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f r BIO-RESEARCH CONSULTANTS, INC. - C©NSV.IaAiiON R'.E5EARCH~ DEVEIOiME~NT F..HOMBUROER„M, D., Dl•.clor P. 6ERNFELO, Ph. D., D:r.ctor of'R.w.rch. Dr. William U. Gardner Scientific Director The Council for Tobacco Research 110 East 59th Street New York, New York 10022 Dear Bill: 9 COMMERCuu AVENVE CAMBRIDOE, MASSACMUSETTS 021/I- (617) e64-e736 I am writing to comment on the Council for Tobacco Research recent decision not to continue support for our studies on cigarette smoke inhalation in inbred Syrian hamsters and to make a plea for continuation of these studies. I am aware of the fact that the Counci'1' is supporting inhalation studies elsewhere but n one of these employ inbred Syrian hams te rs. I am fully aware of the arguments of those who still advocate the use of mice and even rats for such experiments and' I am not going to take issue with the questions of species suitability and/or relative advantages. I should like to point out to you and other members of your various committ'ees who are relatively new in this field of research that since 1964 the CTR has spent at our institution at least $765, 000. on the development of the Walton reverse smoker and' on feasibility studies on the use of that machine with mice and with inbred Syrian hamsters. I have retraced the history of our research in an appended chronology of events. It would seem to me that for no other reason than the considerable amount of money expended, a most careful review of a deci'sion to discontinue this work is in order. The scientific reasons that were cited to us as having led to the decision to discontinue were primarily two: a. Concern that our hamsters were infested with Sendai virus, b. Concern that no lung cancer wa's induced and that th'ee malignant nature of the laryngeal lesions found' in smoking animals was questionable. 4 t

Dr. WilliamC, Gardner -2- C There was previously criticism of our machine which led'to the construction of a horizontal modification by CTR'without consul- tation with us and which sacrifices some of the most important design features of the Walton machine. We understand that' the original Walton machine is not included in..the_current_machine eval'uation at Oak Ridge. No report was ever made on the testing of'the-unmodified model. In view of our past association with CTR,f'or many years (since 1954 I/ believe), I consider it my duty to point out to you that no scientific basis exists for the two concerns cited above and that, in rny opinion, the decision not' to evaluate the original, Walton machine to compare its performance with that of t'he CTR modi- fication was irresponsible or uninformed or both and the latest decision to discoaitinue our inhalation studies is most ill-advised. a. The Sendai story, Ever since positive results were reported by the New Jersey Coll'ege of Medicine virus laborat'ory in our hamster sera for Sendai virus this has contrasted with the continual and consistent absence of pulmonary disease in our hamsters and with their failure to infect mice upon being, placed together with them. Now ITT Research Institute working for NIl-i has determined! that high anti Sendai antibody titers were falsely positive results and that our colony is negative for Sendai virus antibody even though positive results continue to be reported by the original laboratory on the very same samples. Thus it becomes clear that there never existed nor does exist at this time any Sendai infection among our hamsters. b. Concern that' no lung cancer is prodhced and that' laryngeal "cancer" may not be malignant. We have shown that inhalation studies in Syrian hamsters, at least in the inbred strains so far studied, are not a method to induce cancer of the lung by cigarette smoke in animals. We did not expect to cause a lung cancer that is not even found! in these animals when nitrosamine is given by various routes where it most certainly reaches the lung. While massiveiintratracheal injections of' carcinogens cause bronchial and pulmonary cancers, this merely means that under ex- treme conditions hamsters may develop such tumors. We believe that cigarette smoke is: a co-carcinogen not a carcinogen, andAits co- carcinogenic_activity is_weak.~-We would not expect it to cause lung cancer under any conditions, except in carcinogen-primed animals. Hence failure to cause lung cancer in the straighb smoke inhalation t

Dr. WillhamC Gardner experiment is a valid argument for continuing such studies now in carci'nogen-primed animals, not to tern:inate them. Furthermore, the laryngeal observations mace by us in high percentages of larynxes of smoking animals, nearly alli of which had so,ne anomalies and' l0Tc of which had microinvasive carcinorna, are ioentical! with those des- cribed in human smokers. In 1955 Ry,an, R. F., Iv;cIDonald, J. R, an.iiLevine, R.. U. in an article entitled "The Piithol'ogic E.ffecte of Smoking on the Larynx", (AMA Arch. Path. 60':471-480, 1955)', described in hun an biopsy material! all of the changes which we have observea in sn,oking hamsters. There was a"disproportionate degree of epitheliat thickening due to hyper- plasia and! keratinization and these changes frequently progressed to keratosis and leukoplakia (hyperkeratosis vith ~:yakerat'osis) both of whicit may eventuate in actual malignant ad'ierauiun, particularly if exposure to i rritation is continued. " In "Cancer of the Larynx", a monograph for the physi'cian, American Cancer Society, 1963, figures 1, 2 anu 4 shoN histiopathology of human laryngeal lesions which is indistingui'shable from that observe&by us in smoking hamsters. 14 hile in humans there is a statistical relation- ship between smoking and cancer of the larynx, son ewhat less close thatiifor smoking and cancer of the broi:. r.is, thi's relationship in the animal experiment (our own and that of f;onten.+il'1) ie clear since the controls are negative. Other factors that have been implicated, such as alcohol consumption (N ynder, F, L., Hross, 1. J. and Day, E.. : A study, of environmental factors in cancer of the larynx. Cancer 9: 8'6-110, 1956)' could now be studied in the hamster model. Clearly, there is a need'for experimental stuuy of can,:er of the larynx. 1!ts incidence is 3 to 4 per 100, U0U' huanan population. There has beerL an increase of the incidence by 75°,'., during a recent ten-year period. Seven percent of all cancer deaths are due to respiratory cancer and 12. 5Pb of these are due to cancer of the laryi~x. lv:ost of these cases occur late in life. The tragic crippling effects of so-called successful .therapy are too well known to uwe14 on then; here. '.% e believe we have developed the first .vorkinr ani'nial model of carcinoma of the larynx. To accept this, i't is not necessary, to agree with us that our obeervations include microinvasi,e ancer. lt is only necessary to accept the induction of leukoplakia by smoking on the morohology of w.hichwe have all agreed'and w.hich, our sa,oki:ni{hamsters show.vithhi'gh frequency. Leukoplakia has been ~,eecriGed as "the most important precursor of carcinoma which oespite re.peated anu adequate removal and the elimination of chronic irritativn :+.ay ultimately snow the cytologic 4 1 1

Dr. WilliarCi. Gardner -4- C criteria of malignancy in the deeper'cei'1 layers (carcinoma in situ) followed by actual invasive carcinoma. Of benign tumors the papilloma appears to be of importance as a•precancerous lesion. "'Dhese pre- cancerous 1'esions we have induced in inbred Syrian hamsters with frequencies that allow statistical evaluation of modifiers of carcino- ' genesis. We plead with you to allow us to exploit this model'for•a study in depth of' a disease (cancer of the larynx) that cigarette smoke is alleged to cause. We should prefer to see thr CTR support these studies. If, however, they will persist i'n their refusal to do so,, we must seek other support'since continuation of this work is clearly in the public interest. Yours sincerely,. , . ~~c~,~CC f~7 Fre.ddy Hombuy'ger, M, D. President an¢/Director I