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ROCHE MEDICAL IMAGE & COMMENTARY SEPTEb1BER 1970 164 ` s~~~1~~~r~Q~ ~9 ~ : - ,.-i i - - ~.: TRACHEOSIOSIf'l,ED'BE4GLE inhales cigarette smol:e puntpcd hv niach'ine Ucft) tlirough' tuhe attachcd to tracheal,stonta. ' Ci~ai~ette-smol.mg canines answer the demand Who havc`corititiued io quesuon t e proto- t', b eol of the experimentand the interpretation `'for laboratory confirmation of the statistical of its findings. As the results of the studp eome under fulll:r review, viewpoints : cancer link by developing invasive lung tumors among ~ oncologists maYdiffer enfrtnda• h li io l h quest ns, suc as t e app caty menta I I OR MnAE.THAN'.A DECADE,.everymajor report linking eisarette smoking and lun£ cancer has evoked a standard rebuttal from apologists for the tobacco habit:; i When watistics indicare a close association; beurcen rco factors, one factor must be shown to cause the otbcrin an experimental 1' mrinrnl before a causal, minn-onship b'e- heeen the t oo con be estab'lished'heyond donbt. To date- no one has produced'can- eer of the btaeg in au e-epcriu antnf nnimid b'J',eApOslnQ 11 to tobacco LAoke'or treating it' rritlr cnudCnsates from tobacco srnnke. Thus; lrrbnruron• cor{firination of ihe statis- tical asao; iatrionus stilllackinp, In view oflthc severe technical difficulties entailed in making any laboratory animal 'smoke:' the shadow of doubt cast by this areument on the growing body,of epidemi- olocie evidence seemed ineradicable until last February; whcn the experimental stale- mate was suddenly and dramatically bro- ken. At a meeting of the American Cancer Society> ncw findings wcre reported that' appeared to proside the long sought bio- locie proof: '_2 invasive pulmonary tumors had'bcen, produccd'in 12 beagles among a large colony that were placed on a cigarette smoking regimcn for pcriods lasting from 20 to ?0 monlhs. This achievement was promptly chat- Itnccd by tobacco indu..trn investigalors of the experimental tumors to lung cancer in man. But regardless of its ultimate as- sessment, there can be littledoubt'thac'this development is a majpr ad4ancc toward laboratory confirmation of a carcinogenic mechanism in cigarette smoking. The technical,feat of inducing a large ca nine popul:ction, totaling 86 beagles. to in hale the combustion products of 4!15:00 cigarettes Nvas directed by two sciintist- who are pioneers in the epidemiologic in vestigation of,smoking butivirtual necccom ers to animallcxperimentation in the flcld. Dr. Oscar Auerbach, a wedl-knmsn p~ thologist and senior medical im•cstiFat at the Veterans Administration Ho.pitaGi [:ast Or:rnce, N. J., aokno\cledFes. "1•m I \

.( I f I I 9CL7 250° j"'25.1 ..250.~.. ,.>. w - ~1-----~'=--~ ~' -- IhumH, whn n il cEtmc, to mel h rnie:d ,4- The',ocJ t+f the hE.i,lt nriijcct ++;t, pllmtcd lum,, ri:n a ha, heci,ltynr," uihc. 1\ hctr Iho tail; and nr:rn:rcin_ anim d,." 1. . ( iirl:r late in 1`iG3 hy'a chancc coTnmcnt „f [)i. lcam nirJ ta carn out thi,:rpproachs hu1+= Ihrmmr,nd. Sc.D:. tho' r\n,crican (:mecr ' Aucrhaeh to a soreical cullcainc artho Fast c>cr. it rrr,c tnfrunlud' In, a Ii+rmiJ:)ble \oci ti"-. aice-pte,tdc•nt for c[,tlcn,n6,c~'I Orangc \':), ho.pnal '11'nuldWL.il he crnli ,crit.',+fpruhlCm,:, d ,tatiqio~. h;)aliundort,d.em+ne .mtm:d f%)ng- tic rcm;nf.cJ, if a nrcthod could ht' One of the ma„t .erioul pr++hlcrna .cns aq audr many year, ago in ,ctrich he e%F,„vdl found „herehy Ihe prn_rc"is'e ptdlnumarc the dc,clnpnrent t?f Fcr,ivint irrilatiun cmd eagcJ mice to an iMlr,y,,of ci,_:rrette nroko: chancc, ho'haJ often noted inrthc lumg lis- , ii,fuaiun in ihe trachcal qnma,-conditica,,, The c\Farimentl conducted :n l':ide. ,+a. .uec E,f hunran smuil:er,=1o« of cFiihcliid Ih:rt' intcrfcre(I With, tlie q+;dcnc)' n•quirc•d ah:xnJi,neil +chen the rodents Icarned to - -- fni ;ti,ucce,cfid e\pcrinrenl. rKnnther +Ya, block [hc smoke inlcl +Yi1h'ilhrinh,+Jioti. li:u I,n:d cell h1[rrqd.niaM nn.'I:ar :n)p- thc 1tndenc) nf tobacco tan to clb= Ihe Dc, itc ils' Iramatic re,LhS_ the hc.i_lo t m: I ncnoh,m,l lihm.i,-rtnu,l he in- ft.ttnlt',Fc