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v /1 Cigarette Smoke Inhalation Studies in Inbred Syrian Golden Hamsters ' 2 .r-- _... , ,. EXHIBIT NO.J ~i T•'s -,. ' _ '••a~:. ... . . P. Bernfeld, 3 F. Homburger, 3 ' E. Soto, ' and K. J. Pal ° ABSTRACT-Invaelre carcinoma of the laryna waa Induced In 36.6'•. of Inbred Syrian golden hamsters from strain B10' 15.16, susceptible to this type of cancer when exposed to smoke from reference Illter cigarettes for 59-80 weeks. Nearly hall the animals (47.4%) showed laryngeal cancer, Including nonlnvaalre carcinoma and carcinoma In altu, which occurred with daily smoke exposures (twice a day for 12 min each time, for 27 aec out of each min) 7 days a week at smoke concentratlone of 22°'e. When the smoke concentration was reduced to 11°,, the number of Induced lesions was reduced proportlonately. When a portlon of tobacco was replaced In the cigarettes by a tobacco aupple• ment. Cytrel (a trademark of the Celaneae Corp.. Charlotte, N.C.), a reduction of carclnogeneaU prcportionate to the Cytrel Content of the cigarette took place. Smoke from cigarettes eontalning only Cytrel and no tobacco induced no carcinomas under tne cond!tlone used Other ooee-reiated changes observed were laryngeai papillomas. iaryngeal ep!theru, hyperpiae,a. Ire• cheal eplthellal hyperplae!a. and metaplae!a and accumulal!on of alveolar macrophages. Tar deposition In lungs and laryngee was determ!ned In a separate study by meane of a marker deca• chlorob!phenyl, added to the cigarettes. Admixture of Cytrel to cigarettes reduced tar depoeiUon in the respiratory tract. which paralleled the decreefe in t0le !nCldence of laryngeal carcinoma However, the amounts o! tar depoe!ted In the larynx when 100;: Cytre/ was smoked were $w+ •:gnil!cam. even though no carc!- , !, ' nomaa were Otieerred. Thus amoke from Cytrel tobacco eupp!e• ment may be less carcinogenic than eQual amounts ot tobacco :moRe -JNCI 67 675-683 1979. ::• I Ir..: I, l r! !- •.,• . ,y.:: ;r::. -!t, i JZt ..r tnh. ' ur !nht r. It.!n!,i~!, r!. il!, tlnl!•,t ...~I.!.!ttll.r~t::. •.!•t l! I! Il' ,. !'l Il!tt!1-!tt, i, i,t Ii!,.ittr, . 11 tnrr;t (..:;tl l!,c (r:c•.ni Ir,l!rllt.utnn tlt,rrl!,r. 1:•,i t' ! n:rth ,! , _ 1 . r., .. ,. .. l'.11. .. Ntr!:.:!I,..i. (.tttt.l. {! ,1 I ti~.lrcllc tutnlt'I,ttI t,l .Il', 1,t„ .u!,: _" !' ( strcl. Inll l,1 tiG.urtlr rt.ltIr tl!t nl -,11' !rr!!. ,' 1,! ( tntl I.ttll rrl tl,t,t I„r!t ..1,,, r,l ;:Q.ut' •. ., .. ,Itlrllt'll .11 tt,r' t!'t,t' It\t'I, ,rl ,Ill~lwt' t'~Itt!Illl.r'!"Ir __ .Intl II°~ ( t.n rtt'q.tu% t• tnnttul eruul„ t,ctt• .tdr!t .+ I.,n!: .. !• c~(lu,til tu ,lt.tnl•,tn!rlutk: tuntl!n,ln, Int! _ . ;ttcn!ttG nu Ut.lltnrttt t.l~r hr lt't t rn!t: '• I., ! , In t trlt' nl.ll t,r t nnuul /;~„ul, t..:, rl., :.:I, .. _'. ,Irt, ..- o! ._ .. . I!:,, .,rlt .n!.r. ,•.! !i.: !t!,`:!t I !{•, . .:I. t,-l .i It'.,i u. MATERIALS AND METHODS tlllt .1, .1 It :l :: Ilt l . _.i , ~ ~!, fl, ...i 675 . • !• !.: i~. ,:, ! . 1 , ,,. In!t' ( '. - I ! lii~ t• r il l \1 tt' r , CTR NN 0421- *-50

