological questionnaire and compare smokers with ltmg cancer with two control groups: a) healthy smokers, b) smokers with non-malignant lung diseases. This manuscript was discussed in some detail. It must be ~mphasized that, as a matter of principle for all projects, we VERY scrupulously avoid discussing the substance - as opposed to format - of the data and experiments, since this is entirely the responsibility of the researchers. Professor Blohmke submitted to us some months ago an earlier version of her manuscript, which left very much to be desired because of the poor quality of ~erman to Fmglish translation, and the lack of clarity of the manuscript in general. The ' revised version only very partially incorporated the redactional changes which we had suggested in writing and by phone earlier, in response to the first draft. This time, in our face-to-face meeting, Professor Blohmke and her associate Y[r. Stelzer (statistician), were more open- minded than on the previous occasions. These suggested changes in the text and tables - if implemented - would substantially improve the clarity of the manuscript. The data confim the importance of psycho- social parameters as lung cancer risk factors. An essential finding of the study is that the smoking factor does not substantially improve the discriminant function of the analysis based on these psychosocial fac- tors alone. But smoking is still found to be a key risk factor. Several, but not all, of the initially postulated psychosocial~ hypotheses were confirmed. It was also ascertained that hospital stay, per se, did not affect the results. However, the validity of the data is not as "sig- nificant" as might be desired. This, according to Professor BY~amke and her associates, is minly because of the '~alidity~' of the questionnaire used, and did not live up to the claims by its author (Bahnson). Also, " out of necessity, the quantitation of the smoking data leaves something to be desired. A further data analysis is in preparation and it involves non- smokers, again comparing healthy non-smokers to non-smokers with ltmg cancer and non-smokers with non-malignant lung diseases. Professor Blohmke and associates will also try to determine whether or not a meaningful analysis of smokers versus non-smokers is feasible. An entirely unexpected, but very preliminary ancillary of the first project finding was that there may be an association between some of the psychosocial questionnaire responses and the occurrence of some lung cancer cell types, but tmforttmately not with squamous carcinoma. This data was tmcovered by Professor Blohmke's (then) pathology associate, Professor Jacob of Heidelberg, and is discussed in our report on our meeting with Professor Jacob. Professor Blohmke and her associates also have already started work on project number two, which is entitled "Psychosocial Factors in Smo- king as Kisks of Lung Cancer in ~ales, Using the ~.ysenck Questionnaire and other Questions". Project number two is similar to project number

-3- one, except that the ranch more frequently '~lidl)~' tested ~ysenck questionnaire ~rill be used instead of Bahnson~s, ~Lich, as stated above, has been found to be somewhat vranting. The project will even- tually involve about 1,000 probands plus the same number of controls. Data collection is about half completed and is expected to be total- ly completed by about the end of April 1985. There are a number of difficulties, such as lack of cooperation by some of the participating clinics to furnish probands and complete medical data. The latter refers especially to pathological diagnoses of the different lung cancers. Another problem is that many of the probands referred by the clinics do not fulfill the previously specified criteria and are, therefore, useless. There are also problems finding sufficient numbers of non-smokers with lung cancer. Initial data analysis is expected by the end of 1983. Professor Blohmke has promised to furnish a brief interim report, especially on project number t~o, by the beginning of December. Professor Wolfgang Jacob University of Heidelberg Professor Jacob is one of Europe's foremost pathologists, ~ho often represents West Germany on international beards. He was in charge of patholo~ of the first Blohmke project ( see pages one and t~o of th~s report). He made two unrelated ne~ research project suggestions to us. Project idea number one: Relationship between psychological profile and lung cancer cell type. Some preliminary data fro~ the above mentioned first Blohmke project on male lung cancer suggest a 'tsignificant't association between psychological questionnaire response and adenocarcinoma and small cell - carcinoma, but not squamous cell and less important lung cancer types. Professor Jacob explained this lack of association with squamous cell carcinoma by ~hat is, according to him, a, relatively recent, consensus among pathologists that squamous cell carcinoma, especially if compared to adenocarcinoma, is not a well defined entity, but a conglomerate of sub-types. Also, due to some lack of cooperation from some of the clinics and problems related to the relatively recent German data release legislation (see also the section of our discussion with Dr. Lock), the number of unequivocally cytologically diagnosed lung cancer cases is only 332, i.e., only little more than one-third of the total 888 probands. Professor Jacob is suggesting to cooperate with a major, diagnostically and cytologically well qualified, German lung cancer clinic in order to expand the number of available cases by submitting to them again the psychological questionnaire of the first Blohmke project, and then to blindly analyze the cytology. This is to verify whether or not the "significant" relationship to the above two lung cancer types and the questionnaire response persists, and also whether or not a relationship to squamous carcinoma or some types of squamous cell carci- noma can be uncovered. Project idea number two: Stud)" of linguistic tape profile as affected by lung cancer, stomach cancer and attempted suicide.

