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. r. ' Eh'wx IT Oscar (Diseases of the Chest ~.-- 020

, , L'FFFt~T ; t1F CIi,/,F *-Cl"~. StNJ~TYf IfPCJ;~ Df~:S Puliarn:nry Yeopl;so:c.a - •- .- ~ ' -" ~ : i ~ Auerbach, Pi.D,, E. .r;uylrr h:1,smond, Sc.D., Dr.F;ed. h.c.. 3 . 4 DeviC Kimar., B.S. and Ls*"ence ~.ar.`tni:r:l, H.A. _.. Saot Orsnge, Now Jersey and New York.'Hcv Yortc : An exporir,ent v'ns mdertaken to deterniac tahar.her mol;ieg; c:isurettatt filter ct2arettec; and to de3tezaaine 4tr?ther, zfter sufficier.t durAtion of eqttipped with an efPf.cient ' filter iti any lefa harrful tlegn amoKing nan- oxpooure, inhalation of cigarette t-noke will pro-d2+ce Irmt; cas;cer in dogo. Y£ndinga in recpect to raortnlity, ccuacs of decth criG tliCtoi- ology of the Iune vartncltirra have Llrtadv Lern rPnnrrnrl in rt.& Ff rr.F eaf v61"e _ 1 . - . . . Eet. In tkia pcritr ve will report findingc in recj.ect to tit: occurrcrce -of r.on-invFCire and £nvanirc brohchir~Io-elvevicr te:;or& and early invcaive broi:chiaI c€retncr~s. dtt:er findirigo will ba reported st a lAter df-te. New York, lieer ioi•t;. Supportcd in part by a reeenrch grcnt frc;fa the Arx.rir.an vocfety. the Y}epartc:ent of l:pideaiology and Staticticr. of tha Azerf,ccn Cancer Society, €rcra tho Vctorrr%~ h,=LniEtr.?tfo-n Horpitr.~1, Esct Urr,abe, Now Jersc:y And Profcuror of Potholo-y, New York 1•TdS.c-cl Co11<:Pw. 2-~'ictt ire.^.ic:,nt for f'cipi~ie<:.iolo,;y c!nd Steatictictt, f,r.:erican Cancer Socicty, Z•Srrnior h:cti¢r.l Envcr;C4~c~ear, V. It. Kc-r?frel, rs:t t1ta:-Zc, New .Iere.cy and Inc., I:cu Yrrk, I:er+ York. StattatLcG, ls:erican Cancer Societ}, Lnc.., tr'-ew 1'ot-1:, I:eti I'orl;. 3-1'roject DirGcto-, Animal I:ece.arcl, SecticYa, i.-.F:oretory of the f'eaor t-:cd.ceL Yn'reetii;;.tor, V. A. :rospiral, Grct Orrnge, 1'_tr J: rcey 4-Chief, iricld cnd Sf-ecirS. P&eearch Prnjects, ~c,~ar*.~n4nt of I:pldo~ic~faC}~ and W N . ._

TYacbto-3tmcy was perfonwad cisz r..nlh bo.Agle 6o,;a; diGht vero btpt so ao=-5r-_kiag cc-atroLg (CrG:tn, C) . All ott:ror do-'-'a ct-'s'xed cit;r;;-etta® Gaily t#7 =aua of tahing caagccting the trcchao:Jtc;.a to a ciaarottc ho26xir. Aftar a 55-4-ay trntning 1-criosl, the =&-,inII Gogc y~ra ~?:.v4dcd into fmr grc;6psi thrccsgii day f€75, Crc~p F OaZs rc-_AYad filccr -tip ctZeratito© cmd grc,--? e Lp 13 ctzd heoMv Fmikrd mas-fi.tcr cigercttca. Gro4s-9 L dfG cE~.eked t~1t' eo tj._nr_y cf€cr-,ttes ea tLe at!