/1 676 Bernleld, Homburger, Soto, and Pal t)f Ihcsc• hrt•t•dinEz f.lcilitirs dt•rrst• thrtr brcctlcr, frrtnt the same foundation stock C)nls m.tle hant.ters lvcre u,t•d. I hr, t,rrt Irt)In ~-U to "(1 d,lss old at Ihr bcGinnlnt; of trc,lttttcnt Intl brts.rcn 64 and 119 g at th;lt time Thc•t t,t•rc hr,u,i'd ul ftl,lsn( bc,\rs t, ith t, lrc-st rrr n lul„• ti h•Inl,lt rs f,t r hu\. :lftcr 60 ssccks u( tr(•.Itntrnl. .III ,Inlln,ll, s,t rc housed tndi\tdualls. The% recelsrd Purina l.ab (:hr)s% and fresh tap s,ater ad libltum, were heddt•d r-)n ti.lnl•1• C:rl• deodor grade, and were kept in a roo'n at ""--W F with a light cccle of 12 hours' darkness and 12 hours' light from (Iuorestc•nt lamps All antmals. tncludin,, those of the c.li:c•hclJ tonlr„I group, were fitted t.rth permanrntls ,lttatht•d felt nld aluminum collars around their nt•cL.s Thrcr tnlLlrs held Ihe harnsters in the sntnl.ing m,lchlnrs so th,lt onls their hr.,Js t,rre In contatt s.lth ;mr)i.t Smokntg ntocl11,tr.-Ihc• rnodiflcd W.liton rr•srr,r smoklnK m:,Chlnr „a, used .ls ln prrslnusl, puh!„ht•tl r\f,rrnncnts 1 it Grnt•r,llt•, smni., ' t,n(lrr i,•,sl l,r ;)le,sure. ctC,trt~trt•, Lrt• burncc! In t}Ir trrllr•I) and the nurrtl,cr •li n2arrttrs sr:tu c: :I:ui:.ln •,•:,I, d:'terntlnc•c Ihc snl. ~c (r nttncc.lllr,n r.t .:,,"... IrJll"ll jll:, !n¢ Ina•rntl~:rfll. .1. ,: r'\;sr,s„rr I., 1rn[.•l.t•. ,7s III i,:ut{.in ,11lVnlrrt; In ;ht• ilrr,rttl ,It/t!, ed.h rii)-)rtnnl; srl:,i.ttt4 (ttlr cr)nclslt'j t.i .1 :"rt"n,! 1)uif r,f ,rnc,i.t• n. 7; ,t•tond, -•• i', .r't .ultl t„r ,/~,;, ,1 t'\'iU~.lrt' tu II"•:: ,R rr/nsrcull••e snt ~i.:n~ c)r I,ul( ctrlrs .,.IC .,,!Inln:.rrt:rl durlrlt; t'dt Il ..• 'w• ,., A• (\: Io 111 .Itlttll.l" .. Inlcr,!tl, 4 ,t ,r.,.t • hc),Ir, "nc• ,n tLc' :n,un,ntz .,nJ ;!I[ vi:ItY lrl ,:a' • •.;,t i,,rfat'ri• .,:.I••, hr h.lnlclrrs r,i Inr „rrL;I•..,.c! .'I 1I Ifl.i,., ( l~.lrt'llr,, ., . Il1,t'rIr a !:111t , O(lrlnl; rJ,:l i).,;:. .) , nll r,( Ilr ,,./, III1t•,- .:u,t'J Int+.t •.r,t: burct:niz t:.:.,rr:;c. f,r,li,tul~ ni.ltrls aU n;l nf ntokc l\ hen 4 cli~jrrllrs t,rrr ,nt„lr•J slrnult.lnertu,l, •hlgh dose..t i) ii C,lullnn 'r( .ntr,.r ':'? (oncenui ci-)n/ t%Js ,I(hlelyd nl Ihr rlirtl,Utr (h.rtnbt•r ti_5 nil su11 R'k: rnrrrz a,rd :Ilur h I, thr Ilctr',t.lr, Ir,l.ll 1)ultt!vr ~,1 h.,ln,lr r, „I c(fu,ll •IL;c• t,,ls nui olrl,llll•Ih!c ,(t rtnr Ilrnt•. tl,t• irtcnl t.a, ,t.Irit•t: :rl tlte ;u(ct',st\(' ,tt•f), it ;. I„ y.„r',I. Illlrr,,ll) r1,t•r ,1 Irrl.ll ul 2i 01 II, k!r'r:i„ "1 1„rl,. 1,, r? t,rrr h•;it „f, , Inui,. nr u•:t I hr rtlt).lIttlltl I I;r,)llin rrreltlnE •Iilnl.r I( thr in„ IcsrI ,.t•rc LrL:L~lnt; h, lunP ub uurn ' I" 1 I t"r 1,. F•.r t 1,!1 i-( IlIC (Ilt• Int.lkt, t!:C Jt;r. .'! tll' :1,:•i,;'.•, ., " t,l(hln _:,) t7,n, J\tI tttt o! \U 1 ,FPIt\tBtR ,-'4 a I 1„In ;'= It, iti .Illln:.,l. ,)f r.,th :It,:::/ .1 lI r,( i i h.,m,tc•rs• ••,c^e l.tlirtl bclat-'r; t; .,,.. ._ ,, r.. tJt•.11(nt'llt .\!U h•In1,it r, ,I,r, It Illl .. . r'.., 1'.. trt•.IUnt'nt NrrC k111,'J t,lr!Iln t•\(t•Pt for 5 anlm.il5 IrC.ItrJ .,.I!1 ... fl,}/.1( tt, f I~.IrI'll/', .11 1}1t' hlkz!1 1!.,,r' I, tt i ,Itn t,clc •Illut,td lu lltt' unlll t!.cs ,!It•, n•Ilur.u,, C,Irbo\shrmot;lubin t,,ts ntr,lsurrd Immrr;,:urls Ilu' Ihr fln,ll cs,pu,tuc 1„ ,tnui,c brf„rc• Ihr l:,nn.lrr, s,cr• I,Illc•d. .utrtrdinG to the :nrt!toJ or Ctirrtnlln, Lis,lher .9, lli,lnlr,tilC tlt,Yt+, - I!)e• I(utt;, tt.l f t.r,. i,L l•,! , ,tnP ub•,Irts ssrlc (I\rJ Irl Icll,r,nlt, , s u;)I•I In(I,,tlon of Ihc• Itlug unJrr cc,lllrnll•'.'• prt•,•::• .,• e(It•r rrrnus./l uf tht• I.Irsn\. Wr InIL.u, 't•' t}.,• ;,,r.c :., .,: ,If)!):Ir•Itus tlc',rs(•t1 b, (shll.,tt,,l I,% :1\.• lltt' sulllltt,tt Illt() t}It' Iuni.~S Ihirit.l'h ~ ,,::rt.