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(` sIIinm cy wa? USiAM with e®phe-sis upon ?OSSIET? C'.?kDa- S F'ROM T:1&ACCO ~ Exh'bi 109D Data DR-lID A Cn?::=E AD b7 C1aud• F.. Te~.,qwe,qwe, Jr. 2 Fsbrvarrr 1953 J C/J7 7 Hl l 043168

(' IlM 2F 22MA-M I. JGS ~L`f . P&P 2 II. ~ $~SC~Og• 2 a. ?ol~;~,lea.~ -oma 'c pz3zrocarkn.e Lad ml.at.A Het,.r2oycli4 6 B. Q a~ Ca: cinoa.nic a a. 9 d Seterocs4lia C.omnouid~. l. Ali~hatio ~~ 9 , 2. &r2M Lic Lx:a+s• 10 3. X1sceLr.ma.e r"a. 10 1•• ivJpiV~IJ hNJ 4•l.ny,~~ Arid~I • . 10 A. StaLintiGal S 'es. 10 ., . ~$L'.,udi e s vi t.h lo Dncoo Ss~ as ~a noe a• 22 C. :z. -en;s I9er.tiilc3 Lg fob°eM 2aLxjARM. . 12 , D. Cr_-_-po :ae-a soi ~.~s o ,~~stancsa g~' + L'4esibili~ _o~ 13 Cs.-~no;-~~a a ri a:.n¢ Tbesi.. y. '41oDa.ooo Adi ; inj. 14 i4_ J+?hT. J 16 -1 - CTR MN 043169

!'h. ob jst of i2sis report is to g,tvs a bro.el, general s¢rr.7 •f oanasr r.saarch, with -iapbaais os •tuiiss artoallar or poteatiallJ r+Lt.d to careimge3ss Sron tobasoo. Pertinent xe.fsrsnoes are sit.dy whero possible these are review artieleu vit,h oosprsbenaine oonrage anr] bibl.iogr.p2q. Ib attsayt has been mede at oo~stabsss of oaverage of various topios or oo+L;Ilet.- n+ssa of oitction of orig•i=al .vciroes. II. '~T "MMIOg Caaosr ia one of the aost aaeieat of b=Ln dis.ases and its ooairrence is not.d in the earliest reootd.d history. It is on. of the srsat universal and eosron of all dia.asss and attacks a11 foss.s of lif., including plant life. In strict sedierl naaQei eenaoer' rafsrs only to saligmnt tmors s.r± sinz frsa epithelial tisane, that is, from otlls sontained in the skin or coverin= stuoosa or ssrous sbesbransa. Kalignsnt taors of non.pithelial, modified, oor.n.otiw tiasae are knovn aadica117 as saroosds, aW various other ar.zss a-_e ap;tlied to other intraaite, sialignant growths depending on their origin. ard ahsraot,aristiea. A arsd.ioal 42usifioation of Lusxa, both aalis-- aant and banign, is given in Table I. To the 2tpz,an, •canoar" haa, through long asags, oose to be an all-embraaiw tera referring to a11 fo.rzs of ral3.gnaat, invn.ai.e tusora, and that nsap Yil: be followed in this discissioa. As used in thi s di sau as io n"earaino geni o" xsans oanoe: -givdncisg, a nd a •ca=roinogen" will sser.a a oancer prodsoing ageot, tGss" being gsuerally aaoeptad ;iaszss. S~ I Cle.saifioation -o_° Tumors _ e:Az n M-alirnan 3c sot in-Tesive Inrasir. S: ov grovi.z~g Rapidly growing Jo not -.etaataaise lieta.taaise "~o not intarf®r-s vitz hsalth Det-imntal to bsalt:, ofLen fatal 1. CMNb..^?IV_'- 2ISSGZ TMcaS A. 3anigns 1. M.roma, co"sad of fibroas tisaue. 2. Choadrova, oanpos.d of cartilage. 3. Cateossa, coa,xssd of bone. ti. Lipom, composad of Yat. J B. Na1lgna-- ts Sa:-cama, a cellul.er tAmor cxon?os.d of any ooaasec'.ivs tis..i ealls in d.lsar'!a_iy a.r.^a:gnacnt. 2 I t- U 0 ~ W ~ ~~m R ~"~~~ 043 ~ ~~ ~

(N II. II I. Ma.a TL45U SiMTR9 -- B+aigns Rjvssap eorposd of iaooth sms41e tissu. , Y:- ITFffi.IIL tQNOW l. beaiWu 1. 2. AsFil.Zom, acx,xse!d of sarrtio* spittxlims, Adsn=ti eaa~asad of glanQnlar spitbalita, $. . Nal.ignaat: 1. 2. Epitbelioss, sqt:aasors •pitbalia; oella in disordecrlJ ai-rsnQs-eat. Carc..'mwa, glanhul.ar spitheli.al Calle in disorderl7 arrntszeaent. 17. RK~Ir..~ 1~. ,IlL ?uMIRS A. 3cnigas 1. iiamaneioaa, oam:-oad of blood sas.ls, 2. ~~, oa"aed of lyaph ? sasnls. B. ?~.alianant i Sr--Iolholiam, an?oaed of •ndotbali.ai oa11.a in diaordsrly a..-ranCessnt ?. Piao~:?D 2UW,)3S A. 3enign.i Sevu.a, a r-izaecrted sals . °. ?+_w 6-n&at: Mel.a.ncaa, Pigne-rtd t.z=oi darired iram seolo. C&=sr bsgins as a sizp14 body eall or group of o.lla vhiah s7a&..nlJ s',s..--ts to W.i1Li,^.ly vittrnxt restraint. In •aposrtaaeons" human canc5er this au?+ 4 ;1!.ontion is initiatd by nDkaovn csnae or oeusss. s0ooupationnl• aanos~s is :.-l,.e reau:t of p:rolong.d axposure to imovn oaraiwg*alc agents, a.s radio-- actiws cs;.c.-ials, z-.remT, ooil tar, aad others. aRxperiseat4l" oanoes' is the :eaul ;, of dnlib-sruta snd often, repeated, applicatioA of oaraimgsnda agents for '. ;a parpoee of produaiqq canoe-. T:w unrestrained aad nava]ly si;id milti.liaat.ion of oslls takes place ind.pendantl,y of the reat of the aodr, servizg tb use11i1 bodii.y Panc'.:=; ar-i iaRdsa the surrounding tissuss er o ras r.s b7 :i rsdt agrea.d. Jiagm r•ed aod treated at thi e s tsge, usna117 by :adiczil erarzsry or radS.ationi t.he oanoer "y often be rsov+ad or aads to s._bs±de before the aatire o-,,4r: i= =r-olaad. A].loved to proeeed unchsckedg the -T~ovth a,r^s eads throuot,oat Uoo body. ':lxall groups of o.lls ba aak off from •..ba pr'..--ary Zy-ovth a-nd :sc by tbs body fluids to distant tissnes vhe re they i n turn pr->du,e~a grr e*.!-~- - i.=Uar to the priea,ury tn.4 _r: It i ~e+.-~ ~,~• c ~:1+: : S ~'a ~.ic ot s`t2'ea.Cl o.^ :6 3tasc,r:..°'c33~ i1 3t dittiOgLtia~ s ~g~t •!"" a benig-i, tumor, CTR 11N 04.~ T"I