machinc: built to FtunF ,mt+Ldr F du:od ii,~ILhur:u oc anint;il uai ;ndi_,; stod). ,e;ra undutal.en «ith'owt an) .pcrinl' I hc ,ur rnn: Di..lomc, 1\oI,,onhrdineie- inlnthc;mim rl, lung,Dc+in+ngF ?ccduic1 sense of urgcncy or dedication. Dr. :\ucr- for tntr:unin_,ntice dog, and rnn,liliunin_ " IxmdcJ to:thi,uli•a. 11'ilhDi. h-uhitc:dl. HaYine_athcredmieht,flh ' stlieml,ylolcrate ,mo{emh:rl.manpte,cnleil %uluminunl. cl,u).lic:d!,md Fathol i- cc) uCllaat ,md hcll, It,+nrlli. ti imual L'r II , k. .. a' a Ihird maj,a ch dlenc to th: imot) irt n. :\,.nlatn~ ~~- {~ Jenoc aeamst mol inv. ncither J \' c(crinar i m hE he_ m imE h_;nnrt I,crimenls ,ciih ,r nuill eroluip ul tl ,,,,. I Dctcrmin d tiycireum+cnl'tlre,.0..hme,d heDered that, animal dcmunslrutions ' +ccre ' ddhcultic,. 1chich had h)oucht th pi,acct ~' Shorllc ihcre:dlcr: Ihi, m J et', cntcrpri •-__- nccc.xary to inniminate. Ihc oflcnJine i~,ii)cd ht Di. N":illiam C Cahan: i\i,r' Icx'r stimdctill. Drc. Aucrhaclr;mJi\1'olacn- a,_ent. •'But at mcctingc rce ,+crc ,n oRcn y+,tk s)ir,con rrho ,c;r, c'unJlictinc a Ji(fer, holmc carh' in 1964 enli,tal the fidl!tim; cr,nliunteJ bs the q,icction of n h) lun_ can- I I, cnl hul rcJateJ db, wiJs aml rcantcJ kcnnel cern'iccs, of Dar id I:irm:m, a\" i ho,Fil:d eenc,+ulil not ho Fro1hmcd iniamm:d,." the ~F)tce fori hi% anirrr;cli. Dr. Cahun also research a~sictant and .hemifil'tshi, ha,l No,+ Jar,ey patholoci,t rehucv- thali the xi,hcd [)r. Aucrh.ich', a„ii,lancv iir c,;du- ,«orkcJ tcilh animalll at the Roa,cfellcri ncedlfnr esperinrcnl;d proc?f r,:rcapU:rre.nt. ;)tin- . ihc'icwIthuf his pm(,o.edilcch'niq.uc. - Imlilutc and gsincJ.:t re.putation fi+r' rtme- if onlt to alLrt': people': JEwhtx:" I Ibr inJueiir_ tc,chcal canerr: The Fracetlurr chanic:d incenti, enca. 1 hc fira acps in EIe,cluRin_ an c\Fcri- cntJilcJ ur~icallr rcYCr,ins a scgmcnt of \ltaclcing the problcm of mnintaining mental appr,+ach rccrc c•irric t+,ul hc a„o- the Iruchea „+ that the ulia unuLJ hcat, patency in 1hc tracheall,tom:ts a, hi, fir•I oiint.S of [Di. .-\uc.rhnchahilc. ht Jn'J Di. , a_.)m,l eac h othcr :nithc cuturee linc- tra ,• ' Hammund rkrrc ctill Jco114y cm_tn"cd in ~ ot iscU,r- \lr. I:irman su,poa ~ that thc x,Fm_ c)_,nollo t,)r th;nl had hci~nunuuJuevJl htch failure ralt had resulted from tlie use hum:m smokin_ %tuJicc-the Faih„h+~~i't init, thc nnim:)I: lune,, of comrmionaJ metal tr,,elieo,tomt• tulie.- in dh.crihinF the imerrcliniomhil+ ,?G \iui- R,nlinL ihcii oh,cr,mian,, the Fsn-tiinc They can he hiQhh"irntnting anJ R:rt'e the ou. hiitologic chanr•cs in hronchi ;u,d'lunc c„IL)hnr:)t,u, ,oam c;mtc tt, the iml„+rtunt 1ca,t for infcctie+n, especialh in acti+c antl p.lmnchyma. Ihi uaumician in an;)hzinc tcchntcal doci,itm th;n human ,mt,kin_ uncaoFerati,c animal,. .A'fl0r rieorouac tleath rates from ,ariau~ c:m,e, arnon_ 'miclil'6o'clucolt apprucimatea ht' mcchJn- , screeninc a hroacl r;rnce of z)nlhetic m:r L(100;n011 men anul reomcn +riih 4.nonn ~icallt ~utnhine ci •arettc ,mnl.c intn ronii,c teni;dc-hefinall. selcctcd'felli,nJ, the idlcal .mokinchistories. ~'i--- T~----- --. -- --- iA~'W,-1, 4,5 -:-~FR00 TI0^1,OLS AND FINDi'vGS OF THE BEAGLE SMOKING S T UDY ~ ,.- .. -_ - .` .. r- K ~,D./~6! ER50 IIGXT '1JiER5 Y ~ , VpKERS , riE1 SVOKEF50 ~l ER ,!JtlAJIr~LGRO'J SyC`_J~ ~T~~. f LTE' T+ • CirJ Fi^TER C ©,n ER DIOA.i 'TE E[T-'D€C •.'EpT E y. Cfr ETT 5 CGA,E:.TEG C WFERE$ OWTMELIP.GES D„5),.. ~*l.e GtGaS -- . s .' ~~ 8 .41 9 : =-t 12 - x 24 , ~-ot. 3-:., c..4g. ` ~'370.3 _ J _~ -- ~ ~ •m Err U~. ~ Y~ :fk r.alr-;rs T+:. nC.; .~r sacnroc?q -•i~r _ ..; ..,;D^3.` 103.5 F 1 ~ .. 't~ pr- ' 0 ~- -J` W r C '~f I2 ~-t2' ~ '1 . ..,., .,.~.. y i A [ ` _j .. . -3) IC -~ ac ~Y .~a (E 0.,. ~ 129.: ~i 213~ ..x9 9 3'!. ~1t e3`.6. t SAJ: 0 e o ~t tt 1 u-.1 ~) R. 11 -~ ~ q _ ~ -_ ~~ --- 1f- -~ - -- -- --- ± 2--- a: .(Y°rx~e:y•eC 0 O