•..I ' .. nc(tcJ lo the Ir-/thr.t .In! .1!i,tt,ut~ In •:_r. ,. •. Ir•rn,ll pt,inir,nJf, prr,sures t•) ,•.:r.,;t; .:1 rn . , . I:ucn ,It i i,rrssurt• •,f 3U :nnl }i.: \ :l:e ,.rr,,,u(• ,,.n I})c'll hCd:l. tr.ttl-,r•l. ult! r\ „r: I ~:r , ;'.. ..,. . .. , . ~ 'ktt• in„t r ,11 :ir Ir1: ,,., ~ . ., • . .. . . . . I,.Ir.111tI1nL .It n !tLll~ ,,'•rt• ,I,,I:1t" I „/th If rln¢ .,: r..r,l { ,ttln,r., \It 1.1t1 ! :uc i„r 2nhlrr 1!lt• tf.rt!ll'.I t,.,, ,rrl:~,Itttt . ~;'~:: .... .. '\. :. , . h}:it h r( i,,'t'y'll!t,l , ~~„t' :U .~., Ir.l( hr.l 4r) i r!:nt I!ir !Irst I n :.Irllr,l • :tt1 I f ~• F J,, u!: 1' - ,I!tr'r \I.Ir(irtj: .II fhr ~).lw ,'i :!11• _ II,, uclr,l. I!1• f•,l!r,,, In~ I,rt c• , „• •• l:x ,•,,;nlln t,u.rr l.,tuk. rl.p„c,tl•nl trud/rc -C L: In t, llh I)(.lif' .: nw r lLz .,rrl:c• .,,, ,1.!,r, Intl Ilrne.ll;c •vl. InJ the Jrl>r„itlnn I,i .,.,, „ Ihr Iurt`, •I•tcl l.lr, n~r•s •,f h•Inl,l, r, ,,.IS .. ,Irlr)f.r Inh.ll.llu,n .\ ntntllf,l.llltilt •n d„t111uJ I„ l,,,l, r't it l•, !; t, . , . . I,lul,rnr I hl .Ilnr,,,nls „f 1)(.lil' .Ind , r , Illr Irt.l,rl,ll••.Int ,n1r,t.r rf 3 ,li :ilr . !t: , 1„r J In .!:1, ,,,,r: t,r rt• Jr u r:n,nt';! !,•, ' P -.. , - _._ ,- .„n :,r R F 1.-" t. '.. ~.r• ) i"~ ) 1 ) 7 '~J~ ~ /~ Y7 5.1+

/1 a Cigarette Smoke Inhalation Studies In Inbred Hamsters 67 drtermin•Ition :,:ts tlunr unclc•r smc,'Ktnt; t,'nt:tt:,nls tdenuc.tl to thu,c c•mflll,sctf III r,ur t:",tniait, .In,1 chrontr mh.ll.ttlo.n srudtcs Bc tnc•,Ir , c,f thc tun,rr„'•n f:utnrs thll< c,!,:.tinrti for r.lch t•.l,r c,f c,~.nrrtc. t!Ic .tntc,unts "t ;tl.itkcr Inuntl III thc• t,,pt:.u1,r. tr.ttt t,crc• ezpressed in tc•rms of amounts of crt;uc•tte t.lr tie• pust tt'd. RESULTS Mortality Rates morcllitv t,as bt•loi, 10 o in all t;rnups unttl about the 50!h t.rrk 'lf t!;r rx!,rnmcnt •tert•ftg, I. "t, %,hrn the :tnitrt,l'le t,crc :11?i-rr,vcn,ltrls 59 t,t•cks c,lti \inr• Llllt, urcrra,rcf ::i ui•t!I, III .111 thrrr.ilicr nlti rr.l,!Irt1 hc•!ut•-n , i.,ttt! 1I 1 t.rrl ••It t,hith i;..,r hr rJrri t!ii(r..l.tl t.lit', Ilt ... !\:. .. .. .. :r kIilmt.' t.•i. .Lt•'fl:l,~~•tlrl! •r,rr.l! i. ~ i . . , ..,. .t ~ . , t . 0 ti„n „i .1 frt, rn,nor ,Ind bnr( -,t :hc 2 tnntnol kr,cuN, Changet in Body Weights During the initial 2-3 H•eeks of sm-ke e\po,urr' tn:lrkt'd hods \:etGht Inssrs nccurrrd 'Thc•,r In„r, t,( :c• Inr),t c•sulr•n at thr high du,r Ic,c•I of „mlkc' .Int! t„ Ir t;r.ltitl./ll\ Ic•,s fxtlrtotlnc rd as thr toh.tcc n t, es rc ;'!•lt ! tc In thr c tv.lrcurs hs (atrrl. I'hr h-Itls c,t•14hts of thc animals in thr tc,nu„! Gr»ull, c,cre higher than those of harn,trrs r\p",ct: t„ ,mnkr. tnde•prndentiv of the tspr of r,g,urne ,,r thr c1,,,r Ir\cl of ,tnoke trxt•ftKs 3. 1' Grat!u:ll !1"'t, t,rtt;ht lo„r,, hrlte•,ed to hr srnr.tent turrrtl .Jtcr 1i-"0 wcrks in the cr>wrcll group, ., ., .. .1, In rn'„t "f ihr c\1>rnn:r,,r.,; r;.r.,ll, I!tl'tC h.l, .1 t!tflllltl' Ihr !rul% u! ,•t. •:c. \',• • .. ..., .. •trrs n tl. " h'l,r nl t!'r t,_Inc• ,I 4 4 a \ \,4 I 1 . Z: 3. •.. _.. f' .. 'vt:MeEQ oP WELKs !., t,,, .,, [.r' Tf`'c. f f f''f S..A "°f' aC.. •75*2

A 1 678 Bernteld, Homburger, Soto, and Pal a . f i I 10 z: C .a so 6C ~ NUMBER OF WEEKS 1 I :.11!Ilnti !"'' . ( •.... . rnt•IJic~t itic' ,l:t•I/lr•! . ..~ . Findings at Sites Other Than the Respiratory Tract III "un at• fuuntl I'! /1.1 !tl l l~il n'!:unrt~. ut, I I,i:n; •. ;tt,t.lnlr~ „f pncu:n'.nl.l. Itulc !t.lului- ,t;)c ,tudu', .1, brtulV, ui rnittnr !ntl,nrt.lnll inlt u,u•11 III thr ,!Gntt; h,lm,t/•r. tulh ,ts t%cln tlll.itttlrt /,f tht• r!nt!Itl%lnl,. c„nt cullu,. ultt•r,, •II„tt'„1, It Jnll,l sltt,. :utd .luntul•Ir thrnrnlttJ,ls. Ihl•rr t.t!/. •Il,n Ihll•r tn,t.lnlc, nf .ttmlntt'•n,l, I,incl/lnt.l uf tl/t ,!,I. ,n. I .Illl nur)1•1 ,1rt11 3 t.lrnctnnt.l, nf tllr- .I/I!