Tobacco Documents Online

® r e ri Pav F. Hombuvgerr (Cambridge, USA) ~ M t

i Sntroduct9on epuis plus de vingt ans, on sait quc la ci;arette est la cause de 1'uu:mentation effra}ante de la mortalite par cancer du poti- nion, cancer qui tue actuellenient en Suisse entre un quart et un tiers des hommes qui meurent de cancer. La cigarette est aussi vrai- semblablement la cause de 1'au;mentation de nombre d'autres cancers, en particulier celui de I1 vessie. A cet efCet nefaste des sub~'tances can- ceri;enes contenues dans la fumee des cigarettes s'ajoutent I'action dc 11 nicotine et celle du CO sur le syst~me cardio-vasculaire, substances qui precipitent Ies accidents cardiaques qui se produisent alors plu- sicurs unnees plus tot chez les futneurs que chez les non-fumeurs. apres unc longue pcriudc au cours de laquclle I'industric a rss::: c de nier 1'evidence, elle s'est eofin resolue a etudier des cigarettes nloins toziqucs. Depuis plusieurs annces, de telles cigarettes (enNiron trente fois moins de soudron canccri;cne et vin;t fois moins de nicotine) sont sur les marches amcricain et suisse. Ces resultats ont ctc obtcnus en traitant difTcremment le tabac et partiellenient par des filtres plus efficaces. Nlalheurcuscmcnt, en Suisse, nous n'avons pas encore pu obtenir que lcs tencurs en ;oudron et en nicotine soient inscrites sur les paquets de cigarettes. Unc now-cllc voic dans la lutte contre Ia nocivitc dc la ci;arctte s'ouvrc aujotud'hui avec 1'utilisation de produits de remplscement mclanbcs en dif[crentes proportions au tahac. Cependant, actuellement, cc type de ci;arette n'a pas encore atteint le debre de detoxication de plusicurs autres marques cJcja sur le marchc depuis plusicurs znnccs. Nous dcvons cependant salucr cc nouvel cssai vers la neutralisation des effets catastrophiques sur la sante, et aussi sur les finances publiques, de l'usage de la cigarette. (Red.) i ~. I ; ~ CTR f f N 4r+ "°f' 260"~„.'°Ic

i / T (zo) ; • c ~ ~ t 19~. Les inc-csticaticns anal}•sccc c Ic rrcccnt rapport ont ctc conduitcc par +t3io Rcccarch T E'If• (2QlC ~+ 1 t 1 1 Consultants. Inc... CamhrtJ.:, sous contrat avee Ic Conscil pour la rc:hrrehc sur Icc tabaci y ' 'Cr(2961 ~ " ~ =0H • EU. New York. et Ia •Cclanese Fibcrs Corn- panq.. Charlatte. Caroline du Nord l 'nc par- ~ n 30 L 1Z~0! ~ I , tie des :ec`.:crcacs dc base rappurtccs dans Ic ~ Y present article a c:e rcalisce au •Hio Recearch Institute. Inc.• dans le cad:: des octrois de cub• ;, ~~I i 0 (2<;) Y s•cntion pour la rc:!tcrchc I:SPHS• CA - 10101 1991/55 957; 5 9 !95?i6! ;952 53 e: CA • 13:3: t.Instrtut national du canccrl• et ' d un octror de subc•ention pour rcchcrches non specifiees SOI - FR - 05525 (Division: Rcs- • 99•.: co-t-eemce I+n,t sources et cquipe^tent pour la recherche). Introduction Ca~ce~sare Sco ' I T I d r 1 Les risques quc comportcnt Ia pollution dc l'air et I'inhalatian des fumces dc c!:arcttc suc- g'erent qu'iI faudrait sttppr!mer I'habrtudc de funer. L'experience nous enset;ne qu'ttne mesure aucsi radicale n'est pac realicable en prat!que. A coup sti:. I'ir.terdic:trn dc `umer se retourne:art contre ses autcurs. comme ce !ut ie cas acec I'cr;,er:ence b!en in:ent!onnee de Ia proh:bttion des aicools en Amcnque. La eonso^:-a::: n de ciyarc:tec cst resttie 5 un niveau tiic,6c les mises en garJc mc- di;ales. cc ur sc::cur notable de la p:p~aa:!or. dc;end Faysto!c;iq::c:^ent cL ou psc:ho!.ci• quement de i'hab:t cc de `umer des c::arc::cs et court J'a7tres ::sc~;:c c:a'.emcnt Scne7Y• tcis que et :cs r,c%roses ;t~es s:a s::,r, rts• s,on (cr,cc dcs c:carcttcs Des c:uc;cs statist!• qucs coa__.,;a : :es ..._'acics en :ar;.cr: acc: I' a^„ Cc de .r::rncr t:;s c:c_a: _.:cs cus_ -ent abf:^:ern, _nc ..:at ,.. .,_ Josc a 11 } a t;oac ccs arg.t•,c^:c soL:;ics en d'u-^ _:rsc...r:a::ca c:r-ra:._ic a%cc une be:1Ge c3r:e _. -.: cur%ie. areJrne.'.ts qut -ou:._..'t ...:Tt ^rC:.:Ct 3 ._,:- :he2 Gu! ._-.. ,,.. :a-ac ~st D cu :a :cr.Car;: ncnC:a:e a Cc.e:~~.er des ct• ga:et:es nlo:ns er:a:`ccs Ce r:caucs. D!%erses !n(:cc:ons dans !a technelee;e dc la c:_::c::e dc,U:s :a a^-ees :95() o-t a:~out: a la prc.,.,cucn de ,:n:_r:an: cn ec-c:al ^:c:ns de goud:cn ct -c:ns dc nicct!nc Gs'au- paravan: c: ccr.:;or:a-t unc act!.rte carc!no- gi!r.e c:rn!ct:ce !a:;x tcs:s S:olos:aucsl. D!%ers ;,rocc~rs. e^ ;)!us des te:hniGuc% de (:it:at:cn, en: , c:mts de rcahser ccttc J:m:nu• tion dc ter:c::c et d'acttvttc carc:anecne (cn bic•rss.iil des c:;arcttcs produitcs actucllcmcnt. Ahsir,cnon f.u:c clrs typcs dc tabac, I:s mccu• rcc 1•ris,•, crns:ct.ncnt cn cci,ansrrn Ju t.t!:ac I+ar Sno(Ic-n.:tt• ul irsunt tlcc h.trttct de (CU:lla, nrn mc!::•cs prcc~Jcrnrttcnt Jans Irs c:c:trcttcs, suus forrn,: J: :ouc!:cs J; tabac It:+rtloScncice ou rccnnc;muc. t.a f:cuuc IW'ihres II'~n./<•r) cn J~~nr.c u: cccnrp!e. Clic dcrnonerc la carctno5c- ntcu~ r~Jt:itc des c!Sarcttcs actucllcs pour Ia pc:,u Jc souris :xpoccc dc fa;un contmuc a' Unc C.+r:inot:enCSt Cl::rtliyllc. Nous a%ons pu• blie cn 19%_ (_) L;r.c rcvuc mcthoJUlcs!yuc dcs tcs!s b!clrg-qu;s c:t usi_c pour Ic dctctop, c- Ijnc!tt dc ::;a:cltcs a rtsqucs rCtJUt!s. Med Hyg 34(1216) 1976 Dtminurion dtr nanb.e rts rume;,rs t-, rr; c^:r stts,orltsion d 50 O's de cot:denuur de Ju.nee sur :sne ;,frtcdr pt+r CO'^purGtson arec celui tr,C:~ir ectC 0.005 r o cic Ur,l' 1176rre;rriodc. (Les ehi/,Irrs cr•rre parcnritcses trte.qura: it r.o,••_-• !• s0uris pur Qroupe.) Lc , rcccr.t rapport cst ::m:!c ~ t:n ncu%-cau pru:.'uit anorr•taoac• rn!roclt::t sur Ic marchc w;:c Lr rttarquc Cytrcl`0 pir !j .Cclanesc Com- ; any. (1). Cc, c:+Jant, ics f•rmc-pcs ;c:tcrauc ct I.s corc!usiunc Jic,atccs .'--nc cct ar6c!c pnur• ,::-t rtrc ar;'IiG^ ic ~ n';in:-ne c.;c! t},~c aC~- qu.+: Jc ;.roJ:.it .ncn-ta5a,:, mciarEc a du ta• bac Jc c.iarettc.. U corccpt Zi I'orisinc Jes produits S r::r.:c: Cst ta ~nh.l t..t .•n done (:in:c: r,: Yas. ou mu~nc. J. ~u~~t~:rs ti.u~ca ciaaa !a Nrntie dc tatac. Ce!a ; c.:t i• ..u:rc t"ut , r.ipic. nla,. ;ct c: pra: ciL:c -_at J:if cllc. .:Jnt Jenw: :a fa;o:, Jan: ,cs c::-rc::cs sc consun,cnt: !c cc~Inor:c:r.c-:: a l'.ic-;ra.on et Ie gout J:i.c:it restcr iiccs Jais .::cltcs l!nrtcs pour c:re ac:c~,lablcs pour I.s Pour ctre utarsahle, un ;.rct:u:t i fu^::r •ncn•t.',-ac' dot: b::;!rr d'une :,,an:.re sc^•.`iz• blc i !a conbastinn du tabac: !1 nc dc;: :%ol: -i Scia nt oclcur dtc?la!sa!tts et, bicn cn:e;:Ju, !1 dou c:re unl;cablc dans Ics mach:r.cs 5 quer ics c:4arcttes. Le Cltrcl rcm,:u ccs c:n- drtwns tcchn:yucs. Dc plus. Ia (umce prcduttc par Ic matcricl a ft:rr..r .non•tabac. Joit ctrc biolo;!qucmcnt .nof(cnsivc ou noublcmcnt mo ns toxtquc ct carcmcgcne qu¢ Ia (umrc Jc t.tl:ac [Ilc nc doit contc:ur aucunc suhctancc nu:t crtuenue Jans la :mncc Ju tahic. ct Ics r!gprcttcs f:,tt;s J'un t,:l t:ratcricl Jetra:cnt Jcca~cr Jcs qt:ant!- tcc moint:res dc tous les cnn,urujnts troutcs Janc :a (umcc tIc t,thic. II nc Jutt y ac'u!r ttc c~ncrl;!c cntrc Ia (nmco Jcs aJJit!fs cy'nth~u• yucs ct ccl!c du tabac. En thcoric du moins, unc tct!c syncrg,c pnurrait ctrc plus carcino• g,:n;: yuc I'un Jcc compncantc rtls ccul. Dc mcr^c. les proprtctcs trntantcs ou ta tc+c!cttE dc la comb naison pourrarcnt• thcoriqucrtlcnt• ctrc phis granJcs yuc nc 1'rndiqucra t unc strn,^.ic ad..'•tjnn I',tr cr:n.;q!tcnt. unc analysc :himty:tc ::;c::rc-.sc de la (u:rtcc Ji•g.tscc ; ar Ics rc:npla- ;arts Jj tabac est nt:ccsca!rc, ct t:cs tests otolo• y:qucs Jc Icurs pnnc:palcs actrv,tcs sor.t !ndis- p:nsahlcs. CTR HN 04'2*606