-4- Based on positive findings with other diseases by a clinic of the University of Berlin (Ms. Fmgel-Wodack), computer analyzed linguistic tape profiles will be examined for "significant" differences for the cancers, etc., mentioned. It is hoped that analyses will lead to a blind predictability from the tapes of the medical diagnoses ascer- taining thereby a potential constitutional factor of these diseases. This rather unorthodox project idea was su~ested by empirical clinic observations that prior to diagnosis, people with different types of later unequivocally ascertained malignancies seemed to have very dis- tinct styles of speech. Professor Jacob has promised to submit to .us for appraisal, written proposals on these t~ project ideas before the end of the year. Dr. l~ilhelm Lock- head o._~ .thee German Tuberculosis Organization, Hamburg. l~e met Dr. Lock in Mainz ~here he attended a medical meeting. It is recalled that Dr. Lock, several months ago, published the results of his first P~TRT-(~ubH research grant in the second most important German medical journal, which was followed by some favorable German media re- action. The results showed that, using the unique data bases of the Hamburg cancer registry, there has been no change in percentage of total cancer m~rtality, including lung cancer, from the late 19th cen- tury to date (i.e., since much prior to the widespread acceptance of cigarette smoking), provided some very reasonable corrections are made for the change in the age structure of the population and the improve- ment in cancer diagnoses. In other terms, this shows that - contrary to medical Establishment opinion - cancers are not predominantly determined by the environment (e.g., diet, smoking, pol~-u-~ion, etc.). According to Dr. Lock, these very important findings have not been challenged to date. FGC's original plan was to continue this project by trying to relate the causes of death of the immediate blood relatives and an- cestors to deaths of lung cancer victims, using again the unique re- sources available in Hamburg. The intended purpose of the project was, of course, to ascertain the genetic factor in lung cancer. After in- tensive efforts, Dr. Lock has regretfully come to the conclusion that this project, cannot be executed as planned because of the current ve~/ stringent German legislation, making the access to such data impossible. Dr. Lock proposed, however, the following two simultaneous related projects: Project proposal number one is aimed at an alternative method of assessing the "genetic factor" in lung cancer. Project number two is aimed at retesting the overall constancy of cancer incidence, irregard- less of environmental influences. Project idea number one: In 1953, Dr. Lock initiated a special lung cancer file within the Hamburg social security office. This com- prises to date about 6,000 case histories of actual and suspected lung cancer cases. Each case history includes detailed anamnesis data inclu- ding information on alleged causes of death for relatives. Each file also has inforn~tion on earlier diseases. Each case is carried - gene- rally during life - (only) to the point of "definitive" clinical diagno- sis, i.e , as to ~hether or not there was lung cancer. Assessing this unique data base should permit to determine the extent of genetic and]or familiar factors in lung cancer.

-5- Project idea number two: Prepare an age-adjusted county by county "total cancer ~ortality" mp of ~Vest Gertany to determine deviations, if an)', of each of the county rates from the co.arable overall German rate. The underlying hypothesis is that the overall cancer death rates for each county will not differ "significantly" from the overall German cancer mortality rate; if the hypothesis is confirmed or not, this can perhaps yield data about whether or to what extent the environmental influences affect cancer rates. Because Dr. Lock is engaged in the organization of a major medical meeting in his immediate area of expertise, these two projects could only be initiated during the last quarter of 1985. Hoover, Dr. Lock has promised to transmit to us the two project proposals before the beginning of this December. A ~ry tentative cost estimate for these projects is about 100 to 120 th~and I~t per year ($40 - 48,000).. Professor Dr. K. H. Staecker University of ]~ssen The thrust of this - two phased - research project is to determine the relationship - if any - between respiratory ~unction and psychosocial profile. Freed from "jargon" an essential, but ~ preliminary finding of the project, is that the ]~stablishment allegation that smoking by it- self determines, or is one of the most important factors determining respiratory ~unctions, was not confirmed. It also seems possible that respiratory and psychosocial--~'actors max determine smoking and not the reverse. Another finding was a very decided difference in smoking moti- vation - including the ETsenck extroversion hypothesis - between men and women. An earlier and a very recent progress reports are on hand. There are, however, a number of problems. The investigators made a major error in not contracting their probands and obligating them to have to carry both the parts of the project through from the beginning to the end. The first part of the stud), dealt with the administration. of the detailed special psychosocial questionnaire, the second part with the respiratory function tests. Out ofan original 125 probands, about two-thirds dropped out and only 59 remained after the completion of the questionnaire, to undergo the second part of the study, the respiratory ~unction test. To date an additional 14 probands were called later to go through both stages of the project, yielding a total of 53. It is planned to recruit additional probands to bring the total to 100 (one-half male and one-half female). A well planned facet is that all the respiratory ~mctions were done a) as the average of seve- ral measurements and b) were done in double blind fashion for the same parameters. An earlier finding (questionnaire only) was that the ~.ysenck extra-version concept was found to be only valid for female smokers. Allfindings are very preliminary because they are based on complex statistical manipulation of a large number and, with the avail- able number of probands - in our opinions - excessive number of vari- ables. Also, the determination of the quantitation of smoking remains a problem. Professor Dr. Diether Neubert University Berlin Our current research project by Professor Neubert deals with the