(I In i;dte of obae.rwationp rsa.eroho and theorizing for the paat 2000 yrars, tbs awas+ cf spontaa.oess bmean eanorr is sti]1 unkncva. By obsavatioa end Ly oorralatioa of -qlinio.l data vitb ooaypation, ea.irosaent, and the lik.# s.rv.ra1 at.ete eLvA a8 ooovp.tioeal aaa4ar Oave bwa diavo.rtd. ibovgh know 1sd=. of Mv or vlq tb.se agents att is v.rr 1a4arql.U. Ear1y in the present oant=7 it w r*aUsad tbat wrlcers in o®mpatLona insoltiaR prrolAag+d az.pome to ooa.I tar products sboV.d an a.bnor.alLy high inoidsam of W-n oaao.r. In 1915 Zssisiya and Iobika.a dlseorsred tiAt. as edaAaz of tbs skin sould be prodzsosd by painting the sars of rabbits vitb soal tar. D.tailod infsatigatiou into the aature and ia.satitT of the earcinoesnic agenta in oaal tar indi.Qat+d that the ageats wers proDahly poly- noclanx s.zoaati.o 2qdr-..sarborsa, probably alated to D.rsanthravev.. 1A asrDer of oospocmda related to b.nsant2iraotrA were pr.pared and found to be oarainogsaie. Conai.-re.ntly, imnsatigatar9 wrScinQ on ooal tar iaolated j,4-bsaspyna.• tonnd it to be idsntiaal +dt.ti aynLaetic 3.4-b+nspn'sae, aLd shoved that both onspound.s had identiaal0 poaitiw aetivity. R.oent work has shown that ooal tar oontaiar other potvnt cmrcinoeeme. By 1930 the work of the Lond.on sc3ool under Keisaaw&7 and C*ok bad t-~-orouz,hly estahLahed the fact that oarrtain Pctre, synthetio) pol.ymaal.ar a.xomatie oom-_poands ~,~ere true carcinogens. Ls a rssalt of wor3c of this tse=a, to;;ethar vit?: tfia'.:;o.° A2-- :aesrioan group b ead.d b7 Fi.asz' and Zat.b...nai it was soon found that a la.-Z* a.aDa~ of polyirclic aroaatio , togethar vit2: ssa.q of their Itixtional derivatit+esp poasessed carcinogaoic aativitr. Later work s3oved thzt anb3tancea skis to po2ymaolear arQba'.ie bjdzoc~na b:.-t eo ntaining he tero a tocs al so po s a+s scd carcinaecs'e c a ati ti ty. i s re se.."ch activity e.z;~snded sierera_l otber ola.ass of a.~onsYis vere fomi to be {~ oarciaogeni.o. Those reoeid.ng moat attention he.yd been tse sustar+ds, rari-Als a.ro^...at,ic anlm coapomds, and oa:ponnde related to 2-4.ainofloarene. Mup o: :er classes of orn,-ounds have bssn investigated and asnah work is oarravtly Dai.og doae on this bhase di the proDlea. / / 3aw~a1 seet-hods hire been used for testing of tb6 o&rciaogenie gf_ sate of +ea.rious substances on amixt . These test netboe:s are accsxxtep '..hough rath_r alov. Waa,7 kinds of teat a.aisdls have bein usad, too~ pazn strain eiae seem to be used most widely. ?u.re strain mios abov ndar27 Us arme a~copti bS1i tr to ehesd oal aarcinogs ai e i s and are ot .e ry siad-~ir gene ti c oonstitution. S4isoeptibilitJ ms:: vary oonaiders.'u17 from etz&in to jtaz!n, in one test ssat':od a dilute solution of the carcinogen in inert so:rent is B-ppIied to the skin of a test anisial. Application is sade, tdd.r; :+eekly, for a-period of aeversl veeks. Aftez a more or ieea p;'v7Ja;ed latant pe r? od an a ati ve onsti~no a-e n gi fes ri a e to a ca noetti+us ~-.~ of f be ski.a. ~ Another method involves injection of the agent su?+~.ite *~aso: intz•_`- pe:-;toneally into a test aniadl. The quantity in,jeoted ;:z„ solv.nt is oftea used, ard. more than oAe injeotl.on is aosetisisa >ade. k:.~6t''•iw car- cino;en.gives rise to a canoer of the oorsmeoti.e tissue, ,-;`~ti at the o_ i 1 j= ot.io n. Kar;y o:L-s...- te s`,.a ha ve baen na ed. Exps ri =:~aad ik^..hai dp e.ra 3ale to detarnins within a day or tvo the t.ime at vhic--', a U-:ek°n-ing of the t.iss:be is indicativv of tunor forzation. PRSthological z;-~~ss e-2 used to e:,t,ab.lish whether or not a tumor was aottLallJ present. - 1 - C• / V 1  ! ! 0• 1!' .A `/e-e2-C