su:.,tancc_-nnnirrit;uint, dtnahle. ;md4n,- 1 Finall tftcr nc;u11 a ctar nf\~nrl;, \lr. _.,._. ' ~~ y• h F` f mounted: Facer to Ficc tttc procedure a Iain hc:dthy patcn y' nf the tr,ichc;d ,toma, ~ thorough trial as an expenmcntal' mod'el ~ b 5 . c ~ cTStomy tuhec. fty~ cmfloyml; th~•,e tuh ,. the teehnieal diffiiulues had hcen sur thc int'eai ~tnr, h7tc hocn thk Io m nn-' t cc,med-[tumuhiChiott In+ntrncC-: .}~ . • + Kirman w'ts •thlc t~ tcll IJr ~ ~ luerb -h lh n 3' amonL the ynohm, tiog, for pcuoJ,as Ivnc F Dr Auct Hach tur d t his l ti l . nt o ons- mc co i as three ecars. ~ laborator• Dr. Hamntond t,hose talents,as 2 , t?r[ , a ciudy destFner had pro%cd ur.•tluahlb to • tl l, PltlioliiFi st1 in ear n utqout htsclinicall A10RE tljxu ai rF tech'nical chal.lenee the >,v:•cs todcvelbp a rcliaHlt ntachinc th,n' ' invccUratiuns, The stau,tiaan• tvclcoming A Wotdd collect thc smn}.c of a hounmc ctc:r l e oppurtumty arext`enmental augmer,tn- I thr stickv derostts nf tar thatiaccumul:ued fcastNle plan for an estcnded pilot stutl, :•. I P. ; dieeard because the,r could not,tcith,tand' lawrcnce Garfinkel• belicved they had a 1' mnciels, all of r,hi.h he wa, compelled to mondi and the httter's statistieian associnte. •r''-7 =:' I emnpli,h this. ~fr. Kirman built se,eniof Dr. Aucrbach, Airt Kirmam• Dr. Ham- '`- halation by this route.~ In an effort to ac- By the end of 1964. Ithe ceam: consisting ; l:een,s via the stom:ror pcrmit,colunt;try in- ing;sct to wnrt: drawine u0 1,rotocols. rcite and then either pump it into a doe's tion of thc epidentioln ic cace acainst smok e..d ~nh1..,r v.atrnc .ritr d,hnniv_~ n.,.~ _ ~~F- `:. . ~ hopcllcsly, mired after only tt+n ci arettcs., group was cnnsidcrcd adl'isahle , in ,'iew ot ~~ - I became eoated: dtanhracm ral.es became to appear. Staitinc with this small tcst r t x~' ' ` + on thetr ~corktnF parts. StartinF %ruh sp- that \routddetermtne uhcthenaFroup of 10 pAi ~ •r r stieated eomttnnents• he discot•ered that } ~ r r ; pcdiFncdlHcaclrs cnulJ he madc to sm„}.c thermistors ceased s, orkinc as soon a, they }ong and heavily enou^h' for lung chanrea ......,~.. __...__. _._._ ~....._..., __,._,.. ...~.~.,u.u0 unuuuuL~.ur,u." r,wu~ac •LA A.. : ~~ JJ~ -- /7,1 P ,.me.nzod.nvthe chemical actton nt the tanc l reqmrcd to carrpotd thesmoking tcch- Oo the eiFhth trp. he decided to disf nsr.. . e mqu .(Ten othcn cca; I,• ttiro,«rtliitr•tchc- t ' with delicate modcrn{,arts. By usinF.hirahlc ; NAhIiUI_Uf:ISI O car autrhectt searched metal'%alve~ and sim1'le eompe,ncnts that ostonttcs:wercm;unlwncd:ucentictl .l 7o dClcrmtnc the tc,t dogsr tolcr:rncc ta many thnu mds o clida of the bcaFlcs eau he eacilj'rleaned. he r,as ahlc to de,i_n varviitg numbers of uv:uctles., Dc H;rm ! Dt+ln}mt tn tissui to hnd in.a,nc tunturs• a"smokinc ma hine.. thati perform, do- ' - °-`- prndahlcdecpitecantimmuceApoctuetnt;u. I mondJisidedthemintoltroFrnup,accord- tfr oRaut,+kI •tecltmuizetion period The iast maior ch,ditnge-to develop a inF to weight. Once the docs were '~rnen.mtese,cr.ilundcsuthlcrraeunns. s.~,tem for makin, dogc accept frequent accustomed to smol ing. hiN plltn called for : Aiany, of the docs at ( r,I u icd to hold thoir s.nmkin^ se,cir+nx-reyitired a,crie, nf ;td- I giving one Froup-eompeued of thc h rvt # breaths :a the forced puffs of smoke entered d'rlinnal innovatiimc on tlr. l:irman c p;trti est animals andi sonic of ar er r „.rght ;, their tv tch~~a.• buti thov, sonrn rcalizcd re- Snterd,rilc anesthe.,ia nr sedati,,n enwild~d, -two morcciparettesatlaythcmiueregn•en sistnnve was ftnile and cuoperatetl!hy in: ri.ks of harming the ditgs and imalidiuinFl to the other groutlt: whiehicompnmd'th ' haling the smoke rvithout a strucJe. Thc e tQte re.ult. of thc studv: a Ohy~sical meth++d1 lightest as tvell as some avcrrFe-t,ci,,ht beaclos initially alvo.dcvclopcd symptnm, ot' re,tr.rint that ~coudd he welll tnlerated' dogs. Cigarette concuntpttnn %ras to he that were rem:ukably sintilar tu tho,e noted' aas needed. By tryinF heavy cioth._i+cl;et,; 1;^tluall~~ increased iit each FrouO until in beginning human srnnkers-sali\•atinn.l a[ fira. he I~•arned that severe ra,triction,` signs of acutc toztcity appeared. then tem- "dilation ofl the pupils. redness and tearinz of a tina-, movemcnt, tendcd to encoitrace - Porairily cut haek to aid'suroival. of the eyrs. diPzinecs• n:niseai and occa- rather than discourn_ce rc,istance. The,olu- hir: lvirman„tclro directed laboratnry cs- sional vomitinc. On the slow scJiedtde. ticw to this pn,hle.m he deeide.d.,ka, to de- ecution of the study. introducedithe dbgs these responses suhsided r,tnidly:. After a siem controls that „ould alloiu theanim;ilce to'moking in easy sta,•tt heFinninF ,tith r+'eekorut•o.snmedo_secenunanifestedan rrtttisr freedbm uithin aJimitcd ,Iace: A,"sham smoking;• Iror four Jiq's after their aplnarent' likinc for ciearettes hy^ wagcinF s1--el hos juct I:uee enouch forth'e doFln,it ' trachcatl stomas had healcd• the he.t!