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J a /1 i EXHIBIT NO•aL ~, "SMOKERS' LARYNX" AND CARCINOMA OF THE LARYNX :N SYRIAN HAMSTERS EXPOSED TO CIGARETTE SMOKE • FREDDS• IlONIBCRCER. NI.D. Cambridge. N[ass. AEaTRACT. Several groups of investigators have recently I,roriucecl ca;c:noma of the !arynx in Syrian hamsters. This stud>• reports on the effeLts of c:varette =moke from Kentuck}' reference cigarettes in an inbred strun 1 610 1\ Ihl nf S\'ri:tn hamsters. After "amoking" five -ia>•s each .\eei: for t%to Years. °0 percent of the surviving animals had cancer nf the !arvnx: 11) ; ercect had severe epithelial changes. The:e oi~:er\'atlons emphasize the rnie •if •. galette =r~~e nf !arYnzeai c-incer and respiratory *ract cnncer i1 zenerai. .an axper:- mental ^.7E:Fth1 ;s now .1\•11!3i>le for ^.^^11+aratl.e ;t:7(I:es of '.:.J!'eae~ ~F.~l u a z.li++e :o ward !ess hazar !otu smok:n¢ r.^ater:aa. 1 N TRODI.'CT10N. I Tndu>• there is rather unan;mous azreement ,Imong the medical plore;- slon throughout the world that cigarette !;moi:inc is a•`actor :n :he caa=a- tinn of !ung cancer. This has come to be accel/ted even thousrh the .L:,sump- tion is based on statistlcal correlation, no one ha\ inq :nduced undisputabie !unQ cancer in an experimental animal. With cancer of the larynx there is less comensus as :o iactors And the statistical association between exposure to tol ,1cco :r.ohe• and the occurrence of carcinoma is less striking than in the case of bronchogenic carcinoma. According to Chevalier L. Jackson and Charles N(. Norris: The lrtryngeal muc0art of henry smoker•c hns ;+o n'ntlnel to <how ^ dr.c- propnrtionnte dopgrte of opithvlinl thickentnq duv Po h!IpI r'Irlnsin rtI'd ker1' lini:atton, afrrl thlRt chnnyes /rtqrienNy pr•oy,ocR to ~'rrr•M6r:, ^,r.1 plrtkin (hyperkeratosis nnd tlysktrntosis)• both of r,hich, :a r•r'nin In' ctnnctd, may er<nhiatt in rtchta( malignnnt nltrrnhon, pttrfic,ln,fy i~ posurt to irritation id eontinutd.' 1 .\t Ih. \1trNne nr Il+c E.rac~n ...rlwn. n (ltolnClt~l ~.rnrtS•. Inr. • Un.ton. >I r.... J.nuarr I:•litnr. \nln TMi. \Llnufcript ~rt^n'r~l In Twr I..uc.:••~-rr'r QV • r 1 I.cation Jrnwry li. If7S. Rrnura for Rrpr/nN snnuld e. •rnt to F•••tdY 11ame-:- N D Ili••H.+ .r-n ! Cnnvnrrertl .\+••nup. r'imDn.lfr. \laf+4 v:lll 1874 Ln I 11 7 1 / ) 04.fe..+ {.5..! ..9,.lF

HONIBCRGER 'FMOKERS' LaRYNC" & •:.>RCINONtA vF LARYNX. Wynder implicates, in addition to tobacco smoke, excessl•:e intake ut alcohol, chronic cough and dental caries is the causation of caucer of the lar)•nx. A study of occupational iactor= ,howeri a reLatlvelt• hluh inci- dence in bartenclers.` In the larynx several pathologic entities may be observed as precursors of carcinoma. Of these the must important is leukupiakia ahich, despite repeated and adequate local ren:ov:d .Imt the elimination of chronic irrita- :lon d'.le to toh,,cco :moklns[ or Lnem,csl exposuie. may uitln,ately show a:e C)toiOSllc cr::er:a Qt a.:~:IKnar.~. :n :re -ieeper ced i:tye:s Icacelnoma :,t •,hul io;!