f` Caroimgs:as s..rr oonaideraDly in potanq and taiaors app.ar in traated aalsnls only after a aonsidarabl• latent prriod. This period irari.s iroa oaa to two srrntas for very aetirs eoepoand.s to two or .ars years for fsbl,y active ona. k3dle the test a.t.hods dire very good qvalitatiw rssulta as to tbe aarcinoC*aieity of oompouadsp a*outat* qsxntitatiT+s rssalts a.s to r.].ative potstaiss are ditTisnlt to obtain. 3ersral systeas lsavs ae.a devised for rating eoapotmd.s aa to .araizoCsaie a.otiTit,, bat atw s*ms to be entirely satiate.etorT. Suoh systeas nsaall,y ta]es into aooosuit dosaV l.ewl# dosW periad, latrat period, and p.roant of ani.als d.valopins active eaoosrs, Witb tb,. Yaowledge that spsaitia, pur., organic oo.qoaads could in!uoa .acpariaarstal oanosi sim33ar in every respect to apontabemsa oanosr cxam natuY.lljr an atLwapt to aorrslat+ spontanwm hsaman oanorr vith the prss.aAe of Ynovn ch4wical oaroino"as. ihils s•aores of potsnt ds.mdca.2l o..rainog.as •ure m.r Irno%rn tkwro is m dis+st eTidaaes that tbV ars indssd rsspeasible for epontansona Aissn oseoar. It is possible that tbea" ah..daal odraiao=.ns say ba proc:naed in the body by abnorial prooss"s, bat substantiating evi.d.noe is 2. cdd n; .'• o da te m hvn c3emi cal oarcinafe n bas be sa foand i n oanoei+otu tiesi:.a or in body flni*ia. Fiosmr, sneh an agent xs,y have aet.d as sa ia- st±3stor of aali3na•nc7 at an earlier itage in the lif. of the organisai being present in vaniahingly azsall e.9o=ta at Us t•7sw of attempt.d isoLtion. There is much czi..-rent reaeareb aod apeonlati.on on this phass of carainotanisis. I t i a a1 so po s s i ble tha t s po ntansaus carrxr aay bo Caus.d by ext.raal c:aseiaogenic ageats, such agenta a=„ering ths body with too3, during respiration, or boing aheo-bed trorn the body anrtdoa. Sose such ag-~ata, as ooil tar products and x-ray, haTa indezd been aho:rn, by esaa`_ nation of clinical data, to oamw an abnorr,a.i.l,y hig.h rate of ine-ridenae of oszoar (oocupational ") in persons BubJeated to lone and repeated azpoa:,=a to thsa. " other external ag*neias hcTr beoome a3spect, and considerabl• rese4roh haa been ddw s.nd is in proirsss along l.4sae 1Leas. Several atal.istioal stsdiea, based on elinioal data, on eanosr of tbe reapirai,or.T systea hare bc~en cads, and t.bsse etad.iss indioata an s•bnots.l ix-ease in the inddQnoe of e,4ob oanc5ara, paxt.loalarly among aess, dzzrizg the :_aa t a ava...: d acades .: has e a t:xii ab i ndi ca t. tba t soasa Qaroim gsn, either ain bo: n or ar'..::ia_ally inta•oc?uo.d into the raspirator7 eyeta.t, is responsible for canoar of the respiratory systea, sad taat videspread expoauro to tb. aar- ;s=.-:n, va..a.-ly azoN nen,Lcs b+aa fairlq reaont and is inarsasinQ. The reoen t ra'.o of iac..-saae o' eanoe7 of tbe respiratory syatem rathsr alos.ly ;>azrnllels the racent int.rocturtion and rate of inomTsie of cigarette oonitmption, and Lhia, toge;har with the fact that until Tary raoentl,7 the vast wforit, of :;igaratte aaokara haro been sen, 2ms raised a wsJ oonsiderable quosti~ There appears to bo a groving s-.ust-~idon, or e-Ta.n ae~tano+, a~rong s*diaal men and c5ncer resers-obers that the xra12e1 inc-rease in cigarette oons:mption and inoidenoe o: oanoer of the respiratory ays',sm is core than ooiacidsaos. The atatistlor._ at.uies oontixms, and their iaplicationa 3save bcooze the subject of esucr n?.ec-sln:.ion. T'hia vork is disc+.iasad in more deta.il in a later section. Som wrze:-a have atteapted to p:vd:tioe txperizen:al ea.noers in t..at by a.ppli~L:on of lzrs obtainad fros tobscco, tabeoco =oke, and otb,47 _ 5 _ CT~' H~~ 4~~~ ~ ~ ~f`~ ~

a,ate±1a.le derir.d fr+oa tobaaao. ?be results of tbes" teeta, aoae atrong,l,jr posittiive and other ooapl.tely bsZativ., bsvv bsa iaooQCluaivo, tmoagII ronld tes to iadi.at.. the preseaos of earoioogass. Other workers hare atte.qt.d to isolste a+eraaaogena fzna plrcnlJtio -produota fYva toDaaoo, and the i,dsntiti- oation of knovn oheaiail oarad.nojeas is rsported. A l.at,er seotian will .ona.id.r this work in aorv detsil. Beonnae of the pouible oaaneotion betwsa tobaoco sooYi.ng and oaneer of the rwpiretory sratom it is rrs11 for aarsnfasture.rs of tobaooo produats to be aware of pns+t and present oa.aoer rsaearoh, Aooording1J, tLe re.aiaiag aeetioas of this disauaaioo villl r+-ri.u in .osw detiil tbe prs.ct st,.tua of caao.r res.a_rch tidth particular eaphsaL on statistioil s tudiss relating oanoer of the respire,tors sratsa to use of toDaooo, and on knoun osrcLogeaic ompounds aad their ral.ati.on to awyoands present in tobaaoo or tobaaoo saoYe. OM?a CAL Q RjRCxs= :.. ~l~oleer AMMU r 1pd.-ogarbou.e ind ".•gjajgd RejeroaPello QoZ2UWA. (1 - 16) A l.rge m=ber of polym}clear a.ronatic coupounds, togethar vAih suq related hcterocyclio ooapounds, have bean tounsl to be carcinogenic. on azr~ration end diacsesion of all suah ooapormd.s is obrioitsla baToad tbe ecape of tMs disanaeion. Reprtiaa.aesti.e ooapounda vill be oone-de.red;a very gcneralisdd eor^elation of aotirity r.ith strnctare vi:_1 be gissn. Cbol.anthztiane (I), 3,~--~eas?y:ea. (II), 1,2,5,^-c.'iber.santhraoers (III), 3,4--aaasa;-hexian:ti.-wne (IY), chrys.r.e (V), aud 1,2,3,4-d..ibentphecanth.-ene (PI) a..--e a11 car-,r-"m;; ans , and are re ;re sea ta tis o f the bns i c ring e truotur,sa found to sccampany carcimgaaic activity. II 111 J V 6 I a/ CTR HN 0431"A

:?yese ooapou.ads, toetKor vith their derivatirs, lu.e De+a studied raLaer =t*zisiv.ly. 1• saaabe.r of allql-# arrl-i 6.].Ag..ao-, Wa.no-, lll4'l*2C''-# and. Lydrwqmat2q1-de: irativsa of tbe parreat tyd.rooazboas ba.e p~ to be .otiw, often anre aotiw tban-Ua parent eoipaaad. Mozq ral.at.d bateroa7olie Oompouads hn.e alao Dsn sbo+rn to be oaradavgenie, rsprsstatatirv erasP2as b.i.ag 4,9-di- ostb71-5.b-bnnsthiophm,nth.-S= (TII), 1,2#'Sv6-dibensaari,dins (7I21)q s.nd 7i9-4i- met2yl-3,lv-beauorid:.ns (IX), ,j , . ~I . -I GZi I C N~ IX ConLsaction of the oaatral ri.cq of dibansanthrarxne or its iaolog (VIII ), as i•n 1,2,5,6-di8onsfle..orane (X) and 1#2,5,6--.'SDaasaarba.sols (z.I), disini•ahes Dut does not aDolish activity. The lower 1.init of moleoul•ar sise oo"t.ible vith cereimgenlc aativity ap- p,--:s-tD hase:beem reaahed in alkyl subatitxsted tric,ynlie hydroosrbons, of vhioh 1, 2, 3,l,-t.eL.-a-%ethyl pLlanszt.hreaa (ZZZ) s.nd 9f1C,dirsthy2a.nt8raoene (XIII) are ezaaples. ~ ~ '3a u, pe..r L•sit of sol.c.itar sis" is still wso*rtaLin, thossgh no ooaponndG having w; e than siz fused rings has t~ far bien sborn to be earcLooZeaio. 7yi--Ag at the a;)p&rer4. ttppar l.ialt of siolscul.ar aisa art hesaorolic oosyonnds sucy as 1,2,3,.4-dibarso,-jrane (XIV) and 3,4,8,9-dibersoPO'T+ne (2V), both extresa¢lJ po'..ent aas•cS.aoreas des;•ite their high s,olcculsr veiZht s•nd i.as9uMlity. i I .i 7 IN IV L.r T f'4 F iN 0 4 3 17 ~•