! _ - ~ L'analysc chimique des fttmces produ War + oes cigarettes (aitcs dc 100 o/e de C)•tret et tic miJanges Cytreb-tabac a ete faite en grand I actatl par lcs laboratoires de recherche de la eCclancse Corporation.. EIIc a t:te cn grande ~ partie misc 3 ga disposition dc I'atttcur (3). Le debit de fumce par cigarette depcnd de en des variables. tcllcs que la Ioncucur dc la .garettc. Ie type dc tabac, Ies addittfs t9ccn• :uels• Ie rempiissaSe• Ie type de papicr, ctc. Par consequent, nous ne pnuvons eomparcr ces ;roprietea que dans Ics cas oiu Ics dic•crscs ca- racteristiques des cigarettes sont spccifieec. Dans ces conditions. nous pt?u%ons comparer entre elles des marques (ie cigarettes du com- merce ou bien. sur un plan expcrimcntal. Ies resultats d'un test de controie. Une scrie parti- cuiii:re de tests faits avec des ciQarcttes sans (iltre de ES mm a revele 39,7 mSlcisarette de matiire sous forme de particules retenue par Ie (iltre Cambridge pour un type de cigarette i tabac dit eAmerican Dlend•, et 4.2 mg/ciga- rette pour une ci¢arette comparable. i 100 e.'o de Cytrel Type ?bl. L'emploi d'un filtre effi- cace pourrait redutre proportionne!Icment ces chlffres pour chacun des types de cigarette d'une faqon slgnlficattve. En icncral• la fumcc de e:garctte est censti• vce de troic phases: vapc:rr. ccndcncit scmi- olatil et condcnsat non %olatrl ou •(;oudren.. La phase vapeur est definic comtmc la rart de !;:mcc qui traverse un ccran ctanJ3rd dc frbrc ..: verre du t%pe Ca:r.br.d.;c Les pr:r;cirat:x :cnstltuants de la phase vape-r, .n ;!uc de i'atr, du CO. du cyanurc ct Jc I'accta,1-cilydcc ccont: CO:. HrO. azolc. arccn. ctc., qui cttt %-ra:scmblablcmcat pc.t d'cffcts ph%swlcc qucs. La fracticn scmi•vo:cri:t de Ia f:tmrc tic ci- 1.'Ct:e cSt ^.eile qut Y:JI C:re (IIC:II!ec a utlc nrcratu:c dnr,ncc a par;ir d ~r,c rl,acc c!c artlculcs rctcnue dars la matr cc d't,nc cz-rtcu- :`.c dc (Iltrc Cambridge. Cette ,`raa nn cerl• ; rcnd i pcj pres ?00 ccm,^.,•cs alorhi!; yacc. •c!iyues e; arcrtatl;Ucs de potjc mciC:ul.ilrc -;,;tot bas (hc.vocar.-ures. a-tl:tcs. cc•anures. rar.ts, nltr tes. c:hcrs. -henrllc• cstcrs. r}r,ncs. :oiines. ctitures, lactt>aes et autres) Dcaucou(+ :c ccs compeses sont ; rcc u::s ^ar la (}rcl.cc ..: !a niconr•c cu de la ncrn,ccl!ne c:. bicn cn• ::ndu. sent absccls dc !a fur.icc de C~trei• de- ^curvuc de ntcct:nc. II y a mc:nc de compoacs 4nns la phase scmi-o!at ie o: la fvmce dc C}trel que dans la fun:cc de tiI•tc. Apcu pri~s 1~0 des 300 composes. trouvEs dans Ia `.:a:tion serni•vnlviie dc la fumce de tabae, n'cnt pac etF dccc!cs Janc Ia (umFe tic Cytrcl. l;nc anal.sc citlmly':c tlu goudron dc (umEe -c cisarclte i tan-ic c:emVnlre que cette (rae- i I •:on non volatllc• i p uids moleculalrc eicvt:, cnrrecpond ] cn% trcm 45 o/e du eondensit• ator% : Ic conJcnsat tlc Cytrcl nc conucnt quc de soudron. Cc ;vudron est un mclanSe ;,-mp!cxe d'hydrocarbu:cs allphanqucs• aromi- r:qucs et polycycliqucs, d•acldcs, alcools, tcr• ;cnes. isoprcneidcs et autres matcr,auc. Les + hydrocarbures aromatiques ct polycycliqucs ont c:e I'oblet d'unc plus Erande attcntion cn ral- I con de leur action carcinoccne. Quc!uuc _•: hydrocarbures poi)cycllqucs arom3tiqucs ,rnt e:e identl(ics dans une fraction dc goudron - Cytrel correspandant i environ 0.1 ^.o Ju .ondensat. Tous avalcnt ete antcrtcuremcnt I trouves dans le ccndcnsat dc fumec d: tatac Lc ~ benzo(a)pyrine est souvent uttl,sc comme indl• i cateur pour I'c:sscmb;•: des hydrncarbu• Irn. matrqucs pol)•cycliqt::: dans Ics ~oudrons Jc fumee• ct Ies tauz ••nt ccrnblables dani Ics condensats de Cytrcl ,t:r-, htcn quc d.tns cclui du tat:ac. Ccp:rtdant, rompto tcnu du faiblc dcbtt de matlcre paruc:ccc de ia (umcc dc Cytrel• cc!a ne s'elctc qu'i 3-5 nanncramntcs par cis;.rrcttc de Cytrcl conlrc 15-»I) nano- Srzimmc% par crEarettc dc tabac. En 1975• unc e:garettc eontcr:snt :0 t!e du prnduit non-tacac C%-trcl a ctc offcrtc aux fumcurs suisscs. Le tableau I compare Ie ni%•cau des composes Je (umee de cette- crga- rette X aux valcurs d'unc autre marque de ci• garette scmi•goudron• populaire sur Ie marche suisse. Dc ces donnces. i( est possible de con- ciurc que le deblt pour Ie fumeur de tous Ies constitttants de fumce est sentlblement moindre (dc faCon statistiquement slsnt(icatic•e) pour la jahtt.iu I - Cnmryir.okon c"'rt Ite cnmtnc.j: fumic dr: oece p:ir dee eic:iretlec \ rr ezuc d'une nlarque suiac a taus de t;oudron mo)en. C lo,rrttt C R:'r rr-,,,nt T:~ac /tXl'; ec dr r.r.Soc bf"; y w,l(Dr.ia r.d• csNri . (. Pho~e Aef parricu,rl A. Nicotine (mg'c+g ) 0 9 0 1 D. KGoudron» (mgicig ) 1%.9 6 3 C. Dcnzo(a)pyrtrrc. (mg;'cig.) 15 6 cigarette contenant le produit .non•tabacs• It. Phait lopeur Biotests du Cytrel inhalation aigue D~••, trJ (5) a re:emmcnt standard,se une methode pour dctcrmtner la texlci:e de (umee de ci;arctte pour Ia suurls CAFIi1. Eife con• stste a mccure: Ie temps tic survte de suiets fu• mant de `at;on continue par bouffees intermlt- ter,:ca 05 ml en 2 secondes toutcs Ies 60 se• condcst. Lcs antmaux sont exposes a 19 ore de tt:r,:ee ; cndant 25 scccndes de chaquc minute. puts i d: I'alr (rats pendant 33 sccondes avant Ia prochalne bouifce. La sunle mocenne pour 11 rr.ar:::;es Je c garettes commer:lales etalt de 9.5 i 1"5 ^t:nutcs pour 18 i 26 sourts. Aucune dcs cnur:i exposees i la (umec dc ci5arettes cor.st;:l:ccc dc Cytrel n eta;t rr,one au bout dc ISJ ~+nu:a d'un trartement Ide,t:quc, mor-~ent ou I'ec; cr:c-ice a ete terminee tresulta:s non pu• bi:cst. A%cc !e contriile dcs cl5rrcttcs i tacae, la sur:,c mo%cnne etait de 20 minutes; avec un melan.e S0/50 tabac.Cytrel. ei:c etait de 53 rm:nctes. Les ctgarertes de C>;:el ctarent done blen morru toxlqucs pour Its sourts que les cigarettes de :abac ou de -u!ar.se Cytrel et tabac. Inhalation subaiCae Etar.t donne que Ic-. rats et Its couris sont p!us susccpttble% que !cs hamsters dc Syrle aux cf(c:s toslque% de Ia lumce ct de la ntcoune. ces dernicrs anrmau: sont plus appropncs pour des ctudcs ;t Ionq terme. II a 06 dt:montrc que Ics hamstcrs syrlens de la souche DIO 15.16 sont pius suscepttbles s I'enductron du cancer larynce que d'autres usuches enJnscnctlyucs ou dcc himstcre s)•ncns J'elcv.ge c%occnctiquc (A) Pour ces ralsont. Ies etuJcs cornporant tlne ex• position 5 Ia (unsee pendant des persndes pro. Iong,:'cs sont souvent faltcs avcc des hamsters de Syne. L'etudc a laquetle nous nous rapportons ict (et qui scra publlee cn detail a llcurs) concerne 1-7q5 CTR HN 0421-160'e'" A. Monoqde de Carbone (-o/cig.) I S.6 .. B. DIo.yJe de carbone (mg;cit{.) 53 7 :J.3 C. }I.Jroearbures (ug./ctj.) Stcthane E:hene (t!thatne) _) Acc:h•vitne E:'+ane : i 5 1:' ('ruptne ::3 $7 rrc;ane :0: iI t`roraJitne 6 I C`!or-wre dc mcthyie -6 procyne I1) ~~ 2•ntthy!1•rt,-ane 5 1,)•CutadlcIe ~i Dutane ~3 I? Trans•2•bu::ne 9 Cs•:•but~n: 43 9 I,:-bulad:ene 5 I C•5 a;kt,e "- Y Isopre:+e I mctangc C•5 `?9 67 D. Mcools• aldeiydes. ec:oces tr, c.e I \tethanol :I0 E:hanol : ncet:i,dlhyde Acro;e:ne II:: `) Prc9l(.,naldch.%de Isonut.r.Iich.Je li: < e3 Crut,)na:.'.:h) t',e 41 Iso, 3 craldchyde A.ttonc < ~a 454 - htethrivtmlcctone 2.)•bulancd,onc ( 2•butancnc 2•r-e:ntannne rursncs (ug;cig.) Fur3ne I`: 41 2•merh.l(ur:ine :9 2•5•d-mtthylfuranc < 4) F. Nitnlcc (u:x,g.) AwnnauJe I'n•niun tnlc Icolwtyronilrile I: t < i l 23 Itulyromlydc 6 14 I _'5 a 1: <15 4 E= )I 17 !0 6 6 :I < I I 4 1