•)%%,e,l h% :ILtual ;.trc:n,)m.l. This .,as ittzn ueen oh;ervt-i in ;e,lal speclmen_ :etr:u%ed tor ulopsy. Pachydermla iaryniru. a ili:uze :nucosai 'hickenrng seen crletlv :n the ;~~),ter:or ;-ol tlon ut tiie ~.u ~, ilr .1^,: ~h.~:'acte: :ze•i :>> mar~ea r;.ltr.ellal plull!?iatlJll. is (Inothel' SheC::,,: I.at:o52 '.'.:Ct'. ... ::mea aroglesse, :O !iwnant (Irftener:ltlon. We have recently pubiishe,i vli,er:anons -.atie in inbred Syrian hamsters %khlch inhaled clgarette twl,.«cu bmuke for uu to two years. In a susceptl- Lle line au percent of the smuke•zxpused animals showed epithelial Iaryn- geal changes Indlstrnguish.lble from "smokers' larynx" in humans, and ::e.lrly '_U ;.rtcent .hu%%ed mlcro:n%.isi.e c:u•clnoma of the Iar}•nx. Some .1Il:mals had m,lilsmant carcinoma of the nasoph.lrynx.' In the same issue of he Journal ur the National C.Incer Instltute. Kobayashi, Hoffmann and ll'y'nder produced similar changes :n !ess than one year, in hamsters in- haling cigarette smoke after pretreatment of the larynx with dimethyl- I>enzanthracene., In December, 1973. Dontenwill of Germany, also in the Journal of the National C.a,ncer Institute, reported that cigarette smuke inhalation in non- uli)red h,im;ters caused lalyn¢enl epithelial ch,tnKes and carcinoma in 1:1 hercent of the animals.• The present paper illustrates the laryngeal changes which Nve obset'%ed in inbred Syrian hamsters of the suscehtthle EIO 15 16 line inhaling cigar- ette smoke generated 'by a Walton->furrlssey Reverse Smoker• f rom 1 R 1 Kentucky reference ciAat'ettes. METHODS. Male B(0 hamsters of the EIO 1.,.16 line were fitted with alumtnum•felt collars which they wore throughout their lives anrl which permltted the in• sertion of their heads into the smoking chamber of aW;tlton-Morrissey Reverse Smoker. Smoke was generated from 4 IR1 Kentucky reference cigaiettes bwn- inA s:multaneuu.ly' .ulri was ulminuteleci to the animals in 6U-secund puif I (,..r i f'1. MN 0""f' 2a...iF rR r3

l'T l; ilo>tBCRCER: •',M )KERS' LARS•NX'• .i ••>P.I ;\*(' .%,.>. F :..%RS N\. _--------~-. :,uaRET-E _ _tE SMGM•~MCKI NG > 7 z ~ 6C~- I ¢ W V y t :~SE•- E_0 S10'S 16 rAMSTERS -~ . . :. = 9C ?! '. %.49EQ _9 NEEKS , , ~N f'-p I~rh ri~ht •n..nqrf lurlng •TOke rroilm4Vl) )0 •la)o Obl CTR ~~~~ 04~=.CI4

a /\ HONIBCRCER '-:M,/KERS' LARYNR" & CARCINOMA OF LARYriX. 1~i7 7•I I11J 13 !i m.rle Ir.unet.•r ..paer•.1 In sniuke fur f! l.rrke P.rrancCrou. .-y.UleIrrl ~~ Y:.~•..+ r~.l - t,){+1~.., w.11r I.)Yark.rrlv.r.. ...nllru.r. n.l nu.l.,f .rt)p.l.rl~ty in t/ii~ l0 n~.ir 1-1 .n . (•.r il ~ki I~:~rly Inuaar aVu..nwu• na 7 I:IV e! :V nr~IC ~•' (..r '. ....k. .1 uw ln~ cycles. Each cycle consisted of two seconds of smoke generation followed by 1•i seconds of additional smoke exposure and 43 seconds of exposure to fresh air. The settings of air flow, chamber size and other physical machine factors resulted in a smoke concentration of 19.2 percent (or about 20 jjat•ts of smoke as it left the mouth end of the cigarette diluted in 100 ml of air). Each of the 102 smoking hamsters was ext:osed for eight minutes twice a day, five days nweek. Two simultaneous control groups were maintained: one group of 60 cage-held controls wns kept in the same loom ts the "smoking" hamsters and treatecl exartly like the "smokinR" animals but was not exposed to smoking. Another "Aam sluuklng" i;roup undet%%ent aII manipulations, in- Liuilnlg exjwbure nl .:muknlX m.lchlnes operatetl •,tlthout ClKalettes. ' • CI p -. ' H• l •..I• 4isn {v..T ..r^ Lsr'

