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Low-Risk Ciigarettes:: A Prescription Low-toxicity cigarettes hold I,ip;nificant'promi,c in'thc prevention ufdi,casesrelati:dltu snruking,. Gio [3. Guri During the last 30 ycars, epidemiolo- gical studies huveestabli.hcdlthad diffir- ent patterns of cigurcttc smoking behav- ior lead to quantitative diffcrances in smoke: inhalation and have shown a di- rect relationship betwee'n dose and risk of disease,(i, 1): Afteraltnost 500 years of''experience- smoking has: become ingrained in ncarly, all cultures. As n result'.uf this. two re- cent decades of antismoking education ii n our society have men with only partial success: today 55 to 601million Amcri- cans:still!smoke.andthehabitappear to be increasing among teenagers and wom- en (3). For the casual smoker. thekinc.thetic and cultur.d'aspectsof~the habit may he easily forgulten. but for the serious smoker-almosn invariably the problem smoker at high risk ofldiscase-the ph: rv macol'ogic, physiologic: and hedonistic rewards are not easily, overcome, even with strong motivation. Since smoking occupies:sueh a promi- nent position in the mythology of our~ daily life, it is unrealistie'to expect that a society of nonsmokers could be created after a mere'_0 yearsofpublie education, particularly in'the'prevailing sociopoliti- cal climate; historic perspective suggests that many, decades may be needed to achieve this gonl.. Until then, it is: important to protect those whoeontinue to smoke dcspite all warnings. 1'.e:rvinlp:tharn totheir flilc is neither humane tturecununlic, pnrticul:a- ly when thcre is evidence that Ihcir risk can be'reduced substantially, in at len.t lwoo wny,s:. Fir.t~ ic may tie possible to rcmuvcc toxic ..muke components ,electivel j'anJ thus reduce specific hazarJ,: tiocundt the well-estahli.hcd I do.c resprm.c: cvi- dcnce suggcsb.thal.,iflh'es lot.d iittukeul l The auttvor, i.the deputy direcwr orithu Div~i.iun o(Cancer Came and . Pievenuon and: dilr<ctur o6 t he . SmukinQ and:Heulrh Proy m. Narlonal Can¢er In.n- tnie, Nmionu4lnaiuvtes.uf Health. Bethe,.la, Ul:,ry-land 20011! . 17'. DECEMBER 1976 .,mukc in the pupulutiurn.c:m he reduced. :ufle:r :ut apprupriate limc a reduction in diaetse' incidence should I:d,u txcur. a.. JJ:,monvlr:ucJ for smokern ufl ftlter cip,.r rcttus(4).. Many tudics (d-7)) indicate that a combination of these two ap- pruachex is fc:uiHle. limited unly by the market con,tmints: of cigarctte: accept- ability tmdlby the Jynamic, uf't:nlc and pa:rceptiun mudificatiunin therun,umer. Rcductiunuf Tbvi¢ Smoke Components M1lethoJ, for reducing the smoke yield of ciutrette, include, genetic selection andd low' fertilization,of plants: growthh and harvesting practices that provide "leaner" tobacco Icafi; curinp,muhoJ+ that remove leaf components: use of high-porosity papers, filtcr.: and smoke Jilution devices; and tr.lntiform:niunof tobacco into reconstituted sheets through a process ah'ut removc>unde.ir- able plant compunent,., adds incrt diluenh,and increa.e the volume ofthe original tobacco (6. 8'-/S): Most of these approach'es reduce,the, amount uf "fuel" burned during combu.tion, favor mure, complete, combustion conditiuns, arnl Ji.courtce.pyru4y,is, pyro~ynlhc,is, anJ. formatiun of utr, carbun monuxida:,anJ other undc,iruhde contpuncnt.:In :tddi-tiun., the, tur'of cigarettes so proce..eJ ufiuaVly, shuw~,:dccrc:c.od C:ucinaEcnicilys whrntesled un :m, erltc.d-du,e h.nicN aE:iiit,t thc'.tluufnl'udlliimal cipucttc, in tluu,c kin av,:tys (6;, 9, /6;, l7); Ihis is rclltLctud in lhe,+teadily decreasing activi-tyufthe lan.in-cummc,rci:d Amcrican cJp;irettc.,, liver Ihe'.Itlul Jec::tdu'1181. Allhwughnc:uly.1(XkI cumpuunJ,havc been iJenlifie.d, iocigm'ette.,moke:n only a fuw.h;rve hccnirelatcd tu ,pecihc.hc.dth h~iz:urJl., Ilydrupen cy:midce i.cun.iJ-cred ,pucifii.ullylitxic, for the ciliated respiraturyepilhcliumdl9l. The insult of' nitrogen oxidc.,mayhavearolein acute and chronic uhslructivec pulmetn;try, di.-aa,r and in the. ,luwJevclupmcnt of rmpliyncnt,l (1?. :01; Variuu,4Uxir .tnri• bulc, have hccn :ucrihed to u numVtcr uf :Jdehydea :md phcnud,, ucrolcin in Il.:ulic- ular I6. _'f. ??'11 The kaz:ud' uf thc.a, cumpttnenh, however. appcars ,m:dl when crtntp:uud tu that uf lar, c.ulwen ntunusiJa :utd nicrttine; except :t,they. affect lung clccu':tnca mcch:mism.: r.tr iv a mixtureuf manychcmic:dy amJ!i, .,nm- mutnly undcrnluuaJ lo conlain nuel smoke :c:u'cinugcn.: , it'.:d.,u cuntain, t,lh-r er iiritcml, cmJ lo..ic ncucri:da uf uuidd•n-tificJ prupcrtic,, (6, 21. 