('` ?he oa+Qrusxie desarib+d abors servs to illnstrats the i"rtant cLss.s of aeraiaogealo yol7saolsar aroaatio tqdrvosrb=s aaS related oospounds. YAuV wazice.rt lxve sought to oQt7t2aU aarcivogsaio aatiYiS4 with struotttTs in this olass of oompouads. Ptr d.tail.d oonsidsration of stroctur+ 7+..rsss atLitiV ia a larQe namber of smh oo.Qound.t osttain Caaml oonolnsidas have ti.ea drawa (1 - 20). Dadgsr (10) has aaaaris.d ttye.as oooolasioas in an sxasll.aat review i-rtiC.2.11 • 1. Cartai.n triarclio, t.dj„rsqvlio-i psataqalsa and h.zaoTolic lyd,ro- ,vLrbonr or their boa,olop an eano.r groduaing. lfost of the aotite oor,wuac3a, Dut rot a1i, ars deriTStiyss of ghenanthrem. 2. lidny oloanl,Y related het..roeynlio ooapouads a."s aleo oaaosr produaing. So ars aerte.in dibensflmrenas. 3. The in',zvduation of ase'.2:q1 _rroape into beasanthrAo+na, bsnsph6canthrenss azx3 .b.:7aa.ae raozma11y 1ssds to enhanoed activity. 'h+o x*tbyl trvoQs or oore aciraally aat additi,nl,7. on the other hand therm sezas to be a lisiL beyond which the intraduation of tuz-'.bsr set2q1 groups doss not lsad to enh&noed aa'•iYit,T. The S.xzttroduetSon of sqtiql groaps into the angular ri--Ag of beasa.nt.hraeene dop not have this aft.ot't and al.' ezeoh caapon3da a_ro iaa.atir* or have only traot activity. L,. Similar rolntionsbips hold for the beasacridiaee, exowpt that the 1,2-bzasacridinas are much sors oarcimgsnio tha.n the 3,4-bcssaaridi.nss. 5. The i.ntroduaLian of xeth7l jsroupa in baaspr:aie ar.d diD.asasthraotns ia mo:v camplex. Ia aary cases this diminishss activity alt2'roagh the oppoaite sea be trus. 6. il.kyl gr+ar.aa other t,2a-- iethrl are yrograsairsly lese efteo'.ira as the mabe: o f aarbo n staas in the ohain i ac.tiaasa. 7. genrv ol3,e: suDatituRn'ra in "tavoraDle• positi.on. oan coarert aa in.lotiro paraat bydroca: boa into a oar~m4eaio deri~rstivs. Both elec?son at`.raotiag and e.ootoron repelling grou?s nay bave this p.-v~erLy. "Pavor3b.le" poaitions for aetr,yl gro" are e»ti nsaessari]y the saae es for other groaas. 8. rart:.a.l hpdzogsnation of a carvimg®nio ooapound soaetixcs but not aluaye de$ctiratea the substanca. f 9. Attempts to relate carcinogenie aotirity vith (a) shape anci sise of tuae mleau? a e:.nd (b) elrctron ~^-ge on the ph,enant,hrao9-type doubl• ban,3 present 3n wst carainodens have b-.3en only partly suecssa1u1. .,tudie2 of aot._+y±*_.- and li is reasomhle to 8uppose tbc t vi th ia: reased da ta and s t.udjr vil : e ome a mo re p.revise und e rs Land.ing o f t.s ftryiamental relations`sips. 8 CTR HN 043'-1fG

I in e, Ann&j. (1,3,12) ` '!be diaaor.a-y t2bet oata.in polTan4lsr.r a.ra.ati.o eoupouads are stisulat.d a s.arah tor-otber tLassas of ooayounds wS1oD tdght also yroTs 1bo kave asti.ity. While tb. pol.Tau:cl.ar aresatic 00apou.n3s hnn rro.iT.d the .oet atteotion, other st.rjatarall7 unxed.,if..d al.a.asq of oosspoarnis ha.e inrS.eQ ba;a aLown to be earainagaiio. The s.arch for otbar. exraiw`sm is tar traa oasplst.e aad oontinsasa to be aativ+aly qurswd. Compoutrds r.prsssatatiw of the var3ons alassss of earGiao;ens ara 7ist,.d and briefly dsasribsd bel,QSt. 1. &Utbotio and H4 gnan"+ xi troWn sastards (1TI) aad sn1tur. av.atards ZYII ooots`iaing two aotive oent8rs haie besn sbmm to be o&reinotvado, apper.ntly dms to their action as crose-l.intiaQ e.gtiats (21 - 24). Other snbetano.e abl* to aroas-liaic add groups by este: iS:--ti,n- azd bocvn to be ' g.nio ar* ontadians diepozid. (lE=), t,rimet.t7lnl aal,amina (XZZ), a.nd disarylglyools (YX). (1, 25) 1 C~~ C::2- C1 C3z C~ -"C1 , ~ 2 / ~ ~ S Cx--CH c:.2 C:?z C'_ ~ C?.2 C::2 C1 z 1 x71 ctf_ Ca2 ~0~ xti_I %,7III / ~ . _c-- .-- - c C C~OH c~ cHz o-soz c~3 ~ , ;, ~ F h CH2-cx2 0 --S0z-ca3 C ~ SE Cr.2-C XX Ot'm- a1ipha•Sc ca.-c:1no3er.a a.re certain •t2~ylensi,ninea (7.II), ana c..-ethaae (ZXSZ). (1,25) ~- - C -ti 2 2 2 0 CH zcHj- o-c-sx2 `•"-X I XZI I 9 CTR HN 04311 `~~