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/1 HO.%fBC'ROER: "S>IUKERS' LARYNX" & CARCINOMA OF LARYNC. 13i9 Animals were killed at 4.5. 60, 75 and 90 weeks. Complete autopsies were carried out. The lungs «•ere fixed under controlled pressure. RESULTS. Figure 1 shows the mortality rate which was not affected by smoking. Figure 2 shows the body weight curves which indicate a suppression of growth in the ;moke-exposed groups. HISTOP.ATHOLICICAL FINDINGS. \ot ail :erynxes were examined histologically, since 36 larynges out of 84 :wtopsied .,:::mals weie :.sed :or a transplantation ex;,eriment.' The results ower•:e1 in the ai I:ir}•n;res studied mre -ummarizerl in T.able I am1 iilus;r.i:e i :n :he :;2ures. No soKnitlcant aatho!o>t}• •xas found in any of the controls (sham-smoked .fs "ell as (.dxe-heid). tu contrast. 40 percent of the smoke-exposed animals showed epithelial anomalies •.%jth 19 percent microinvasive cancer being fuund after 7hweeks of exposure. Tracheal and bronchial papillomas %%'ere found in ;S ;.arcent of the smoke-erposed animals. In atout half of the smoke-erposed animals, clumping of alveolar mact•o- phages .ti.,s seen ;n the lungs. Only .5 percent of the smoke-exposed an:^ als ;co%%ed iaronc~;ai met.+plasia. There %%•ere two nasopharyngeal tumors: one adenoid cystic and the other a fibrosarcoma. With the exception of some myocardial degeneration found in about 6 pet•cent of the smuke-exposed animals, there were no other pathological lesions other than degenerative changes usually occurring in aQed hamsters. DISCUSSION. We, as well as two other research groups, have independently shown that cigarette smoke induces or promotes the formation of laryngeal leukoplakia and cancer in Syrian hamsters. It may thus be stated with some confidence that cigarette smoke is one of the causes of laryngeal cancer, although it is also evident that other factors, such as heredity, modify the susceptibility of the hamster larynx to cigarette smoke. When animal experimental data coincide with implications of statistical associetion, the conclusion is warranted, at least for practical purposes, that the fnferences drawn from the statistics are correct, hence that cfst- arette smoking can, indeed, cause cancer of the larynx. We may legitimately extend findings made in the respiratory epithelium of the !.u'.%•nx to the loti%er respfratory epithelium %%•herein no cancers were (~ f f`~. f fi f"f 0'"f' 2-9,1197

