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CTR MN 042201

Chronoloqy of Events On December 4, 1964, The Council for Tobacco Research initiated aa experiment on the effects of chronic exposure to tobacco smoke of populations of mice of various strains, to explore the effect of tobacco smoke when applied directly to the shn of mice as well as to various other organs of other species such as rabbits, rats or hamsters. It also was to support design and construction of a smoking machine. This was financed by a grant of $350, 000 in five equal annual installments of $70, 000 each to Bio- Research Institute, Inc. A first smoking machine was des:gned and constructed by Richard Walton and began to be tested by us on December 2, 1963. Exploratory studies with various modifications of the Waltorn machine continued to January 1967 when the first grov.p r)f 100 C5737.!6 m~ce were subjected to chronic inhalation studies.. These were replaced by 200 Millerton Swiss mice in May 1967 because of high mortaliry among the black mice. A great deal of work was done on acute toxicits of smoke of various cigarettes in mice and a paper was published on this a: a meeting of the Society of Toxicology in 1967. On November 1, 1967, a patent a---,)l_cat:on for the smoking machine was filed by Richard tiValton. On Octebe: i, 1968, we suggested that "tae time had come to decide whethei or =ot :he Walton reverse smoker should be universally accepted." We sta:ed that, based on our experience, we. were ready to begin a new chronic es?osure e cperiment. This was based on a review of data on 34 sur%,ivz=g mice exposed five times per week for 55 weeks. Slides of these mice were 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 jucge that your technique for expanding the lsgs by the intratracheal instillation of fixing fluid is satisfactory." From 1968 to 1969 the first large- scrle experiment Eor skin painting with native smoking machine jet condela:e was carried out and the lesse= activity of fresh smoke was first =oted by Bernfeld September 5, 1969. On November 7, 1969 the use of i=bred Syrian hamsters was first sng- 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 work. CTR declined to support :hi: project. - 1- ~ m r CTR CaNTRRCTS 005643 co ~ r 11225384 C TR N N ~"0 4 2- '02-

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 (esceDt for gas phase inhalation) have since been met. On September 10, 1970, differences 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 (all by the i. p. route). In August 1970 (letter of Dr. Hockett, August 11, 1970) concern Ras expressed by the Advisory Board regarding the positive findings in our hamster sera for Sendai virus antibadies. Dr. Frank Rauscher wrote September 10, 1970, commenting on these antibod+.es: "For long ter:n carcinogenesis studies it is reasonable to assume that these two viruses (Sendai and M adenovirus) should not cause problems unless now evidence is uncovered_to the contrary. `' [On October 12, 1973, we obta'_ned a report on a study initiated by Sam Poiley of NIH with IIT 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 a:.eep cells, zot any particular antigen. " Thus the serious concern about virus infections that influenced Council decisions since 1~-70 proved to have no scienLic basis. ~ In September 1970 we were first mace aware of a new modification of the Walton machine engineered by the Ccuncil for Tobacco Research end commented September 9 tha: we did not consider this modification to be workable. We cited four major d_ acrbacks of the machine. In March 1971 Dr. Guerin of Oak Ridge National Laboratories visited our labora- tories and was shown our smoking machine technology. On April 14, 1971, a report was made on nicotine (i. p. ) to:dcity in ham- sters and on the effects of «-hole smoke at a 19. 2°,'e concentration upon several inbred lines of hamsters. T-he outline of an 18-month study aiming at 40 to 50 surviving hams:ers in each group was submitted. Provisions were included for monitoring the CO level in blood and daca 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 horizontal modification. On October 8, - 2- CTR CdNTRRCTS 005644 11225385 ~ i...'' T/ _ IwIN 01- 22-,..,. ..3

1971, vLr. Hoyt for CTR approved a publication on "High Nicotine Toler- ance of Syrian Golden Hamsters. " On April 2, 1972, an interim report was sub:n.itted (with hamsters then having been exposed from 32 to 69 weeks). Observations were reported on clumping of macrophages 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 21, 1972. On August 23, 1972, we suggested that studies on physiological oarameters (breath sound profiles) be included 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 li=e known to be resistant to s. c. polycyclic hydrocarbons, increased rate of exposure to smoke, effects of dif:erent housing (singly) of the ani=als. In Septe^zber (September 12), -)r. Hockett approved publication of "Pulrnonary Histooathologv of Hamsters Exposed to Smoke" iSocie:y of Toxicology, March 18-22, 1973). In Ja^_ua~y 1973 a site visit by Drs. Hockett, Lisanti, Charles Sommers and «'. U. Gardner took place. In February the question of Se=da: infection (memo from Dr. Hoc<ett, February 11, 19731 was again brought up. The virus was described by Huebner and associates as an :nte=feron inducer which could thus have an effect upon chemical carcinogenesis. Since there was never any valid evidence of Sendai virus in our hamsters, this "concern" ap?ears in retrospect most regrettable. On February 7, 1973, Dr. Homburger wrote to 'Mr. Jacob of Laucersteia and Lauterstein, lawyers to the tobacco industry, pointing out the indecisiveness of CTR on continuation of smoke inhalation esperirnents and his reasons avhy 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, transplants of smoke-exposed laryn.=es into comoatible harnster cheek pouches were made in February 1973 to -3- 0 X CTR CCf~(TRACTS QdE645 ~ 11225386 . C', r R 11N 0422-04