/ n I L:I IrtIL /i kInithnnt.rs. 2 t;,nuutnlt•,t!n,ll ,,utlntl.l,. I ,.n/lnn.l ut Ihl• (hr,t c•I%II,. •utt! I !ntl•,un•11 I.ttuntlnt.l \c /IIJL!./1 frllcu thrlr Ilntrlhutttn! .,n!nutz tht• III tzrnli!,,. II„nl /,f t!t!,. Ilnt!tnG, t..l, t• i.r.l l1 tn crn/,l,c tnh.ll.i;!I,n Blood Carboxyhemoglobin Levels \ tl!,luu t tlll,r•rry,/,n,r 1 f ft l t t,.l• I;Intl Il,l !rl'. ,! t.ltlJt\\Lctn 1.1!,!r I l\1!h \i, • ,II•11\'!4K rl)t, Ilrnll, fnr Ili i !l;u•, nf , :S .. .. • ,Iqntllt.lnll\ Intl;, t 1t 1.11 t! t.u', '~\!: In h.lin.lll, .I, I"IJ.111~1 l,,l\ rl';,LI•'l! III i!1" Illt,t' .I:II•(C!t,t, :It I,,IIi./\l.'at.;,:i , t1n.15 .,f ,nt,,~t l.•. .~ t •'. J~ :.: It,r'I,l Il.lrtt,ttr, U:f'•.I. .riQ .tt!- lr.r .. I,IJIIInL In/) j ( .!r11 ,/ll.] .~I, I,r 1\ ;,. .,. rlthtr nl thr -+ Inh•ntn•tnnt.!Inlnt; I\!It, ~,; Iht' I'o ,I~lu!1,•Intt' Iltrl~ t.tth tll/ u.t tt ~t. Histopathologlc Changes In the Respiratory Tract Uf lit(- L,Im,ttr, .!! t!tr I.IIr t,l ;i.,. ...:. - .Inrtrt.ll, nr 7(I •1'c \.1!t- nnl,tlc,ultl I'I11',t• .Illtllt./l, nI l IIJI!1L 1! i iU - II h!rn.llr% t!1.1i t,trr i,i:i,t! .t;!tv "i-•- '1 .ullrtt.l!,. .ill (Ir,in n"{c Itl,ln tl¢.rrrrl,, ',f I0'1'~ Jtlt: t,!L11 h t.t'tr .I...,t.r.! 1:) In!.::! ...i ,. n..• i. . CTR HN 042 ....x 53

/1 The htstopatho!ogic findings sho%.n in expressed :u prrcent of the numbers „f rrther at 50 weeks tif smoke exposure •iuntz, .t',,! tracheat or at 59 weeks +Iarsnxi Brc:ruse of !hr cttcd facts, these data srt•rr riot rnarf.rdl+ •tiiccttl h+. nor corrected for, intercurrent mortalits. l.unqs and broncht.-.after less than 50 weeks of trr.ttnlrnt• unls nlinur thani.;cs duc tu smul.c r\In-,rc s.t're se•en .11sro!•tr rn.ICrt,phatCrs sct•rr ,!Il;ht!, In• creased in h,tmsters rnh•tlrng smoke from lul ', r„h.t„o ,It tttc high tlnsc Icscl. Smokr exposure for 50 weeks or more resulted in n:, unusual changes in the Iung parenchsma, ~,rth the exception of some tncreasre'd freyurnc+ of and of alveolar macrophagrs see t.,b!e ::. B.,:h ,t :!.r- phenomena nccurrrd in all e\pers^iental ,:`.' appeared to be unrelated to the c"r.;,:•n,tr;,,n smoking matrnal I,r thr t'.;,sr !r,r•! •Ii ;'Ir •n, t• In the brt,nchl. no rffects ot stn!,:.r In~;.,'.I!: •,. ,. noticeable In :he PAS•stalned src!tvns. i !t-., z ,r!I, c.crr tr•n In thr Ltt¢••r hr•ir••thr, '•f ;''.: Cigarette Smoke Inhalation Studies In Inbred Hamsters f spans Ithey died after 87-102 s.k of smoke exposure., 19 hamsters that had died spnntaneousl, after 'a-QO sverks ot smoke exposure; 181 hamsters that had d!e•d spnntaneousls after 59-"r3 s.eeks of smoke e\pnsure: .5I hatnstcrs that had died spontjneous!v :Iftrr 30-.',d s.reks of smoke exposure: 14 hamsters that had died at sarious times before 50 weeks of smoke exposure: and t'~pt,+urc 18 h:lmstt•rs with c.trtoits Irngths of smoke and sshou• histologic sectinns pr(,srd to be unsunab!e for interpretatton. most!s hccausr of auto!ssls of their tl„ut•s. Histopatho!ogtc studs of the chrnnlc effects of smoke inhalation thus included not onl% animals that s.•ere killed or had died aftc•r more th•rn 74 ,.ecks of smoke rnpo,ure (315 h.,m,trrs~ but also animals .+hlch had died spontanrou,!•, brts.ren 50 and 73 Nerks of expo• +urr _3^ jnrrn:u, C onbt•quenl!,. as man% as 547 of ri:il anlm.ll, or +n "' of .,Il hatnctrrs- h.++tng rrarhrd ur cAcrrdrei '~u t,rr:.< ,.t r1.po,urr vAu!J hc rn.!ut'.eci in tfir r+.ilu.r.l„n. or I'!,) „f ;1u ha:na,rs c!n i" r\pu;rd li, -r . „1'r-! !,,r '..'