_Ics thein tail~ and juntpin, coluntarily into the in.va, mounted onia table behind the ,mok- were taken out of Ihut cages twice d:uly smoking bosn%hen their turn arriveJ. ine machine. A licht leather harnc.ss uith andiattached to dtc ,moi,inc qiparatus. ' Dr. Hammond?s plan call ed fbr,addin^_a chain, at the sidcs rermitleJ thedoc tirbe without aJicdrted ciFarcttc. On the firsfday cigarette cvcry four or five days. The in- ( tethered to the sides ofih'e hox ~u tn:u n i of real smnking, they stcrc exposed in the creases seemed to he going well through ! faced the machine hut tva, still able to,shift' morning to, one li;htcd fdlcr-tt0 cr,arene the 23rd J ty• at rr ht h tinte the dnFsnrcre I iKM,stuon rcith'in,the enclo,ure. with a low 1ar,mcotine contcnt and• in the . smokin six or eight ciF:ucttcc tiaih• aa The methodlthat \Ir.fCirmatt chose for afternoon,,werc given another reassurmi cording to their gic+up,: On the 24th dity. I IirB;inL the tr•rcheal'stom:r to thee smoking session of sham smoF:ing. The,econd diro however, one of the-lightcr smol.tr, suJ- nuchine was do,i[ned:to minimiie di,tress fidlo wrd the sarnc pattcrn. Thcn• for the dcnl)• devclnpcd com ulsiuns that pra\rd anrl Fain the do s"cunfidl•ncc: Smoke was next seven days• the afiernoon shamvses- fattd-suggg ttng that tnaic Ievci,srcrc a1- I' ptrmp¢d into the Irachc:i throuch a rubhor sinn w;a rcplaoed hy ' a, sccund' filter.tip rcady hunC rcach di prrh ip, hccauce thc I1 teafx: that could he qutc1;14"clamped sdtem eicarotle. After a week of Fro,un, accu, 'smokinF quuta, htd b:on mcreo,ed too '. c%tir thc animal'sho,%cd siQns nCansic.lcar tomod talu«-tan smak'e: the dbeswcrc I ~rupiJly. lu os'encome thrsohazards. Dr... ~' d-iseomfotl: AIr. Kirman fi,und'that immcdi, stt''itched to nonGller ci;,ucttcs for the du- -- -- -- ately allowing a dog tobreathefre.h air at ratton of thc espcrument~ sarlr times not only provides reassuring re• Gcf that the do^_ learns to count on htn alsn ----_- - - "` a.vid.c the dangers of progressive :moxia. 8

Hammond ordcred;m nnmtJi,ul cnhack in I Fivc •such dht:.-t,nic results the pa+ Ua+ht. 87:t J ry e.cpcrimc•nt +.ore csuced by such thc dailv numhcr of a;-,v.ttcs anJla,nutch I gist dccl.uc.: "t hoy strA,n,rly .uFiul dll.~i:.nrn,ry, d,i.ardcrs as cmpltv•ema. fNra- mom eraifu:d schcdulo of incrcmcnt,. 'I!hc i Ihat a larFer:md'longcr study ruuld proJuce sis„ eor pulmun:Jc, puhnator,oy iitfarction, .' heacle __roups ++'ere put back on a conRCrva- hmg cancer." Nevetthelca, c;+rcinonta ini anJ brnnchopacumonia. t ti+e re_imen of threc andl 0ve cignrnrto, situ was Iho most advanced cytologic An:I;zin^_ the dcath rates in thedili-erenl j daily. Ihon slowly rtisodi to sis :md cighr change th;+t Drs. Aucrbach and Iianunondl smokinF Frnups, Dr. Hammoad fotmd th;d over ai Ikriod of three months hcforc .till thought vvnuld be produccd when a full- thcy cJrariy rcllcctcJ the dosage of tarand % higheriquotas were cautiOut,ly institutud. scalC.expe•rimcnt with 86 smol,inF beaglcs nicotine Ihe (logs received in rclatitm to { and eight controls was undcrtaken in the tlicirhoJywci@;ht.ThrproupofbeaFlcsthat C I I I I L I b It' i 1 h' ' F p sccUons of parenchyma tn __ secuatts e u ments crceicJ Dr. Auerhach when he made , nonfitter cigarette smo4anF• Dr:,H; mmond animals: he also studied somc 40 random his daily rounds amonn the do;s- Suspence ! heagles into fuur (cst rou s - J~n divided the spring of 1967: , smokcd a m:rcinmmi of ninc flter-urped _ A majorohjective ofithis enlarged sludj•„ cigarettes a dity had' precisely uhc same along with dctermmin; the tumor-pro++uc- death rate-16.7 per eent-as the group inF propctty of cigarettes. +vas to demon- Fivcn a maximum of four nonftlter d_a- stratc whether sntohhnG eigaicttcs wuh' an, rcttcs.. Thcsc results paralteled the total ' efficient filter woodd tic less harmful toahc zmount of tar in the cigarettes consumed doFs than smolcing the same brandlwithoty by the hvo groups: srncc the flters reduced a fltcr. With these Foals in mind• Dr. Ham- tar production by 49 per ecr,ti In the uco mond designed a ncw set of protocols. Hr other groups oCbeaFlcs. +rhich recci.