I ,c•sa i ia cumce .ie : qarettcs C;:trei. -Mi- carettes a tabae et de ciyaret:es faites d'u. tc• !snse des deux. pendant 9 scmalnec eonsccu• tivec. Elle incluait 3 cicarettes et. plus speci- quement• des eisarcttes 'de tabac seul, sem- :`IablCs a t+Cs e1SarCItCt cCTTcrcialtst:es au Rol'aume•L'r•t. des cisarcttes fattcs d'un rne- -nge a par:c c;alct +::r rr•cmc tabac Ct dc C•r- I, ct des cicarettes dc Cytrcl sculc:ncnt. Tou• s Ics ctcarct:cs ac'a:rat !c mtmC t}~C dc (tltrc a un papter tdcnttZ.::e. Quatrc groupcs de a hamsters mlta D1O 13.16 9ges d'cn%ircn ?0 jours furcnt uttl:scs. t;n groupe fut soumis i toutcs les manipulations. y com, ris le scjour quotidien dans la ntachine 8 fumer, mais sans consommat:on dc cigarettes (groupc de pscudo- fumeurs): les autres furcnt exposes deux fois par jour (7 )ours par scmainc) 3 12 bouf(ecs c:;)st:cutlves dans une machine i (urner en rc• version. Les cigarct:cs ctatcnt fumecs jusqu'a uac longucur restduclic dc .3 mm. point auqucl elies tetaient remplacees par des cigarettes nou- %elles jusqu'9 cc que !es 1: bouffccs cussent cte ac:ninistrees. Les bouffecs tftatent dc 35 ntl .:'a,r p:usse i tra%crs chatiue cicarette Pendant = seeendes i des tntmaiics de 53' secondes. Les 1C:,T,aux. Yar y'roures dc 5. Se.ICs !Cs lCtes e:ant ^auses car.s la bnite a fu:r.cr, restatcn: e*xposcs ^er,dant 25 scecr•dcs i unc conccntrat:cn de fu- -.: de :0 ^ o cnvrror.. suivies d'unc cxYostt:on i :'a,r frais dc 33 se:or:dcs. Dar•s ces cond,t,•or.c. Ics anc:naux cx;oscs i •.._ (umee dc :ata: se;tl a16a:_r:t des :Sux de _r6-,ox;: ac^ot;c^me dc 3 1.? ~, en r;e: cir.c. r~ sccondCs a;rts !a :Crj`.rto::C t1'Ct^J• ,•:.on a la fu:r.cc. revcr)amt i des ;ttvcaut dc _. .:rJ!c de _.9• . c^ _ hc.res Lcc art- -:ux tn-a:znt :a ._-_- :ss::c d. C-•:._• i .° o a%atcat „n t:_x cc nc:'Mn. ! 1.3 . et ce;:x so::"t:s a;a ._,.._e C u'1 .....,, : 7 C•, rc' tacae, -.._ ,. Lcs psc...:o•fu. -.-.rs :1'cxcCda:crlt ~a.T.:ts S.: a , c: :artcxv- -..-ct .,-e. ' . Les an:m.a;:e ,n!:a:aa: !a .;::-,ee dc ta~r. :de _:re::cs tc_. :a:... ,. , -:;: tes C'. presc^:a:c::, une _..,.•. cc ;.a,ds tntt:_~le. L's -^a:ent a::ne cr::ssa:::e ne;-a;c plus ra• - r.cr.t a%et !e •...._ _ au C;•tsei qu'atee :a:a: Des ]':CC;auC ClresCs a Ia (u- __de C•• Lrcli i'.'J I ~ ne r15 d' ?otds. :~ quc :c_r aucr-lc :cic pc ds (at un peu '_trs rapiJe ;ue cei:e dci !_;:x fccteurs. .7es Lh«:r~-.^."tclll: :.ato::s:;ucs au n,veau .es %•oics res;.t:atoires `ure.^.t dccc!cs %-crs la fin --:s neuf se-a:nes d'ex`er:c::ce. Les dl:(crences _•a,ent marq•iees entrc :c;:x des antm.:ux qui :va,cnt inha:: !a (ur-•.cc de tabac et ccux qui .•rent rnhalc la (ur:ec de CVtrel, des altcra- •^s rntcrmrJiiucc cur:cnant che?. Ics antnmauc :.r.ts aut cfic:s du m~!arsc tabac ct Cytrcl. II y a~a:t unc au,mcnti!,on s,:c:ficau.e du T,bre dcs ma:ropha;cs accumulcs dans Ics al- cc;cs d•an:mauc tn11--!ant 1a fumec dc tabac, :c- mrne le mc-:rc le ta,icau ~. Au niveau de !a :ra:hce et des broriches prtn- ::; 3!cs. Ics cc!lulcs a;ct-c!ct (::rc-It colorecs au --:t:cdc PAS. cc qui !es r•:ontra rerr.; itcs de °„cus Ccs cc!lules 6:atent censtdera`:Icscnt s r.ombrcuscs chcz ies antmaux a%ant inha:e a fumrc dc :aba:. un peu motns accrues en .mbre c!:e: ccux q::: ac•a:c^t tr.ha!_ :a (umec :a me!ansc :a=acrC'• trc! c: absolurr.cr.t ,nck»- :cs sous I'cffet de la (:::-ee dc CJ:rcl (ta• '•icau 3). no.r.are :es :nac:opna;,es Tabtcnu ;• - •,ar•,attons du nor,.nre :et eel:_:e al•coiaires apres neuf u^•tinet d'inhalation ,' trachcales a eobe!et• en microkopie directe aprr - scmaines d'inhitation Groupet erp:}intenrout Code Cegrou;! A B C D rrottenrlr,r •:e ,YOr,t~rlJ X.'ntnrCUr O,fc ho+:Jre•J C~l: ~rr•C:J:~rrrl~l ::.aJ'7nllel .O,~ltrr,ee !e tl[ ltJ ;opui0r7Un :CJ cteererreJ .:e n•ac•e•,••l:a{lr ::,enr'e,rer pCr ;;u r.on.±••e tor.rl J'an,rtrou.t e.+ e.c: r•te-ire Tatac I0.16,61 ;l .%tc:an;e :0:50 l i;16 (69';1. Cytrel :I (0.5••;) ContrBle • 1;17 (6';) • Simulacre de traitement (faux fumeursJ. Quclquc ;)eu inattcrtduc apres Ic temps re- lativemcnt court de ncuf semaines. ttne hvper• plasie de la muqucusc lar}•nSce etait prl:sente chcz a pcu pri:s 40 0/o dcs animaux ayant inhale la fumce dc tabac. chez 30 e:e de ccux ayant inha!c ia fumcc du mclange Cy'trcVtabac, mais abcente chez Ies animaux soumu a la (umce de C}irei ou n'a)ant inhail: aucur:e fumre du tout. A prescnt. dct ctudcs scmbla.!cs d'in:;alat,on sor.: cn cours; ellcs cnt etc protetccs pour durcr de 70 9!C: scmalnes. co qus permet d'cnre• c:svcr Ic dcve!rrpc:nc^t dc carc,r•cmc du !a- rynx, conr.u nnur cur•:cnir chez Icc hamctcrs 1110 15 15 au bcut dc 70-90 scmaincs i 1a suite d*it:haliticn dc (urocca t!e eigarettes Kentucky prises comme refErersce (6). Tcct_s d'appfic:+tion cutance 1.:s Cx; cner,cet dc vircir,ocenccc par inha- la:.c:t sr.accnt ; Ius d,rcc:e:::c:): cor-(+arablcc i 1•ind::ct;on dc eanecrs du rot!n:on ehcz I'hem-,c. t:en cue Ie cancer de I'cptlhciium rec- ;,ratc•irc. ;.rcduit chcz Ic hamstcr dc Svric D10 IS '6. survienr,c au niticau du Iirlnx ct nrn c:ct br:nchcs, .:mme e'es: Ic :as ;.our Ic sci•"saz: ::nccr du Ycumon 'cs hu::tatns. Pour ce!a, nous dc.ons arlendre Ia fin, en 1977, de res cx; -,.ccs d:rhata:,-r. cn :nurs Pcur ;c rr.emcnt• Ic rn^;:cn :e plus Ec• ncralement acceptc d'evaiuat:on de I'actt.ite c3rc:nr•ccnc dcs (umecs dc tatac consislc i ba• di=:onncr !a pc3u de souris avec Ics condcr,sats de fume:. L•ac::v,:c bicloS:quc du Cytrcl a c:c ctu- dice cl cr+mparee i celle d'u:+ r.te!an;e :!e tahics dc clcarcttes de t)pe imc:lcatn en a;.pfiquant Ic condc:tsat de (un)ce sur !a pcau rasec dc sou- ris. Au cours de quatre exrcrtcnccs dist,nctes, le cendencat de (umfe pro%;cn3nt de produits i (umcr .non•labace fut Jc (iccn concordanic Ct marqucc r:totns wrnor!Scnc quc les tletcs tJcn- Itqucc d'un condcncat prcvcnant tI'un melancc dc lahnc dc ctcarcllcs ,ic Iyt+c an,cncatn alsplt- quc simttltanctncnt ct dans dcs conciitions ldco• Itqucs II cn ctatt a,nu pour des doses de condcnsat dc (untcc variant considcrablcmcnt dc 35 i:ari mg tle cnndcncat nom aqucult, admtnistrccs par souns ct par sct:nine pcn- dant 63 i 92 sc:na,nct. La rc;+oncc au condcncat Jc (umec pro•crtarlt du produtt •nun•ta~ae• atlatt J c !'abseneo totalc t:c paptllomes et de carctnonus c;tdcrmottfes. aux detet les plus (at'oies, 9 une ir:c:dence de 25.3 eio da antmaux tcstcs aux doses Ics plus elevices. P;r contre, le condens :t de (umce d'un mclinge dc tabus t%l•tqucrr.cat amcrtcatns rro• voqu.iit ccs mcr.:ct Icc:u; s cccz 15.9 i:9,I o'o des antmaux. l;n condcnsat dc (umcc d•une (or- GICYpeJ el•Jlrt••'e-!t_-%j Cocc T.o rl~.-r .., ue rrc:tpl ho•,srt.: J,ee !o !v,•:+e .!e a Cni•c'rr s.r etir:rerret ~'e /r ro:e; s'Cnu-,_ JOUJ tt~Ce A Tahac 101., ,'1 0 10::0 " 15 i4'•,) C Cytrel '!:3;;3 D Contrcle•• 5;15 (:-,•,) • Re;onse c=ulative, grad::ee de 0 1 :-, c`ac_e antmal. • • &rnulr.:e dt rraltemcrlt (faux fume:•-s). mule de Cytrcl, type :.•1. fut ,rpC,yuc a ia plus clcvcc cncore, dc 365 m, ; ar sourts c: scmaine. 11 n'y cut des ptr-u;nmes et des cinomcs quc chcz 2: ~, uc c:c an:r-iux, cnmharaicon %t-cc :M ' , dcc s()Ijr,s ees Icsicns apres ac:r.iir.istrat:cn ;ic :45 rncnndcntat dc f::mcc Fro~e:;--t ~~ ••.-._ amcricatn dc taea: a:;-.r::::•. .: a,.•- dPtc ia p;us GiccCc •;u'il• i^!t j(~tc;i ,_ __ aucr avec an matcr:ci ii :cs::r) coa:-, ; t: ntcotine. Un con;!c-s: c: ... c: un n;c!ansc 1: ! dc C:lrci c: garcttes prod:::stt br_u:=ua :r.c:ns dc .. cu:anCCt auC dCs1;Cs plus .as ;~S et 5. ^•: ccr.tlcntm, ncn par tol:r:s. :-r C:S:.1•L>:,. (:1:C, Ct S. 9 CS !crncn!ccnt,. 13.9 c: _. pour Ia rncmc quan:ttc dc ; ru.caant dc _n-c:.es -... :~ ~- sa,cc plus c!cvc (113 r.'_ , :~ c rc-rtc . mcmc I•c+ur :c -4_ . lant,.c , 1 c::c ., l.1.•_ _. ,. a 1valt l'.r_ CCCCi;cl:_ r::.l: _, ....- CitC .. r r+nsc •,c::r Ic t%Pc :cs:c i•: a:rc , a.....`r..-. . 1 :c p~r SJ;:r:c c: i.Jr Yl. 1 s dCS eutnnecs Sur la base tI: .rar.:c .•!,.;re • s tcc:'lrtq;._ du oa~„^cr ^,;-. Ic C;:rc! at . CTR HN 042-~'".~ 08