~*r Zb-;,a. to -dog in grc-<? C Gicd; 2 r;tc~ 19, 2 12 Lrcn:2 P. Lnd 12 :-rc:W h d~~8 Zicd. 11r.e reM, ri~:riC gro-,7,c C, P, L cwi 41&a-r. were 6ACr`sfieaa ctertia,- an dcy P876. l2oa-inraoiva brc-mchioLcs-clreolcr tum-or6 u-cre fc-:.xnd in ca-~ 4na of eract; of tho fire gro;.pa. rr.vcaiL.e tunora %:-ere net fc--jLd iw lungo of any of cIra gro~.? C, F cud L doKgn. Tm.msivc broachfolo-n1voolar tc_atto t~:sge fc,Ltp4 in 2 of tho 12 grcirp h clo; a Vaich ltcd, 2 of the 3.2 gro:rp 11 c;c-ge vMch Gied, cud fi of tha 12 grct:Q 1; dno viifch w-rf cccrsficcu. I`£vo of to tsei-c: r,&crifLccd. inve cfra tmc-Tc exCenGcd €r-te tM p1cLre.. F.'t:r1y fuviscivc aqu3::c~~ co11 ct;rtiutc;;, uoU fe---d ia thc treactii of to of ti.r 12 ,r.,r") 1' Lc--e uhiclt

Trucedures ..Since tiie deefgn of the cxporiercnt vas dcocribed In detail in the firat from 1,7 to 3.3 yenTa, The trachenstuva woe krpt open by e hollqrw tuhe uade Trachcoetony vaa perfo;tred on pedSgrced male bengle dogp ranRing in ago paper, an abrLdqed det,rr(ption v1I1 sufficc. of Teflon. In cmoking biteiona, the doge voluntarily inhaled cigaYetto amoro throvgh tubing connzcting:.t{u Teflon tube to a cigarette holder. Attho ^tart 8 doge were oeleetei by random numbera and retcintd ao non-cr`r+kinL cootrol .All of the other doga cc~oked filter-tip efgarettea daily for 56 consecu- tive dnye. The firot day of smoking vill be called day 01. On day 657 the tsokir.o dooc were divided Into fovr groups: F, L, H tnd h. The 38 heeviaet wrs nnr inorp,hrnn raFanf..fno dnon (whfch w~rw Ifchror 1nvafrhf) divided by rnndcea ninbera into groupo F, L and H. Ytirelve doge were put were grcduclly trancfcrred from filter-tip to non-filter cigarettes, and frozs fLlter-tip cigarettes throughout the ezperirr_nt. The group L, Hand h dogs in group F, 12 in group L and 24 in group H. The group Fdog: csokcd only then on, caolced non,flIter cigarettee in the -eornina a;-ij af:ernoon of each dey, eevFm deya•a ueek. The daily number of cigerettea wac gradually increauad un- -.day 057 to day [E75 the group L doga amoked covcwhat leac than half no tzany ,'til each of the group F, H and h dogs w~:e anol:ing 9 cigarettea a day. Froe2 cigrxetteo an the group F, H r:nG h doEa. Sao`ka frc= each filter-tip cigprette contr.it ed 17.8 Pg. of tar and 1.17 tsg. I of nicotine. tean-Gil2cr cigarettec vere obtLiined by re-oviug the filter fro:a tigarcttoc of tho eace brand. Y,ithout the filter, the rr.uke contc+fned 34.8 r`g. of tar and 1.C5 ng, of nicotine. The total tcr end nicotine concuredfu 875 daye by each of the tun•i•ring doLC vac: 109.3 S. of trtt and 7.19 C. of nico- tinefor group F doLr+; 103.5 g, of tar end 5.56 E. of nicotinc :or group L.