•ed the incrcased the daily quota of ciFarcttes mueh Iti hest dosagv a maximum of nine non, F ~ those he haJ observed in human smo{ en. more gradually than in the pilot study and filter cigarettc, •r day-50 per cent of the i Mr. Kirman also made a welcomc di:• ~ pVacod'somc beagles on,half quotas, hopiny, li hti.vciFht (logs died as against 31.6 per _ covery. Aften a fcw momhs lie fbuml',th:uit F by such mcasures to delay cmpfiyscmntous cent of the hcavy dogs. ~ the does no IonFer requited the pumpin, ~ damage, which had hastened the death.s in SeatchinF for even the sliFhtesLcvidciice , acliomof the machinc to keep th'eni smok- ? the earlier series, so that the beaclcs in of malignant change, Dr. Auerbach pcr- ~ ing: but hadilearned to inh:Je voluntiuily. k the new program might live IonF enough to, formed a thorouch microscopic eianuna- ~ muchdil,e their h'uman countcrparts: ! F develop malignant Iung eJtanFas. 1 j' As the ++'ccks went t;y„no new devclop. ~ To study the rclative effects of filter and se enf pulmo nn yolob s of sthe trd a c ceasd i~T ZIIF. STRATEGY sncOeeJell. Noo nlofe t 1111 Jcstlis occurrcd for the ncxt 'Ot Jas .. j On cxamiuinp;th'e lunFsof thc fr.t c t,u;dry ~ thervafter• Dr. Auerb:rch maJe t++o srFnili- cant findings: padlikc attachmcnts on the alveolar septniin all lobes and focal diLd:r- t tion of Ihe alveolar setiu lie was hiFhly cn- couragedlby the appearance ofithese early ~ patho!o_ic changes, whieli wcre similar t+. ~ n cnmg v+ t. u^ ~ pm1 ++as appenm^_ tvhtcH varicd aceardinr to type and dcFree i b - +r I '' ronchi r ma n stem t l f bm the npp :+:cn r ~ 1 e a h b sngs as ot u r c croups +vee , I of exnosurr ac rclatrd to hnd.•u: irl r hnr I . anu u~a ~ radu dv ll d k f g a y a ance to a pca qtmta o l IC i table). The formidable loCislics of ca rrying, cigarettes daily-a consumption com-1 out the massive tcst'were again managed paraNtb with cxtremelj hcavy smoking in ; by Mr. Kirman: who required the assistanec man. Finally. on the "9ih day, a sccond l, of 21'technici:ms to ma4,o five l:enncl-roorns dog suddenly succumbed, this dm~• to brou- ~ of beaols smoke their, cigarette allotment5 chopneumnnia. Iniits lungs. Dr. Aucrbaeh ~ every morning and afternoon on a; scven- wa, escited to find ntore advanced paren- days-q-tveck schedule. Keeping the project chymal chanscs-fibrous thickcnincs of'thc stitffed with patient'and dedt~cated animal alveolar sepmnvith areas of rupture. Similar handlers was a crucial factor in its success. sicnsofdamaeewerealsodetectcd'~inathird: Perhaps the biFgest~ technical prohla:m doc. ++hieh died'of pulmmntry thrombi on confronting Mr. Kirman was to pravent the the _7Fthdsryh l-volumihous smoke released by 10 dogs The seven remaining beagles tolorated' smoking simultancously' from becoming a this heavy smoking regimen for four adai- healthihazard zard to thc workers, contaminat- tion:rl months.,after nhich U+o of the doc, ing the controls, and giving umcantedlcxl'o- suddenly diedi within, onc week of cach sure to the other d'ogs between their other. -'Tficsc deaths were caused by m:a- smoking pcriods. To eliminate Ihis,thrcat, sivc pulmonary infarctions that dectroycd he had powerfulleshaust systems installedl most of the dogs' lung tissue." Dr: Aurr- beside each smoking machine to carry off bach recalls. "Now we were prdlal in t++n the smoke as soon as it was released. directions. 