/1 I I sidcrabicmcnt ut sicnifimi\cmcnt mn:nc tun:o• n;:ne quc :c scra publlcc alilc:lrc nccc piut do t!c:•ro!. La (ieurc : c:,•nne tl ; qul app•trllc.cnt cntrc icc n•u;:lar~S t:C ;~- I+lilcmcs produla par un c^r~lh:nc:t dc C;• trcl et de wux produits par trn cuntlcnt - c:c (utucc dc tnL•ac. La (iccre ? mnn:rc Ia rc!stlnn uncc'c!(et !Sllc•jal• ('!1lct~;;r: IllStiS (It(Ii1C:11- ,1'llll s:(t (/%: (;y'Ircl .oltt ap!,IulurrS .1 .'•t pcJu Jrc souris. Discusslon Lcs c(udcs cltimlqucc de Ia (umrc dc,s;•_°c p3r des cirarctfcs conslrtuccs rro 100 1'e dc Cy• trc! nc mr.ntrcnt Iucun comr rscc cfc (uinc%: .lul nc so,t rres:nt dint Ia futnec tI':rt tab•t: orur- nalrc. Cct s'y trotlt-cr.t cn quantl:~'s bicr. Inier:cures a ccUcs (fcccic:c 1lans l.l (um:e de :icarcttet dc rc[rrcr.;: ou I!c c:C1r:t:cs ccr.t- mtr::•,icc tout•f•lOaC L:.r t;aut!r :n• corr:c• rJrd a ca-•..^n i. dc .,;JI ; ro•._•,:ct ,:u ta`'ac• (:':s: . •1!Irc ?,5 n:S ; :r .:cJ:_•:c lco-• pvo a•:c: ?r,.(i ._ r.ltr Ic t3'a:,1 et. blcs cnt:r•--.j, 1; n`y a F•,;d: nr.::rnc :\Ir.sl !: rc~t( ..a ^r:a. .! .. :c :~rcact. d•(:nc ~.1P:Ic uu tJ: ,c ;.lr (;:. C; t;c! rC-17u C:)a• lcr..•;c^..nt li qu.ir•.rc de et dc .^,i• .n:.^.•_^ r.:ir.s .., .....:._ .• ul:ir.. •._ [c,,. c~;a•^..a• ..C:1 L C: :i. , r:_.~ ...:1 1...a ... !ul^.i. ..:3t dc Cj .:! a .1.taC]:. ..1~a •...~t ..• ..,••1 C:C;....._. ^:er. .. •,r.t ia c'.. .,. . .~.. .. :ab:: T;_.., ,.s. f ,. p :a 3It.:nl cst ,;v: :c ,on- c.,r..r.: ;no ~c :•c ]aCac ;,ar ,:;a:::lc ;.:n:ec q.:c :~c ,.. . :.,re„cs ; rJt:t:••:t el ....._ic :n Irs su:'s:.tr::a nuls,iacs. prc• Sa: a ••+-•s l!c t:•t:•1c. Med Hyg 34(1216) 1976 :\u:.:su c:IJcr::: :t: :acrr. G~ :n :cn st:-...~.. Ja mc:J: ;:c c: d: Cy:-_.. .i r,:t.•: iq rctuttc'r •1!cc f• ;i~t•,.<<. t/ul ne c•• c.^.t Ju 1 JU:rC l;_ Cc\ Toul !ct ctcat SiCt Il..li•!IA•tll unC J':~tl:~ nlulnllr::!~ ;J ftla:i: J'un m.IJacc t.r.•a, Cylrcl ;s.rr r.r.prr•rt.a t: t!c I•t (umic de taajc. AII Cnurc Jc a•js ;l I: Cn il.tlt .rlntl Itrur I<< Lc.t. Jc I•.:• •ItltJllt l!Ul' I~rrllf CC:I; 11C tOt:CIIC pa r inh.rlJ:wn til::r ct cui,.ir;ur Ues ct::.:cc corc•r ar.lut-cs t!c carcinuscnc3c tir Inh.:!jt:nn cr•trcrrlc(:c ;tt-cc d.s h3nts:crs dc S%rlc sont cn• col o en cul:t•t. Stir la bite Jlct dennres celcntl!1,;'•I,. aca:r:- Icmcnt a nntre lJjcrll•lt,rn ct en :rrrllqu:lnt irs crl::rcc c:) tlNt.^.c pnllf io;i,luct cnr•ccrtla:tt !c. c(tCt..,J%c:scb ls-j •.. .. sur Jcs ar•la)iu•c J; i.tl•critc:rc. i c,: r.: s:•:• nablc d'cm^l:ycr C. :! cn pr-pur:t.•::s •a- ••_,lcs Iir•i ict :c ;es cffc:s sur .e (u:r.eur Jc Ld ...OI:Oj•C~~:re ;C!aj:r0 Lr:r,S at •.~rJ ;: • R;Instl:dcc• C;c,:'h USA Tire i part `o 6nJu C: _ ......:et _ - . _ . a:•_..• .._is,•. .. . • -_ c-. c( s:a• .1 ..:..__ ,._ri l':• f 3ib!iographie u.,.r,•. F I .,nJ ll.,•I„r.r,r,r n T. ~.- J ,..u Smnte ci„•i~ t .. r.;•a, ' . . r n-r,..,. \te;h,•.a -e I C.t Il,a f il (:.~,rc::o ~.:n : 1•• rm•rn,ctt„m pcr.r+nnelle ,C.V rnt•e C. l*. I!r: Icc.Jlh (',•n~r,lu.'n:ic r•t ~n:,•. n: .\ 1(,t•-1 •d IhC cur1:1.•n (:rner.,l t•\ 1),:l !l. • r I i.n,.unm.,nJ 11'•N.:.r. / 1/'//i S/(, -r,(d I'. nC•nC lutr.rl) nf \n1.,..C rrom Il,l(.•:,nl Ilr.rnJc rr( Cr4+rcn:c \li,wr;•I ~n \I;r 1. ,,..1 Ir•P/ 1'ber•ru, ,d..11• JI' :It 19't 1f 1'. Ilr•..rl...a~. l,-.,n•I I H \r,rn n thc ...t: n( I.~ ..1 \.n.•n II.•..i•I:r. t,• r•,: I'r~ 1 It. •"r,.1J 1' and 1' tl,,~•e 5: n ..j r .,n.l.' ..ri (:-rr \,,nr, .` •:•,• \ nr. ,~ . i,..-t. / \.N~`('..n.rr 1 y'r• CTR HN 042- 60 9-