23). Carbon man- ux'idc is linked to Ihe dcvelupmrne: uf aardiuvascul:tr diwr.[cn and tu :i:alc tuxic.ily, phenomena (?d). The :mu.\i.rit proJucc.,may precipitate:.uJdcn IL;dh whenan insufficient myu¢arJium i„ncr- ly stimulated by nicutine (?5). Nicotine i.recugnizrJ :tsa d:mv.r,"us alkaloid! but, at the: duse% deliver c.d ~ly cigarettes, the smoker:wtomatic:dlv :,J- ju.>is intake tu fdcvor ph':umaculugtc andd physiologic reward (26). Ei'cept, - in- die:ateJ above-the ,uddi::n toxiunv of nicotinee too a damagcJ myocardiwn' in relatively anoxtc condition.-no chr.nic toxicity effect, have been elcarl.:, an'J consistentlyattributad to nicutinc:, Bccaux,uf ita overwhclming ph,u ma- cologie contribuliun, however, ni;,aiae plays an impon:mt't rulein cuntiolling ..muking,heh:tviur.. Within,moke . ti..: :d-k:duid cxi+t, in huthithe, proaun:Ltr,I.mJ unprutomueJ7urm.,,The latter ftii :, in- crcaucs with i incmasing alknlinity, •d the ,muke.'(ZJ. 28) and appears to he r., tre rcad il y ab.,urbed lmu re', i m porta nt ~ a i R. it has decidedlysalisfyingy effects unIh'e.mukcr'~ tatitc receptor. (18). Within;er-IUin v:JUe r.tnEe,; hi4h luvel, uf nic-,linc. hi6h,mukelrH vnluc., and high r,tut•, of unprutunatedt lu prolonated I nicutine in- creax, the satiation effxtin the .m-.:rld tend to dep,re,s the cunsumption of .^a- rettes and the'Jcpth and fi'cquenct of' inh:J:aion 1?6, ?4); andd therefore rrduce the intake:of,moke,, Thuss it appe;trsth:ns the hazanr uf' cigarettes can be: reduced by a.iirm!la- neuu. reduction ofltarand uf it. rr, ifie c::u'ciuuFeniu:t¢,livity,; liy a redUili1 -I' lif' c:utwn munuci&, ttilrugun uxielc•, hy.. drupcn cyuitidc. aorullin. anJ ulh n utt- de.ir.th4e toxic smoke compunent,. wd by an :tdju,4menl of nicotine lavtl, md prutunutionc.unducivetac<ul.unle.r•. it t-. tilln. The technology toochie,vcth'e>r t. ,ult+, h':n, heem develitpuJ emd c:.ni Its: applied to th'ee nt.muf:iclurc uf ..,,rrt-merciallcig;ucllcz 16:,7: Il'. 12. Id. ln;. /7). Not .urpri,ingly. such manip,l,- tionsaltcrtrnditiuanal Ihrvor p:ittcrr . ..1 produce: variutu% degree.uf wnllic,t ••r h eslhhli,hdd ,1and:uJs uf :rCCeptancc i hc 1241

l:0blc 1. Diuilycritical cigarelte: con.umptiun. Citlumnr1„2, and 3 repre.entthc luwesti avcr•studia., It: cuul& he arguetl, howeverL c.pr^..Ind highe.ct critical valuexol.tained'frulnametn);~:dllcurre>punding..tndie.% lhal cach.muke eom omenttihould he p , C C Disease:mortality Canccrof theolnd cavityCbtceraf the: pharynxC:ulaer: . of tLe esoph:tgus (:': m cer a f t he pancre as. wn:nof the: larynx Llun~ cancer C:I,nc.crof the, b4adifenand, kidncy. Co^nnary a'rtery,disea.e Curonary, heart Jisease. Aua I icaneuri.m Grqphysemn, brM onchitis. or both Ait k~m..csfor current smmken Studfes Cigarettes ( No. ) (No:) -(II 12) (3)~, - ~ Lnw Averaµ Iligh~ 3. 7-t, s.)t to: 1 2-3~ 2~:5 2-3 2~ t-5~ 7.3 lo: 1 9 9 9' 2' 3-4 A~.I( IIII lo: 0:7'. 5.7 l0: 2' 9~ ~ 9.5 Itll 3' 3-4 4.2 4'-5 I }-4 i.$ 3-t 1 4-5 ~, 4.5 .1-5' 1 101 ~ 10 III~, 4 ~. I .I _ d-c prtlhlem„ however', is not in, surntountable: because consumer pe,r- cupciun can be made to change. For in, stim;e; the strength of cigaretteN today'iy ne:niy half oflwhat it,was 15' years ago: when modem cigarettes, would have hccn considered too weak (l0). There m:.~ he loweriimits of'acceptabilidy;;md the " success of some new cigarette brard., containing 2 to 8'milligramti.uF tar :md 0.2 to 0.8 milligram of'nicutinc; in liaates that',these limits might be quite lut.. Future commercial cigarettes can bc expected to challenge consumer ac- ceptnbility and to callTor cautious m;lrr keting policies. These new cigarettes will mili~e compensating ffavor% and fr,t- Er:mces (3l). and it ap,pears:thatnafctv renqtire,menti: can be'met„particularly iN ::dd"_d' flavors are natural tobacco com- panacnt.,, andl arc little pvrulizcd or al- tcrcd during smoking: this being the maximum number ufc,igpe rettes than the averaee individual could smoke daily without';Ipparently incroas- ing his expectedlrisk of murttditv .ignifi- cantly above thatofa non.muker• within the atatirtic:d v;lriationi