/ allow survival of the larynx beyond the life- span of the originally espos ed animaL A paper by Dr. Hornburger for presentation at the March meeting of the Society of Toxicology was extensively rewritten by Dr. Hockett and Iyfr. 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). On 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 FASEB meeting in April 1974 on data from t:ne final report on this project. A complete final report was submitted to the CiR on our inhalation studies concluding that the Syrian hrr.jter c•as suitable for studies of the efiects of cigarette smoking on the epithelium of the lary-a.e ar.d for studies of such effects upon certain lung parameters. A feN days ago we were advised that the CTR decided not to co=tin:e the s:udies on smoke inhalation iz inbred hamsters. - a- r l cTR coNTRRCTS 005646 ~ ~ 11225387 c~~R ~~~~~ 0~' ~~~~~

- 2 - Dr. Gio B. Gori Division of Cancer Cause and Prevention March 24, 1977 I also reiterated, as stated in my January letter cited above, that "The Hunter Committee of Her Majesty's Government has ac- cepted our method as a requirement for testing new additives to cigarettes"i and I pointed out to you that decisions on certain British cigarettes based on our inhalation method may be forth- coming from London on March 25, and that the question might then arise in this country: why, if there is a valid method to measure irritancy and carcinogenicity of cigarette smoke in an experimental model, do we not use it in the U.S.A. to alleviate the confusion now existing in the mind of the public as to which cigarettes are safer than others. You then nointed out to me that NCI would never undertake this type of brand-oriented study because political pressures would prevent it. You said "remember what appene to e clearinghouse or smo xng and ea t" "We wou e ead, if wE did such a h'n ." . . . . I took this to mean that you might change your mind in the face of opposite political pressure from those who might have the interest ~ of the public at heart, and you agreed that if such public demand- ((( arose, you might be able to do something obout our type of study. It seems to me that, after having discussed this with Jim Peters, Jim Sontag,and yourself, I have exhausted the scientific approach to NCI and must now follow your example and go the political route. I am sending copy of this.letter to Senators Kennedy and Brooke, and to my own Congressman, Speaker of the House O'Neill. Perhaps, I-can obtain through the appropr,i.ation process the wherewithal for a reluctant NCI to do what it owes the American people. FHcc 'F,reddy Homburgdr, M.D. I /President and/Director >a„M wIg R HN 1d• 4'2220\..+'

TELE Cocaca. FoR ToB.Acco Rssssacx-ri.S. a., Iac. 110 SAST 39iu STREET NEW TORS. \. T. 30022 March 2, 19T3 Freddy Homburger, M.D. Bio-Research Consultznts, Inc. 9 Commercial Avenue Ca.nbridge, Massachusetts 02141 Dear Freddy: Under the teras of our contract vit3 Bio-Rese&-c'c Consultants, Inc., I must cell upon you fc_ a copy of the pcper you propose to present at the *or.hcazL~ Weeting o° the Society of lbxicolo5y on March 21. - we have approved your presenti-.b a re_ort of actual obser.retions aade in ;jou: prelimina_-p szoie i_-ihala- tion study v.rith hsnsters, follovin3 our reTiev of patho- logical ch-ges you encou_ltered in these •^1-1s. Since edditional e_-si=rls a_zd tissues are being esaz-ed, hcrwe•ier, we are ve_f anxious to be kept cursent wil,:: respect to findings. Be;ro=d the area of direct obsern at`_on and des:: ip- tior., scie3ti.Yc reports usua.lly incl•_de sme inte^reta- t:ons and :•_=y...e-ts of significar:ce. Taese i_evit3ly co=- trin a subjective eleaenc of an i_d.ividul _^c personel c=rrecter. ?or this reason, a collective co ns _asus of se-reral persons femiliz: with the observat'_ons and in touch .rth the res-•..?ts of ot^er correlative stud=es is t=port3_%t for essuriy sound perspectives. I aa sure you will z,-ree that s::ch review is soun= procedure. We :-ill endenvor to hendle it p.ro^-ptly. With kind regards, Sincerely, Q r1- RC3: gh Robert C. F.ocC:ett Acting Scientific Di-ector r i ~ CTR CCNTRRCTS 405718 ~ 11225459 CTR 11N t..,T 4' 2220•i