TABLE I. Tahlron 1- Comparaicnn rntre Ies composiels de (un4e p tr drs ci,;:IrLttcs X et ceu: d'une 3utre V twirc;nc sui:ec :i 1.111% dc l;ouu'ton tnu)cn, Cis•,,•rcrrti l.vnOinl 11X1'; rl, rohae Cirursnrr X 7u;!4e comrninblt, an % r.tlnry!ondp cyrrrl 10•/, I. Pl.nn d.v porrlcultl A. Nicotirz (mg/ciQ.) 0.8 0.4 B. «Goudron» (mg/cig.) 17.8 6.8 C 1lsnzo(a)pyrtne (ml;fciz .) 13 i 11. Phort ee;ew A. Monotyde de carbone (mB/ciS•) 15.6 7.4 B. Diocyd: de csrbone (ma;iS.) 53.7 23.8 C. HyJrocarburrs (ug./cis. ) 1.lcthane I Elhe:!e (ethykne) 69) 234 300 83 Acitltyl~:le 32 6 Eth;,r.- 316 147 rropcne 1.58 17 Propatw 201 8t Yrcp.ilrene 6 1 Chlorure Je mEthyle + tuupyr.e 213 59 2-rr.eth~lv:cpane 27 6 1,3.9ut:.IteDe 48 7 Butane 84 la Tr:r.:•`•buttne 37 9 t CW:•o-a2ne 43 9 I,:•but:C:0. 6 1 C•S : kCr.e 52 9 1:ov-ene- mclan`e C-S 599 69 D. A'cxls, .,t~c!>des, citoees (uQ;ciB) M:ih.nol 210 14 Ethanol 2 1 Acct.ld,hyde 1124 215 Aau:, re S0 4 1'ropionaldthydo 132 12 1,ouutynl,:;hyde < 88 <15 C:.uonAl&-hyJe 41 4 Iso.a!enW :.tiyde < 69 7 nc;tone 488 62 Stcthyh7nykttooe ` 219 31 2.3-buum-a,o ne ( 2•butanone 152 19 2-pcauA.V 39 t E Fur3nes (u{/eig.) rur3rx 41 10 2•nwth>I(urnne 29 6 2,S-drn:cthy!(urane < 43 6 F. Nitriles (utt'ci9.) Acttonunk 124 21 Propiomtnk < 61 <11 Isonutyronstnl. 23 4 Duryronanb 6 1 Table I. Co`pariscn between the constituents of smoke delivered by ciCarette "X". and those °rom another Swiss brand with average tar content. CTR HN 0402-610

-' ~ 1 T,tir.r.:, i :. Tahl:-m 2. -\':~ri du nm r'm• C%:s m.rcro;!•jccs nltEol.rircs apris ncur •cinaincc J'r.r :'I :Uun Gr oupu erprr irrrrr• rcrr c l.nrle T/J:IfJ•lenr d! de proupe ha••urrrt nrcc la finnrc d: tirorerfet de .Yor•:brci d'nnie,nnz erce aCCnrtL. ^•ra! t:r~.'arlNel d: !rt ~ r; u l; rwn dc t rntrnt;•hngec ulvroMirt.s par rOrparr ntr r.nn:irr lorc.' d'onirrrouz en erpr'rierue A Ts bac 10/16 f61 D D1c!:%nrc 30:50 11/1G (t C Cytrcl 2/=1 D Contrble• 1/11 (G;;) (um: urs). • Sirnulacre de traitenxat (faux Tab1e 2. -- Yariatic:zs in the ntz-:cr of a:.v,_olar -r3crcph--ges after r.i::e wec;:s of :nh31c: tl. a. Ezpcri^e^ta1 f,resps Grcup cc;ie Trr:a`.-Ie-:t of ':-ste:'s aith i+umter o: a::ir=1s .:it:n a s-oke of ___-.'c:,tes =,ide o.° suDstcr.tial _:,c: c:.se _.n t::e alveo:ar :r.~c^cpz~; A lcv.'`.cco ccw^d.:l'c:3 •rV .•.:? .^.°r o° e>:,^er_:.e^ ta1 a:ri;-:ls ~ : -xt~:re ;C, v ..~ ~t: e1 D Ccntrol* *Si ::'.:1ated „r e-~t.^,e.^.t (sha-. s:-ckc: s) L..r' TR { f f'i 0°'"f' 2C"'..~ 11

VeF.?,;. 7 T.I. A 1 Tablrju 3. -V:•iaions du nesinbrc r!•s crlinlcs traehr_Iri i t'e,ln:Ict, cn mcero•.evl ir e:, itte :+17cs ntuf satn3incs d'iair,rlalioa Groupef trpeiimer,renz Code Troirmrnt dr de rroupe howri:crs a+ee lo fulra. de cigrrrerres de Drpri te rr;-nnrr•: Xomjie t!t cellultt d Rn'nlet sur k rot:l d'or.in:o.z soas irudt A D Tabac MclanCe 50:50 .l0lla (71 n 7!1S C Cyttcl 7.5/23 (73 m D ContrSlc" 5/15 (33y,) • 1(c;+u-ce cunt:~'eri:e, erlduce e:e 012+, pour clt+qvr anu:r:1. •' Simula:rcc!a:r:iteaunt(h:Lttu:r.:LL's). ^ablc• 3. -- Vs:iations in thc a.-er of tracheal go~le; cells, as per 1:~,`]t _croscopy, after r.:ne v-ee't.s cf _^`alatica. .rrOLl'J ccCe =r^_at zc:.. Cf !':^'.'.s .crs 1CCrCe C.:' : e3" .,5°. *: s=ofe c`C-ret:es ,:ade of tiw:ber of i,ct_e' ce.?s a :cbacco . cvcr the tc'=- :f L^•'°r st,:cy 3 Y:.x.urc ;~/`J C Cytrel D Coatrcl" -::r..•sla°ivc res:c^se ,;racle•1 frc= 0 to 2+, for each a:'_.:.al *-Si:ulated treatment (sha..n snokers) L.r f f`~'. f f f"f 4-A'"f' 2-612

L~:UT U A ii.) ~~ ~ta?..~.~.'L:~ ~~.. " tj~ ~ ~ ' . . •.,~rst't!riL~ivaC~ll.. Z„ LCS cif,^ .rCL1:C5 (:C :^1tCrl. .1::^ ..1:: Ft1:,,T~..,~.z q, ~C 7C ..]!!%LC. ~~ •-1': ?:1 ~'.r~~... .i . . . . :.. G..... !....': ......... 'i ~: .:i!:lli~' : HyLiCn:: C:..^.77~.'te Lr:1:F:.11L:Un) I::~i~CrJC rlcl! (r,y ^li: I: 1TCr:) i•'or r.lore th::n ta:e:lt}• yc1rs, it h:s bce:I krlc.+rr thit the cil;nrette is t'Ie cause of the friahtening increase in mort.%l.ity from cancer of the l.ung, cancer which currently kills irF 3witzcr;and bct::ct:n 1 foul•t:I and a third of ncn of cancer. The ciearette is also caost likely the cause :n incrcaae of a n.:.rber of other cuncers, in particular blldder cancer. To thirs evil cf:ect ef c_rcina- genic suystances contlins:d in the szoke of cigare_tes should be added the act-cn of nicot:.ne a:.d thut of carbcn I^onoxide on the cardio'nscula:• s;; stcr.., subst~~nccs 1K7].Ch prCci^i _3tC C:.I"ii :l^. a:., iCiC::"s an:'. -h:::l i r O!u',~: th_ : t'_^.y jC't.: s LOO ne^ a^OrlS E:7 0 1:Prs t.^.aa il^Un f,- .^.0;1S2:G`.:C: rS . ilrtcr a:C^;; r^= 7 c;: d '.- _^,; th e C^'1r:.e cf . h1Ci1 L.^.C ..:C1u, sL ~~ •!:7s tT) C. to (.e^, ::).° t`7:!C.^.CC, J.: h3s .^.111y to st:I^_ less tc:!:.C C1,,: 1•.^.t=C~. !n recent yc :r s, so-:e s•..^h c:,-ai e:tes (ar, .^d ,0 t~. es less carci::c'l;enic ... ,,.r.9 20 ti-:cs rlic-otir.c) are cn the ,...!. _c_r. _..:1 =r;ct^. rest:lts h--:c bczn ..otaincri ~.y ci::=rc.^.',: tr.,:,-cn: c: t:--acco and i artia:l;; by r,:ore c::'_cicr.t filters. l:r.f ortunrtcly, in Swit::cr land, ve have not yet bcen able to get the levels of tar and Cf nicot;:ne :r.scribci on the~c=E;are: te A new aporoach in the str,:C-01= again:.t tihe noxious cjgarctte is ope.^n te3ay wit'I the utili::ation cf substitute products rrixed in di:'ferent preper :ior.s wi~:: the t0bar.co. I•:ever'-'1^le.^s c:::rcntly this type of ci;srette h:s n-t yct a'.taincd the less toxic lev?l o: :alsy utht:r brar.ds already on the rdr}:et :o:• nany years. Wc shouli ncvcrthelcss su,ut_ this new attca%pt touard the ncutrsl- ization oi tile cat.u::tronhic cffects on the health, and also on the public finances cf the cigarette haui;.. I C/ R V/N 0422 6 1°....••