I I I I I /1 1RR4 HOMBCRGER: '•_NI'IKF.R3' LARYNX•' 1'•AR(:IN')>lA of L:\RY%,X. llttrlucerl in our studies. There r.ia* v he =e\eral reasons ;'nr •his l:e'~a;ive t•esttlt. =uch :ts mechanical factors pt•eventin¢ adequate exposure nr 'ocal tissue resistance in the experimental animal; hmt'e\•er, the causation of cancer an~•\t•here in the re<Itirltor.' tract t•e-emphasizes the importance of cigarette smoke as a carcinr-en. In addition, our ability to induce respira- torv• c.incer in experimental animals in sit:nificant incidence now makes :t possible to compare the cal•cinofienic potency of various smokinA materials. EIBLIOGRAPHY. I .I t. ,....~ '. 1. .te+•I /: \1 t'an-r nf '4r L;trcnx \•nlum• ':. Ca - .\ t"anr.r Jnurnnl fnr Ctin, ....s .\rn.rrran t':tnc•r Snr:.•'.•. \.•.t 1'ork. N 1• .:11+1 ~' \\•r.nt:t. fi L. U:a•.<. L J tt'trl D.t. f: .\ St,dr nf tntit tnm"ntal Fi to . :.. .. ('anc.r nf 'he yar.'nc r •tnr..• ~ c;.11n ;r,R • .1 ntr.,,.,n. anrl rt..•n.i. \ IS' Stra:n Ih(6•r+'t.•s in :h+ R-~ •ponse n( (nluvrl S.rran Haaa'.rs 'n C:car•tr• ~:rtnk. Inhalation N•,rt V'-.•• t I~ -m. \ :1•q• ., .%,. :I 1"d it Tnn1^.r.. r';-•-. - +ia Xlf F:ptth.lia! C9anz•s :nd':^ad :n 9• t'aror R.aptt;ttnr.' T:ar•rs of Syr:.t~ :.. . .. N ,n . ., :r , . 4S : •.4 In..r..~.,nr. '.C ~ t. Inv..tteat ^na :n 'h. F.(frr'a it l.•arnn:r -:n;;e ;{hu',r,... ly a•td P:,,, . E L r•'!..mh.r h•r~npr,.r.t i^.I .\+:n..nl i):a'•.rarnn I•t lnnn'.r'., n.-tr .. ,..c,n.: s''.1 !{ar:tt i \. •.,,.,.nt :n.t 1't t.or:. i,:cr• .\E! P. r.I in ,( .tr. ns• a t( ?Zy't t,tn Hima,.rs /'' .. ••n Fn rr r. w.f :f 4 r, 0 : 1: :IC• I t'i DISCUSSION. In tr:,r.. >Itt.utc I hxtr :.tv,l-d Dr Jnhn .\ Ktn'hn.r. the Il-a•I •?i 0- 1-i'.\: ::.. , of OtolarynRolnt) at YJIe U:ttcersry \fedt.'aI Srhonl t., •Iratuss Dr. Hrmburc•v s•-;•-r J•'t. .\. Iar.rrt•rP• %l D . - V+w Ilat.n. Cnnn I To 'h. trat of ^tt' kn.t.'• :c• t:cor nf the I:frync has h..n produc+d in the •i,t+orim.ntal rntmil in nnlr nn. nr rn.-ibl.• t•.%n nth.r lahontnrvs in r!t. ,.nrl-l On- rnaann for rhis n:ay '.. 'hh( :n.r. ni• pr^•.at ~,' ro more than thr.o or fnur lahnratort+s in rh. ,tarld 3tud)t•+c tlua p,nhirm n-n' 1-pt1: Tn mv ..'., ,.hat /+ae in sorr- of Dr Hnmhurpr s••rrlons unuld q'raiif.' mn pro:••cu:. • lv as r:tncer in the opinion of any patholotttst in tho wnr'Q On# nta,v ohj.r t'htt Cancrr hy d•f:nition rn.tastasttes and that none of Dr. Hntnhnrr.rs hamst.rs hacp ahottn m•• fasL•fst7 This may be a refl.rtton of the sl'nrse I.'rnphaltc •trpnly in th• hrmst.r Jutt aa is true of the huntan vnral cnrrls or t•, rh. .mall nun,ber of tntmalq srvJi+d in this group I hotx Dr Hombnrcer will continue h:s sludie•• and that h. „tll ly ho able.to answer sev.ral otlt•r tuesttons sch .h • c^u:r-I to nv• I,.h, do t1e pat::o- Ingto changes in the smoke•zpos.d hamsler otxn- at th. aquamous rolutrtnar ;anetion of the vocal cords ratMr than ahove tt, D.Inw it, or in the IunR.' _ Th. q arn:trn uc.d in this laboratory are all malea. and w'e know that t•anr.r of the larynx is rrodortnantly a dlsease of men. It would be tnVrestint to know how the larynx of the f+malo h,tmster would respoed to this type of +moke e.posure. t. There w•r• tMo dt(fer.nt stralns of hamsters used in some of Dr. HomDurcers other esperirnents, and tn.