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~• ~~~~~ EXHIBIT NO.Z~.~ e A BIO-RESEARCH CONSULTANTS, iz~;c. .CDNSUlu.T1oN EESE.ecn DEVttDrMENr P. N0MEUEOEl. r. D, Dlr.cr.r /, slENfaO, ~~. D~ Dlnc~pr ef 111~~e1 • COKMEECUI aVENYI GwEEIDOe, Ma33ACNUfEn3 O:lal - (e17) .fs-.7is Dr. William U. Gardner Scientific Director The Council for Tobacco Research 110 East 59th Street New York, New York 100t2 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 a.aaz~e of the fact that the Council is supporting inhalation studies elsewhere but n one of these employ inbred Syrian hatas te rs . I am fully aware of the arguments of those who sdll advocate the use of mice khd even rats for such experiments a=d 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 met=bers of your various committees who are relatively new in this fie?d 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 e:cpended, a most caretul re%zew of a decision to disccntinue 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 i:Sested with Sendai virus. b. Concern that no lung cancer was ir.duced and that the snalignant nature of the laryngeal lesions found in srsoking animals was questionable. CTR CONTRRCTS 005639 11225380 . ..: CTR MN 0422803

a Dr. William U. Gardner ' -2- There was previously criticism of our machine which led to the construction of a horizontal naodification by CTR without consul- tation with us a.nd which sacrif ces 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 evaluation at 0ak Ridge. No report was ever made on the testing of the unmodified model. In view of our past association with CTR for many years (since 1954 1 belie. e), 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 evaluats the original Walton machine to compare its performance with that of the CTR tnodi- fication was irresponsible or uninlormed 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 virns this has contrasted with the continual and consistent absence of. pulmonary disease in our hamsters and.vith their failure to infect mice upon being placed togethervdth them. Now ITT Research Institute woridng for NIH has determined that high anti Sendai antibody tite:s were talsely positive results s.nd 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 3me any Sendai in'ection among our hamsters. b. C.^ncern that no lung csncer is produced and that lary,geal "ca.nce r" 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 lu=11 cancer that is not even found in these animals when aitrosamine is given by various routes w•here It most certainly reaches the lung. Wh:le massive.intratracheal injectians of carcinogens cause bronchial and pulmonary cancers, this merely means that under es- treme condirtons hamsters may develop such tumors. We believe that cigarette smoke is a co-carsinogen, not a car.:inogen, and its co- carcinogenic activity is weak. We would not expect it to cause lung cancer under any conditions, except in car,anogsn-primed animals. Hence failure to cause lung cancer in the straight smoke Inhalation CTR coNTRRCTS 'aoss4o 11225381 CTR HN 0402"804

Dr. William U. Gardner -3- I ezperiment is a valid argument for continuing such studies now in carcinogen-primed anirnals, not to terminate them. Farthermore, the laryngeal observations made by us in high percentages of larynxes of smoking animals, nearly all of which bad some anomalies and 20% of which had microinvasive carcinoana, are identical.vith those des- cribed in human smokers. In 1955 Ryan, R. F. , MeDonald, 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 observed in smoking hamsters. There was a"disproportionate degree of epithelial thickening due to hyper- plasia and keratinization and these changes frequently progressed to keratosis and leukoplakia (hyperkeratosis with dyskeratosis) both of which may eventuate in actual malignant alteration, particularly if exposure to Irritation is continued." In "Cancer of the Laiynx", a monograph for the physician, Asnerican Cancer Society, 1963, figures 1, 2 and 4 show histopathologT of human laryngeal lesions which is indistinguishable from that observed by us in hmoking hanisters. While In humans there is a statistical relation- ship between s*noktng and cancer of the larynx, somewhat less close than for smoking and cancer of the bronchus, this relationship in the animal experiment (our own and that of Dontenwill) is clear since the controls are negative. Other factors that have been implicated, such as alcohol consumption (Wynder, E. L., Bross, I. J. and Day, E. : A study of environtnental 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 study of cancer of the larynx. Its incidence is 3 to 4 per 100, 000 huma*+ population. There has beea an increase of the Incidence by 73°fi during a recent ten-year period. Seven percent o: all cancer deaths are due to respiratory cancer and 12. 5!'e of these are due to cancer of the larynx. Nfost 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. • We believe we have developed the first working animal model of carcinoma of the larynx. To accept this, it is not necessary to agree with us that our observations include tnicroinvasive cancer. It is only necessary to accept the induction of leukoplakia by smoking on the morphology of which we have all agreed and which our smoking hamsters show with high frequency. Leukoplakia has been described as "the most important precursor of carcinoma which despite repeated and adequate removal and the elimination of chronic irritation may ultimately shaw the cytologic CTR coNTRRCTS 005641 11225382 CTR HN 042280~~