I L: c!::, :.,:! 4 by Tr:c-:c~ clrch Co;a.rlt ~nt,, Inr. ,:;~r? ^i i, n, ..:~ !c r c:r :,r.r:,ct t~ ?-c :.c:: ;^.^ 'I'c,l,:c_o I cccllr:•h, .%::) Y:Ir: ...., :~:^. ,.c). Carol:na . A part Or L'iC b'l.'.].c .^nr•srch in t!l(. rl'f:^cnt :,rLic)f' !3^.S been CCC: :,)1::!1Cf~ b)r MU-f.cSC1r:::1 I::3titilL•'., jn^. :iL`in t.1: ir:11^. o: !l resczrch grant frois t':c U.S. :::b).ic Health ^urvicc, CA-1C101. and r,,1-132?? (;: L.ca^1 _,.r.cr I^,.ti Lute) ,,rn:, a), th an f;c:d re :: .rch i. •-r_:.t ?_nr-~r: . .,, . (Division: Resourcew and equip^ert for researc.h). the ~:..:on o: -;'.---- sr.:oke av..:_t i: c' rr.I a1~ a.:a =:.,_' . Le s._ ^sc!c crc_ us t!r: . _ •.... ._ .. t L,, i .^.t ert_..:1 ..f r. ..._G' .:v.:i. :' ..:t...C. 7 ..:C: :.'.C . . -. ", i:.. ..... ~.._ . . :~ . . ... ..... ' ~:J .-.... ....... .. C•.. . ......~1' :•., . C.._ti._ .. ... .J~ -~ _~...._ c:......:c5 ? : a ...-.. .3 'tC~ .....r.. ...~ .. ••~••t•7~..~ ... .... ..:~/. :. ... risFs c~ .. '.ly sr. _o;:s, s::cn ,s c;,er._ti nf•c:reacs 1:r..:cd t: °e: cc•,. .lJ1. of c: ...:s. S;.atlStlc=1 ctuc:ie:. ce::ee::i:r.? d:sreses as:,ociatea th ..t ti.a21:t o: _.^..c.}:lan c:.-1t•CtT•l:3 5::L;Csl.: _.^..'~.;)t71t:aJ)y Fta tloSC c^.ntl ::.°:CCt T:':crC re t::rrcfcre sClid .^.l-.^.i°rlts 1^ :•AYOr cf a :.lCf°.^rp.te cCRsla^c%t:Cn with Cocc1 }ialtLh a:u? lo^-- survivr.1, arg,•.::.c:,ts :+h:ch ccul.d even profit t^ccc tc ti:c !,c~it of tc , ~c o i:, i:•i•c:ur•: u:_. :cac•c L•nc worlc-...•.:c .c:r4c::_y to ct.evelcp ciC<rcttcs or 1o•.:ur risk. V,irioti:s chan,-es i:: t::e tectinolc2y of t::c cigcrette since t':e 1(,150's have res;:ltcd in t!:e pr cd:.ction of c:iCcrct tcs ccr~....g ing iz (;cr.crtl lczs tar nnd les: r.icc;,:;ie tl:1n heretcfcre and carry:ng s careincp^i:... rtctivity CTR HN 04'226, 14

Vzriour prnccsac-, in rac!.Licr. tc , perr.:it;;ed realization cf this dir::unition of tor.ir.i.y :nd car;:.-.c-,cn,c act:v_ty (in tic:lsLay) of li.?':rct4.:eS t!.~cn o: tztacc: 'f the neasures taken consist oi t! : in:lati::n of t1Z',c:o ty air, Lc::w_, p::r'.s c: t:;= l.clvcs not previously includc•i in c:E,:rot,tes, ucdcr the fcl;m of hcr..r)~cn_s:cd cr reconstituted sheets of tobacco. i igu:e 1(after 6tyndo:r) is given 1s an ex :,:.ple. It aecson:trates the rerluced car_inc•~enicity of ci::'rcnt ci~r.rett~:s on r..6use sl:in exposed in a continuous fashion to chemical. carcino;,cnesis. We hnve publishcd in 1972 (2) a revicw of r:.ethc-;c?:.L;y for biolc„ical tcats in usaGc for the devclop-ent of less hazar:?cus cit;=rettes. The present report is 1i•:.ited to a new "non-:c.-_ccc" pr-oc'.uc t:r oc t::e :rar%et Lr.der the brar.: n.,rP Cytrc~ y:::c ;,ee ne: e cc°i?ar.; (:) •!eve: :.raicsfs the oe.•.er.^.: i.ri:c:Dlcs a:.C~d tile Ccnclu:iC.^.s ..-ECu=.^.d in t!::S ,2:ticlc .^.C ^?: l:c~ to '^'/ Ci: _,..) ci: rcttc tct:acco. .'::e cri„inal cc.^.ce?• ci "non-tobacc a" r: cd.lcts is ,.r.c subst_ .. _. -.. .~: 4 ..m0.!C ^.i.r'i~...._.._.- r...._.._..r ..'.iie,.iie, or _='.ti, of ;af..' s,: -c c° .. r=.:co. .-=! very ..--):c, - -' given t^e ::-.S:+ic:, in '.rhic:7 clZarJttCS ure CQ:7s"cd. :'lc 1.".c:..1od of i•.^,. '.2 taste :rust r c-ain f.xed ti+ithin r.nrrow 1:r..its tn L'e acccut,'lblc :or sncker s. To be useful, a"ncn-tobscco" snoking prcdu:t r•.:lst burn in a maaner sir-4lar to that of the cemtustion of tobacco; it :,ust have neither an un- ple;.sant odor nor an unplensant tnste and naturally it must be adaptr.ble :'cr usc in ci.aarette-cakin,; m{chiaes. Cytrel ful:ills thc:se technical co:,aitic..... Flirthermore, the snoke p-•oduced by th., "non-tobacco" smokin^ ^tteria'_ must be biolo(;ically i:lof °ensive or notably less tox+.c and le: S carcir.o«e.^.i.- than the smcY.e ef tobacco. It 1hould not contain any substance not centained in the smoke of tobacco, and the cigarettes c.::de of n;lch -1ntCrial sboi,l:'. yie:~'. L r f R HN 04,22615

0 ~ lf:-1 :.•: 1' (=:1'.:l..1 :J.:.. t.~' '~ ~.~ ~~:~: ~:... • ~.. ..:'. .:... a .•ll:... .... V..'- ..... ... . ... . . . ' 1): no I 1-MJi•Q7 i.ll•. t.N' U, Ln th'!t :7f Tii :.:C.)ry i:i lO:.J:/ SI1'~. . /ar....... 1:.% r:.^. :•?:iG :1:t: Co21st?tuelAs t::iCcll ilcr.c. iit _al; S+-r'r: il'!'~t'lt.n.i, :.1' Ll:Xic I.l'.^.,-)Q'rtiCs r • the coa`in'ltir•n lr.i;llt thc:Jrc:ic:i :^ T , c ti lly i. ucil :r •1' =r t:l::a wc~u1(1 b iad;r:ateJ ..y a simple ad'li tiion. Contra,uently, a riourous chemical an:ll;; si s.:of the s:ncke Ofr t•r rUr i."s n.^cf:!:.._:y,L:!'l .^.1C110.j~. :l tc:a.a or thrir princip.ll ac'tivities are ir.dispnnsable. C}^::i:,T: Y C: Ti:r: ....,.... Gi' C~: T:::L Chc-ic':'. n/ii.lysiJ .:f thc r..cl.c: pr:;duccJ t; ca;.lret'v^.J ma:'.c c^ ?C^° Cytrel ar.a of ..'xt:1re: cf :;;trcl;t=.:acec ..:,:'c or-en ecndl;ct.::! ;n L-r__: 1 _. by t!:r resC::.. zL: li:b.^.ra::'..IrJCL Of thC C:n1:_.'.C:C ... '}^.:j`._.... ~: r.-r^_t. - _It_. _t hAS .`CCn put .^.t the cf J . 0 .: i '. - % . ~ °: .7~. , . .. „ . . . ~.~.- (...:1~ 1::. i~ ........ 'r Gi ... ...'.t! su::, _s tf.c :c:.;th o: -.. . c- .,-• the • J^ C-~ etc. A.^. C7:'.;: C,'. :.^.,:°, .:C 'lO'., i:',^1 c ..,. c: ...... -.r:,__ .:c-^^_^'_r:. :7 Of ciLCI'C;.tc`L as as, crl ati Cx;' eriI:C^t_l leV.'1 r: , re;tilItS of a cOnLrolled test. i. psrt:cut::r series of tPsts :radc '.li'h c: •i et:.cs w: t?lou t fil l.cr of (';, r.:l has rcvca?l-d pzrt:culate rr.Rttcr rct_ir.cd by thc C::nbririi;e f:ltcr• for a ty-pc of ciCl=reL.e cetlled "i,rlericnn Blend", af:J ?L,2 ra,,7%cirlrettc :G1' a C0r,1,7ir:Ll:1:: Ciccrette Cf 10~'. ', Cftrcl 3(J1. Cltnloj'LlCtlt of i.n c!'llcl^!It filter pr(1Uortior.'st('?y reduce thc fiCures for each type of ci:-arette in a sippificant fashion. In gene:-al, ciharctte srao;e c;onsi: ts of three phasc::: va-por, - con?cnsnt•e, and nonvolatile condel3sitc, or "tar". The vapor phase is oe!'::,ec: as the part of thP ,^•mo!:E: S!h!('n CL")Sn!•C 1~. ::(:;'ccn Gr t?:i'• t..t' TR I 1 1 7 0421..A i. 6