11'e would have liked to kceprthc - lasti fice survivors smoking but fclt cnm- - pellcd to sacrifice thcnr before more died 5 eeroita, each beaglo +vas gradually, of causes Ihat might ruin thcit luncs for ~j raised from a quota of one filior ci~a- dctaile'study," 'i rettc a day to whatcver level of filtered or Tlhc lung tiscue oflthc sacrificod'does tnlJ nonfltered smohing had been set for its a consistent story: 4?t) da+s of hcavy cmok- particular group: •'The cxpcriment went ing had in cach casccauscd dilation of the remarkably smoothly," says Mr. Kirmnn, animal'c air sacs to a state rescmhling with a touch of wondcr. "1Yc had none of emphyscma in human hcincc. 1loicovcr. a the epidemics ofl rospiratory infection tlintt majority'y of the dous' lunF sections con- run through kennels in ++~intc.r, even thouFh IaincJ cpilhclial Icsions in +chich 50 to 69 oun dogs wcre vulnerahle to lung diiordcrs. pcr cont of the ccllx sho+cc•d nuclcarch:mFos It was as if fatr looked Cdter us." lhat Dr. A'ucrhach bclirvos arc part'~ nf a As had'becn hopcd• fatirlltics occurred at dyn:rmic process Ih; t may 11:rd to the Jcvcl- ; a slowcr rate ttrm iit the pilot studj ;anJ the npmenrof carcinoma in situ. i protective effect of fliers aas confirmcd. "1 ncrcr JrcamuJ'Ihr pilul stuJy, %woulif htost', of lhc 2A'spa+mancous dcalhs, ih Ihc T i tts ttRSr ttraT of tumor formation apr- peared in a dngthat had died afYeronly 135daysof-smo4:inF the high dosaccof non, filter cibarcttes. In the parenchyma of'the beasie's right lung. Dr. Auerbach discerrtid' a tiny neoplasm arising in an•area made up of terminal bronchioles and their alvcolii Allhough the tumor, did not invade the underlying stroma„tho pathotocist'found Sts mere existcnce provocative. He was auare that although carcinomas of the larger bronchi',are the most common form of hu- man lung eancer• hronchinloattcolar carei'- nomas are not rare in man. \ltith time• perhaps this inconspicuous tumor might have bcoomc im•asiwo. The ansvvcr Dr. Aucrhach rcahtnd, if indcod thcre+vcrcweh• ticould have to await further pathologic fir>,i- ings from4he colony of smokingbcaFlcs. As the tnonths slowly passed, he found othm' broncliioloalvcolartumors-three ina heavy smoker that died on the 259th dar; two in a liFlrt smoker of nonfiter cigarettes - tfint died on the 34ith dJry, hvo in a heavy smoker that'succumbetl on the 563rd dar• and one iet another heavy smoker that died on the 60f,di day. This merely increased the suspcnsc, howeccr, since all but the la,t tumor were unqueaionahlj• noninvasne. and' Qie final l ona discovered +vas jost on the tantallY,ing borderline. Thrcc weeks latcr, ho++rvt r• the patholo- giht fmally f+lund a growth lhat had pro gresscd furlller. A dog that died' on thc 6'_Gth day exhibited a hrnncliiitloalvcolar. 4-

•.., ~-.•- h • •. r0 .t\-I -..,, : . +, tuulul~ lu.u neu unavia u/c"uulnn.. fue. , .' i ~. 3 ~r seek furthcn canfirmadion. Ilc toa+k hi. ~C7. O4 slides to Itoauni:md sho„cd thcm to Dr. t l •+. tmportant Ihar Dr. Aucrhuch dcnJd•J to l irnlllicatiun. of this di.co,•cry were so O tumor :,as im°ISiv ~ nnd said (hc cs crrmcnt ~ +r> >nlcias n•trrcn• I:mcntus1'tolcssor ol C r... _~\ PaDholhpy at Harvard and a Icading _ + = authority on u+nccr morpholny: . "1•II nc:cr forget that momcnt;" tteclares • r~ rLEURt,. ',~ Dr• Aucrh~rch. "Dr. 11'arrcn •tgtocd th:lt thc ~ .•; iseemed +eell on its ,eay to ptuducinm hmg ancer inmimals... 883 da)s,.originatcd in alteolar lissur ltlarkcr hut(nm laycr).and imadcdd thc: pleura. ~ than the undcrh'.mg strnma. [xaminlnS aJ- ditional lung tissucs, lie discovered tv.o .' s,_ t^ ucsnuc sucn reassurancc, no„-cver• ur. ~'IAuerbach knc:v that some con.crratikc ~pLathologl~tstcmfldnot'considoranim~-tsii•e f~Ihronehioln.Jrcolartumortohcunqucstion- f3ROXClt1OLOAL\'GOLAIt TII\1OR'(nno++1, in Iwr; section uf a dog that sutnkrd for '!ably malicnant unlcss it had spread furthcr i h a dog that I ( ItJ on tIle , t T •p„ hut t (~ 1 ul. d "< ~.a+ } also wcru cnnfineJitn the strnma. I [ [ I [_ 1_ j. In h3ay, 1969. after thrstnd4e had passed irts scconu nnm,clsaly. vl ~,ulauafcu i, Isearch rcachcd' a new milestonc. \I'hile jjjexamimn Ihc lun, seotions of a hea,•ily t('.