('` 2. &mmti o Aai mns (l, 3) lfaiq a.rosnti e.ad nas h&ve been sLmm "U be ca r ci no- en1 c; • t.~e .'si~plest=bbi ng .(:-ae~,~naskp~rLhalenh :(xxuZl, LtiaoascDsst~s uIY) asl~stl.lbines (IUT)t wdnodiphmip •ls•ls (zlrl), .xdnotlsoruass Zi4us, and bi4•(/Q-a.lopao.tlp'1)-•esis.o. (uVuI) aro seprssatittss of this aasa of ooapov,ias. m XXIII =FL 3. IV. . - CH2aa Cfi - g' c~ cxz Cl ~ ca.z Cl~j- Cl XXVII • XXVIII i eoa;~a~aua Aueate. (1, 3) Physieal earci.nogeaie aVats ineloda appliention of looalised oolds izpl.aata.i otll.ophsnei and ioaislW rwdJ.at,ioaif to •cseas onl, a tsw. RMarons inorganic s.g..u0s suoh as setal1io nickel and salts of Xine azd bery7,linm baee Daan sbotra tA prodzsat eaaoars. a+ow An Q=K2mIC=m A. $tat'.sge+e.2 StzY.4iaa ?hsre is rat2,er genw.ral agreemeat that the incidence of cancer of the zoapd-ratory systsn ba.s inareaa.d greatly ia tbe last balt os.atnry'. bsveral :eoea'. statis+doal sCadiea have sbovn this rarked inarease and indieate a ooatian.ing ratA of ia=-*&as (26 - 3Z). Autopsy statiatios UraugLaat tba world sSov a great immva;~e in the inci.d..noe of eanoer of tbe liusg in relation to aancer in geseral (26). Yhsreaa cancer of the lung wa.s a rare dis.asa 25 Temra aro, it nov oacurs nearly as often as oaaoer of tbe atozsoh asd aQZe often then aancar of the colon. 8eeeat stasdiaa at aararal large tmriaaa bospitals (26) ahav that it is tmv the aoat treqm.nt visaeral cancer in s+sa in thia oocxatry. :8sils tbe inrsidenaa of lung cancer in females has l.nersssed apgsvaiablJ', by far the g,-iatst incredse has been in aedles. It is estisat.d tba t the s,al.e to feaa 1. incidence ratio is now abozrL 8 to 1. Th* increase in the incidence of cnnear of t2se lung vhiah has ocaurred in the pre"mt century .Lggd5tJ1 TbY or imT'6ased OOetaet Yit21 Qu'Oj.flopIIlO itimalli, such 3timul1 being either ai2'borne or artificially introduced into the lan.y-s. Tbs svggestiox that anoY3•ng, and partiettlar atgarette aaQ3dpg/ axy be a causative factor in the induetion of eewc~er of the zespiratosy apstem, inclndiog the orel cavity, 2aaa been aa4e by a3a;r vritar: on t2,.* sat.,.~ (26, In 1941 3chaner and D+3alosy (4S) oaliel attention to tbq aini.Iax'~ty oS' the c.uve of increased salea of cigarettes in this ooantry to f.he grsster aremle u~ of primz7 onncer of the 2zoQ, They enphasised the possible •:.iol,oaic relationship of oigarette eacgixg to this voadltion. \ m ~TR HN 0431 "~0

3sv+sre.i rsoant, vall-aaotral].ed, large seale, tlindeal stnd.its on oorralatioa of t.obaooo saokitY with. aaoesr of tbe ltung hats be.a aade (26s 40, 41~~ The ooaaluaious rre4o~d by L~er and G,rahaa ia their z~sosnt •t~ (2b) as+s su=raris.d balrovj th.ir .urvq ras a.de bq+ direct intsrriev of aore than 700 patisnts with b3opq-prswa pciaax? M.nocr of the lzrsC. l, sucssivs aad prolotCed es." of tobaooo, .spsiall,T siqtr.ttsar s.ss to be aA isspo:taat fiator ia tbe intnstioa of lwq aanosr. 2, lrie iaaidanoa of 1zmQ Karosr is sonsi,d,arahly higher a" aod.r.t.1T nsa.T to chain saok.rs oxipox.d to the C.aeral tsaspdt.ll popa2ation xitbout sanaar. 3. Tbs oacuxr.woft of lnag eaaoar in a ssl.e aonssaker is a t+sn phenomenon. J,.. 2'bbtaoo ae.e=s to play a tiailar bat 8assh.t l.as .ri3.nt ro2* ia the induatian of Inng CLncar in wosta, d.aon;g this groV agreaiwr peso.aLage of W naaoktrs vere fou.ad t.tsan aaon,z ssea, with 10 to 25 beiag zonsackars. 5. 96.=x of patients vith oanosr of the lungs .ho had a history of smoking had awisd for over 2, years. Fw ww= bave saaked that lorg and this ia probahly the renson for tbe gr.ater prseat 3.acidsacx asong irtn. 6. 94.1% of the *&le pstients with adnoar of the lan=s wrr* found to be e-garstte saaYera, 6,04 ,-dpe'asnk.rs, a.nd 3.51 cigar s.aakers (sow use a~rt thas one fora of toDaooo product). This preTS.2eaae of ai.garette saoking is ,es#,er i'san aaooa the general Lospital popa2ation of the saaee age g.roup• r The zroatar p;racLios of inbalation aaong oigarette aaokers is believed to be a.actor in the iucrsaaad inaidancw of tbs diseass, 7. There ess,y be a].ag of 10 Tears or aore betvean tbe osaaation of smoking and the occurrenae of clinical sysptoas of oaae.r. 6. Three in:eper--~.nt studies 2&v-s resulted in data so unifora iba.t one v&y d*a1ice ',.he eaes oonolusioas frva thea. The iae,-ican Caacar Society (46) haa reoentla initiated a.+az7 1arp-acala, lorg ra.nV, oaretbl!y ce-nduetad atady of tht relation of the sacldng of tob..aoo to tbe incidenoe of oAnoer of the rsapiratorT qata;, The survaT is being ocazucted uith ths help of tbousands of .roluasers %rho intervisY and keep detailed h:a!.aries of amaX.ers of a ctrtaib aV group ors: an estended period. Preliadssarr re~ts fr:.* th-' s atudy should be a.aSlaDle in aDc-ut five yasrs. It is ezpoated that this study, ineofar as a rvi.ationahip ca.a be proved by statiatloel metboda, will fisil,r establ.ish or disprove the rslationahip between tobaooo smokiegj alid c_noer of the respiratory aystea. B. an ,-!,j "tu ea 0 wL cg ba ~~ta~ A mmaeDar of wricers have eudo aarcit~-enicity tasta on animals with s-.LWtancay de=irnc: f'ron iobacoo. The resulta of these teata are smssrised b.iov in tabulsr form. 11 * C T R M N 0 43" 1 f7.91

50193 2959 Zns "SRr • . Zds= AM#at "isSLiOn TSn Btt11 Sc Dderng! 3ubeta 1900 ftoaob Jriio. Outna Pis l.lntiag Yrolitri^i~tloa 47 I 1911 liaaker and Pipe Tars Rabbits Injeation 21 Days Proliteration 48 1923 SalwOlaaCO 3 h d d T P ifi I{l P i ti Yrobable onnoer 49 a rew aa ar ur e o. a n ng . 1 28 'l.urb.lls H 1 2 tS 1Y XS 1( ti P i Beni n ulcers 50 9 v *, ; .. . .oo a.- +e io. a n nQ g etbor axt.raot ot piptl t.r 00 0 • l ti P i n Uloers 13.ni 0 Aas- -5 4 oe K s ng n g truati.+e distillate i l - thaliaac S l 51 1929 Liaklat Tar na ln p . bbi t t k Bl S i ovnr growth latia Leuluo 52 1930 Sottb Stirolc. a b ox +oo a rg p 1931 Chiakaa.t.u Condensed 9wo)ce in water Tar Rabbit Rabbit Painting Paintiisg 8 iooo. 225 llays Cs.roinomn Canooroid 53 1931 RafCo Jet of 8wk• iiabbitt Directed at 3 Yeara Carolnoma 54 1 i T l ear i P ti - Qiroinoma 5 5 193 Cooper, Lamb ar P pe os K a ng n and 8and.rs Too Toxio 56 1932 Naully Tar Rate 1.932 &orro Water 3ola. of Swhs .%aok. Rsta RnbbiLo 3 prayi r~; Llirootod nt 100 llc.yo 3 Ye~nro No • f f u o t Gnr Tumor 57 on.r ~