•astc• canc•r •tas tlce tfm.f more frequent in one strain than it ttas Sn the other. \\•hat then are the genetic implications of Ibis work' {. What t•omponent of ritzr.tte .moko is :hp rar:loo• senie aR+nt tf there is any one! ". Tho han,sterlt in this +:Nttment ,t•r. esposed :o smoke which had already pasaed throufth the l.nttth of the crRatett• How does s-tch smoke dlffer from that emtnatinc from the burtnne entl of a ctitarette' I hope my good trlends w'ho are smokers wtll for_t,e nre for t•Iltag you that •orte intnut;ators now report that there are mnre ranc.r producing aK•nLss :tt the fun,es •nttnannL (rom th! burning end of a eirarette than in the matn strenm sntnke inhaled ny the snloker. t,o. CTR HN 0422598

H0MBCRGER: •'=MOKERS' LARYNC" & CARCINOMA OF LARYNR. 13ti1 I in an .,rdinary ottie+-yiz.d room. for example. a ci`arette smoked every tour minutes will raise tbr suspendrd ;,artlculatr matt+r loncontratton to over 30 unies the natrnnal qualtty atandard for ambtrnl air. One final ubsrrvation on a non.7lrcln0[en. which shouk nie it. a little bit ••%h+n I read it Sirk and his group have shown thal crgarette anwkiug in an avrraaed -1z«d tar. I4n pruduce carhun ntonoxlde Iev±ls of 91r parts per mlllrnn. and that this is ..utrrcrrut to rmpatr ttmrdinten•al dlscrtnunauon. %rsual acurty and audlt•,ry Jlsclrnunauun. ^ot onl)' in the passengers but ecrn ..orse ,n the dricer. F' Hount rr.,u. M D . rt'ambrldee. %t.lss 1 tclosintl: One of the reasons why the lei,onq app"ar I:t tn•• site ••%hele they are app+arlnc Is probably that tne drposlul,n pat• -:n .,f paruru:jr n,.Itt•r ,, most row•r:tl.U~d in t..at site. This has 4•n snoH'n by I),n:+:t,,:,l by -J..; ,f 1'J::,-ta :I .Jr.-,J sla'.+r:a1 It n:.,y :,e a pur.;y ph.s:cal .+a. 4J,1 Th M 'J.t :'I.IL •~a ..1- :I.,t JiNtl :-n:aW :I:anlstrrl was for two I-a.ona.nM, :h.ll i.l:)'lia-:11 ':11I ::'-,MJ f 1•!Jlr tl--:li- ••-0 I-.^.:.1:+ ,:ar::il+!s are •C:r-'::.,.y Jll[r+ssll. -••atJ:'da .11 .,.. .. 'J :'1- . ...1.-a .. ..:nt. .:r 1:.I:r JJe• ::)t ..%Jt .-.•t:al:l! :J ne done' T:Ir •-caal ,iltf.:-•:.-: ::r •.uc:r:u••nars iuscrpt:brllt)• In hanls:e,s :nr thrr n.uplainis :u,:l . ':•.e :1. :^."r:j f ' .. . in ar+ t Ite st..k ng. and I :^.at tac:e -:Jy h.. one -xi:r:r.S :.+r+ : n.,,- •:o Jr:•.,•!t •.) 'h• lher thr+e •~•l+,t:,:^a ., I ]a ..at ..:rk I .11J.t . .. - .t . . ...... ANNUAL UNIVERSITY OF IOWA COURSE IN HEAD AND NECK ONCOLOGY. The University of Iowa announces a basic course in head and neck on- :ology to be held May 9-16. 1976. Designed to provide the surgeon with r systematic approach to head and ncck cancer, a broad range of topics will be covered in didactic presentations and cadaver dissection. Included will be: tumor immunology and virology, clinical and radiographic diagnostic tech- niques, princillles of radiation therapy, and drntal evaluation and pros- thetic rranagement, with special emphasis on principles and techniques of surgical treatment with immediate reconstruction. Enrolln,ent for th:s course will be limited. For further information, contact: Charles J. Krause, )I.D., Department of Otolaryngology, University of lotva Hospitals, Iowa City, Iowa 32242. ~~~~ MN 042599