207,8 g. of tar and 11,12 g. of nfcotino for trouip B; nnd 2M7.8 Z. of tor and 11:12 g, of nicotine for group h. Althoudh or rrp A snd aroup h CcVa ro- I ceived the same t.ital s.nounF af tar anJ nicotine, 2,roop h doRo recoivod a I ' or dotn`e that group N doar, in relatton to thc(r bod~w~ht. Yvaotq-eitfa of the taookdng dogs died betceen day 457' nud dnq, 6RL'i. Theoe fn~ luA~d: tvn of t!.e 12 group F dogx, two of the IZ group L dnra, 12 of thr: 24 group H Any,p an4 12 of the 38 group h logs, gone-of the 8 graup C control d-,a died. All of the recaain- ing group F, L and P dogo, and all of the grnup C dngs were oacrificod bottmeen day WS and dny frR06. The group h 3o•ga cere not tacglficed end ccntincad to t:S:e non-filter cigarcttes. Findin.-a on group h dogo Yhich died at a later EBte will bo repqrtod in a later L&gcr. Avta?op raa perfcrrn°d at eoor; no poccible oftOr tho Lseth of each dcd. After czrrsir.^.tioa of the pleural sxrfaceo, th^- lur.go~ core reaac-ed cud infictod by gravity-fed inctillt:ticn of forz4l2n into the trcc.hce, The itmra of tk.o tica f,1e do,Zo have eaven lob~en, foar on the rit;'at eide cnG tt•reo on the left nid<.. A c£izsn of lung pcxrenchl:,a aac ramcrvod frc: each of theee *rteven 1a%.ae end or~ at sG eier"cc»ically„ ;4io reaaining pertioxe of the lunge vcra cearched for groaaly vicible raacea of e•:y kind; ond thocs r.ecnd were aoctioaed end nicroaca;ticclly en- tsaieod, The trache:.breachiel trca nsa then diar.e•:ted out ef the It-n;,a and diviind into 131 porticno, each of u°tieh raa ambxdded in purofYin. A hiatclo;;ic r-ectie:: 1i^a L,,-:an Frol-.nred frm onch cf the 22 Farnffin Llk-ck.a coQtcicie8 the epaciL~-nn 4ren the rper r.~in btnpche.a cnd frc~m the right cnd left c;eiccl lo•ra br3nch£, rrMra twra boon rUcraecc;.iealir eecrchad for brcx.crcial tr_-orR. In odGitioca, r.ca--plra of t.-t:-la of the re=iran8 lrng tiscti^!o uct'e prtpcred for r.fcrc,cc;4c oxc~Srstfc-n, LL r2* at inctmeoa, abaet 40 cuch SGCtSC.nG l'erc prefar4d in'cGditic:s to the t;ee;.~n ro:tit--) ltm3 p,rcach^L1 rocticr.a end tLe 22 branchinl cectic_*_n cccntioaad ci ~-Ye, • All or 'haca eGatfc-:c tperc aoerched t_lcroecopi:cally fcr- (--a11 tc:rnrc seSich c.iEI~t L^.ca l•.~w°o avorlc..-ly,d by rtQcr: em:inAtitr'.. 1".•.w-cectic*nn fro= each tr'.~r uad the ourrnTadinL if.lcrz tcero tjicrn-

•seopicalby esenineat to debeM!ne --br_hJ'ctolo;,ic type, utte of orlEir'ond rlndtn~r " . tmaors veet• Iutmd, the nuab.rr at at:f..*-,rLLea -okcd, the age uf the do& at tims :_ vf death, the type*of tuoor and the loce;ion in which the tweor aoo found. For _Tbe maJority of trrnors, both non-lnvcnii•e and iaveaive, tcore found in the Tfndines it, re:poct to ttxors are e.ir+y.rtted In Tn41e 1. It ehouo the vt our, {r~ 9, 1 N or h), the day of de&th of ea.:lt doik ta vhilcii onc or more luos dogo will be referred to by group and day of' death._. DoEo vhich, were aacrificed tao:fng doga, the dAy of death r®e•na the number of -ay,o of