ini e;lch .tudy (451. Tahle I'summarizes theresulte oCthif analysis, The low v;due is thcJuwe,.t of' all critical v;dued o(+taincd from the .lud- ie% revicwed; the average and high criti- cal volues are defined! ,imilarly. The .mallc.t, critical value on i record is 0:77 cigarette per day for lung' cancer: it should he mentioned that Ihi, low point is the ru.ulFUf'unly one study (??) iuf thc ten surveyed for lung,~crmccr. the nther ninculppotYing a low value ciuur to five, cig;lruttia% perday:. Most of the studies in this analysis were hsacd un' data collected durinu the I95Q'sc because the di.ca.c% can,idd.redd have a long, latent periudi ir, is fair to tion he- conelitde that cigarette con.um p Low-Risk,Cigarettes " fore 1'Nv41 contributed to the . ri.k,,oh- fhe feasibility of less hazardous cigsr rcltcs, poses an obvious question. Arc there limibuf eigarette:and smoke com- p-ition th:u'.mayapproach,retative ..afc, ts:"In pragmatic terms, these limits can ht; dcfined::rs the smoke intake dosc, at which the risk of disease in smokers i., appruxim:ttcly the same as in non- smokers. Vsriouyi ways of e+tim;uing thc,,: v;tluev arravailahle-in panticulin:, thc: dose-response analysis of .e,verull cpiutcminlitgicat studiesand'theextr,lp/t• lauwn uf hlotxl'concentratiund at ditfet'- cnf', r:dcv uf' inlake for ccrtain .Inukc unupetnenls. such.:tscarbnm monoxide. fr, derive :t do.e-rc.pon,e rclatiun- aiip•.e.pidcntiutogical studies associating (:'ilv cigarette cun+umption in malcs with increases in risk of mortality frurn lit specific diseases: and of mortality in /:crver:d were :ma6yzcd I(-t1,-!J). Acriti¢:J valuc was eslirtt:lle,d from euch ,ludy. +crvcd: Table 2 li,t, the :Ivcrap,e dclivery, of some significant smoke cumpwncnts furcigarctte.r manuf:ictured bufarc 1960 (,ce al.u (tt-4v)1. Cim.ervntive .e.timates of u.pper'~ limiisufldaily.muke intake should con'cnpundd to the lowe t intake drt.es u. +nci:ded with increased ri.k in cpidemiuloEic;d Table 21Avcr.lge. delivery ufl .make com- ponents of cighrettesmamdactured, hefure. I'MW. _.timuke` Avera);edyliveryper crnnlnmcnr clpr:ncue --- Tnr(mg)'43Niaotlnc9lng)'3.W CC1lmplr 'tNO, t/a;) t . 27(1 HCN(µ(;lt: , 41(1 Acrolbinilµg)t:: 130 'Vdr.v-.wtiMhileJ -<i.,I- l-.. 171. I.tirc Il.'1; judged'only in the contex't of the associat- ed di.ease:furinstance;,thereis no clear evidence that nicotine is related, to lung c:lncci;,hnt a case could he madc fur iEs role in curonary heart'6sease. Ati present, the countcrrrgumem, is more appropriate becau.e the cau+ative :cttrihutca uf' in'dividu:d smoke com- poncnts,are .u(ficicntlyy blurred to hee of cuncern.. Thepoisiblee involvement ofniuutine in the etiology of lung cancer has not been ruli:d ottt; in fact, its in- direct rtle',has beenisuggc tcd'.hy a re- ccnt study (SD). 'fhus: a, conservative' approach sug- gests using the critical values that apply to all causes of death in smokers. Al- though "aEl causes" may inclitde some that:ere not'tobaecn relltted, this compre- hensive category represents the effect of cigarette consumption on mortality ini gener,tl. These: critical values are listedl in Table I, and the:related critical values of smoke components are listed in Table, 3: Blood concentmtion of carboxyhe- mog(obin (COHb) is not directly propor- tional to CO delivery, per'cigarette; it is influenced by the,smoking andlrespin- tion dynamics of the individualland by the number oflinhaledlpuffs that a ciga, rette dclivers: Based lon standard consid- er.diun. (Sl; 52). T9ble 4 indicates howmany cigarettesa.moke'r could consume -daily'befure reaching critical COHb val: ucs, depending on the CO dclivery'per cigarette. If'th'e low critical values of the range appear difficult' to~ attain-a smoker cuuld',;ugue that they amount,to a non- smoking prescription-the upper values are in the range of current cigarette mar- keting.:md manufacturing realities, al- though they would necessitate modifica- tion of the acceptability requirement+ of the smoker. It would' be errone;ous to interpret' these critical valuesas indicators of atfe smoking Ievel+, since: the e'xperimental and ,tiltiatical uncertainties of the stud- ies surveyed are well known, cts'inmu.t epidaniulugical work uCthis kind. Ah,o, reylydlc.sof how,sophisticatedthe sta- tislical mcth/wis might he., the data .huuld,nut hc interpreted a* inndicating .;dc icvcli., and .pecial pruvisions wuuld. still he nece,sary, for highn'isk group+' .uch as ca:dl umnium, and a.hc.tuss w.n kcrs: Uncsrtainty, howevcr,,.h'ould not be, adlowed to dilute the implication iof these dfua, namely„that a r,lpid .h'iff in ciga- rcltc cunwmtption ihahit..lowurd Ihe, pru- puue.d range of criiic,al valucs would 1244 YCII9NCH, VUIi. 194