Dr. Williasn V. Gardner -4- 0 eriteria of malignancy in the deeper ceL1 layers (carcinoma in situ followed by actual invasive carcinoma. Of benign tumors the papilloma appears to be of importance as a precaacerous lesion," These pre- cancerous lesions we have induced in inbred Syrian hamsterf 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.lar)-az) that cigarette smoke is alleged to cause. We should prefer to see the CTR support these studies. If, however, they will persist in their refusal to do so, we azust seek other support since continnatioa of this work is clearly in the public interest. Yours1sjncerely, Freddy Homburker, M. D. President an Director CTR CQNTRACTS 005642 11225383 CTR MN 042806

r Chronology of Events On December 4, 1964, The Council for Tobacco Research initiated an experiment on the effects of chronic exposure to tobacco smoke of populations of miee of various stra•ins, to explore the effeet of tobacco smoke when applied directly to the skin of miee as well as to various other organs of other species sucb as rabbits, sats or hssnstsrs. It also was to support design and construction of a smoking machine. This was financed by a grant of $350, 000 in Sve equal annual installments of $70, 000 each to Bio-Research Institate, Inc. A first smoking machine was desLgned and constructed by Richard Walton and begaa to be tested by us on Deceasber 2, 1965. Exploratory studies with various modifications of the Walton machine continued to January 1967 when the first group of 100 CSTBL/6 mice were subjected to chronic inhalation studies. These .vere replaced by 200 Millerton Swiss mice in May 1967 because of high mortali:y among the black mice. A great deal of work was done on acute toxicity of moke of various cigarettes in mice and a paper was published on this at a aeeting of the Society of Toxicology in 1967. On November 1, 1967, a patent a: pl_cation for the smoking machine was filed by Richard Walton. On October 1, 1968, we suggested that "the time had come to decide whethei or not the Walton reverse smoker should be universally accepted." tVe sta:ed that, based on our experience, We. were ready to begin a new chronic exposure experiment. This was based on a review of data on 34 survivizj =ice exposed five times per week for 55 weeks. Slides of these micewere reviewed by Loosli who called them poor and by Thelma Dunn and Fiarold Stewart who commented that "the dilatation of the alveolar spaces appears to be excellent, so we judge that your technique for expanding the lungs by the intratracheal instillaaon ot fixing fluid is satisfactory." From 1968 to 1969 the first large-scsle experiment for skin painting with native smoking machine jet conde_sa:e was carried out and the lesser activity of fresh smoke was first zoted by Bernfeld September S, 1969. On November 7, 1969 the use of irbr.d Syrian hamsters was first sug- gested by us as part of a study of the effects of rodent viruses on tobacco smoke effects then proposed by Dr. Sim of Yale who wished to join us for this .rork. CTR declined to support this project. -1- CTR CONTRRCT5 046643 11225384 CTR HN 04280 . 7

r On February 26, 1970, two smoking machines were given Mason Research Institute for evaluation. On July 31, 1970, a renewal agreement was signed to cover the period from June 1, 1972 to May 31, 1973 for studies to determine the useful- ness of the golden Syrian hamster as model animal for inhalation studies. All the objectives of this study (except for gas phase Inhalation) have since been met. On September 10, 1970, difSerences in nicotine toxicity (by intraperitoneal route) between hamster lines were reported. Also hamsters were found far less susceptible to nicotine than either mice or rats (a11 by the i. p. route). In Auyust 1970 (letter of Dr. Hockatt, August 11, 1970) concern was expressed by the Advisory Board regarding the positive findings in our hamster sera for Sendai virus antibodies. Dr. Frank Rauseher wrote September 10, 1970, commenting on these antibodies: "For long term carcinogenesis studies it is reasonable to assume that the.e two viruses (Sendai and 4vt adenovirus) should not cause problems unless new evidence is uncovered_to the contrary. " (On October 12, 1973, we obtained a report on a study initiated by Sam Poiley of NIH with III Research Inst.tute concluding that no antibody was present in our hamster sera against Sendai virus and that "false reactions were probably seen because of antibody against the sheep cells, not any particular antigen." Thus the serious concern about virus infections that influenced Council decisions since 1S70 proved to have no scientific basis. ) In September 1970 we were first m,ade aware of a new modification of the Walton machine engineered by che Ceancil for Tobacco Research and commented September 9 that we did not consider this modification to be workable. We cited four major drawbacks of the machine. In March 1971 Dr. Guerin of Oak Ridge \'ational Laboratories visited our labora- tories and was shovm our smoking machine technology. On April 14, 1971, a report was taa2e on nicotine (i. p. ) toxicity in ham- sters and on the effects of whole sswke at a 19.2v,. concentration upon several inbred lines of hamsters. Toe outline of an 18-month study aiming at 40 to 50 surviving hams:ers in each group wss submitted. Provisions were included for monitoring the CO level in blood and data were given on such levels during smoke inhalation. In August 1971 it was decided to carry out this study in its entirety with our own smoking machine, not using the Council's hor:zontal modificatian. On October 8, - 2- CTR CONTRRCTS 005644 11225385 CTR HN 041-808

