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k-v'n 6ry. : . . 8IO-RESEARCH CONSULTANTS, Irc. co«sv«a1oM ttil&ICM OtvllOrrtMt 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. Concero that our Aamsters were infested with Sendai virus. b. Concern that no lung cancei was induced and that the malignant nature of the laryngeal lesions found in smoking anitaals was questionable. • t. MoNIulOtt. Wr ~. ~tturtt o,.h. o,o:•ww r e....Kk Dr. William U. Cardner ' ' Scientific Director The Council for Tobacco Research 110 East 59th Street New York, New York 10022 Dear Sill: • COMM1tKlAl •viNUt c.M1.1oot, r.ss.CMUStrrs Hfrj ....ers$ 1 ' 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 none of these employ inbred Syrian hamsters. ~ I am fully aware of the arguments of those who still advocate the ttse of mice and even rats for such experitnents 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 committees 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 rnachine with mice and with inbred Syrian hamsters. ,• I have retraced the history of our research in an appended chronology of events. CTR MM o2.6491

Dr. William V. Gardner -2. ~~NFID~KTjAL There was previously criticism of our machine which led to tDe construction of i horizontal modification by CTR without consul- tation with us and which sacrifices some of the most important design features of the Walton auchine. We understand that the original Walton macbins is not included in the current machine evaluation at Oak Ridde. No report was ever made on the testing of Me tmmodified model. 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 baiis exists for the two concerns cited above and that, .!n my opinion, the decision aot to evaluste the original Walton tr+achine to compare its'performaacc with that of the CTR rnadi- fication was irresponsibls or tuwiaformed or both and the latest decision to discontinue our inLalation atudies-is most ill-advised. . a. The Seadai story Ever since positive results were reported by the New Jersey College of Medicine virus laboratory in our hamster sera for Sendai virus this bas contrasted with the continual and consistent absence of pulmonary disease ia our hamsters and with their failure to intect mice upon being placed together with them, Now ITT Research Institute working for NIH has determined that high anti Sendai antibody titers were falsely sely positive results and that our colony is negative for Seadsi virus antibody even though positive results continue to be reported by the original laboratory on the ve ry same samples. Thus it becomes clear that there never existed nor does exist at tlsis time any Sendai iafection among our bamsters, b. Concern that no lung cancer is produced and that laryngeal "cas,cer" snay not be malignant. We have shown that inhalation studies in Syrian hamsters, at least ia 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 nitrosarnine is given by various routes where it most certainly reaches the lung. While rnassive-iAtratracbeal injections of carcinogens cause bronchial and pulmonary cancers, this merely means that under er- treme conditions hamsters usay develop such tumors. We believe that cigarette smoke is a co-carcinogsn, not a carcinogen, and its co- carcinojenic 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 straight smoke inhalation 4/' ip f "` \ ' N 02B492 1

ifUilCSwlCa o0n3VLTANrS. t..• . . r Dr, william U. Gardner experiment is a valid argument for contir.uir.: ,u:h studies now in carcinogen-primed anln4ls, not to terminate them. Furthermore, ~ the larynQeal observations rnade by us in high percentaSes of larynxes of srnokia` animals, oearly all of wbt,,h had •on:e anomalies ana 205, of which ba0 rnicrolAvasive carcinorna, are l-tentt,;al with those c:ee- cribed la ttuman •mokers. In 19i5 Ryan, R. F., I"cDonald, J. R, aa.l L~c•tnc, K. U. in an article entitled "The Patnolojic 2.ffects of Smoking on ttie Larynx", (A1vtA Arch. Patn. 60:472-41i0, 1935) described in human biopsy material 411 of the changes walch we have observed In ac:,okind hamsters. There was a"dlsproportionate degree of epttneliat thi;keninX aue to hyper,- ptasla and keratlnlsattoa and tpese changes frequently progressed to keratosis and leukoplakta (esyperkeratosis a•ith .:yskeratosle) both of wbich rr.ay eventuate in actual malijnant alteration, particularly If exposure to Irritation !s contlaueo. •' In "Cancer of the Larynx", a mooograpi, lor tnr physician, American Cancer Society, 1963, fiSures 1, 1 anu 4 ahcrN histopathology of burr.an laryngeal lesions wbich is indistinjuishable fruni that observed by us in smoking hamsters, vlbile in Aurr.ane tAere is a statistical relation- ship between smoklnQ and cancer of the larynx, suineMbat less close thatisor smoking and cancer of the bror.cnus. tr.is relationship in the animal experiment (our own and that of Zoontvnaill) tr clear since the controls are negative. Other factors that nave i.ren implicated, such as alcohol consumption (Kynder, F.. L., isroi,t, 1. J. and ILay, E. : A stuJy of environmental tactors In can:er ci the larynx. Cancer 9: 66-110, 1956) eould now be atuJied In we nar,.ster model. Clearly tnere 1s a need for experimental stuay of can:er of the larynx. Its incidence ls 3 to 4 per 100, t10u hunian population. There has been an Increase of the iactdence by 75',' during a re.,ent ten-year period. Seven percent of all cancer deaths are cue to resptra,:tory cancer and 12. $S. of thess are due to eancer of the larynx. 16.ost of these uses occur late in life. "Tbe traji: crippling eiie.te of so-called successful tnerapy are too well known to dwell on then: 1t'e believe we have de%eloped the first aurktnj anin,al rnodel of carcinorra of the larynx. To accept this, it is nut ne: saft.r~ to agree with us that our observatioos include microinvasl.e .•ancrr, lt is only necessary to accept tne Induction of leukoplakia by snioVing on the morphology of which we bave all ajreed and which our stt.ckic.s r.amstsrs snoM with bijn frequency. Leukoplakia has bten .,ee:riL.:J as "tne rr,ost important precursor of carcinoma which despits rv;,raw: ana adequate removal anc: the elimination of cbrontc irritation .,.ay ultin.ately enow the cytologic •3- CONIDDFNTIAI. ~~~w°~ CTR HN 02 2