aooiCir.g. Individisal after day A)S (includimg one dog which dteA after dep-{•075) are further identi- fled by the letter "a" or For ezawple, '118192o identifieo one gro-up 11 doII vhieh was eacrfficed on day f892; and "H692b'' identiffeo another crovp 11do3 spicel lobe (rJ.), apical lobea, sore being found in the left apical lobe (IA) thcn in the right Treralence of Tumorc = l,2 !la Che-vn in Tab:e 11, cca,e of the dogs with tu~,orc had only non-invccivc . I L L ttraors, oo" hadonly invaaive tumorc and cor;e had both invaeive end non-invasivo ' - tcnors. The relctlvs prevclence of tuaora in different grmtpa of do6s raay b~a coa- -_pared by diartgardinl, prer.ence or rtbccnce of invcaion of the Table 2 Chowa the nunber of dogs In which one or uore tv:.ora -nuaber of lobeo in which one or more tv.nora were found. The cao hf&hect in dogc of group B end loa+eat In doga cf groip C provolenco wae eo.-teehet htLher in group L thsn in group 1'.. underlying otroc~. Here focnd cnd the prevclence of ttnord (contsol dogc). inc 4

rion -Invrsice fironchiolu- Alvonlnr Ttn.arr. I t l+on-fu-safve tuaRors vare fout.d in the l~tt:ga of 24 doQe. SEnco they were :.xeurrallv mnltfcentrt~. it ic difficult to ctFte thc nuaber of truly ind*pendent uooro. Rorever, in soce dogs auch tunore were foaind in tuo or three difierent - ..•lobes; and it a,av Jr nsstmrJ that nun-f~rvr,c!vr toaora fownd in different lobec are lodependtnt. hon-invcsive tu:eura vcrr Cnun& It, 41 of the 1 x 29 ~ 203 lobeo Invaefve ttmors ware found In the-1 w go of tvr- of the 12 Sroup 1: aon-filter ., eeokerc that died before dAy E87G, and in it of the 12that.uere cocrfficed aftor i 1 of the 29 doga. :doga were very eatall and a3ght va11have been wfteed except for the fact that vo It Is of inrereet that auch Lunoro were found in tuo of the eight coa-t~moking group C control doge. T1sis was aurprisfug to ue in the light of thair rarity in 2,3,4 doge sa roported in the literature. Penczpo they are not ea rare e.e in gen- erclly 66elBed. It ahouid be pointed out*that thocc fo•.atd in the tvo'non-ECwking ntcro9copically exetcined a great esany oectfone of lung tieeua frc:n er-eh dog. Invaaive Tasora The tera "iovasion" as used here, &~eana penetrAtion of the ttror into the : Ifo inviceive ttratora were found in the langa of any of the S group C control -doga. in none of the 12 Srovp F filter-tip emofxra, nor in any of the 12 group L noa-ffllter =oNcra. day fFi75. Inveoive tmore were nlao fotmd in the 1unEo of two of the 12 group 11 nca-filter mokere tlLt dicd before dap C-F.75. (l:me of tha group It dcEe voro eaerificed and-noao dicdbetucen dny'(97G and dtq Tcble 3 provic'ea a brief deecriptioa of oGch of the invcofvc tc-)or(r,) fox.~cl in the luoLe of the 12 group II and It doLC a.:ntioncu.~tbovc. th= [v.:or eao found in indicatcd by 1. , LD, LC, etc. i^ne loccticn in Ohicn