! ,,r••.k) ,tr . . ., . .._ .. ' .... ... . .... .. '!. .., , , , ., I)„rLll:: hlt: : ,.1k: I( If•.I !!ci: lult:e t;rrrct.thlr `. ,rll„•lc i~:.1•1Q•.i! .,n:+ ,!:izh!I, tr":n unr I!: ::, „;!,- •:Irr t cv h. -.,, r•n I!,r Itnllf, „f fr,,:n ~„• ,`!- 1- •„r .r\I,,,,r,\ f„r thr ,!.iltrrn.c• In ,. .. ., ,• \i • .... .,I.. ..,. r\: • ~ r",p,„r-td lu ,mc,f,c Ir uu h:.:h ., . Ir+rl ,•r Th;, i:nt,: lne ~•.!s rt,,t IUf!ca!It Crathc•.,I ,q;:.tmou, c•plthr!I.,I tn: rr.,,cd Ilt .rll _ 4 ,n -f. tI• , •.~ ,.,.~r .•• . .. ~H I • • N ti ~ Ni N •I I a ~ •a• • ' ~. - - • • / a J a i• J ~ i 'O4' o C w- 1~P• __ ~ '_D 4J ti_rrEEQ -r Ir,,,-,..wr Y-\" „ . a~c ~ Cct 1otec:o BCS ToDOCCo 5:t 'tta:co - 2CS - -:t :.rr.•, ' . -5- 0.. s'D +EE5 ..., .,; . . i,. .,.,., n , , ,.~ „ .. I CTR MN 04*22754

/1 680 Bernteld, Homburper, 120 1 I i 6C %.utaE4 Ce +.EEaS ..,. .. ,... ,., .~,.. ~ ,.. . .. . . . „ •r.. . tnL.ll.u,nn. Iht• lu, t.•t, cr nt•r.,llt !:ii.:' , I ,t rhr h:);`~ tlntr Ictrl If•,;,tr;,i.nt.t t.., tnttc.,.t l"n,t ,tl t!1' tr,,,!;t'at 1:1 ,,d::tti _'r7 lt.ith, .i. z- .I,it" 70 - a s e--e ~ CCt 'oeacco 80% SC% 'cDacco - :G1 ,'r rei -CX S^o- S-c4 I _o^••c. :a;rl-- 0 c _. ' . C'. .. 2„ ~ 4 . C.. . . ~ , . ,. , .•,i< i,..-. ..... te cara,.~• , .. 'c:a. r.d^ICR;n.r etr : neT..•\.JL.^ tO:d, c`.[:aret'.t .. LGr.. an;!~,a'.i .J'!. StUJ.eO Mra-l Standar+l %a!..es de,iattons 1~~'~t. tubaiiU e~''* tobacco' 50 tobacco' 1',- C~ Cctrel Soto, and Pal 24 2?5 5r 25 °0 3 ~i 21 1~, 9 " :y 12 6 ,~ P•1 1,, tnhacco i1 2r bJ J~ -ot. wbacc.'' 1 i =u If, n ~ I ~ a•ha.cu' I i °: 11 " (,, t ('.trci 11 U I ) ~ cnr.,. CnRC0 (, .ia li I U :4 i e:rr^ :rrd t,: . . ::' ;ec o! .:rot,e er;-_re ii,en~'ed wttn Cy:rel I\t I 1t,: •\t) • r\I111N tn(rt.,,rtl ,li~fult it) .)!! :r ' :" •'; . .. . \ : 4hr hrl:h ••'tb,•t'ni•.ri'.t • ,tll. Af \:ar,nt r\; " t.::: r. ,! /_r••. •: t -f ;,:f!:t i,.,i !:11,!e•:.t .. ,zr,rurtl L•,un tnrl,: c•, ,c't, .-n i,.,. I- dtli. ~l-t: :!1C r\i,ll^1,t : -"i ..I'•! r• 1,7t11 .1 '.!1./1t' .It:: t;:'fitlri .,.l :.~:I:.It'.' t,lt,•.! If.• ;.rr,r'i,t' h.t..il :n I)!.151.1. ,r,tl,rrll'•~ :ht' \ox.tl tt,rti, I.r.t•r. .h'rt.tttz (ultltnG hu4 tli\nnn h.,,.,1 rnt nl,r ,rr tcr or`.tnvttl he,.il ccll !r In.lanuch .t\ rtttld tI„• wrr:n.il .it;ult.: h.trn.it r rv t.tllt I- .uld '-'+ htlnr(,Ln:.,, t.trt t: t,thul•itrtrti, t.tt!t 4hr,sc t,i .rrt,ln.ll. t,ri'. .. L,rtnQ„ Ih.l,l.t,:.t trll. r. tli.rul,t<t! I,,, . . .rlik:ti:;,tn' I)t , t tUl1,L:.t ( r::crl.t •,I ,.tt:i f r. •u, f1 .i, 111 ~• rt I.. ' nntn. rn vtu ts t1:.t.nnat: ( It'.,rlt ;nt t•it' t u ;n. ' CTR 1 I) 1 0421,

Cigarette Smoke Inhalation Studies in Inbred Hamsters 68 T4 PtF. .~_H..rF.q'k,,'rnnr , Smoke Tua: T)'pe of concen` No of c:warc:te tratl0n an ~. ..,. ..r,: .. ii •:oc,at!,>:,.^. •.r ...nK , aren. . ^-a + , f a° -a a: . , N . ,. F . -r. a 100, tnbaccn 22 ';. 645 1' 1 iS ~1 3 9" ~.rl'% tul,acc0- 22 i :1 ! rl r, .l ~ :1 . ., 5t19, tobacc0• L°_ a' 11 I T'1 _" ! 1 '• i~) . 101-t C :trel __ '~ - - lin't, t,.harcn l I • 17 -, 1 Knl, luhat'cu- i I 17 1-: I li t in'* t„t,accu' I I r;rl 1.4:4 le 1 IVUs C~trcI 11 73 42 9 I: 3 In 4 CF.arr.-cmo,e H a.l ;ontro CaKr-he!d . ri•: 11. 's:: i9 . _. Q .`.rr-., ^.aRP 1•.r~ _' .~ t! :ra I" ll t •,l 1'1 1'lU 1-, _ '." - ^ .'.ra' ^n !,i ai , . .. , •a• : 4n~, ~ 3 :n.l .itli! n.,! ,.,. :s (~r ~t.~~r _~ l\•• •~. ,. .. .. ( •a ~ ~ -~• .. - , r ~~i• :~Ji:l' .. ll~l~t 1" re: jr.an,-rLnKe . .:rn. iJ' 16 1' ai: ! 0. : J ! 3 3 I._ - . n -`1 .! . . . .J` J .~ • ~ - ~ R.ended w : . , .:re ,-a aa:a ~w.... ... .^~ li, ,.. .-^,^.. CurFeS- {'reu- ,., r,_,r .:s^ . ...a !^•••c•a-~d ^•.a.rop^;, es a: - • . •J :!. S. . .i ~ ~ , ~~t •t . . - 3 1~ 1 t S : a - - 7i ,:1 -, 1 J 4 CTR C~°'~~~ 042 `r"G