-' smoking hcagle that died on the 753rd day. !he came upon a bronchioht Jvcolar tumor << t r, ^t) t ~~;,t~ J ttl!'r C d i ~ {n t i/ f "~that had completely pcnotrntcd thrstroma ` ..;` ~ ..lr ~ }' , ! 1! .'~= r~ ~ I . . . land' :vns bcclmmn_ to m.adh the pleura. Si nifiaantly the neoplasm cont :inedlsqua- ,~,~ b4l ua- th f ll f i s cm nd ose o sq oc re , imouscc -`s " tllllllltl 1,.• 'f11UUN ' l~Cll lAllIIn111In• t11C ItIV]t lV ~: ~,r ; >' ) r } I t. :, .• '+ F y r'G 't.'pc of IunS cancer that develops in the Lt ~-~ ~1 t `. tz~ ~4 - r~C c t, s! ;1 i 1 C a\ ~ ~ 4h,, ~ J N'k~, ~- bronchi ratherthan in the bronchiolcs. No,u. y' • ; I rr` iat last Dr. A'ucrbach fclt confdrnt'that + c°~~ `~+ j f ~~ 1 1 l t{r smol:ins,had induced a luns tun:or shou-ing C- ~,J t+ +t`' d ti~~ '~ U sufficicnt evidence of m-Jhgnar•ey to s:nisf}' the criteria of an} patholo,lct. ~~ L3 With this achie,'ement behind them; the SQl1A1SOGS-CELL C:1KC1!\OV A(arr(,t ): found in the same do~ as the tlunnr at tnp• jinrestigators «ere ~challbnged by a last. sho+rs c:vlr imasio,n from thc bronchial cpithc•lium (upt+er la}cr) do,cn into thc stroma. , pros'ocati,-o question: \1'ould any of the ry ~ ~n.~ >,.,,n.a ~~ ~ more invasirc bronchioloalveolar tumnrs in ` . , ~ ' • . , 9 dogs develop a squamous ccll bronchtal ~ rq carcinoma like those found in man? Thc -s of most of the sm, ivors :cere da smokin y g A )~~`~ ~ C +h lC 1 1 e-t \ 1\ dralving tu arclosc bccause Dit Illammond , I ~ ~ t P n~ly had'decided that.,:hen half the dogs in any one group had dicd. ttie rest ,could be ~7 . -: .. \ 4 ~,~~ o ~\,f` ,,,1. . ~ >) ~ sacr,ncen, excCpt tuc tnu fatvti'~um.rul+n_ tr 1 i: t rvnors in the lancr S i ; t d (S h h . t f- u r t eavlcs og e I o ° 1 '~ BG r t' \ l 'I'+~ ~, `~~ 4 1e \ ~~y "~ i r/ {;t eategor} arc being allo,ccd to smoke until J y~ g ~ . t 1~" ~I~~'t~ • they die spomancouslp.)' I on tlio other 1 (r.-i- ~ -e u,, ~ ( r,r d fj L i tt J` Y four yr beaclc groups, the end polnt finally, [~ ceF '~ t ~` r c, ,4 ,cas reached on the fi75th day of the cx-. . g~ .., i t ,~ pCrimcnt in Scptcmbcn 1969. ;r ;,I p e` ~ Itr t.u, c sctuss that ,:rle rmrnrcd t, C; f- ~?f T , ` a qe f) (~~ f., ~r4, t, 1 1 ) f`'' ~ ft t r' ~ t t r' 11 frnm thc 3?'sacrihucd smoken Fate Dr. Averbach cvtcn,lve rc.carchmatcrlalL hut t~~. y he questioned c, hcthcr the smnl.im, cxpcn- ~ a' ' t h r t r' 4w ~ t, ! r t ( ° t ence h td la.tl:d long onou h to inducc greater m Jlgnanl ch+ugc Ih m he had al- ~J rcady sl.cn .AN lie began ,rol LIi1L urrrtime id , C n 0 e C at ttis nucrosecqre, the p<dh+lof+./,t'as>aue LAK(ail(.ItRO\'C111.\I.C:1'\CLIC,di.rt„rrrrlinanf,77-dac.smm~hrr,appuvsasasuli, itliat hc.JrcaJ}' hnd nnce inJnt,ut,+blc casedi+idcd nnf.c nf imaa+r sqnamou. ti„uc funrnusCSlfh in lumnr nla} bc art+f.irtt. I tvith :vhicli lo an,,cl:r a full p u,;c tnhaccn C

L L ~ ~ ., tumor Ihat' had invaclcd the stroma. "I h: ~ ~ ililif Ihi di , mpcaonv os.emcrt• „rre so ~. +. `1. . ... .%.... _ „-tumor,cas invasive and s:cidthc experiment soemed well nniits way to producing lung " -;canc.cr in ;mimals.. uospnc sucn rcassurancc nn,cevcr, ur. Sif {~r4ucrbach knc,v that sonic consen•aticc patholoFists ttioalli not considorien invasive bronchiolnalicolartummtnhcunq(tcstion- ..4. `-- IiRO\C111C3LOAL\'I:OLAIt l t•';'\IOI: (noron). in lun .rcti r o that mad:cd for abl ^ malignant unless ilihadisprcad furthcr SSS da}s [x tiinall[i in a1,cuL[r lissucq[11v1 cr bnttnmia}cril. the plJru a, ; than the trn[(crl\ ing stroma. [samining ad- i ditional lung tissues,.he discovcrcd [ao i ii bhildlti morem-[sccroncoocvcoar[tmorsn a d'og that diedion the 6a9th daSy hutitho.r il,so „'er[e ea+nfincd to the stionia. 