March 13, 1973 Freddy Homburger, M.D. President and Director Bio-Research Consultants, Inc. 9 Cocmercial Avenue Cambridge, Massachusetts 02141 Dear Freddy: I have your letter of March 2 vhich d1d not arrive herc until March 8. In your letter you state that the techaical bulletin you prepared contains nothing that has not been previously published as authorized by C.T•.R. My information is that this statement •is incorrect. To cl.arify this as well as the statements in the second paragraph of your letter, particularly that "-the methodology is ready", I suggest that you have further discussion with Dr. Hockett and also rr. Jacob. Dr. Hockett has not yet received a copy of your proposed manuscript for presentation at the Society of To:d cology on March 21. It is imnortant, I believe, for the suggested meeting with Dr. Hockett and Vx. Jacob be held in advance of March 21. Sincerely, W. T. Hoyt Executive Vice President SiTH : vg rTP rn f-~ lTk~r ?'=, CTR NN 042-1120B

BIO-RESEAKCH CONSLLTANTS, I.Nc. -_ C - V SUlT4T1OP1 __ QES'.eRZ- OEvEIOvMENT F. MOMBURGER..H. ;. Z,•evo. 9 COMMERC14l AVENUE P. BERNFElO. -n. 0..= of a.a.a•c- C4MBRIOGE. MASSACHUSETTS 021ai (617) 8 64-673 5 March 2, 1973 Mr. W. T. Hoyt Executive Vice President The Council for Tobacco Research - U. S. A. 110 East 59th Street New York, New York 10022 Dear Tom: I am sorry that my correspondence with Mr. Jacob and our technical bulletin on inhalation technology are being interpreted as unauthorized disclosures of hitherto secret material. This is not so. The bull,:tin contains nothing that has not previously been published as authorized by CTR. We have of course acquired kno.r-how in inhalation technology during the past four years but there is nothing in our contract that gives CTR exclusivity of our professional skills. We are offering these capabilities to others because in our opinion the methodology is ready and I should think CTR would welcome its application in the field. We want you to know that we are fully aware of our contractual obligations and will continue to meet them as we have in the past. Yours sincerely, Freddy Homburger, M. D. President and director / FH:dr cc: Mr. Edwin J. Jacob rTR rnHT~ ~'°'~PrT~~° `1`_'t-;` f 'tl, C`~` ~ ~ ~- 21~1~1 09

9 COMMERCIAL AVENUE CAMBRIDGE, MASSACHUSE'LS (17141 s~ ' B~ZS l H31 Mr. W. T. Hoyt Executive Vice President The Council for Tobacco Research - U. S. A. 110 East 59th Street New York, New York 1002?_ ~~

THE COt\CLL FOR TOBACCO RCSE.kRCEI-I:.S. A.. I-,,;C. 110 E_%ST S0TV STRF.ri' \EtN• TORK. N. i. 10082 ?eb:uLrf 26, 2973 Freddy Hoxbu-ye_, M.D. President and Diector Bio-P.esearch Consultants, Inc. 9 Commercizl Avenue CrsbridQe, 14assa_iuset.s 02141 Dear Fredcf : I L:.dersta.nd you have been ad•rised we have 3ee n fu--aished cozies of yous letter to N_. Edwin v. JLc^ J- dated Feb:uL:y 7, 13Z3 and of your b=„ciure entitle3"Iahalat:an Studias aithCicarette S.:a:ce - A Technical Bulletin on Me:•r.o3s Used :.y Bio-Research Consultants, Inc." Also L a-m inforad that Dr. Gard.ier in his conversation with you ir. New 8aven on 22, 1973, discussed with you the r.ecessitY of co-me'_e:i.^.c the work called f:= =nde= o;t_: cozt_->-ct "The Deter=ilatior: of the Usef_lr.ess of t.`.e Golden Syrian E-. :er as Y.o<'_el A.nL-al for Inhalation St•_dies" before a.nv definitive conclusions :a-. be .ade. Such conclusions L_:e necessar-., before z-i_i de=isioz can be r_de as to f,_-t::e: expe=i- mentL:ion relating to ci;=ette s-r.:<e e:c=csu:e of ha-sers. In _:ou= letter to N.r. jacob and in yo'_ ^ecacLl b_lle='-n you O'. _.lOc:Ce : ...._ ~_c /__-_..3 of Ol_ c0..t:-..t t~t VO'- reS..i6Q Ls Sollcws 7 'A11 data o'ocainad an_ all in•:ar.=ias, davelct_ent.3`indi-,s or -:s=ov_=-__ w..-.: e: or r.ot p==-..tib:_ -e =y _:o-: ese=c:: Cons::I_a:.ts, Ir.c. -- the cou=sa of, or as a result of, .:c..-+c done under t..'-s a;=-=-,t s^a11 =a t^e so:e andex:lus:*re *rn_ ar=:: of :he Co•_Zcil tc= _cbac=o Resear:a - U.S.?.. Bic-Researc.i Consultants, In:. agrees to 'keep sac:at - conn-=tic:: -.o•:led;eor data obtained .. a:.d cc..:'-centia- any ;c it: c:rs a res_lt c', work done ur.'-e: t~,~s a7xe=ent and fu=tier a;rees not to use such S:4fo:-3aOF. :CT itse!f or :Z' O--IeTs e±t:.a: -iraC- := or ` or disclose -' to •-1./ t1i•. CL='`J- C? _.._ Council for ?.esea_c : - U.=.... wi _.oLt :.._Cou_.ci:'s prior v=_---.n ap:=c•:L1. "All a:uipment, doc'--aents, books, :accrts, notes or other aateria.is or data furnished by or on beial' af ^he Council for Tobacco Research - U.S.A. in connectien with work cole c:der this e=reer.ent shall at all tiwes be the or==e_t:• of T:e Cou_-lcil'or Tocacco ?.esea::i and shall bo ra:•_ned : Bio-:esearc:n Ccns:.:eans, Inc: to .:.a res_a:_ive owne_ as designated by The Co•-*ncil for ToSa=o ?.esearch - U.S.A. at the ter-_ination c° this a;re=ent, or at any tim t=s= The Ccu^.c:_ for =cbLccc Rese3rG'1 - U.S.A. mav :ecuest." CTR CO~~4TC~RCT~ 0057716 11225457 C" 1u R 1-1 11-151 0 41 22-22. 11

