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BIO-RESEARCH CONSULTANTS, INC. __.CONSULTATIONRESEARCIi DEVELOPMENS • F. NOMRU.RGER„M, D., Dir.cvor P. RERNFELD, Ph. D.,D;r+UOn ol R4M.rdi Dr. William U. Gardner Scientific Director The Council for Tobacco Research 110 East 59th Street New York, New York 10022 9 COMMERCIAL AVENUE CAMlRIOGE,.MASSACHUSETTS 071,/ (6171 664-473S Dear Bill: 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 Council is supporting inhalation studies elsewhere but n one of these employ inbred Syrian hamsters. 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 yop and other members of your various committees who are relatively new in this field of' research that since 1964 the CTR has spent at our instituti'on 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 decision 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 was i'nduced' and that the malignant nature of the laryngeal liesions found in smoking animals was questionable.

C Dr. William U. Gardner -2- 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 ~1!alton machine is not includ -~d in ±hP ~urr r„a chine evaluation at Oak Ridge. No report was ever made on the testing o e ~~d In view of our past association with CTR for many years (since 1954 1 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 my opinion, the decision not to evaluate the original Walton machine to compare its performance with that' of the CTR rnodi- fication was irresponsible or uninformed or both and'.the latest' decision to discontinue our inhalation studies is most ill-advised. a. 'The Sendai story Ever since positive results were reported by the New Jersey College of Medicine virus laboratory in'our hamster sera for Sendai virus tnis 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 them6 Now ITT Research Institute working for NIH 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 infeation'among our hamsters. b. Concern that no lung' cancer is producedi and that laryngeal "cancer" may not be malignant. 4; .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 massiveiintratraeheal 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 carcinoQen, and its co- ca-rcinogenic activity is vq,eA. 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 st'raight smoke inhalation A= `=

I /gO4LtSEAI[M OON9ULTAlYT9, j~ + Dr. William U. Gardner -3- experiment is a valid argument for continuing such studi'es no.v i'n carci'nogen-primed animals, not to terminate them.. Furthermore, the laryngeal observations made by us in high percentages of larynxess of smoking animals, nearly all of which had! some anomalies and Z05c, of which had microinvasive carcinoma, are iaentical with those des- cribed' in human smokers. In 1935 Ryan, R. F., hscDonald, J. R, and Devine, K. U. in an article entitled "The Pathologic Effects of Smoking on the Larynx", (AMA Arch. Path. 60:472-480, 1955), described in human biopsy material all of the changes which we have obeervea in sn,oking hamsters. There was a"disproportionate degree of epttheliai thickening due to hyper- plasia and! keratinization and'these changes frequently progressed to keratosis and leukoplakia (hyperkeratosie Nith .:yskeratosis) both of which may eventuate in actual malignant alteration, particularly if exposure to irritation is continued. " In "Cancer of the Larynx", a monograph for the physician, American Cancer Society, 1963, figures 1, 2 anu 4 sho.v histopathology of human laryngeal lesions which is indistinguishable from that' observed by us in smoking hamsters. Khile in humans tnere is a statis!ical relation- ship between smoking and cancer of the larynx, somewhat less close thattsfor smoking and cancer of the bron--nus, tnis relatiouship in the animal experiment (our own and that of : ontenk i'll) is clear since the controls are negative. Other factors that have been implicated, such as alcohol consumption (N'ynder, E. L., Bross, I. J. and' Day„ E. : A study of environmental'factors in cancer of the larynx. Cancer 9: 86-110, 1956)', could now be studied in the hamster model. Clearly there is a need for experimental stuuy of cancer of the larynx. Its incidence is 3 to 4 per 100„0001 human population.. There has been 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. 5% of these are due to cancer of the larynx. Most of these cases occur late in life. The tragic crippling effects of so-called successful .therapy are too well known to dwell on them here. N'e believe we have developed the first Norkini, animal model of carcinoma of the larynx. To accept this. it is not necessary to agree with us that our observations include microinvasive ,:ancer. lt is only necessary to accept the induction of leukoplakia by smoking on the morphology of which we have ali agree&and which our smoking hamsters show with high frequency. Leukoplakia has been cescribed as "the most important precursor of carci'noma which uespite repeated anu adequate removal ano the elimination of chronic irritation n.ay ultimately show the cytologic 1 i

~ Dr. William U. Gardner -4- C criteria of malignancy in the deeper celi layers (carcinoma in situ) followed! by actual invasive carcinoma. Of benign tumors the papilloma appears to be of importance as a•precancerous lesion, " These pre- cancerous lesions 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 shoul& prefer to see the CTR, support these studies. If, however, they will persist in their refusal to d'o so, we must seek other support since continuation of this work is clearly in the public interest. Yours sincerely, . Freddy Hombuyter, M. D. President anY'Director 1