50193 2960 ~ Ukm "Ini 4R.1 ,193Z Dodwa and Tar Ssaw De.t. ltios Paiqtin8 1 Yoar 21o }6tt.ot S8 ~ Loasis Aista. ~ ~ 1934 ~-~ ; Tar t3va btiwk. Rabbit Paintisag 148-182 lk7s Cauo.r 59 .~~:. No Aotivity 60 1935 Sobarah aad wintsrst.3x Cigar Tar ..~... 1936 Rorro Pills ot 'rar liats Iopl.ant 8 Nos. T~n.ors 61 04 ~ 1937 saburah ana Tar 1ros Cigar Rabbits Paint 48 Moa. Caroimma 62 a Wiatsrstsln Smoke ~~ t i Ganoor 63 1937 Taki Tar }iio. Pa n 1939 QuWbo11 9.oln Tar Hioo Paint 10 Hos. C.roinoxa 64 1939 1iatf* Dsut, DiaUllats Rabbits Paiat _...._~ Cano.r 65 1939 Aotto D..t. Dist•illats Rabbd.tis Paint 9-10 G.nas 66 Garoinoaw 67 1w porfo Dctrwted Tiurs Caroim+.. Tyrolytio T.rs R.bbi ts 194 ' F1prT Njs+o1,ptf,:s Tars Rabbi L. Paint 238-600 Dyt Papolloaas Car- olnomuLod tuaors 68 19l,1 Martsas Cigarrtto Saoks Nio. 1~cposore ll.Laplasia, Ulo.rs 69 1941 Rouo Tar Rsts Po.ding 5-30 1'Soa. 4astrio Lasions 70 Caroinoaas 71 1W4,2 Baltb Pyro]7tio Tars Rabbits Paint

lhW of the origiaal artial.s app.a: in pablisatiow that ars ncrt_seadil,y arailabls j in tbo4me oaisa iaforaati.on Das beea obtained frna absLraa•te ear otleer r.fsraaos U the ozigisal warlc. Oftta the .ouros asd sr.tbod o; pt.patatios of tbe tobnooo arubstanAS is' 7ago.# asst at'trsa mdosa;o or inaidrnos data ar" gi.oa. LLsol a tmrie!~r- of tsst aniaalas diffrrirg in suao.ptim2ltar to .arsinoaas` bave basa w.d: -Tariooas ror~s3s ba" tissQ wrions erit.ria for atl,assityini th.., ' tm.or+ons grovttts grodueeds and .to pis•os of ti+ork is dirttt37 aosq~sxab~o to aW othsr vork, In the above table mt.re the t.rts prodo,o.d oaw or sror. saaosrvss Crovths tb,. Lst eerisi was aoatidsxed as positira and, tbe result is tabulat.d as .anoar, sr 23.ke tsra. She positive results ars oosid.r.d to Se ssss+. - si8ninos.nt tban the neotiv+e aa... . Bessim in sdnd Ve above quaIiAriat .rtstwsntas o.rLais geasral ooaalnsioaa ..J bs dlfa SYt.^st the data prcssnt.d., Za al1 bat a fsv easss osa os aarm hmrs# asn.lly of a~+~t~~ ", resulted from application of v.rioas ioba.so suD- sts.nos to tbW sM.as of avariaV of t"t asdarls. In mwat oasss thA tsnrs appeared only after a sore or 1aa prolonged 2atAat p.riod. ?!w rssalts are soz.wbat imonclusiTe bat indieats that saDatanoe.s derived !`roa tobaeoo haa aoae dagree of careino~gmnio aotiTitlr. C. Ss-Cioorsas 1dwrtmll 1D ?-thm a4bgUam• Very little work oa isolation and oharactszisation of oasbir4gsns tyr+oa tobaooo .ubstanoes has bsea reported in ihe litarature. 8offio (72) ia 1937 reported that tydroaarbona vith aondsassd b.assne zmclai ws* grsssaA in aatasials obtained bT direct disiillation of a+aiq vari.tisa of tobaooos at texperatn.-os zamciag tYoa 8S° to 350°C. His rs?ort was based on sp.atrosaopia data. Zn 1939 Roffo (73) r*?arted that aprodmQt was obtained fraa a osrtnin easo.r producing toaasoo tar by distillation that Lad tbe a . qualities of bsaspTrws (II), and stated that the product was a pot..at oar- oi.cogen. In 1939 8nf:o (?n) d.earibed a dsatavatine distillatioa vb.ro fractions were obtained aZ 1OG-120', and at 350°C. 2b. Iov Do,i2.inQ fraction aboved no carciz*geaio aatidty. The high boiling traation was reported to tonts.in anthrc.o~ p3samnt2z.-~aras, ard.baaxprsa.{ this trsation was atrong.l,t aareimgsnia giving a 9$% incidenos of ta.aosr v-wn paiated on the skin of rabM4. Tbe residue oontained eoadana.d aenieae aual.i and was stzeng1.T o&rdmgeaio, tbrs-.tgs lesi so than tbs bigh boilin3 distillate. Tbs spectra of tars from 9 different rarietisa of tobaooo wars all sisdl&r to that of pbena.aib..-ema. In 194.1 Roffo (75) reported i.olation of a Deaspyrenm from a P7 lrtic distillate of tobaaoo. The bansP7raae was highly earai.no;essis in an121101 t4sts. 1~sL The ori¢nal articl.s referred to above were sot readily avai2abJsj of the infarma•..ion given wa•s obtained from abstraata and other raf.rsncss to the original work. On tbs basis of the inforststion at hand it would appear that poly=ialsar aroaaL•ia coapounde oaair in the pyrolytic products of tabacao. Beaspyrsne and "a aanspyren.•, both carcimgeas, were identified in tb. diati.Lat4s. Though aoffo appears to be v.li known and widely Koognised as e.a authority in :.. :iuia of cancar iaeOarcD, it is perhapa uudss to draw sweeping oonclaaiona 4'roa the nnauJported vor3r of one a..n. !lore work is needed in this particu2ar field before 1Yan1 ooncluaions sbaul.d be dravn, 12 CTR HN 043182--