/ Tiai: CoL.crz, FoR ToB.%.cco RESCarcu -U.S.A., I.c. Freddy Hcoburger, M.D. - 2 - PeSr.:a_-y 26, 1973 Consent has not been given by us to yous disclasure of infor-zation, :a3owledye or data o~tair.ed in connectica with or as a_esult of work dor.e under our agreen,ent nor has consent been given to use such information. As you knc,+, the work to be perforred under t.he contract was in the r.zture of a feasibility study. To date, I am informed, the results are incocslete and inconclusive. Your Technical Bulletin refers to the Waltoa -%5orrissey saoie e:cposure maahine ycu have been using and states aaong other things (page 2) that this is your aacisine. The aachines you have been using are our oroperty and are su:ject to the provisions of the second paragraph csuoted ebove frea our contract. As you kaa.+, we z~so own the catent on the m:.chine. The eachines used by ycu are not the kind to be used in future work, there having been scztstantial i-.roverae^ts since the model used by vou xrs const^:cted. Ov-- relations with you and yo;ir coonanies `3<rocgh t.e years have been cor: ial a:.d we dislike iavi.n.g to write you in the vei- of this letter. Hoaeve_, we nust insist that ar.:• party entering in a contract with us acn^.e_e to the te=•os of that contract. Sincere?v. W. T. Fioy• Exec:tive vice _resident cc. _c+ir. :. CTR caNTRRCTS1 005717' 11225458 C ~~ ~~ 1-1 ~~ ~~ ~) 4 ~ ~~ ~ ~

A?ri1 16, 1974 Peter Bernfeld, Ph.D. Director of Research Bio-Research Consultants, I::c. 9 Co®ercial Avenue Cambridge, Massachusetts 02141 Dear Doctor Bernfeld: In response to your letter of Aoril 3rd, concerning the application for a contract to test a precondensed s.oke concentra_e and an instant s-mo}:e condensate, I car. now state that it will be impossible to fund this contract at this time. The unusually lasye nwnber of grants and co^-ra--ts that have becose available for cors ideration by the Scier.ti'ic Advisory 3oard has :.a'_e it necesaanr to establish priorities. The very extensive worK that has been supported by other agencies using the skin apolicaticn rethods `as • r,.oved the percutaneous applicrtior. of tars and fractior.s to a lcver priority. Iwss impressed by your detaile3 report of the caper'_ner.t that was eecn, leted 1rst 'all and do hoee to receive soon a copy =_ the «enusc=iot that will be submitted for Fu:hlicatic n. It aiq` _ be advsatagecis i° it a^+ea_e:'l befcre the large studies dor,e b? the :. ._. were reYorte3. I have iPar3 that they are noc+ bein" s~~^arized. - agree with Lie sta`e-ent ,.iz` you c•uoted Cro:r. the N.•nu_1 Rc?o=: :: The Council. Cr. :!oayet' anc' I have talked about the nee'_ ef a cor.:i^s=o^! ex•peri:nent :+u= it cannot be _°uu:dn•: at this tine. Sincerely yours, ailliaa U. Gardr:er, Ph.D. Scientific Director t4UG : ek CTR CCNTRRCTS 4Q5519 11225260 CTR NN 04-22-1-3