make il reasonalhle, la crpccl thal the cuncnt epidemic prupcn'tilun, of ,mok- ing-M!Ited diseases could he reduced to mir•.m:,; leve,l,in,lightlyover a'dec¢de (,;). I'hi , expectation is plausihlc hee:w,e, cumctrt technology can reduce thc specilic toxicity' of smoke' condensate well b,low'the levels prcvailing before 156(I Iu'l. 16, l8). All.rflhirevidence is not new„a, mu,l oflhc, ep,idcmiil4ugical vludic,' reported were :.rmp,6eted' 10 years ago. IC was disrcc;uded„how•cver, for two rea,an<. The.titical values were thoucht to lk too Idnt and beyond manufilcnlrcrs' capa- biliticv. andllheru wus;mettt'ic(Jlcantlict's with pi antismoking attitudc, that' h,lve recently, ggiven way to a more, pr.lpnladicc approach. Thce technuldlgy for prod'ucing', c'iga+ i I(t'taCO of whi¢h perlday deliver cmukr within the ucge,tcd r.lnp,e, has becn dcvclup,ed :Indlc:m be applied on a ma,+ ,:;Ilt by the skilled cigarette manu- factul rr: Thus the',singit:, most,importcmt and pc,tenti((Ily successful disease pre- venlirm opportunity in cerntempor,try .o- ciely u:m be ,et'in motion hy responsible markcting'deci,ions in the cigarette in- du,t I p. hy a major public education drive. Ie'adinp smokers to new patterns of ;tc- cepl..nce, and' by, the promulgation of jualk:i;m, legi,lative'incentives: Nt•1 the least promise of low-hazard cig::r,Hes is that a low delivary of nioo- tin~ :,nJ .moke'will',reduce their hahit- forntihc feature,, and will make itlcauier fUr nr•rkcrs to quit :Iltoyctherl. Sir.;e'.these', apprwtche,:tre fetuible„ delit5, are, difTieult tu jmtifg; Ihe' .Ilterna, fivc: is the continuation uf'' hundreds uE' thtnr.rnJ, of prcm:iturc death,:md m:lny mule (livabilitiesevcry ycarl. Sumnoary A'r.li,mokingg education c',ampa(ign.inour •„Jcty' have met withionlyparti(d suc.,.„t toal.ay.55'to fAJ0 million Amari~- cann ,ntokc, and the habitt is incrcu,ing among teenagers and women. It'is impuv- tart lu prate,ct' indi!*iduals wh(rcontinue to,mr,ka:despite :JJ warnings. Therc is oviJ, nce that this can he: :eceompli,h'ed in ;d Ira,t twowtty.. Pira, itt maty, hcpo,>ihle to rctnatve tuai. mukc, crmtp(mcnt,and thus rc-ditcc •pcc,ific hazards, Second, theduse- rc,p,m,e evidence suggests thnt. if the totid int;(kc, of smoke can he reduccd, ;dt.r n :(ppruprianc time srcductiun in di,c: ,c incidence should occur. 1'he, technology to achieve these re>uhc hn, Hccn IC•.vchrpetl ;mdd can h\ Ipplied lu Ihe, munuLlclhree uGconunal'c,l,d ciNuelte,. 17I/Irt~M1111R 197A T:ihl~e 3. Critical vuhlev.uflrlailf' intiekeaf',e-Iectcd.muke cumltrncnh h:rsed un d:ll:r u.ao- cixtcd with :IVI c tu,ev. of disease moi fur' current'smuker, PorCOHb, critical vcJdtesarc.expre„ed interms..of the percent:rge'in- crcnse.af COHh in Ihe.,moker'chknt<Jl,:l, de:• wrihed in 1.57). Hur the: rem:lininp cum- ponentmthe critical vsJues ll,tenl in I'ahleI fLr' ,d.l c:m,e.+' for cavrent .mukci were multliplied hydhecunre.,twmJing',xcer:,ge.dcliv- erie,af 4muke components listed in il:rh4c_' lo uhlxin criliccd valJuc+,in terms of ,mukc,cuno- ppni IINererrces~~ and' Notea. I. H. C Himrrnrmll Y ll'. Canrrr Inn. ManaRn 19: . 119h6/;:p. C7'nE i m ral'FacrarrinRr ...p r,rv~Dier rr H:.K. l.eei,Ed.(Academic P're 197_); O. Auerbach:.A, P. SI,nt, IiI.C. Hamm.md. 1•. Garfilnkeli N: Enixt! l, tled. 7b5: 251091 2.: U ti. tkpamarcnr ofHtahh, Education: andK tt c 1 l'x nd !! drh R' p rr of rhr. : mrrrr ri, Ihr Si.rxn n C:i•nrralaf' A,h'...... ' (,,m rhrPiii llrrdrh'.Sr:rvirro (Guvemnnent, Pnmin` ', 1RRu. K:r.hing)un, D.C:,. IvMI; The HrulrhB,~ re4nr af .\m~dinx~-J971(GovemrnK:ne Pr,nl,ng(nfice: W:,.hiinglun, D.'C., I970); Wuu1d. Ile:Ahh (rng,miwalirm, WJl(1 Te. h. Rrp. Ser. Nn: ?hK.11975). .. Smoke Critical vcdtltea~~ li.4b. A. Schneiddnnan and, D.' L. Leirn, CanrerJ0:.137p1 lv7 ) F.t Wynder. L. S. covey'. K. compunent: hr(mK) _ 111', Low. 65:. (_) Avg.:, 86 . 