Tobacco Documents Online

('` 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