I :amhrjc_P tjpA. The pr;.^.cirzl cnnstitucnts or !rc v^nor -':iSe :n a-'d±+.icn r„ air, CO, cyaniwe anri acetlldchyde are: CC2, ozone, ar;,en, etc., :+::ica mcst likely have fcw phyaialcg=.c c"f•=cts. The ser~ivolatile fraccion of cigarette sr:o:,e is tl:~:t ::irich c-%ti be distillcd at a given terr,perature startina from a p3rticulltc phase 4etained in the sratrix of the Cambridge filter cartridge. This fraction consists of approxisately 300 aliphatic, cyclic and aromatic,cosspounds of ratl:er.loa molecular weight (hydrocarbons, amines) cyanides, lLrans, nitrites, ethers, phenols, esters, Fyreces, picol:nes, acetones, lacto::es and ot7ers).• Many of these ce:apour.ds uree prcc';:ced by t':e p•,•r'lysis of nicotine or of nor= nicot=ne and, of ccurze, are absent frcm the ;,ytrel szoke which is devoid o° nicotine. There are fev-er cor:painds in the seMivolz:i:e ph=se of t^^ Cytrel rrr.cl:n t^an in tcbacco smoke. A.ppro::ir.s:ely 150 cf the 300 cc:;,onents found ~ i^. the se:.ivo. ..t:l?'~..t:l? fiact'ca of ~ t,^^a••_co s-o:: 'e ~r:r_ nct ,. 3p:e^te' in ~~•*.rc: s.^..O::c. Chemicil anslys:s c:' tar :rcn :cblcco ciaarettes dc-cnstrates ;,hat ;::is nczvc:atile frac`,~.cn w:ti : -o?.e•:utar .,ei~^t corrcspor,'.s :o 1.j'. of .`..:_ cG.^.':c'a::e, the L::• Czntent ef the :~'.rei cCndc::s,te is oal;/ 2v`, 7"ll.s tar is !l c:.'plex ...ix:;ire O.° aro,-.=tic and rel.ycycl:c hydrocari;ons, acids, alcohols, terper.es, iso- pr eaoids and oth:r r^ater ials. The arc:--ati^: and polycyclic hydrocarbons have been the object of greater attention because of their carcinogenic action. Sc^:e 24 polycyclic arc:-.atic hydroc:.ri,ons have I)een identified in a tar fracticn of Cyt=el correspuzdin; to anproxir::ttely 0.11', of the conde.^.sate. All had been previousljy found in the condensate of tobacco smoke. Eenzo(a)pyreae is often used as an index of the tctat arorsatic polycyclic hydrocarbons in smoke tars and the tevcls are s:rnilur in the Cytrel condencatc•s to those of tobucco. }:owever, taking into ac:ount the small yield o_* particllate matter in the Cf R f f tj ''i 0422617

(;ytrc). .^•m!'/i:L, thi: only tJ:.:t: '.1-5 nar,o!,r1:::s pt:r rjt.'i:l Ci,:ar'^t.t.lS n.^- v;)pos~•:d to 15-'c0 pt:r tnbac::a ci;;.ircLtr. T-t 1 ".•ti, u c•i;~rk r:L-,: cL:.V:...t: • : ; ' .. ..,::-t%;•" :r.c, ..r••;:I i • . ',;•...:1 , wz: oficrec: to :;wiss Tzb)e 1;r.!:rarr's :r ):vc) c:f t:!tc s-cke rr.m,rncat.: in th=:. X ci,;.rctt.,: tj tlt•2 yi•:1dz r.r cit;;.r•-tte popular on rhr ;wic:: msrY.et. Fro:t these fIni;:L, it is po:.sible t.o c:oncluue t',al: for 'Vic srr.ol:r.r, the ;•in)d of all ti~u s:r.oL:c cc; st:tu~:~ts is considc:r.^.b1y lesr: (in a stiitistica) ly sienificant r.aarF r) .^or the cirarc:tc containing the "non-tobacco" product. ~'T?,~L ~IC:~ST3 Acutc :crnfe)d (;) h.s rcce::t:y :.•ta:td::•di•:cd c ^cr ::!lc of c:,'^.r•et~ eY.^.X:c: „ i:. t'1C ...al /j ': :j S o(' tt:e v.l••Ji \..1 L1::.^ c. ...1.'•... rc::t_...v1J1 j w1 tl: :.1 P :il.....1~ t:\'l': "':" _.....::1.C Y.•.. (... ...'~ to l~.i/ of ~J:• 25 seco::ds p=r r.:irn.tc, then c:, .*rpz.. a:. c3r 33 nc•:t .... A•:^rat;c s~rvivll, fcr ).l :_ ..._.. ci .:c ;•r.•:rcial ... :G ; •S . . 1~ Yo 3c „. t.::e ..... ..~ u^ cis;=rettcs :.:=c?c of ';;t.rcl h-~d dicd :.t thc end cf 1r:J c:.::::tcs oi j;;e::tica) treat^cn',, the ti:~: at •.:hicn tt:;: cxpcr.:c.ra ti:at rcsults) . '.:_th t!;e :o:,:ru: t': •!c: o the sU: : i.-:? tir..a was 20 m:nutes; with amixtur: of 50/50 tcbscco/Cytra, it v:.s 53 rninutes. 7hc Cytrcl ciCzrcttes Werz, therefore, :r•uch less toiic for the r.tice th:n the toblcco cigarettes or those r..a•1e of t'.+c, C.-tre7. ::r.a totacco r..ix ture. Subacutc inhzlation ptible thln Syrian ha:::sters to ti.c Since rats and mice si e more su :cr toxic effect of smoke and niccti.ne, the ltttcr ani!r.as are more appropriatr for l.onr;-term stsdi^w. It has been dc•m:.natra:ted that Syri:tn h=sters of thc t.r f R Ni`'{ 04,2618

tlIO 15,16 strjLin arf% more susrc!ptihlP to the ir„ucticn of lx^yn ;.11 vtnczr th_n other inbrcd strains, c,r rantlocr.ly-bred Cyrian ha:ssters (G) . For these z cr.s:,ns, stsdi.cs inr.ludin~ ey.ponure to ~acke c:urina proicnCcd pr.riods arc o.°tcn con :;ictcl :rith ;;yriun ta:.rstcrs. Thr! study to which we have refcrcnct% hcre (and which will be pnblish:d in detail elsewhere) concerns BI0 15,16 Syrian hamsters which were exposed to smoke frcr., Cytrel ciBarettes, tobacco ciCcrettes and cigarettes'made of -1 mixture of both, during 9 consecutive weeks. The study included 3 cigarettes, and more specifically, ciCarettes of tobacco alone, s:milar to cie^.rettes r.urreted ir, the Unit:d Y.inCdcm, civ:crettcs :r-,c:e of a r.ir.ture in equal parts o^ the sasnc tobacco and Cytrcl, and cigarettes of Cytrcl alone. All the cigarettes had the samc type of filter ar.d an ide.^.ticat paper. Four grctps ni 24 rrale BIC 15,16 h:.rnsters approxi.:.ately ;0 days of age were utilFzed'. C:n_ rro•-'p vas subjectcd to all the ^-tinipulaticns, i.^.cl:.,._:,; daily cc^fin°_-:ezt ia a sTo}:ia„ r.chinc, 'aut wi;,houL cc.nsu:.in- c'__ a rettcs (, ;roup o° sh=..-.1 s.mcl:er s ); the others .,crr: exposed twice a c°ay (7 ds•,•s/Wec'.:) to 12 cc.isecutive puffs _•. .. revcrsc =r..c}:ir.g c:achine. The cii3nrettes were s::ckcd to n res:dual length c: 23 :,•-, at vh:r:y point they :-;ere rE•;11ace3 by nc•.+ c.~;zrettcs until the 12 :: s had been ae-.anister ed. The psf °s cer.sic :.^d of 35 ^a a: air puahea t::rout,`i each cigzrct;.e for two seconds at 53 second intervals. ':he animals, in groups of 6, with only the heads er.closc:i in the smcY.in- box, re.:.ainc3 exposed to tt smoke concentration of about 20. for 25 seconds follcwed by exposure to fresh air for 33 secor.ds. Ur:der these condit.ioZs, the ani:.-alrn expcsc3 solely to tobacco smo'.:c had average levels of carvoxyhe:no;lobin of 31.3,1J, 30 scconds after the last smoke exposure period, returning to ccntrol levels of 3.9 to 4.4~ in 24 hours. The aniu.als inhaling sno.ce from 10010,*' Cytrel had a carbcxyhe:,;oglobin level of 11.3%, 30 seconds after the last puff, and those subjected to the sccke frcm L..r f f"6 f fN 042619

1:0,~;~ tl-.;i . „ . : n . _~,_ ..:1._. ........L... ...:~.1. Lai•-i_^~ tc:;,:t c Lr 1 :c Ci[ ircttc•::) shoved .'.r"r initJl) lc•'^. R.^.cy rC:.'l:rnr•a ".o ,,i . n .r°. ~`r.•,. i • ~ll Lare r'.i ~!)1f lf: ~a ::+C '.'JLI'C1 1aY. ~..."c t11Cn S:i t•)l trrc'. tc:.:. `•!i. An:.:111 :'^ cxposcd to Cytrct rlao}:e did ,lot lcsc wcieht, altho,:;-h th=ir .:ci~;ht rain ti;a a:i.,,tle less ra.~J,•i '' ta1:. t!ut of t!:^ iiistnlnmic ch-rrfves in t1!•- r^spirdtory tr:ICa ::erc c'.utcctc3 to::2rds the cnJ cf tac ~ r:•_c'r.s oC Lxtcri=:a^L. ' T31'rP c.:zr';cd di_'f:renccs b_t•,aeen anir~~..s which )lad tccr:c:o sr..c'.:e t:»=c whi_h ~sd :7~,u1 =d Cytrel s:ackc, :1tcr- L'lediatc c!:°".(;eS C'cc:lrrinj; i'1 t.::E .°.r:i a)S -L'!•j!Ltc': to C!':,:c.` s to: •.::e ^Y*.rel . . ... . . . .• ... //. . _ J_~.1.. nV .....t.-e irl w..c, n:.....~.. ~f :~cL~rh..~... ...=4.-..... i:l t:.o ..l'i•:^.. .7., ::Il.:. •.1: 1•....1 J. . t.~...~r: .. ~..~', ~... ....... .. ~...: . ~ . I'1 t::C a:.l '.C .. :.1' : r7::. ai, :h2 the P:,^ :i11eJ .:i:'1 mu__s. ::se~ cells _re ccr,::.:^.r- i -1 ... ...L..V:l ~.. '''.. . . ~' ~ r:1Xi.111'e a!1. 1 c1)^O1 l1LCly U(.1:11:1:1.~C: t.~lc e^r••ct cf Cy :Tr:1 .:'.e+%~ c+ ( '.:llP. Z) ~~Y^C'.:~lt tlr:e--!1'ctcdly 3r:^.• the rc)rtivclv :rti;nl'! Cerio~ o~ '.•c .:ecl•z, b~;~crpL•lsia of tae lzrylr;':al. ::w_ost wa- -pn.-scmt i-n ahout. 40! of thr• which ha:l t:.bscco sr!nlcc, in 30;'• cf these ti:hich hxl ial.^).ed sTokC fthe Cytrr_l/tc):;:cco mixtal•c, but absent in the zrli~.~ls sub,jcc:ct3 to Cy:rel sr.o'r.c or not ll.;vin,; in:1-:1ed rlny salo'r.c at u11. Currently, si:n_lnr inhalaticn studies are !n profres:; these llave been pl.arrncd to last 70 to 104 weeks, which allows for tl:c clcvelop:-cnt ot' cr.rcincma of the larynx, known to arise in 1:I0 15,16 h:u^stnrs rlt the end of 70-;0 weeks as a result or inhalntion from thc sr..ol:n or Y.enLucl•.•r rcfcrr.nce 0;-nrcttv: (6). C/4 / '7. N/ , 0 ( \si 2..wl'