11) Iligh 151 \t.,hu¢hi, J. Null: Glnrenlmec Sl, 391 1 U.S; lkp:utmcnt of Hc:,Wh: Education. and WOfarc.. The'. Ailuib Ure;,,fTnhmrco 1970 ICcn- Icr (nr Di.eax CuntruL Burcuu o(Hcal IA Eduaa+ I ium; .A'nwmL. 19731. Nicuaine (ntg ) 3 5' 6:0 5 ~ 10 4. f:. 1.. wynder. K. Mahuchi. E. J..Iteunik;Jr.,J,: , COHh(increase.%) ~. . 2~.6: 3,2 . 3',8'. Anr. .71rJ. .1v,n..21J..:?21',(19'70): :Jl D. Brou aml R. GiM-, Am. I:.PYMiaHralrh S(t,.1396' NO, (µl„') 405. 53U ~. 945 11Hti!). . IiL•N~ (µg) 492 NJ): 13:15~. 7. E. l...Wyndenand D. HoRnunn.J. Ndrl:Can- AcrolQin (µg) ~. 156 ~ :60~. S 455 rrrlnsr. SJ; 513 ( 1973). 6. _.T Aurru and Todarro.SmakrrShndier Thesee cigarettes.will not conform ao 4r.1• dition:ll' flavor p:utern.., but cunaJnter' perception can hc made'tir changc and cumpemxling fldrvor, and frugr;mcc+um he added. The feasibility: of lesc haz:udi u, cig,r rettes rai,eathe' qµe,tiun ufl whether there are, limit+ofciyarette and ,murkee composition than may :tppru:lch,reliaive vlfety:,The.,e limit, can:be defined ;n ahe ,muke', intake doses at which' the risk uf' di,e;ne in smokers appro;(che, thut' in nonsmokers. Such vaVues: can he e,ti- mated by dia,e+respuncei amdy,i,(if ,ev- e.ral epidemilialugical studies and by c\- tmpoLltirln of blood cunccntrutirm, ;tt JiFTerent rates of int:tke, for ccrlain smoke cnmploncnth, ,uch aa c:trhun mutn- uxialc. C'rilieal values determined by these muthrxl,,huuld not he intutpretedd a,indic:lturn'of+afe,muking'.levcl,; they do imply. howcve,r, thuna r:tpidl,hift ini cigarette consumption hahiti:, tnwar(I the' proposed ranpe of v:dueswill nmkl: pu,-,ihlc a,uH,tumti:d reditctiun in the c.ur•rcnt cpiJemicpropurtiun, uf,muking,relotcd, di,crose,. Table 4: D:uilycigarette cansu.mntiun,ncuded loo reach urilical COHhdevel<, a, st funcliun iof CQdelivcryper cigprclte:.Il.iaa.'+umed thm Ihe, cnn.,umplinn off cv6urcttcsi.cvcnEy, ,ppracJ luvc.r :r I n-hauv' p<irnht l,c.c 111). ('fDdclivcry' Dailycitiarcttecrm,umptiun per' Low Aver:lye Itighl cig:rcctlcc critical critic:d critic;d (mgl. vaiwcvcJYlc. v;Juc. 19 __-'-=iS.. S R' 10 16 101 e' 5 7 IS 1 ' S 20 : 2•t' ' ~ Erpmmenrnl' Cmrrinuxrnerir IAcademlee rPre•,: Ndw York: ,1967); 7: G. B. Ciuri. S. P:.B:,tcixat.P. S. Thaycr: M.I R. Gucrin, C. J. 1-y+wht Chr-ivey'nnd Jd VirroBi•nr.,urofSmakc fromflrpr-rnrrJ Cica• nrrre IDHEW Pvbl. (NIH)761076'. Govern, menl Pri6tfmgUthcc WO,h-ngtonD:C. 1975t. >G. 1! F: Chapirn. in S.mpruidm an ChrmicrJ Re- yrriremrnri uf rhr J,,burcu Jddanrry. RI D: Dea, nin. C Skarl. P. G. Hercld, EUs: (Amsrican Chemrcal Swcncty, Chemical Marketing nn1 Ecu- numic,l%vi:iun, Broukllyn, N lY:. 197t), p, 279; . D:.F. Matzinigerand, E. A. W2ru,mani. in Pro- «rdiner.uf Ihr5ih lnrrrnariannl:T.,hurra Sri- r Lunxrr.r(Hamhurg; 1970). p:6g. 9. E: L. Wvndlr and D:,HaRmann. N:.Enj/. J. Mrd. , 262. 540 (196U). 10. D. W. De.longl. l. lurn. R: torve. E. Yoder; T.. C: Tw, B'eirr. TnM,kfinnh. gi 93.(1975). . I I. 6. 8. Gun, i Prnrrrdrepu of Yhr', Jrd WorldCunfrrrnrr.ue Sm,r(inR andWenleh. E: L. Wyn-der..D:.HuRmann. G. B. Gori:.Eds. (Govem-ment,Prinuing.Gl6cc,.Warhinigton, D.C., 1976), pp' 091-a61. 12,.T..C. Tva: R. Lowe: D: W:,De: Jong: Beirr. Tnhukfdr.ch: g. st'I197!): W:.H. John.on, inPrnrerJinei ,f he 7rh fnerrrtulPnnul'Tih6cro. .SPienre.ConRrev(Hamhwrg,' 1970). p.' 142. I}. G. Reznuk;.H. Reznik-Sahlullkr. H. Schnneekl, K. tkppp;, U. Mohr. A sri',n. Funrh'. 25. 9'23'. 119M. 14. W: Donucnwild. Hi 1.. Chkvaiier, Hl P: Hanke'., U... l-rCrenz. G;.Rec.kzeh. B. Schneaer:l: Narl.. (',nnrrr /rir/.,St• 1781 1197)'.1. I5: W Duntcn+rll. H! J.. Chkvalier, H, P: Harkc: H'. J,. Khmd,ch: U. Irfrenz:. G. Rcckzeh, B. Fleirchm:mn'. W. Kdlkq Z. Krrhfurmh:78. '36:(1972). 16. G 8: Uori: Ed.. Repon No.1. To.mrd (r+r HmrJ G iovrrrr: The F n'Sir aF'Eryen- mrnr,JGiGmnrrufOHEW Publi (NIH)76.9q5: C,vemment PrineingQBce: Washungtan, D.C., r+761J 17. . ald M! Hutrci frt 1: Ito,J. Nuul. C6nrrnlnrt. ig- 1961 q 1972); D: HulRmarun and IE. L. WvnJer: ihid„ p. 1613?tE. L. Wyndarand D: Hulfmann, l.' Am: .tlrJ: A.na-. 192. gg111965), Ig. hi. L. Wynder'and D..HuRmann,Sdence'.163'• g62 (l9hgl. I9.' C. 1. KenJCr :md, 1 P: Bartiiln; Am. RtvL W.piir. /N:: 93. 93(1966/; N'. Ens(. J. Mrd. 269. 116f111963): 20. O: Auerhach..E..C.. Hammond. D. Kim+an„L.. (i.irfinloel; 1/SAE'C Symp. Ser..1g. 375' 11970): G: Frte-m, S. C. Cnne:,Ns 1..Furiosii.Rl J.. Slcphcn.. M. J. Hvuna. W. Gi M6one.Am. Rev. R7 , ni r. I J l.. 106; ,561 11972). 21. U.S. PwMic:Hd:dlhl Scrvice,.HarmFllCunnirw rnrr „f('iKnrrare .Sim,lv. 11)HEW' Publ. IIISM)7:',751b, Govtmmcnr Pnhring' OIBre:. W:,rh'ingtmn t D C.. 19721, D. 137: , 22: S. S. Hechta d EL WyndcrinPrarredidgs nf ihe trd W:,dd Chnfrrenrr ,.Smmklnc and' Nradlh, E. L. Wynddr, D. Hv,nrnunre. Gl 8:, Crti hd.. ((io emment,PrimBoEfice Wamh-mgl n IT.C..1976)pp. 19'I 0d H P SUutlfcri nd. 1. ttuuqul , !felrn TOr k/,.r.rh 6. '1 119711; K. 0. Brunnc nn, H I C. (.ac, D HJR, mann. in prepanrnn: S. SLHecht. R. Thornn.. R R' Mi nertD Hu0lmeon•J Nnr6 Ca.rrrl I'SS IlN (II7S). 23. . t..P. ItutG la. in Plnrredlq(r f rheJrJ.wadrl.