1969 ft I At d ! ^ h d h a n at .e s!u y passc[ r t . a " I ,its secnnd annicersrry,. Dr. Aucrs baeh ~t ~ ,\\\ t.. ~ S is~ ~, Isearch n.achcd a ncw mil•stonc Nhilc 7t . I vt ~ ~ t kl S~+ ~ ~r t `. ~4 rcaamntm tltc tunc seclrons of a hcavil} t ~ I r~ {tc ~1 t 3t - i• f 1j t`7 l~ f'[~1 ) t~ti t 7J r s-nnl;ing hc:+, Ir that dicd'on the 7S3rd d;tS. he eame trpon a hrnnchinlo d,enlar tumor ;t that had eomrletcl)' pcnctratcd the strom:r and' was bcf.innin^ to invade thc pleura. ~ T r1 J ' Sc c i Sicnificantlq• thc neoplasm cont::incd squa- `• ~ ~ IN - mous-cell faci resernbling those of squa- ~ Nr mous-cell ca.rcinoma, the most commor. C' ` "~r 1 ` ~ 1 s~ h ~ r ys{ •- r J , ~. r , C r C •tcpc of lunc canoer thatidcvclops in the bronefii r[thcr th tn in the bronchnlcs. Nm:. ~- G~1 +~* 1; ~~•r r£ 10 +*` ^~ tn t~ 1't ( ~~ \_ ~t~i•c l i, smoking hnd~i[duced a lunle tumorlshotvinc _ . sulhcient c, idenec of m:dienancy to satisf\ 0~,,~~~~L th\Yith thsnaclric rm otnbehind them-the SQUA\IQC'-CCELL CaHCt\O\1.1 (arra,[). found in the same do-, as (he tnrnnr at'tuft:, inccstigalors trere ehallenCed by ai latit. shorts earh- incasion from tlic broncliia,l cpithcliunt (uppcr9aScr) do,, n~ii7lbdhe stroma.. :' pros'ocativc question:' \;'btdd anS•of the , --t t~ a idogs develop a squamous-ccll bronchial ~ P , t , t ~ 7Af carcinoma like those found in mam° The C . 1 F.P imnking daysnfmost of the wrn•i,nrs tecre dra„ing to a clbcc, t ccausc Dr. 1'fammond ~ ,S, i f, had !decided Ihatt, n hen,half the dogs in anr one group had dicd. the rest t,ould he sacrificed, except for the group containinc 7 `r~* , r U: + tr . + the heaviest dogs. (Surcivors in the latter ~ ` ~ 1 t caAegor} are being allo,ced to smoGc until i ; i c y•` they die spontancoarslS'.) I~or the othor. four beaclegroupse the end point ftnallS[ ~~ was reached cn, the S75th day of tlic cz- . pcrnment tnS ptcntbcr, 1969. I h d tnr s t at were prctu[re 1,+ ne nu~o st- ~ Q~ i r~"ri lf Ct,r~ cr t t,r" ~'( -f~1i 1 1~"•nl~ c.~~ 1:!~ ~1', frnmllre3?saCtificcd5mnl.t+gavcDr. Aucrbach estcnsive research mvrri:d: but t .u , c.y~ur t - J u cr rne ry t, (; t ~" `~ "'t,. t 1 ( , ^ tY~ [. `ot ~S ~~A 1 t ence had Lrstcd long enough to induce t E . r1 ,, !9 :'i Ji-- f ', I.AKCIiII t:i10\'CI11:1L C:1\Clil.,tliscnrercd in an K77-d:re sntuhcr• :tppt•ars a.n suh- 1 grcatcr malignant chan,,c th m he h:rd :+l- rc¢tdy scen, As lie began aurl.rng overtime C at his microscope. the p;ohnl[ cist ,,:K sure 4',th'at he alrcady had one indispulable ca,c a af ll- c tobacco liieh t h ~ ~ o:m.,cer u p \r it +~~ .hcartifarls~. dirictcd ma~s ofintashesyuamou.ti+sucfarrnosl:.Slits inHunnr ma± l1} imporlant that Dr. Aucrh:rch [Iceidc[f tu scck ftnllicr confirm:dion- Hc tonk hi: t'r slides to llo.tnn :mdlshmt°ed them to Dr. ~, t+? Shicld. \Varrena Fnicritus 1'rofessor of *r + I'atholns}• at' 1,9arvard and' a Icadinl, .. ~ }•. authority on cancer morpholog r,' ""1lllnet^cr lurgct ILat montcnt;" rlCclares t( ~URA' " Aucrh:+ch \\;incn arce[lhhat Dr..Dr.g the =v 4 ~ \

I I I I I I I_ L compan}• atlrertiscment Ih;tl had aphcarcdl in (he ,Yric 1'nrf,' T'irucs ju.ll a fcto rcceka, e:u9icr. cLtirning lh;d "aftcr Glicen,~' e;irs of trying. nohod%, has induced Iimg cancer in anim:ds,wilh cigarctte smokc.-' A more spectacular rebutlnl turned'up' +' almost I immc.diatcly. however. LtouLint at a sectiatn of the left main hrnnchus of the second s crificcd boaCle; Dr. Aucrbaehidis- i covcred an caily inraei%c squamous,ccll ~ff carcinnma that appoarui to hc idemical in j its slruclnro wilHiIhose oofurrim,;iniman..n j' The mountain of remaining slides }~ieldodl ;_ additional tumurs to suhsumtiirte erery. 1 majpr finding including,anath'cr uhr,tmou+o celi bronchial carcinoma. Itln Ihs•y, alko : i,-brought the invcsugators one unc.pccted ob.serration. A'monc the eight non.nro4,inp ~ control beatIes, which were sacrificed alongg i with the othcrs, hso proved to ha%r small I mmniava.rvc lrronchiuloalr•cohrrhrmors. To , i Dn Auerbach and his collea,ucs, this5nd- I find- ing suggests Ihat hcnrFn bronchiolb- ; ah<colar tumors may be more common in . ' dbgs thanbad previousl'ybeen tl:nu_htl The para,mount discovery of this tmique ~ project, the invcstiFaiors helizn, is that both ofiIhe squamous cell bronchial earci- nomas and all '0 of the in~~asia'e bronchiolo- 1 alvcolar tumors that'wcre uhimatrlyf iund. ~ including,5we that had invadtd lhe pleura. i occuiTed ir•, the croupnf bear.lcs Ih~l smoked ~ the maximum ncmherofnonGllerciLareues. ~ i STATIST1CIA\ G.,C. ILninmomd set tirad- + uaih incrs+asin;, cipretib quutas,IhaJ 'enalllai dogsto lulera(c irarsafs:un6'ing. i i •- o.