0 . Dr. William U G , . . ardner -4- criteria of malignancy in th d ~~T iAL e eeper es11 layrrs (c followed by actual invasive carcinoma Of b i arcino hen situ) . rn tn appeara to be of importance as a-precan turnors ~pillorr,i cerous les I ' cancerous lsaions we have induced in inbred S tre ri ion ~~ Ne- sw y a quencies that allow statistical evaluation ut rnud genesis. ,i n harns ~rs ifiers of carcino- We plead with you to allow us to sxpluit this mudel for a study in depth of a disease (cancer of the larynx) that rikarrtte smoke is alle~ed to cawe. We Should prefer to see the CTR support these •tudies. It, bowevere the will - ~"'e tnust seek otber suppo t since cont nu.tiuni ofrth is wo ka s clearly in the public interest. Yuurs siacerely, C ll c -C F'rrddy yombuy ) & er, M. D. Presiricnt anf Director C1 R t t t`t tw 22C7c49"'t'

. Chronology of Events ~~N,F1D~t~1AL On December 4, 1964, The Council for Tobacco Research initiated an experimeat on the effects of chronic exposure to tobacco smoke of ~ populations of mice of various strains, to sicplore the effect of tobacco smoke when applied directly to the skiA of mice as well as to various -otbsr or2ans of other species such as rabbits, tats or hamsters. It also was to support design and construction of a smoking machine. This was financed by a=rant of $350.000 in tive equal annual installments of ;70, 000 each to nio-Rassarch Inatitute, Inc. A first smoking raachine was designed and constructed by Richard Walton.• and began to be tested by us on December 2, 1965. Exploratory studies with various tssodUicatioas of the Walton machine continued to January : 1967 when the first group of 100 CS78L/6 mice were subjected to chsonic inhalation studiss. Tbsse were replacsd by 200 Millerton Swiss rnaice in ~ May 1967 because of hijh mortality among the black m,ics. A rreat deal of work was dons oa acuts toxicity of imoke of various cigarettes i.n rr,ics aad a paper was published on this at a meeting of the Society of Totdcolojy - in 1967. On November 1, 1967, a pattnt application for the smoking rnacbiae was tiled by Richard Walton. On October 1, 1968, we suggested that "ths time had come to decide whether or not the Walton reverse smoker should be universally accepted." We stated that, based on our experisnce, we were ready to begin a ne•v chronic exposure experiment. This was based on a review of data on 34 sttrvivio8 mice exposed five times per week for 65 weeks. Slides of these rnics were reviewed by Loosli who called them poor an,d by TDelma Dunn and Harold Stewart who commented that "the dilatation of the alveolar spaces appears to be excellent, so we judje that your techniqus for expaadinj the lun2s by the intratracheal instillatioa of 2i3dn8 fluid is satisfactory." From 1968 to 1969 the first Iarje-scale experiment for skin painting .rith nativs smoking rsachine jet condensate was carried out and the lesser activity of fresh smoke was first noted by Bsrnfeld Septerrber 5, 1969. On Novsmber 7, 1969 the use of inbred Syrian hamsters was first suj- Sssted by us as part of a study of the effects of rodent viruses on tobacco smoke effects then propos.d by Dr. Sim of Yale who wished to join us for this work. CTR declined to support this project. .1. N C C C tV GD G.% ~ C , E. t :4 "t ()~ 849 ~