-6- effect of chemical carcinogens on pregnant animals and their fetuses, with potential extension to the effects - if any - of smoking on preg- nant women and/or their voluntarily aborted placentas and fetuses. Short-range and non-con~ital long-range planning for this endeavor involves the following three stages: a) Effects of single or t~o established carcinogens on pregnant rodents and their fetuses; b) Effects of single or t~o established chemical carcinogens on pregnant 'higher" animals, i.e., marmoset monkeys and their fetuses; c) Effects -if any- of smoking on pregnant wo~en and]or their voluntarily aborted placentae using a unique "data base" available only in Berlin. Funding for phase 'ta" has been committed. It involves two species: mice and rats. The experiments with mice have been completed. A paper for publication is in the final drafting stage. The experiments with rats are undencay and should be completed, including drafting of a paper about November of 1985. There has been some delay in completing this work because Professor Neubert had unexpectedly received a sabbatical appointment for about six months at the University of California in Davis. However, "routine" experiments are continuing under the -on the spot- supervision of one of Dr. Neubortts assistants. FGC had tried to meet with Professor Neube-rt prior .~to the Seattle Cancer Congress; however, no mtually convenient date could be fotmd. However, by coincidence, Professor Neubert had been invited to par- ticipate in a meeting of the World Health Organization in Geneva, S~itzerland, ~hile we were visiting our other German grantees. We arranged to have a get-together in Geneva. This had the additional advantage of being able to include Dr. Stuhl in our discussions. In our meeting with Professor Neubert, he made the following conmitments to furnish us the following before the end of November: 1. A draft of the paper on the mice experiments. 2. A short outline status report on the rat experiments. 5. A project proposal with costs ~ etc., on the marmoset experiments. 4. A proposal on a feasibility phase prior to a unique major long range study of what has been identified above as stage Professor H~..~'_. t~ediger - l~niversity of Hamburg The project deals with Dht~ related Benzo(a)pyrene Hetabolism in specific cells of constitutionally susceptible lung cancer patients. This is a continuation of a previous study funded by us with Dr. Rnediger and which had shown that lung cancer patients had an increased benzo(a)pyrene ~A adduct formation compared to healthy controls, and that this ~'as "independent of smoking habits". There was also a sug- sestion of a possible "enhanced risk on a constitutional basis to develop cancer". There ~'as, however, some doubt about the biological