682 Bernfeld, Homburger, Soto, and Pal TABLE A-Histopathol,.yu rrcl/lt.it on the /aryngra nr ham-etere (rpo..r'd to .mokt or ron!•r.! rn.;,,+r!;.r, r~ K Hlstopatholon of larynx. i of anlr-.;a at r:1r. S mo' " e Tn;a: Pap.Gcma .:e af , are:u ccnrt•r:- tra:.ont b \u U! ar.,mais st.:dted Xormal' Sr,ere n} per- ' otal Exciud,r.g an:mais Inta•::%e car;.rorr:a T : •:ar: norr' a pras,a M;tb , carc,r,oma lor"ll, tobacco 2= 57 1 E ~S 2 702 2y 1 36 e 4' 4 r, ' -I- tobacco' :.: xt 0 9d 3 6ti 3 25 9 32 e 34 2 31-0% tobacco' 22 46 130 6-0 Sa-, 39 1 130 ~' 1, 11'1- C~trel 1., 44 cl~ ld2 6g nc n 10Ua tobacco 11 44 4.12 568 21" 3 20 5 1; ; ~. 60''e tobacco' 11 42 7r 1 54 8 43 9 42 9 0 5uy tobacco' 11 55 49 1 45 5 27 3 25 5 I e 1~~ 100% Cytrel 11 64 96 4 1 6 0 0 0 :ham ~moke rl 3r+ 5i 4 0 5 6 5 6 u cnr ;rol . Ca:e held -,0 '•d u i 0 2 0 : li .,j; ,,. ... . F~ _, . .. . ? ;- .. 'ir) .t •? 4 Ic..vc.rw an ma,> .t : ..... ^~;,er;,: a•r] rr. :~ :! ; pt:.aera:es.s and 4 an:ma{s M,tn flbrous pe:;; •~ , . . .. ..• ... .. . ^ . . .. .,r••. ] .. •e .. .. ., .. .. : J'. , •^a-: ]^ . . , ._:10 r;• 4 , . . ,.. ,.. •_ . . , .. . ., .~ 1 Q nt•., L: r:ll,.rl nlrlrr ,r . rilQ; •url I i.. h;,trli,. ;h I , :I:l .,•:, • r:ltl ,h.li•r ,1( triia. tr,!Ir,.rI. .In1! In\.I,Irln ....rllL.l!,r1L Irrrrll Il,c ~•1M I1~1,C• It,r I .rr r.ltllr i I!I•. 111L:Ir.,l Int IJt nt t rl ,nt.,,ltt' (.Ill ln,lnt.r t,.r. :n,.lnun.,i, Inh.llrl,iz ,lll•/lc Irnln Irnl; I.11/.1<tn .,1 Ilt, !.ILZh ll-t Irtt 1 Irlll Ilit' Irl, Illt-ntP „( t.Ii. I 1!1-trr,l,l'I! ,11 I 1~111,1.1111 tl/l,r' 1,\, I.,I ,111r11.r'. .r• Ii..'rr:,,:l ,/1 (,It'I ,:1 1!rt !rlcnr!, rntlt.rar!, Ilc':rl It r/,nhr,1 itr,l t,11!t i Iru,"% (,tr(•I (nnrr•nt rll rhr 1 IL: tlr, I hlr-r•I.rttmn,l1111 !rttt,rln rht' ri/ll.u rn rr,n• I!,i Itt rl, ..1n,! I!r, In, I,!, 11.1 •rl Itlt.r,ttr Li.•.n.~r.r i.rr111~,~IR.r, 1{I Il,n1:,1•f, Ir7!ti:n~ ,1n,ri,r Ir~nit ilnr.ll. \,Irlt .1 011 ,r)rIr!,r•,"11 I.ut,rr 1,I /lt/~ Itll.l.;lr ,.I!\Ill"'.li : .,, rc .rll„ nr In Ihc ' rl rl,, : ~r~,ul/, ,11 h.nll,lt r, i ~rr,l,l.: I•~r! ...... .. ... . . . rrtteti slutJlyd. Ihrrt t•>tst(•cJ a tal•c.rt,l/,rr„r ,': .. u, thli rc•1)cit Srnoi,c fronl Ihc Sr, l/lcnt'. It'tl•1 t,lth J ,n1Ui,ii I.Ir ml Itt Ilrc r\ lnr,;rrr• rh l::lh, ,, ,. t nnnl,/. rn /()1 Ili ul Ihr .Inltn.li, r:.r, ,I•. ., Ir'':n I.h/ o:I/hrl(rl) .,( h.,ii :!:.It .. "c '.,..., i r.,t 'i„ Ir 1'Irin /,1 II? ; 1.\ :11! Ia .. „ . , 1... . . . I!:i( „! ,r,\.t,l,r ,..., ... ...r , c• . ,n n:...,!>I n . . .r... ..,.. . ~ ,:III~':~ tl: .: ~ 1!;rr -i t,tckc r,i b!ent! it rht• hlL:h t:l,r i• \unrn, ru,t• ,.,rt:n„rn ,I::Irn.l/c \:: r,.u(: •. . .: • \-/rll,n¢ tcl !!Ir rn I.rl•I/• 1 •... .,., . l ,rn.,l.r Irnln IUII'; .,n,! (rnm -1'_ I..r. „ , '1• . . a.l\ VLIIJ(il Jntls tnt,rr /unt,)IrL:r rlJt ;!•.,tl ., • . • . ,I/ltic It%cl ,/( .nlr>l.c Itnln thc IlIltr It.r, ~ rr-trcc ur il,c Inw tln,t' Il \t I/11 crnr,i.r ,...r ,, 1,!/r• nf t Il ucrlc. I h/',c t!t)I. r• rl„ , t,t ::;, , rllc I', ,r4nlln.ln(( It,t 1 I)% Illc t I; •,.. I 1 ,. .• ~ Ir.l i 1. Ifnt.(•%t'r. 11r1 i1.IIIt11(.111, .lrlt I ntr% t,/•rt• ccn ht rt,ct'n Ihc Inn,,,l I,,:, n;, It ,,, (I"rn ;uu •In,! ~il"I • ,Ir./, , - I h„r ,, ,r:,l•;. % I.rllcil,./l ,It;11111(.intf•,I .,,!:,, Irl~t- :... ... t, hr /h, r rhr~ ,Irt• h.l„ t! 'n :!.r r:l::,,i,r t, Iln/,nl.l. •.r r,n 1L". nuutll,;, „i Il'111t'lil\f I\ C T R N N 0 4:27 57