r .t SquarAaun ccll -iuvasfve bronchit+l carcinazaa of aicroocopic aizc Hc~o . in two duge (r,37: a a-ld E1E185a). t?aa of thcof cRrvin,maa aKa in s brcnch of the left apical lobe broncbnc. The other w6s .a tl.e.le.ft r«af.n'h~r~e-cl~~sa. InvQeive brocchiolo-a1vcoIxr t-xvorc yerr: found in 12 d8So. Six (h626, n644', H7 53 , HS ; 6-k, of t ~38;re and Ei892i,) itud such rmsora in t%co or nore . end it cppeara that these were indej>endent prijzary t%wors rathcr than orie ed the plevrn , one cho,--ed eFrlj involvem-,~ant of the pleurr;, and 15 did not . iavolve tw--or with neteatuaeo to other lobes. Mder thia coauzptioci; at leact 20 indepcn- _ - , _ . _ .. c:ent inYcciYe brvc,cblolo-nlveolcr tt,"sors were fo-snd. Four of th.cse ttcxora invO'.v- It ahould be noted - that r•~ny vAcroccopic cacticn s caere prcpcred froa each of the pleure, the inrEnive bronc:,iolo-alveolcr t"more and the aurrc,ursdin'" tiooc-t. T°ne hictol,>gic typr of eQllc vcriell conciderablj frcca one part hf c~ ti~ar to another part or tho acns tmor. Squmoum cell foci vere found in all of tlM1eae tu...rirc. If ject cmnl~ t•oetioa had bocn proparod frca each of the tu:yorn, sc~x of then QiE;ht hAres boen elacoified eithcar ac cSufmwH m^trplacin vith cd.rcenced ctrpim, or cq,~ ~r,onc cell ccrcinczta. Th e yotuzf;oat do; uith an in~~cniCe t~mor (Go~ P 753) tTct: 3.C ycaYEs old cC lic~ roup li and h, vhich diod erirlier. of r 7~,2 firat invAaivc tc--*or mte found in a d.og (h626) c.~hich diet~ on C.ny 26 after havinr, rz-;,:6d 3,928 ciCA crettca No iavoaivE tt-3orn sTere fp-snd in the 15 dogr. - of death, - the oldeat (do;, 1,877f~) the 14nCo In des,a are raroly ovccrvRd at rutojsy Lcforo the nCe of ccveu yr.&rti. Wnc 5.4 yec.rn old, and the coAn 80Q at dcatl._ of the 12 doZa t:itl. invacivc tiLmora vr.n 4.9 yebrt . _' In contrc:r.t, tt7-:.or:: of - CIA ~- dctniled ecr,criptioq; of the tz.m-oro follo=•tt:

ation. ooas of theet vere found to bQ bronchopncusonia in ortnai.oticn z;hi1e tf2ay aannea vera foimd in the lunfe of the dogo. Upoo cacroaccYpic exe=tn- otGere were found to cmtain foci of neoplnotic celia. Fnc vord "tvaor° aaad hare arpliee only to thoce aaaecs vhScc conteiuod foci of neoplcotic ce11a; but tTse do3o, up to to twny ea 20 tcrsro t~ero foecnd in th.: e=o loba oafiicScQtly in t3o®t iaotcneeo, ouch aaoaao s]s+c.~~taincG non-neo?lcctic tLosng. Ia ot= of olly eoparoteb frc= othcr foci by areas of noa-ncopleotic tisac2.• The rulaCieo- -centrie in tl;2 oens,t that oo9a roci of uacQlactic cclic rare e=posateG or pr:rti- ol.art to n:kc it ap;loar'thati car} usa indapendcnt. Each oxpsroto ttoo: aso eu2wi- hrom.-iiiolc-hlveolcr Tt-coro "ohip eamg the vrriona naoplsetic feci vithin tl3 oc:~o tuoor rnaeo to often t5a- eertaS4. In iainp ir-tcnceo it cp;aorcd that one focca o:i-~t::atod by 4ir4ct cs- _c4_~ '-- .--~c-r s., ,.r~..,. tr.ntr:nceo. it np"cro6 to li.'-.ely th.at tao d:f- -foreat faei of nQo,?lcotic colic eco;.o indepcol._nt_y. The grwoly viciblo Lroachiolo-alvoolor tu--oro faznG in the dwgo vat:cd cr.c'sLns.tiaa, each tuch tt~or uaa feY.:6 to be ccmpcoe6 of nmororz fcrf of tGo- ¢lootie cello to~cfl~r with arco9 of noa-n.r,lcatic ticcra. €=I1 fcei of r.