Ow~rrrnrron .1'mrs4/tl.tonJ7lrnhA, k. L. W ym dler.,U: Holfm:mn, G. H. Gurii Hdv, Ili•nrm~. ment:Phinbng U1f1ee;,WashingWnl. I).C'.. 1976);Z . ,3'i7 5)4; _ , rWIC..J. ht 1Arrk. vdron. llnulrh:20: 12h I)Y701; 1I> 11 r vn,J,. Nwl. Cuncrr lnst.,4g, 182,1 (1972); E. A'.1Mar- tr:I1J Am. S1f:. 63. , 404'(1975); . 24... R, Rylander, SrrmJ.: J. Renpi.. Dr1r. Ssrppl. PI (19741; 1..Schmehz; D,: H61fr:nann. E:.U. Wyn- der, Prrv, Med. 4; h6'11975q'.N; Wald, Sl H,rw, oN!,P.' G. Smith. Kl KjrlJicnn Rr. M.~J. J: II 761 u 1973Y, Iw, S. Arunow'rr n/.. Circr.fhri,brn 50. 340(1974);;E. W. Ander,un, R, 1: Aindclm,n. 1. M. Slruch', N. J..Funuio• 1. H. Krmlwn:. Ann.l lnueun. hfed. 79J 46'(1973); , 25. W: S. Aronuw', Pr- Mr.J. 4.: 952 (1975); . _. J.: fRndingert S.: N I. Rokaw. Ann. hi- rrrn: MW, 74. 607 ,(1971): K. Grcemp,~n: R. li: Edmand,, S:,111 Khochcll,C: FSsch, An'h. Iri- ttnr• MeJ• .127: 707(1969). M; Ml A,.H. Russd)I, C. Wilison, U. A. PateF, C. Feyerabend, P. V. Cole: Br: M.J.' J. 2,414. 11975). 27. K. D. Brunncnumn' undD: HJlfmann;,F,nwl Crumrr: T r.ri. uh' 12, 115 S ( IY741- 28'. H. Schie'vclbein anJ !R. Ebe:rhaNt,l. Nmd. Cun-. crrdnsr. 48. 17815~(197:): 29, C. D. Frith. Psvchophn'rmoaohYgia 191. 188 (1971); G. P. Mbne', ToM. 56. 16. , 167.(19'72): SOL TL C. Tso;J. Nurl. Cuncer Jnur: 48.,1811 (I972); - and G. B. Gon, tnS)mpusrum un C/rrm- icul'Rrquidrmener:oJlh~rTuhoero.fnJusrrv; R. D: Deaeinl.l. Sk'eist, P. G. Herekll Eds: (Ameri- <an Chemical Society, Chemi,rl Marketi'ng',g and. Economic:s: Division; Brooklyn, N,Y'.. 1975): pp zs8-27s. 3/. R.A,.Uoyd rr u1...Toh: Sti: 43', 133'(1975)i Smoking amt Healnh Piogram. Si vur. Report (National Cancer Ihstituue: Bethesda. Md., Jantr- ary', 1976):. 33.. Four source dacuments:.conuined',summariesof Ihe:' d!u used Ito compute the crstical values: af daily' cigareale consumption. Following is a liht of' these. documents; thee studieswithln.each documem that were uxd Io compute Ihe cnticall vafues..:uw/ Ihe resultsof the <amputmions.. 1) From "Smoking;and': health., repmn ufhhe Advisory Committcel to the S'urgeonl GeneraL of the Public: HealtlhService`' (U.S. Public Hirilth' Serv. , Pub4: /10J': (1964.). ppl; 89, . and 13241. .: the loul age-adjunted criiical value (C V) fdr munali-, •ty. from coraoary'heart di'.sease for males(3J) wa•s'.3. to; 4C for mortal,ity from ald causes for male current smokera. CVV was I to:2. in'. a~stmd'y. of men ~in:nine states'(11), Ito. 2I im a., study uf U.S: veterans W L 3lo 41 in an occupationul~ study in California US), and2lo 3 in astudy.of men in:25 states:U6)i and for mortaloly.fromcoronary ar-tery, ddisease for males, CV was'4 to 3.formen in . Isine:statesUl). 3 1o.4 for U.S. veterns(J4);, and 4 to 3 ~forlmen in 25'5 states-U6). 2): From "The htalth cons<queneen of.xmok-{ngf aPbblieHtallJi Service revle,w. I967° IU.S.: PublJn Hiu/rh Srrv: PdM. 1696. (1968): pp. 69-9d, 140; 146', 157, and'. 1041. CVwas 4lto 5forcirrliosis: of: the : lirev, >10 for cancer' of I the .. butcal cavity; 2 to3.forcancerofthe phuryn:x:. and:4 to S'foraortic:anleunsm3 in U.S: veternn . U7); >10 fonemphyse:ma. bronchitis, orbothin' Canadian pensioners.U8')7 and 7.to'.8 fonlung.r cancer in males tnl Northern Ireland.U9): 3) . From "Tht health oonscq4encen :o(lsmok• ing: a, repionto:the: SurgeonGenerl: 1971!" [DHEW'. Pub6 IHS.NI'.71-75i1'(1971):,pp: '-al- 243, 286; 290', 294: 2"YB• aad. 3391.:CV was 4!us 3'5 for esophageal.eancer. >9'for bothppncreatlc. and'd oral caviiycancer; 3Ito.4for caruceruf tNe farynx. >.9 for kidney and bladdercancer. and I I. to r(or lungtance:r in U.SI veterans (37); O.7fJr, lung; concer in males from 25 states:(J60: 7 to H (isn lungl cancerin:malesr fnsm mine'c st:,tesUJ1: 4ta 3flsr lung cancerr inl Britidhl phyvuwm, d4t11: > IOYorldng cancer n Ame -n l gn~~,4ts (1J)7 4 to 3(or, lungcancer in'Calrf'mi r: m:dcr N2U and. > IO far lung cancer in lapanenc m,4cs Nd)n 4) From EpiJrmmVogr. ef Toh u-Rrh,rrJ , Caurenrr w,thl Sprria/ £mphoriron rhe: Effect of 1•awcr TunG'itarrrus (American Hea VIh Founda- tion study' 1969-I9'75 in pness), f' rm Ie•' C V. ss 210 J Yon Krcyl'argltyped lunglc n.cr.8no9finKreyherg type II lumW 'ancer' 7'7 to:81 fnr' eancerof Ihe oral cn ny. >'10.Por cnncer ufhhr. , Iwryna; >. l0:for e,uphuge:d cancer, and > 10 for<ancer of the bYadder. 