WL 11 I 1971, Mr. Hoyt for CTR approved a publication on "High Nicotine Toler- ance of Syrian Golden Hamsters." On April 2, 1972, an interim report was submitted (with hamsters then having been exposed from 32 to 69 weeks). Observahons were reported on clumping of mscrophages in the lung, on mortality (which was low), on body weight, on organ weights, on triglyceride levels, on blood CO level and on isolated histological observations in the respiratory tract. Samples for viral studies were sent Dr. Huebner on April Z1, 1972. On August 23, 1972, we suggested that studies on physiological parameters (breath sound profiles) be incladed In the evaluation of smoke- exposed hamsters. This was never done. On October 10, 1972, we suggested new studies after completion of the current work, including studies on the gas phase, studies on the effects of sex, dose-response studies, determination of co-carcinogenic activity of smoke, studies in different lines of hamsters, including one line known to be resistant to s. c. polycyclie hydrocarbons, increased rate of exposure to smoke, effects of diL'erent housing (singly) of the aniz,als. In September (September 12), Dr. Hockett approved publication of "Pulmonary Histopathology of Hamsters Exposed to Smoke" (Society of Toxicology, March 18-22, 1973). In Js.EtiFry 1973 a"site visit by Drs. Hockett, Lisanti, Charles Sotamers and Sc.II. Gardner took place. ' In February tbe 'question of Senda: infection (meino from Dr. Hocicett, February 14, 1973) eras again brought up. The virus was described by Huebner and associates as an interferon inducer which could thus have an effect upon chemical ca.rcinogenesis. Since there was never any v alid evidence of Sendai virus in our hamsters, this "concern" appears in retrospect most regrettable. On February 7, 1973, Dr. Hothbui`er wrote to Mr. Jacob of Lauterscein and Lauteratein, laayers to the tobacco industry, pointing out the indecisiveness of CTR on continuation of smoke inhalation experiments and his reasons why this appeared to him to be against the interests of the cigarette industry. He was told that the first and essential step was the appropriate consideration by the CTR of the research which he was doing as well as of that he proposed to do. At Dr. Gardner's suggestion, tra3splants of smoke-exposed lasyn:es into compatible hamster cheek pouches were made in February 1973 to - 3- CTR CQHTRRCTS 005645 11225386 CTR MN 042809

, allow survival of the larynx beyond the life-span of the originally esposed aniimal. - A paper by Dr. Hombusger for presentation at the March meeting of the Society of Toxicology was extensively rewritten by Dr. Hockett and Mr. Jacob who insisted that in addition a statement be inserted that "opinions expressed by the author are not necessarily those of the sponsor'! (March 20, 1973). Cm April 23, 1973, support for the study of the usefulness of the golden hamster for smoke inhalation was extended for four months. On December 3, 1973 an abstract was submitted to Dr. Hockett of a paper to be given at the FASE3 meeting ig April 1974 oa data from tae final report on this project. A complete final report was submitted to the CTR on our Inhalation studies concluding that the Syriea has~ter was suitable for studies of the effects . of cigarette smoking on the ep:thelium of the larynx and for studies of such effects upon certain lung parameters. , A few days ago.ve were advised that the CTR decided not to continue the studies on smoke inhalation in inbred hamsters. - 4- CTR CaNTRRCTS 005646 11225387 CTR HN 0422810