D. , 5MPq~3lda IE21AW LMN Za 94 ftb.tancss SW Me PossibW ib 3t .~t IF44 ~• Asads f'toaa tbe po,1ymol.ai1 hWdt'ooarbons disaassed aboT., ta 'othrr eoapoiinds baa.ing lnoxn or aasp.etad saroiaotmis asti.itjr have* 1s.n i.olat+d froa totiaeoo substaaa.s. lhir"dois aot a.essarily aean that sgah easpounds ars"bot'"prassa~. ?obaooo ovatain.s a 1,..rYe tmbsr of orpnie ooapounds and mv r+s:in to be isolated a.nd oaaraotsrissd. hom the standpoint of oararinoesnia aeti.ity of tobahoo' the is4ortant fast to be d.taraia.d is wb.th.r or wt saraimpnss if- pres.nt or p:ndno.ds ars prss.nt in iAUooa amoks after it lsavts the sigarst;.. Ysn if oarcisrogsas do not ooaar in Lobaooo it i.s possible that ea.roiaonaie srobstsaota s.y be forst.d dnying th. " EaoYi.a= prooess. During saokis&toDaooos oont4ivi.ag soorss of oaganid oweponndi, is subjsat.d to a pTro2gtie or dstraotiv+ distil2ation proaeai at slsYatad tsapsruturss. Oxidation, IqdrolTsist and other rsaotions say take"plaae at the sasw tia.. (kreinogsnio subetsnoas haw Dean foraed by si-41it r processes at siillir te,geraturss. Extracts of o4a1 toot are carainngenio. Tars fYoa asstylsns heated at ?00°C. and isp~sne heatad to ?2?°C, iraro cx.rcinog.nia (76). At higher teaparatus'ss dsatsvoti.e distilLtss of pstrolsea, huasn skin., Te"t, cholatsrol, turpentine, rice poliahings, and erude suga.r were a1Jl s2ovn to be csra3.nogsnio, as vert heated astiaa.1 and vege- table fats (68). Of the abore oats.rials, ac.tylaas, and oaspounds siajlir to obalastsrol, a,-e preasat in toaacoo or tobaaac smnks. Pbytoatarols, sterols sindlar to ahrlestarrol, ha.ro bean fozsnd in toDaeoo (77, 78) and Eto1Yo (77) has reported that their reaoml prior to pyro2.ysis distinctly lovs.rs the carci.nogr-zde aotiritJ of ths pprolraate. On r=an' nation of the struaturs of •zgrsatsrol (IZ1), a typical phytoaterol, osrte-in sisdlaritiss to the atxuatars of aholantararrs (I), a potant carcinogen, are eQident. /lrosatisation of st.ro.ls, r4taroids, and like sabsta.noss bT tbs body has been offered as a poasib.le expls.nation of the origin of spoata.neaaa Drsan asacsr. Pyx'c?.Tsia of cholsstorol produaes Qarcinogenia an.ba ta"nwss ra:ated to ebolent hrane (1). I t i s rsaao nable to a a suxoe, parti cularly in light of the woz3c of Roffo, that plant atarols lcnovn to De prwsnt in tobaooo n:gbt givv simil.ar pyrolytic producta. C- CH 3\ I (Shovn on page 6) ~-~rolysis ~ d~j 13 C T R V I N 0 43" 183

Under P7z+o],Ttio oonditions aostylans affi isssioas oth.a cuuaturataa msy polyvarise and oynl.ise to ciw aroaatio riags. ", This behavior is vall knom. Such eoa,potimds bave baa fousd lA tobaooo and tt+baooo saQlos and t&e poasiD;ilitr exists that thol w.y ba-oomr!.d to po17analsar aromr,tia tqdroasztons. '. , A asncb.r of nitroe.n h.taraap~alas~ the alkaloids, are present in toDs,ooo. By oonds3asation a.nd qTalisation of sids shaiaa dn.rinQ. pyrolysis sntls eospoaada night Yirs riss to dariratiYa of (1RI~e, or dibe.nsasxDasols (11).. PYmlris of a s3sqJ.s orgni• oo.qonmd is oftsa a ooaeplsx Ysaotioni and _. attsapte to poatalate pTsolytia products arisisg froa a'a.~cture amtaining covntless orts•nio voapouads Dorders apea pars apscal.ation. Tbe sboTa suggestioas aare37 rspraa.zt so>ts of the possibilities that adst. R, brs ao •'~t„~ In the easvtaeture of tobacoo prodwts a sabor of orgaai4 :atsrials ars added to the lsst tobaooo. Sueh additiv+ss ars fla.onrsta, luaactaats# sad like auhstanoss. It is poaaibls that otss or wre of these cate.rials assy giw ri" to carcimgenia svDsta=as. ?bo writer does aot have acc.ss to information as to the additiy6s used end is thsrafori ttaable to etaltsate thea. Cigarettaa ese enansed in peper, an organic sat.rial vhieb could possiDlT b-.-a or pyroly*e to give os.,-dnageaa. The sm* applies to th4 glue and irslc used on the paper. V. CQ~ ~SIO~ The increased incidsnos of oa9sar of the 1vzg in asn whioh !a-a ooc,zrrsd •. du~~ th.e 7•1st half eventurT is probably dus to a+nr or inaraased oontaat with carciao,b-snic stiaali. The cloaahr parallel inossse in cigarette saok6ng has lod to the suapf:aion that tobaaco saoliaa is an important •tifllogiv factor in the isd=*.ion•of prisary oanaar of the laaQ. Studias of cliaioa2 d.ata tend to confirm the relationship betvaen hseq and p.rolonded tohscoo s4oadtg and incidencs of cancsr of the lung. EtLe±ssive though inoonclusi.•e test.iaj of to*acoo substaraas on a.aisals indicatea the grvbeLl;e preeanco of carcinogenic e.gcnta in t:»se substanoes. Oo* voriur has ideatlfi.d hmo+rn caraimgesss •la a tobacco pyrolysats. Coapounda are present in tobaooo which on prrolTs.is eou2d theor etical'~7 give rise to ooapouada sisdl.ar to known osrcionena. Sbe qossible role of tabsooo adc.'iti.es and aigarette paper in the production of oa;'ainogant o:nnoL be dstesxinad beaa:.s• of lack of access to inforrsat.ion on snbata.nces used. YI . p4QQ-"+1'f1?tiS ! A. It is reoomaend.d that this pnliminsrys broad surrey of oanotr rasea..rah be sup:,liaemted by oospl5teg detailed surveys of tb. i.nd.ividual topica diemissed abare. Such surveys aLauld be ssads at fr.qnenit and ragular intervals in Lne Yut,:" so as F,o ,mita ourreni defelopmenta proaptly arn.ilahle to i•nt,erested persont. u CTR MN 0I 3164

B. in li.ae rrith th. aDorn, it is z+.ors..w:dsd that th. Rss.ucb Librar7 anb.a J.D. to jour=ls .overieg tbs fi.ld of aaaoas raa.arob. • A i1l. oS 'pMLo- atnts aad r.priats, tol+tatr rrith Qartimat Eooks# rs? o:ta, an3 the 7.i.k.# alxonl.d be assast;led. -- r- C. I+t is t~t a?.l tobeooo sdGitiwa, 1..o f2avoraats and huseetants, ne.d by t.bis corapW be exwd.oed aazttttllT with 2'espaat to thels' pcssih2a rolss as *arad.adi'eas or carcinogtn pradztodn ag.ats. D. in .iar of tba facts Drtssat.d in this report it is ssso..saQsd th.t sanagemoat take aogaisanos of the probls ard its lsDliaations to ow in3astr7i :.ad taa.t positive rsasarcb action be pl,taand ud initiated vithaat ds1,aT. - 13 u i.+ f f`S f f f f 0431855