33. While American males :enrolledd by the Amcri- tan,Canur,S'ociety inmine:sure, IE. C.,Ham. uw mJ qmnl Il l. l'. l lurm, l. Anr. Alnl. A s+w'. 166', 1 uw I P,sxll: ihwf. p( I:•WI. 34.,Vc•.ICwhl+ KrveJ bctwccn 1Y17'a'rw) IYWI am,l. w p I''ll oIJrr,rv,d ll \:t t lifee innu,.,r,ua.P'+h1,c.111 FU,,,n,lnr: s- '..1lur., .Srrr. Ant..S"lur. A'cv,.r: (IY581. pp. }4-711.. 35. Menl 31tu:64' yearn.old in mine:sw:culpati,om:in C':difbrnucll. F:. Dwnn. Jr..,G: LinJcn, L. 11nea- krw, Aen. J. Pd)V. Ifvdrh 50: I475:11'.w(11. 36:.IS. C. flammmdlanld L.,Garfunk'cf. Anlr..lavi-n.,l/ru/th'19, 167:(IVh4);. .17„11. A. K:,hn. N.ird' (runrrr Insr. sf,un•xr. 19UYM). pp: 1-125:. 38: , 8. W. R. 1knt, ACa'nuJidm .llmlv rnf'.Drnd7ne . m,l /lru/nh I l>,tpuutnttm r4i Na,Gnna) I Ic.:Jth anJ Wcll:u a. 1lttaw:r:. I'lel,p. 19.,A'. 1. Wi¢ken'. TLh: Rrr. ('nnnr. Rr.r. f"Jp'. 9. (1 wu+), 40... B, 11,41 ,mJ: A. LL 11.11. Jfr.dIrJ: J:. N,•, 3395, . (196:tL pp: 13NJ-1470;:ihiJ: Nri. SJ96 (19M): pp. 14Nr IUn7:. 411.. P. li. I(ucll. J. E: Dunn. G.. 1)rcn4rw: C'iwrcrr 20, :',114'1iY67). 42: ,1. H! Wcir:snd J.. E: Nnn: ibid.' 23. Insf 197111: 43: , T..Hiray;ms:r • srmdine in :Rr6,rhim n, ehv P.rurh . R.rrrr.,,f'2bS;1181.1t- nnd (y„nrrn inJop,un l INaui.wW.C'ancer Center', Rexnnch In,titule;, EpiJcmiolugy, Divisionj . Tokyu,. Scplcmtiar, 19671. 44. K. K]eWun. Smokingg anJ: Athrnvdrnuis (htunk,yurd. Capc:nhugrn: 1YhN); p..24, 4£ It i,'ou1 possible tu d-re ctly.comperc'.the'.cpiJe, miulluglcall stuJlescun dered, becuwx thcy Jif-' fer withi re:•pect todevgnl• quality of Juta. demo- gr,,phi@ chunxtcri,tlcs. andd numher.of,ubJects- surveyed U2).: 1hus; euchl study. wasiniuully, analyzedI,e'p.iratefy. For each st,rdy.the.datay may' fe: typified by: the'.relalive risk a'„axiated with the' numherlaf agarcue, <u umed Jaily; for e:vample. (orno crgamctles Ih rel:utve:risk value'i, 1.00; for I to 10 cigureltes'. 7.49; foci I tu.20:cip,rettes; 9.911 far''_0 to 399 cigarettes., 17.41; and fun >'40I c.igsrtno. 2.3 , 93 , . Fur wmc. ,t:ud:ie,, Ihe': caaegorien of'daily cig:rrette',cun- wmpoion Jilfercd,feomt these. The fii,t :,tcp.in the':nnatyvs:was tu filt thk da1a:. to:a functionl of the form pr,ncnl, tuthernhhn uwt Ilwmole frqnrnlly.tnwd: raluc, uf15 percenl..urI perccnt tu. uw,case pU:Wer: 1TcthoJrd, gy u:applikd t'r 1 n(I:he. ,t:udic+I,sted le•Wing to the'.vsluar-lu,wn' in iP,rbleI. 46. Tars and nicoti':ne'e in' the ,moke of:64' bn:nwJa: of ' cigarettenICunrtrmer RrPorts (Wprilll'n,i), p; 21x+1. 47'. Sa:.le,figunes.u,cd.id Ihis smdywereav i.rynled in ITi.hn.v,. (14 Fchruary I9MIY, p:. I D. 48'. Jr ('h,',.rn •Ne.J. A:r.sn- 271 926 (1 v37); ( u 1 hris- ann and G:.Ahcl. Z. Hvs•..lnJ~kriunaL.' 116, 4 (1Y141; T,.h; SrJ..6t 142.(1961):. 49. M..R. Gutrin. t6. II, Uluinuy, H.,Kuh•ro,.,in' Ri-p„rr N,.. 2•:fuwnrJ l.rs,. lfnenrJ,'nn, riicn• rrrrrr.. The ,1'rrrmJ Srr , f: h_tprrimrnr,J . r ripu. rrrrrr• G. N. Gdni.P:d:. l(iuvcmuuonl !srimg Ualice, Wunhrngtun. D:C:, in pressL N,,,,,o,r,-. tenc record is a,viilable: for aver ge delnsc -• u(' nitrogen os ides, hydlrogpn cyamdc: and .•v,,,lcin I i-garetles'manuf:rctured:bcfuae I'M,tl. r+wt u lis rra:wnablt to cunsklcrtihaIRI rcfercn.c'.Ip;a'- rclte of the Univcr,ny of K'cmucky csrcl+rrwn- lalivc: of lhosee c. garcucs:.The. IRII ur.ucne ds•livcn.an uvcr gc'. uf 270 µg uf NU„ 4+u yp of HC:'N, ;uud 130 µg o(lacrukin. 50.: F: 6. Boek. Proc. Am. A.rror. Canerr Rn,. 17; 2 11976);. 