^o- eisa from one eillf~zter to 3 ca. x 3 cn. x 2 co. (?ig. 1). Lpm aicrcucc=-?:c plabtic ce11u aithS,n a tt':or voro nolvlLr and, to the rat:od eye, rco=bied uiltrAry tut;rrclo6, T-trrj often tc: Ccd to r_er;;e ir;.¢rcop : iyly with the ea.rrc ;d- ing li.•-~; pcrc-ac5T-_i. The oo~-~,ict lar^or foci of no6-, laCtie cello e•zra Lc•nortll:ry coro LLffa3e, grcy, fir_- and flc.t. The 1.:rfent foci c.r,-re Lcrerclly ;ellce ews t1«) ctc^o of 3ray t~~tSCCticr, r.er .irid f3ceG of tl:s :v vro fcraod fa t'.::a do;;o rcam'Ao@ oit~er lc~nr raa~.nfo 1A i f.crc~ccr.<_c t.s~ac_ -c~ V_io lrietotc,.ic p£ctc:e ~~Yiue frc,4 o r t1-_3or to It elc:o c:....cr. fYC-i c---o Eo-aa to cuoct:.er in the tcaz r_icrc:rcc?ic f<_cld. S.ne r.ocplc:e::.e frxi 4ro Sr.e~rir:bl;~ aare<iztcd uith n b:<.ac:;to.c• (i'it. 2). T:w U:c_caiGlc. csy he G ^II

Ksny wsaoovere foauid in the lunrc of the daao. ation, 00-ne of thece --othcro cmro fo-mrd to were found to be bronchepntwic•nia contain focf of ncuploctic coitc. tfpon nitroacopic cxe--ta- ia orthufcatfo;y cl+ilo The vord "tmor" r.sad hore opplieo only to those cssasec chich comtoined foci of aaoplcctic cellc; but in teast iooteneEO, such r.meGOO'sloo coatoinod noa-neo.,~lactie t1o5rf3, in oo= of :tF.o dotye, up to no way as 20 tu~2oro tirro fo%md in tho ea'sa lobo onffLcto:=tly ap-rt to nshc it cplirnr that eaeti c,ce inZey*cndcnt. Erreh oepsrato t=zvY erso ou2tL- tentric in tba aeoce that amo f,ici of raopteottc collc e.-cre osporatacu trc Isa.Ct- " aily sats..a.~reted fr(m othcr foci by areas of aon-«ea~leat.c ifcac2, 743 rolat€ca- ahip cta..-~g the vcrt-cz~a r_soplantic fec£ rita£n t-h* no tuaoz csea it oftcn ~s- certai-r;. In usny ir.atEncco it cp?aarcd t?at c.~o facca osi-~faoto6 by Ci:-cc-, os- «,;-; sn othor iGCtcneen. it cpls rod ra.~ o lil;cily thAt iroo ~,if•- - forcnt faci of tt¢o-eleotic collc sro;.o £ndcfc5?_!•nt2y. The grcwnly viAible brr,chiolo-alvoolr,r ttm-orc focs«4' in t'.a dcuo vEr.cC in ett;o frou one mfllis~ater to 3 m, x 3 cm. x 2 c:~. (Vip. 1). L`rp,= o-crcccc:)_c osrainatios. oach ouch tw.er vao far.d to bo ecFaacG of nimoro-oa foci of eoo- Vaotic cellc to~,CthEr with arcna of noa-nzcnlcctic ticcr,, yr~2l foci of r.oo- l+lastic cella suithia a tc:Aor verc aciuler r.nd, to t;o noG.ed cye, reac`'a=ed cailicry t~e..'~,srcle+t. 'M.af oftca teaCcd to ccr ;o i-^,erca~; .ibly nith two r.,srcw~~ ing I^t;, parcnchs:a. 7he oc~ atet lar„er fo=i of ncvploottc ccilo v--~ra „PCacruliy av:b Giffo.e. Erey, fir,: cad flct. -ne Lcr~ at f.c-ci r.\zrc l;ci+_crcllq ,<s.1ou ©c,~ Viotblc t5rc;la the pler,ra. Gm-o of t-,,s ':c:cro fo•ae4 fn t:a doca roer..r3loC citltcr lc?-ar r~~.;afn LR tha etno of Brey taT-:tir.ctLcn noi IZ7,id f; v~cz2G. . tiicraccc-,ic 7ao 1:£ctoLa;,ic ~;.ct.crc v`r.oa fr.-:-~ ors tc_or to ac.ot:•3:. It aloa vcvLao frc . cco ¢c~.~ to c actLcr in t~o cr~a aacreseo; tc: fic1G. 71c naonlcc:ie foci