/1 a Cigarette Smoke Inhalation Studies In Inbred Hamsters 66: Smoke from the 50:50 blend of to!,.uco ,In('. C\trc•! :It thr high du,c• !rtrl \::Is slgnificantl\ more turtt,,t!_r nl( than t:.)s smoke (rom clGarettrs cunlalnlntz itiu"• Lturl at rither dclu' Irtel: it s.as also mftrr tunlrlrll;rnlc 1!I•In s:as I1`o smoL.r of the ~U: 20 blend ur th.ut t,trr t!Ic control conditions. These differences t:ete stgnlficant at the 5, lesrl on the b:lsis of the oci urrrncr uf invasise carcinuntas, hut thr\ t,rrt• ,14n1(i(.Int ,It th(• 1'0 lesrl t:hrn nonlrt.a,i\r carctnf)nt:l, %,rtr :Il,u t,ll.c•n tf111) J((ullnt. fhr r•Irlic•st in%:l,iac I:Ir\n,l;c.ll (,Irclnl)m:n t.(•rc (Ir- tectr(1 afler 59 t:ee•k, of sntokr c\pu,urc. .In(I thr,r occurred in hamsters inhaling smoke Irum 100% tl,• b.tcro at the high (!o\r Ir\el. No carcinl)In:ts of the lar\nx were srrn In •irr. of 1 f()h•Im,rrrs 10-I/i anlm.lls from r.rch of thr 10 gruuf), i.lllc(i aftrr :i•,_ 1= l.rrl., uf treatmentt art(! nVnr• ,,,1, ,r•rfl In 6!( .Inlln.l!, Ill,lt (!IC'(! spurttancou,l\ ht f'rlr ''1 l.rr l, l( .\1„r,ur. Itt ',! nf thc•,c• ri'.I 1 '. . lr.lst :() Nrl'f,) It) !~i IhJ1 (!a'r: helt,rrn )y •Int', -i r•\nn.:lr:- . . ..tr.\ .,.., ,..., !. -. rt's+)r.I lOl•1! l:I1Clr1(lCl,l, .. . a,l:1al :11 1~~.!'T. relr)rltl\t'!l' .,Il;l!: l!irt: '. t,:'::' L:r:•t! .Illr: mnt: th•In ". bll'. h.t.: :n\,I,lar I.uarlLr•1; a.l:lll:,:n•i, 1!;:, :'711.!•t:,•. .,If!: ''. , f•1!! l: 1:. .,, . ...•./, .. ..• ... rl:, r, .111t1 I. t~s t.If.:1:-:11•:• N J .. •1 . .', : . ,~ nn, '- r . 5~;1'°_ u .,:a. 'a-~ . _ "12 ;y-,_ - _- - a-~ ic:'ied. Tr .+. .. . _ . •_., - lr.:l.J:rg ear car: •'.c'•-... .. _ -:(-- ^.a ..• . i'a • V! f.,) m .1•e `..n.. :~ ^, ]".z :e'. :!t::'.. : a'. . ~. r ~'0 >::- a: t!re r:;^. tson in a:i Otner Rr~ , In .I(cc)r('..Incr a tth Ihr :rt ' l hl,tllf).Ith'/ln~l. (!c•:t•a11r,n '~! ,. , ..,'1 , tl'\t•.II .Itl•. ,ul),tanrl,ll .aI;(:1'nlr• :n ;n,r:rl',, lnln):II, r•\!)•/i('(1 ff]r nlnlr fIr !'•„ .! ;" , un(r •1 mintln!Itn r\(,u,utt' I,I:;e L.II! t)tc:: I.,l: '..' t,k)• In a(lclluon, the rnctdencr of carcinf)m:t (ficl not tflffc•r ,I~nlfuan:!\ !n'n,c111 ,; „1!,,:• nt.•uu,l\ (!\irtV .Irt(I l.tllrll •inl/n•11, ,rr ,r\t!1 In Ililt Ilnc•s rtt t.lh!c Si l.rtr•,rtlrvll pn/~//i•)rnrtc - l ht,c• !).11)i!Inrti.l, , r l'.: I r! avlth hlL~ll frl•tlulrt(\ •1!lrr Y] a,t-t/., llr IlmL:,t \! r..', tu slnuGr frunt :111 Irrll,n(u•(nnl.lll)InQ (I~.Iralu, t.Ihlt•s 4. tii1 llr)t.c\tr. trth.ILluun uf cntul.c Il lnl I i_ I• rc•ttc•\ cftnr.ilnlnr; IUtt° C:\trc•I c!i(1 nf)t c•lu•r ,iL::_:. c.)ntl\ ntc)tt• LIr\nt;t•jI f),If)Illunta, Ih•in c!:t: t!„• ,':1,. 1 (nntllunn, 11 thc• hltzh (1,,,c 1,'.r 1"1 ,r,:.,. !)•11)IIIom.t tn(I(!rntr (!c•crr•I,rt1 .1• : '!).Il,,l ••.. ! • , :n the c:L!.,rt':tr> h, C•\tr'1 1\!: n m.1nlft•.r ('Ir '.Ith Ihl..s I\t,l', r:•. ' \IL •'lr !l,llll,lrr, ,tll(:lrl! •'\fl:'ll'rl: . .:,'t~c.:. •r: r•. il. rp. . t. . - I h( . .i;'.,,1\. -IrrI.It.::lr... .. .,./f I.III:tl I~II' t'rlll.'',I l,•'r . ltrt. I..'. :I~,.i :.1 la 1. , ,.,').Ir t • - .11 :!It' !1'Q!I r• '•( .t'•.I : 1' ,. . .~1'. f .. . ~.I''.af .. . . • \ C'. ,, !Ir t eu,~ r! h,. rlr Irl I,r t: !. , r. .,,tnr .c III il.rlll,ll I, Hittopathologic Changes In the Heads (Nasopharynx) Ahit lrln.llluc, ul Ihtr rl:,lutcl\ I::fr,~y(It•nt l:nl!Ine, .I, \.il\ LI.II:,!,. .i,r . .,! \,!i'.,!I i.lt•.... . . ntrnl,11 ,illl! (;r-i!1, \lu,ul ,,..I.' t _..!IIfllll . ... ,,,t:l.i, . .. !tlt~./~u: ;tnuln .rrli.ll\ :!1' \ .. rlt, !.llll.rtf, ,,,.ll:ill: :II •III:I:I.II, • \I„r CTR ~"~~'°~ 042758