3'.1.. With a poste:xppsurt decay.facton oRl0l.8V^ 1+-r); , the Inc rea,e in Ipercenugc of COHb, im I f c:14,.:+d I ofinacaiv'e.young men Jueto smokingo:.llis. glven by, Percent COHbI increase [4COH"sP"s/'197) x.0.83` 11)') where COO is eaprcssed inl pans: per' mlllhon' /ppml, r is the exposum:time in munute .:nJ r"isIh'e postexpowre', tlme in huur:.: The': mean CO delivery during , smokiruc Je- pends on th'e:CO'.dedivery. of the; cigarc•.Ic, the: smok'ing period r. and Ihelvolume of rn,pi:,.A.:sr; Th'e:ma.cim-CO.delivery, of reiga~c+ica is's re:l:.ted to CO eonantration (ppm) (by CO:- ' Cr„IfT K' I(Y'JRJV.sfaJ r2)) where Co, iss the CO per cigarette (mg). H*, , ha ideal C+s coostant Jliter atm Jcg,-' mole"I: R' is' theventilation:.ryte(min"), N'i.the • :u,ne. uuhaled.pKr ventdatiun Icmiy, .N;,,, s, thu.p.,m nsulecularweig(tr.of CO. T'ts-.theutmpn:a,:rr (ahsoluocl: and Ir is the :smoking, pcnod. Withl R- 0.0821 littr'-atm deg-" mvlc", T- 2:9g'K: R,.-''2; min7' 16. lowel ven'I',e;on rk.Jurimg;lhe smakingl pcrusd woukL !c.;d too higher COHb Icves), arud.?Q„ - 78.g/mwlr:_ l:q. 2 !reduces to . R:•.A. .+A,X+:A~L?(1) wherc'R ilemrtesv Ihe'.relitive: ri•k value: A.. A,. anJIA cueffiklcntvwhuse'vnlw , crec:Jdur lakd.hly the,t.tliitical methiud,of maxlonum like- IihbuJ::md X:is the daily:cigarette con,um~pti'on'. Since the available:daily cigarettel cunsumption data wcre enpre„ed as intervals(1 lo10.,1Ito. 20. and ,oo un): thee uppcr bound of each linterval. ,m' uudl in nhel caleuJations. Thus. for Ihe:ex:- amplc:ah'uve; the; interprelali'onI is that a d:uly' consumpliun of'at most 10 dgarettes-has: anl as.wuiiled relauive rimk of'5:49. a,Jaily comump-: tion of atmo•t 20 cigarettes has an' u„ociated: rcl:vivc ,lo uf'9.91.,and •o fwth. When the highc>t daily con•umpoiun valuc was<xprcnsed: an uflcn-endcd interval. such :.,:>40; the.e v:due: uned, war arbitr nly'ser at 10'0 morel thanl tho'e value.•pocihkd. In~(he ex'amplc:aFove:,50 wJS' u„ed for the highelN daily.wnsumpumn. Althqsngh other( cuonr were: considered. grphic:J oh+ervation.amJ aa4i,ticuU an:dyni., sugge,led that thequ:,dr:licl funclwnl IFiq. proridc,:an csceptiomally glwnl Ifii to espenmen- tal data, •uchanIho•eh con,idered, here. For acampile, the: co:nectedImul¢iple:coeficient of detennmation' in each case wasgrenters than 0.90.: Furthe e.wmple we are cunls{dering,.Eq. I hccomcs R.- '1.188 + 0.393X+ 10.991:x~ I0-s).1'' 12:) The:nest'elep in the analynl, w, ru c:J,hull:ae: f.rr cach I•nuty:. the I<n,l ,ignificxnt I,4,Rer<ncc h•Iwcerr LICI Ilhe:rel:nire ri,k:fira nnn•nw,kerY' .,n,llh.' ( Id .In ri,k,:f ' I ly hn- rrlle rmpaun of I . IO IK ucttc,: h.,lian'Itdtrcl'.dive: k : vrc'cmnpul<JIhum~ Idy. I Thle, mbe uf p ettc.clw dngto mi, la-,l; Ignifiumo ddlfe.renc:e wa,ihen ml:sr-preeedd as (hk:cntwal value:. For oucexample;r anJ using Eq. 2. the cri tical value liess hctwecn J and2'. L:g: nespurd'Y ITe I I Ln fic-l d-If'c noc J p rvd of'i mns thcJ cd,xf b,nifi..ms : h' 1'unthl-m ly i,:the.,t:ui,ur:,lfvnweri,mar..impur, lant th:,n the Icvcl f ignufwun . TN.,a i,. ,t,, . murc importaml that any' auend:mt crn+rdead to . a:lur,wer r•mher Ihion a; hi8her cnticall v:Jue'. Con-52. ,cqwcnlly, Ihe': kvel'lof'nl:gnifi'aaneewas wt at 10 CO - 79.43C,,,:/i13) Cambining Eqs. I and: 3 giyes' Percenlt COHb:ineraase - [0:166C,o ""/r"iA[ x0.8Y(4) The'inereasa.in'the:percr:nrgp ofCUHN im- mediately.after smoki.ng, the last c.ga :. . n'a, seriess of V' eq,padly epaeed'd cigpre0en1ic.,ch smoked over a 5-mimute penr>4• s: thua gp. n ry. Percenu COHb:inarease ~ O:ISOIC;u•""' V 0.854 13) Equation' 5.waru:sed5 ta estimate the inlperce.ntage of,COHb immeducely.after ing'.Ihel lasl cigarealee in a10-houramoki,i;q •,..- siun. The CO yieldd was: taken as. J3 mF per eigarctte (typical pre;l9tA4 cigart'.ttel. :,,w1 the numf+er,.,sf cigartttc, ,mukkdd were the •--c,.,s. the.critical r:uluesfen"all:cau,e,.f:rs w,enl ,nw,krr,")i,lcd'in:culumn, I, 2,::,nd 1,J111J+1t. I. Thu,, the.e .nutiJl Iv:duu,wcre aspn<-...I ,n I<'.nm uf ahe percenc,ge: V UH h m: rea:,e 1o, ., d(l hwur ,mu,king, •c„iun, .mJ I he I: U Hh n:Jm. - . :,rc q?en n T' ble 3. Next:lhie:numben fc g..,,ttes' prtW -ng the'e vme: pe.rccnrage chanrc~i COHb.bul delilvenng;2; Si 10, Ib: and 0 n~ ~+f COO perciguratte; werr.computed..Thm' ne crir-I luas: ITwbleII htned on .. delivc -ng 233 mg;uflCO were umvcnuJ w.. I cal Ivaluen based on cigarenen dclivenng amusunre, of COlhro':ugh the:inoermadlary : -I !+r- ,.. «magc CUHb ancrcuse' m Ihe ,muker: 1 h, wits.arc listed, in: Table'.4.. J,. E. Pete:rsonl ¢od iR.. D: Slelw'art. Arr.h..l n.n. Hrullh.21. 165(1Y70). _Wt trl: _Q2 SCIENCE:,VOI .. Iw. 17A6 WW