significance of the results because of a large overlap between the groups compared and a large inter-individual variability in each group. Therefore, the present study was started to reassess the findings by selectively studying those lung cancer patients who might be considered to have, potentially, a particularly enhanced genetic risk to develop lung cancer and in particular the following four groups: Lung cancer patients aged less than 45 years. b) Wc~en ~ith lung cancer. Lung cancer patients ~ho had at least one first degree relative ~ith the same disease. d) Nonos~okers ~rith lung cancer. The original plan ~ras to use a specific cell type called ~onocytes (like the first Rj~roG~bH project); however~ since the quantitative differences are subtle~ a larger m~ount of ~onocytes would have to be collected fr~n each patient. Often the mnounts required were larger than could reasonably be obtained from a patient. Professor ~nediger~ therefore~ decided to also -in addition- use a different cell type~ i.e.~ fibroblasts. According to Professor ~ediger~ the use of fibro- blasts has also the advantage that they ¢~n later be used for a poteno tially highly significant future project dealing ~ith the identification of t'oncogenes" for lung cancer~ none of ~ich are ~no~n to date. Finding probands for some of the groups presents so~e difficulties. There are no difficulties in finding probands for groups A and B men- tioned above. However~ there have been some difficulties in finding probands for group C~ i.e. ~ lung cancer patiens ~ith blood relatives having the s~e disease. According to Professor ~nediger~ this is not because no probands clearly exist~ but because of the gross inadequacy of the patientst hospital histories in that respect. There are even greater difficulties in finding nonosmeking lung cancer patients if non- s~oking is defined as '~ever smoking". According to Professor ~uediger~ this is probably because for the German generation under study ~ever smokers" are rare~ regardless of their health status. It is~ therefore~ planned to include in this group e~smokers of more than six years~ but later to analyze these ex°sf~okers and the ~ever s~okers~1 separately. An unexpectedly large amount of ti~e had to be devoted to the - no~' successfully completed -development of a sufficiently reliable anal)rti- cal method. ~o~ever~ it is hoped that the collection of the above data ~ill be completed in about three or four menths and that the data can be analyzed and a draft of a paper for publication can be completed to° gerber ~ith a third project proposal by the autumn of 198~. Professor ~ediger has expressed high hopes that the mothodologF developed ~ill provide additional information about genetic predispo- sition and ¢ell specificity ~ith reference to lung cancer potential~ and even more i~portantly~ provide a unique research tool for further studies on the biochemical basis of carcinogenesis~ e.g.~ the role of host factors such as the presence of oncogenes~ etc. .

-8- Dr. Gerhard Winueke - Institute of ~nvironmental ~giene of the U~-[versitF of Duesseldorf. The thrust of the study is to determine whether or not non-smokers ~ho claim and are objectively assessed to be "irritated" or "annoyed" by other people's smoking, are chronic complainers and overreact to all types of irritation. FGC met (~rith) Dr. lqinneke for the first time several'years ago at a scientific meeting where he gave a paper on an objective methodology developed by him to measure annoyauce, in general, without any reference to smoking. At that time, I:GC suggested to him a project with the focus indicated above. Since then, Dr. l~inneke has developed his methodology further. On the other hand, he has been quite dilatory in getting started on the project because his Institute has projects funded by the German Government and/or by the German ~nhr industry which took precedence. The gist of the methodology for the objective measurement of irritation is through the determination of finger pulse volt~e and pupil dilation. The methodology b~s been finally worked out, completely independently of our funding. Some earlier preliminary investigation of irritation by the smoking of others, done at no cost to us, confirmed our hypothesis. Dr. ~qinneke has no~ started on the project. To our astonishment, he was completely unaware that the chief of his Institute had already requested and received a substantial portion of our grant money. Upon our insistence, during our conversation, ~he undertook an official obligation to complete the raw data collection by about l~arch 31 and at least a draft report, including.data analysis by about June 30 of 1983. The effect of smoking on non-smokers will be determined in about SO male and 50 female students in an experimental chamber simalat- ing as much as possible "real life" conditions. It was agreed that excessive smoking conditions will be avoided; this will be done through constant CO measurement and limiting (20 to 410 ppm. During our meeting, we were informed that ~GC's general hypothesis was also confirmed, in a tangential way, in an unpublished incomplete study at the same Institute by a Dr. J. ~astka. This reasearcher found that '~eurotics" are more sensitive than 'h~ormals" to odor level differences (not smoking) and noise levels. Dr. ~inneke informed us also about another Institute project which, contrary to current beliefs, found that odor levels are not the sole determining factor of a psychological reaction but that odor quality also plays a role. Professor Dietrich Henschler - University of l~uerzburg Professor Henschler is one of Germany's and the world's foremost toxicologists. His Ik~gr-OmbH funded research is of a very fundamental nature. It deals ~-ith the chemical carcinogenesis in rats of some specific very strong animal carcinogens belonging to a group of chemical compounds called aromatic amines.- (These specific compounds do neither occur in tobacco nor in smoke.) The wider aim of the research is to determine ~ether or not there is a threshold for carcinogens, in general and strong carcinogens in particular, and to elucidate the mechanisms involved.

-9- We did not visit with Professor Henschler in Germany because, just prior to FGC's departure for ~.urope, Professor Henschler presented a lecture on his grant research to the R6D Department in Winston-Salem. It is anticipated that Professor Henschler .wi.'ll send the "obligatory" short progress report on his grant project to C~lo~ne and to Winston- Salem by early December of this year. ~'~'~/f November 8, 1982 Frank G. Colby cc: G.R.DiM. '~:~/~'" ~ /'~. C.W.N. ~ Oskar Stuhl W.D. B.F.P.