I I / I /1 664 Bernfeld, Homburger, Soto, and Pal M T.+BLE 6-NI• oEr,r'r•;lucl: rc.cul': nn tne lary .; J ha~>.. .;~,r. r4 , nl•.{v I t/ Smnke Tt;;.ii Nc Hlstopathoiolry o! lar~nx. , of an,rr.aa a: T>'pe of c:Farette concentra- tlon. "It of an:^:ai5 stod:e(i N••._al ~c cre h;: per;/iasla Se~ere r.y perkera:os,t F.t r;: s D"•: J lfl,r'r U•: acco 22 16 _. 6A at ~ nn 1•) il llnl ^.5 i••!I'b 51) b lot'acco tobacco- 22 l5 :v 100, Cy tre; IS 33 20 0 - 100* tobacco 11 1" 0 zu Iu 'I ?p4, tobaccn' il 12 S 83 (t 5nw tobacco- 11 Itl itl til l t) 100% C)trel 11 12 c,0 33 0 u Sham-smoke 0 16 50 25 0 13 control Ca¢e-heid n 14 21 36 14 _ / control I Itr I.11 t th,tt Iht'rt• t..1, .1 r.llht•r (.ItL .I,,• , The f ¢' res ati:~ .:P ` r each Rro:/; rna; (•sceej !un. '..hen there wa-.Im :a^t- ,/cc..rect, Lc:eo In this aola `\l'-.rr .r.e a a, of the fl( .re~ r, r a¢roca was c tuol. there Kere t,tner m:nor a: rurcla:.••rs n,. . ca•l ... t. t c,:n as ;u: ....` ^.n. . tes rr uc.~. p:Kr:ert. or ncmorr.^.aFe B;e.^.dec a,..C; ... Jlilrlrl{; I,I itlt ~ ~ . Illt I-illh' i Illl:ltl: :I1 /.It :1 „I _•/nlnt.li• r,t 1 I!.t i.l,t _ Inll:.lr. \•II~ •..ctr •,tl•n,n.lrtirl, ....1. ~~IR I,tirrl,. Il .1 II, 4;.tllt: .Ir,! ,... ...• t :It ,1 •Itttl• I!a' It 1.:.IIrtln` ti t:lntl r• ..rlt I.,I: :. ;.,rclnunt.l rlf fh• .Il;t.ln II1,Int1 i!tt' ,ull fl •uc• ,:1-u% /1 Histopathologic Changes in the Kidneys f11,. IL1:., •, _ ! int I ctrr. .Il;c : ., .. ,r inlll:rr tl:,r.IJn II t'It• / \;r t.ur I.1•t. t .Irnt!,li:• . .In h.1 t,',tl-..ut •..:.,I 2 ,In; lll.t , t. ~lf: i tt~l/!t„I'.I I I~nttU•~• t.•re .I111,t:• nll•i :IL tll .II llIr:,n~ untt l, .., :h.ll Ir, IntuI,rmrnt ot ,nu•Lr Inll.,i.,ultn tui'./! ,I,It Other Miscellaneous Findings .Ind lu::Q .I/'t•r .IntC I.lltit'1tr .t/:,:C .1:{.li'.,•, ,I..: '.,::,1: tn!•I~It .In.ll~trc f.lt'tlru..IrtlluLr.l:::. llr.ltl I.If• t/L.nl. ,If rt\Irr.linlrl ral/,. 11R1 rtl:tlt!In4• , .I,:Inll~ 1.trf I)cr;l ,/r114t! •.. lill: • .1:,111:'~ / . .,,rr I!:r IltIt r\;• ..U.. ' • •.., •• t Ull,!I11l/115 Jfltl ,IQ.III1 111l1ntJl,l1( i% i't : Smoke Deposition Studies I'r/ !In::n r, .lu,!It• ! '1"• •tLIJist•r In Iltc :r.ltla.l .Ir:~.l ,I' ,~ . . • . ItInL~ .:Il,l !.Ilt n\ r I'It.lul•„III'. I, r',.il r. II /;l.,t.,,. • . . :1 I:,nr . . . t.tr( Irl Itl.ln~ Irt\t.llltr, .~• ,al.lii til.,t ihr illit:'. . ,,i ti't .Itt.llt ait. Irlt: ht nc / Iltr Ilct.tulc trrt Illv,lt Histopathologic Changes In Miscellaneous Tissues I{,~Ic,l„Iih//1/rL,l Sll,t111, '•.t'I(' INtfr,rllltt! //It 11,~111• /,• II-II ,II/. 111 I //I ntrn.ll, .lul„I/.t((1 .Illcr -,Il t.rt l., t,r I„ni/ r tlllt.lll n/ I rll, t\I)t rlrnt ut Chl frlldlnl;, Int lutlt II i! ,n.,.lnl •,. I t~•llt ,I,I.II,I,Il ~II /r IIf tt.ll: ;111111•. :tl 1, h.:Ic •,f tile Llrec I ,I r,Ih.tt'•.•.'c. 7 t,f tr-.tltuLlr .tlrnl,l:t. Int! 7 II tlurlltlh//,I, ,/I Ihc .lurltIt trl IIItlltlrln I•, , Itt: l,h ,l•t.l. rt rl.ll .Inll llll, ,illl.,l ' I !• uli, n• t rtl.ltcti P, Iilr .nt,,:c \;,.•, Ilt I\( I 1„1 •.t •1) , •1•PII\IRMR -- In.11% 11111.11 t.llut, I/Ir lhr' lunL:. t..l. ,1• t, ~•III fl~,:,l~ n/•n n,llrlt nl In t/.1I rrlt I!linl - `..• •. (lt/lt li/t.lua„f UUt Hl,tti:llt t/I r\Il-.~urr. t!tc Iltlltt.ll, t„•;I,! It,/;,i ::1, n Itl.lfltt I~ Iltllflt.lnl 11.19 1.1,11 „f Ihr I/,r.li ,/ flt:•,~ r\;m.;,tc I.IJtlIlll' if',Ill /) Ir, ill ull: i,it uh hnltllt:` t. tt ,,,h!t(t I,, ./rl..,.l 1- tI1111.11 t.lll.ulrln. 1\/.• trIllllrrllCti tlllInt„•~ Ia~ I i,•, i I !.. .. _, .,.I1 It It i. ~I, , 1 .. •tt/,nti Jn1! :n.:C';,tvt:•.:( t\: -!f ...a " " ~. CTR HN 042r'`E59-