, SKIN PALtITI!iG 1'E.':?.°, Fa:periwenta on carcino;~enesis due to inhallticn wo-ild be ::.ore dirtetly ccmparable to induction of lun,^, cancer- in althou:;n c:ar.cer of the re•spiratory epitheliuz, produced in the 1110 15,16 Syri::n hi-mster, occurs al tho sitc of the larynx and not-of thc brouchi, as is the cuse for I the so-called cancer of the lung in hu..8ns. For that, we muct await the . conclusion in 1977, of our inhitlation expericients .noF: in prcE;rtss. For the moment, the most generally accepted means of evaluating the carcinogenic activity of tobacco smokes consists of painting the sl:in of mice with smoke condensates. The biologic activity of Cytrel has been studied and ccrpzred to that of a mixturc of cigarette tobacco of the :,merican type by applying the smoke condensate to the shaved skin of mice. In the eours-: of •'+ di:tinct nxperimPats, the smo!:e condensa te f r cm "nor.-toblcco" s;ibstitutes wer c all rurkadl.y less tunori;;enic than t^F identic=: dc=ses of a ecndensate .^rcm a mixture of tcbzcco from cig3rPttes of the ILTericran type simu] tr:.cously a,3clied undnr ident:cal. coIlditlo.^.3. The sa'1e w;as true for doses of nonrquccus 5Sacke condellsate \'ar;/ir:g cor.siclerL:bly .^:•c.n 35 to 246 r.:; aftinistered per :cuse per ::eek for 63 to ;•2 weel;s. 7hc rerpons(, to the sr.c;:e condensate from the "non-tobacco" product range,l,fro:n a total absence of plpilloe.zs and epideraoid carcincmas, at the lowest doses, to an incidence of 25.3~, of the cni::;z:s tested at the hiChcr doses. Cn the cther hand, the smol:e condensate from a typically A.:.erican mixture of tobaccos inauced these same lesions in 19.9 to 39.1% of the animal. A smoke condensate from a Cytrel fornulu, type 3?4, was xpn)ied at a yet higher dose, of 365 mg/mouse per week. Papillursas cr.d carcinomas in only 22, of these animals, as ccmpnred to 39.11, of the mice exhibitinv these lesionar after the acL~ninistration of 2115 ria of smoke coadensste from the American mixture of cigarette tobacco, this bcing the highest dose that it CI R I • I~I .J' I2i.-M .F.nn J.

& - 1.0- / k I is pnnsible to aFrly with a test rrnterizl contninin:; hicotine. A sr-inke condensate released by s 1/1 r:ixture of Cytrcl und cirzrctte tobacco produced far fewer cutnneous lesioas at r.nc lower dosames (35 and ma of nonaqucous condr.n;;nte per nouse per ueek), that i~ to say in only 2 and 8.2% of the animals as compared to 18.9 end 22.7'; respectively,..Sbr the sa.TC quantity of smoke condensate from cigarette tobacco alone.. At'.' a higher dmse (113 rZ), the response was the sa.~ne for the :-aoke condensate from a 1/1 mixture as for ciEarette tobacco. There was an excellent relation- ship bet.rnen dose and response for the Cytrel, typc 30A, sr.,oke condcnsate tested at 14 different doses: F,4,113,246 and 383 c; nonaqseous condensate per mouse, per week, 0,18.7,25.3 and 57.7;; of the a.^.ir.:a!.s developing cutaneous lesicns. On the basis of criteria inherent to the skin paintizg technique, Cytrel is considerably ar.d significintly less tumoriffenic than ciCarettc t: hacco. This study will be published clse::here in more det.til (7) . FiE;ure 2 gives an exsm?le of diffecenccs which appear b=tacen the nu;nbers of papillo._s produccd Ly a Cytrel conc:cnsste and those pro:'Iuced by a tobacco smol:e conc!ensate. Fi;;sre 3 sho•.+s the decc/eff=ct relationship When several dif°nre:,*t doses of a Cy:rcl ecnde.^.sata are applied to the skin of n:ce. ~ DISCUSSIGII The chemical stur'.ies of the smoke released by ciglrcttes made up of 100% Cytrel do not reveal any smoke constituent whicli is not present in the smoke of an ordinary tobacco. These substances are presPnt in Cytrel in far lower quantities than those detected in the smoke of reference ciLgarettes or in that of all-tobscco cen~ercial cigarettes. Tneir "tar" corresponds to about 1/7 of that originating frorr. tobacco, that is 3.6 mg per cigarette (cenpared with 26.6 m3 for tobacco), and, of course, thcre is no nicotine. Thus the replacement, in cigarettes, of part of the tobacco by .rytrel Lr f f`s. { f{ wf 0"'i" t''t"°-i 22

. substantially reduces the quar.tity of tar and nicotine in the smoY.n resulting from their combustion. Such a reduction in the &moke is not proportional to the quantity of Cytrel added to the tobacco, but is of a lesser level, since for each gram of substsnce smoked, Cytrel contributes far less to the smoke than does the tobacco. Nevertheless, the most important objective achieved is that the smoker consurses less tobacco per cigarette smoked than is the=. c3se with ordinary ciCarettes and inhales in lesser quantity the harrsful substances present in tobacco smoke. None of the evidence suggests that the combustion of mixtures of tobacco nnd Cytrel, can result in compounds that are not present in the smoke of either one or the other of these two components taken separately. All biologic assays conducted to date indicate lower activity in the smoke of a tobacco/Cytrel mixture with respect to that of tobacco tr.:o!;p. In eur o,:in studtes, this was so for the skin painting tect::, as vcll as for the hcute and s• :cute inhalation tov:city tests. So:ie cocspzrative stu?ics of inhalation carcinogenesis undertaken with Syrian hamsters are still in pro.-ress. Cn the basis of the scicnti.fic data currently at our disposal, and applying the criteria in use for the evaluation of Siologic stucies con- cerning the adverse effect of tobacco on laboratory animals, it is reascr.- able to employ Cytrel in variable proportions in cigarettes so as to reduce the effects of h3raful materials on the smoker.l , The bibliography will appear in separate reprints. Author's address : Dr. F. Homburger, Rio-Rese3rch Institutc, C3r_brid;;e, l:nssachusetts 02141 USt.. 1Some ciC3rettcs contlznin; 2CY', Cytrel are currently ::iarlccted in Swilcerlnnd and in C^.rmany, nntl arc ui:der st-.:dy in tt:: Uni tcA t;ia;-dc;m. r. CTR HN 0'-f' 2-623

F7CUItE 1. u_ 100 T T 90 p (40) Q ~ (20) ¢ C Y so i (901Q ~ D 'E 70 T (2014 1 1 ' a 60 E M 50 (296) 1 ; 40 o In 30 (200) ~ (200) 1 ~ 20 (246) 1 .. 10 a 0 -A 1954 /55 1957/58 1959/61 1962 /63 99% confidence iimit Condensote BaP" Fig,,ire I. Re:uction in the numbEr of zu.^nors in response to a 50d, suspezsicn of smoke ccnae^sate over a period of r.:^e years cc---)ared ai th that induc0d by 0.005 ; BaP duri;,e the same period. ('r'he mucbers in parentheses indicate t::e number of mice per grcup). C~°`R H~w~ 0~` '6.~4

FIC,L'1L. II. 40 1 I 1 30 < O .. 3 W V I Py 10 0 0 /1 r./ I . Cylrel Ttpe 324 ~.... ~ ~ - ............ ---•~ ~--- - -----~ 10 40 , 40 so 20 30 Nt1MBER OF wEEKSSINCE B(GIwS1NGOF TREATMEVT F:Cur c I:. Cc _sar _sen ,;et•., een ttic r.•=ber s e° pznillc-as result: ng : r cm sk:.^a pai*ti::;. ..ach c; rcur cons_sted c: 1C0 r..ce paintec 10 tisaes/wee{ u_:h e;,.:a1 •.:ei5~:s c: cc::!:1satc. CTR Hi'i 04*2262-55

% FIGUIiE il:. A k 10 20 30 40 50 60 70 80 NUMBER OF WEEKS '^: earance of clear ly visible pap:11cm3s :n ^ice trcatea J wi::: threc dir:.:rect cc nce%:ra:iors c^ ncn-:otac:o snio;ce cccaencate: A) 3F3 -j of ^cna:uec~:s s=o::c ccn--ensa cc a'-pPl_ed per r_cuse, ;.er week; 3)2L6 -" C) 1'.3 ~; .;z . Thc atscissas the nl `.~cr of ':JeCfs since the te~~:.:~~ 1G cf the cL` tanecUs treat-ent. ti.r i R Nf 7 0".i' 2i.,8 2[aA