~. ~ . CONElDFNTtAL . On February 26, 1970, two smoking tzsachines were given Mason Rtsearch Institute for evaluation. On July 31, 1970, a renewal agreement was signed to cover the period from June l, 1972 to May 31, 1973 for studies to determine the usetul- aess 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# differences ia nicotine toxicity (by intraperitoneal route) between hamster lines were reported. Also hamsters were found far lsss susceptible to nicotins than either mice or rats (aU by the i. p. :outel. ' . • - 2n August 1970 (letter of Dr. Hockett, August 11, 19701 concern was a.xpresssd by the Advisory Board regarding the positive findin2s In our hamster sera for Sendai virus antibodies. Dr. Frank Rauscher wrote September 10, 1970, conrunentia8 on these antibodies: "For long term carcinorenssis studies it is reasonable to assume that these two viruses (Sendai and M adenovirus) should not cause problems unless new evidence is uncovered to the contrary. " . jOn October 12, 1973, we obtained a report on a study initiated by Sam Poiley of NIH with IIT Research Institute concluding that no antibody was present in our hamster sera against Sendai virus and that "false rsactions were probably sssn because of antibody against the sheep cells, not any particular aatiten." Thus the serious concern about virus inlections that i,rtfluencsd Council decisions since 1970 proved to have no scientific basis. ~ In September 1970 we were first made aware of a new modification of the Walton rnachine enjinssrsd by the Council for Tobacco Research and commented September 9 that we did not consider this modification to be workabls. We cited four trujor drawbacks uf the mat•hins. In March ' 1971 Dr. Guerin of Oak Ridge National Laboratories visited our labora- toriss and was shown our smoking machine technology. On April 14, 1971, a report was rnade on nicotrne ii. p. ) toxicity in ham- sters and on the effects of whole smoke at a 1N 2^,% cuncentration upon several inbred lines of hamstsrs. The outline of an 18-month study airnin= at 40 to 30 surviving hamsters in each gruup was submitted. Provisions were included for monitoring the CO level in blood and data wsre 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 .raachiAS, not using ths Council's horisontal rnfiification. On October 8, .2- E.y F R ! ! l `t 028496

CONEIDEHTtAL . , : 1971, Mr. Hoyt for CTR approved a publication on "Hith Nicotine Toler- ance of Syrian Golden Harnstera. " On April 2, 1972, an interim report was submitted (with hamsters thea having been exposed from 32 to 69 weeks). Observations wsre reported on clumpinj of macrophates in the lun8, on mortality (which was low), on body weight, on organ weights, on tri8lyceride levels, on blood CO level and on isolated histolo8ical observations in the respiratory tract. Satnples for viral studies were aent,Dr. Huebner on April 21, 1972. On August 23, 1972, we eujtested that studies on physiological parameters (breath sound profiles) be Included in the evaluation of smoke-expoaed harnstera. This was never done. -• On October 10. 1972, we suggested new studies after cornpletion of the current work, includia8 studies on the gas phase, studies on the effects of sex, dose•response studies, determination of co-carcinojenic activity of smoke, studies in dilferent lines of hamsters, includint one line kaown to be resistant to ss c. polycyclic hydrocarbons, increased rate of exposurs to smoke, effects of different housing (singly) of the animals. In September (September 12), Dr. Nockett approved publication of "Pulmonary Histopathology of Hamsters Exposed to Smoke" (Society of Toxicology, March 18-22, 1973). In January 1973 a site visit by Drs. Hockett, Lisanti, Charles Somrners and W. U. Cardser took place. ln February the question of Sendai infection.(memo from Dr. 1•iockett, February 14, 1973) was again brought up. The virus was described by Huebner and associates as asa interferon inducer which could thus have an effect upon chemical carcino8enesis. Since thrre was never any valid evidence of Sendai virus in our hamsters, this "concern" appears in tetrospect most regrettable. On February 7, 1973, Dr. Homburjer wrote to Mr. Jacob of Laute'rstein and Lauterst.in, lawyers to the tobacco industry, pointing out the indecisiveness of CTR on continuation of smoke iaAalation 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 CTA of the research which he was doing as wsll as of that he proposed to do. At Dr. Gardner's sujgestion, transplants of smoke-exposed larynxes into compatible hamster cheek pouches were made in February 1973 to •3- ~ CTR t N 028`'t'9"f

allow survival of the larynx beyond the life-span of the originally exposed aaimaL A paper by Dr. Hornburger for presentation at the March meeting of the Society of Toxicology was extensively rewritten by Dr. Hockett and Mr. 3acob 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). - On April 23, 1973, support for the study of the usefulness of the golden barnster for smoke inhalation was extended for four months. On December 3, 1973 aa abstract was submitted to Dr. Hockett of a paper to be given at the FASEB meeting in April 1974 on data from the final report on this project. A complete final report was submitted to the CTR on our inhalation studies concluding that the Syrian hamster was suitablc for studies of the effects of ciQarette smoking on the epithelium of the larynx and for studies of such effects upon certain lung parameters. _ A!ew days ato we were advised that the CTR derided not to continue the studies on smoke inhalation in inbred hamsters. CpNE[pFNTjAi. 0 C C N CD W tL . .~ •4. . Q~ CtR t t t't 028"t 98