TZZ. B.jw,I~i.1P~Z - 1. &rTL•nd, LS&ao.r Ras.arob ji, T! (1952) . 2. Ban-$oi, Seoord of Cha.. Progresa, Yz*ace-Rooter Sci. Library IL 30 (1953), 3. Bnrtvrll, U. S. Pnblie Hsalt2i Serrioe PublicstiQn Number 149, 533 PP• (1951), 4. Boyland, J. Chia. 91,.2 (1950). ., 5. BadQar, Rory. Aastrali#n Ch.n. 7.nat. J. asd Proa. IL 14 (1954) . 6. Beller, Arch. Inri. RyC. OcaQpation.,l 1[.d. ~, j40 (1950) . 7. Cock, J. Che~. Soc. 1950, 1.210 , 8. Hneper, 1n. J. Ned. $, 355 (1950). 9. Heiger, Brit. J. Inrl. Ked. §, 1(1949).- 1A. Bad,ger, Brit. J. C.-no.r Z, 309 (1948). 12. Doddi, Lanowt alb 837 (1948). 12. Fsaddov wd Bon, Brit„ Med. Bull. J„ 314 (1947). 13. Eaddow, Brit. Med. 8a11. ju 331 (1947). 1.4. Cook and Kenaalay, Aa. J. Cs,otr U, 50 (1938). ~j, 260 (1937). 15. Tieser .L alles, An. J, Caaoe: 2 16. Cook •t a11es, Az. J. Caoe.r j?~'a, 219 (1937). 17. Rob.inson, Brit. Med. J. 1, 943 (1946). 18. Deudel, an_ll. ca.aoar IL llo (19js) . 19. °ttll..an and Pu1.1.wan, aar. 34mi. & 145 (1946). 20. schmidt, ztechr. f. ?hTa. Ghaa. Ag, 83 (1939). 2:. Soyl.and and Borniag, Brit. J. Ca.ncer 3, 118 (1949). 22. Fieston, J. Aat. Cancer Inst. 11, 415 (1950). 23. Hoyl.amd et slles, Brit. J. Cenoer 2, 1? (1948). 24. i.oldac= e et a11ea, Etature "6 , 667 (19,49). Cf R f f N 043186

C` 25. $sndry at allas, Brit. J. Ptussm.ol. L 357 (1951). 26. Xrad.n nad Mrabaa., J. l. X. A. "329 (1950) . ~ . ._. . , . . . 31. Azitb at a11es, Caaaar L 229 (19Sq).. 27. : 6leieaass.n and Bntit, Brit. J. C~i"" 1, 233 (1947) . 28. fi.ady and tennavay, Brit. J. C&koar I, 31.1 (1949) • 29. Stooks, Brit. J. Ceis4+r _[., 99 (19'S3)• 30. Oc2aa.r affi Da]3aY.7i ftrpry ~, 99Z (1W) • 32. Ir.7bQrQ, Brit. J. Gh.na.r ¢, 112 (1952). 33. ibb., N. i.. Stat. J. Ksd. 1 (1915). 34: Brod.ra, J. A. X. A. ?¢, 636 (192Q) . 35. Hloo-A~, J. A. K. A.. M 1381 (1921). 34s Boftaua, Ann. S=Z. 23, 50 (1931) . ~ . . 37. Liddat, Unan.-..*en aad 4'chasc2r 8_2 ., 1232 (1935) . 38. }~tl.lsr, a. £.rebatorsah ~L9, 57 (1939). 39. Y.nbsway ani Zsnaevay, Brit., J. CanesX 1, 260 (1947). 1,0. Doll and aill, Beit. Ked. J. 2_, 739 (1950). 41. :Znft, DO1L, azx'_ Kam.a+a7, Brit. J. CanosT ~, (1951). 42. , Laaoat k~j, 667 (1952), 43. Stocka, Brit. J. Cancer §,„ 8(1952). ". KaConAe1 at allea, Laaeet 2k}, 651 (1952). 4.5. Cchsner and Dvns.ktj, Arch. &tr8. 4~, 209 (1941). 4h. Horn, (a.ncsr b1ew, Pib. 1952, P. 13 . J 47. 3roech, Qirchosrs Arch. Pata. Aast. 162. 32 (1900) . 43. Wacker and Schndncke, }funcben steci. Wchnachr ~„8, 1680 (1911). C T R l N I N l •..^ 4 3' 187

49. 3chrev.a aad Zurh.l3e, D.nt. ..d. iioobsehr, Ag, 633 (1923) . 50, S.1vl8i J. A, M. L. sl, 150 (1929}; 51. L.iokint, E. tsebatbrsah 3Q, 345 (1929), 52. Boffb, Bol. Zast. aed, exper4 eatnd* trat, Canoer 3, 1N, .501 (1930). 330 Chicriat.n, tr. Jap. Path. Soo. ZL 244 (1931)• 54. Roffo, Bol, Inst. Ked. .ocper. utud- trat. Canaer, $, 545 (1931). 55. Cooper et &lles, J. Bneaw jl, 293 (1912). 56. mcYa11T, Aa. J. Caaae.r jb_, 1502 (1y32), 57. Boffo, Beoplaamea U, 77 (1932). 53. Booen aad LooAia, Am. J. Cancrr ;6 1515 (1932). 59. Lu-Yh-E!a.n, r7ranktortj Ztachr. Path. A7, 52 (1934) . 60. Schurch a.nd Elinterstein., 2. X.rebatorseb h.2, 76 (1935) • 61. Roffo, BoI, Inst. zed. exp.r. eatud, trat, Canaer ~1, 287 (19* . 62. Schnrrh and 4tinterstein, S, lssebsforscb 2b, . 4U. (1937) . 63. ?aki; see Xinoehita, Trans. Soc. Path. Jipon.. 27, 665 (1937). 64. Cntspbell, Brit. J. zirpt'1. Path. 20 .j 122 (1939) . 65. 3otfo, Deu'... aed. iiochschr. §j, 963 (1939) . 65. Roffo, Presaa med. Argentina _~`6, 721 (1939) . 67. noffo, Bol. Iast. aed. exptl. estnd. Canc.r ~, 699 (lg{p) , 68. Flo.ry, Caacer Researcb Ll, 262 (1941). 69. me-tens, Z. XreDsforanh 5A, 183 (1941) . 70. Roffo, Bol. Inst. Med. ex?tl. eatud. Cancer 18. 39 (1941). 71. °.offo, Schveiz wed. Roc-bschr. ~„1, 549 (1941). 72. Ro;fo, Bol. Inst. Hrd. exptl. eatnd. Cancer 1~,L 311 (1937) • J UT/ 1 I I N 043.Rr 8de.w

(+\ 73. RoSfo, 8. Krebstoroh ~, 588 (1939). 7l,.. B+ofto, Bol. Inst. aed. rxptl. •stnd. O.ao.r IL 349 (1939). T3.' Rofto, Sokrais sod. Vocbsehr. Ut `j49 (1941). . A ~ 76. Kenndvay, Erit. Ked. J. .3, 1 (1925). 77. Rorto, so.l. Inat. Kad. Ecptl. Batod. Ousoor 431 (1942). 78. Sk>rlv, Ys.aoyuz. Iast. ?abdah. ?Se]c2»rooa. F:rost. Xo, 139. 3 (1937). .f t.; CTR HN 043189

{,..F TR l lN 043190