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........... S •f aNtie1LS OF OCCUPATIONAL SlEDICINE, y.18, 1975._ - HYt..veL tL tp. t-1a. P~ erypmeo ~c 1973. :'titwsd iwGrmt O.iwi. .~ t X SMO~:ING, C~~RBON VtONOYIDE AND A ~A i'L-RIaL j . DISEASE N. WALD and S. HowaRo DHSS Catt= Epidraiolo`y and CI•ir.ial Trials t:ni4 Department of the ReZius Professtx of btsEicine, Radcliffe Infirat;ty, Oxford 0X:' 6HE Abstraet This paper revicws the role of carbon monoxide (CO) as a nezsure of tobacco smoke a3sorption, and as a possibk cause of arterial discase in man. Smoking is the most importr.ttt single source of ezposure to C0, and frequently leads to carbocyhaertto;lobin (COHh) krvsls above 51/;. Most tIltcr-tipped cigarettes produce more CO than plain cigarems. The main fiaors at:xing the uptake and elimination of CO are considered and it it shown thu a sin`le COlib raesswen:ent combined with a recent smoking and eaercise history can be used to estimate the COHb dxi.ed from each dgarette. !n a eross•sectiotul study COMb Imts wera more closely associated with the pre.aL.ce of corona.y heart disease (Cl'tD) than was smoking history. CO exposure f:om smoking has been shown to be harmful in persoas who alt+eady have CFiD or interminent clsudicafion. The etiiGaa ce that CO is also hannful in persons without anerisl disease is ineonclusive, but animal' data suggest that this may be the ase. Some im pticldons re:ating to the use of 'Smoant Tables' and the tttodiftcation of cigarettes are considcred. ) } ) T 'tNTRODUCTION REmrrtx, considerable interest has been focused on carbon monoxide (CO) as a measure of tobacco smoke absorption and also as a toxic constiticnt in tobacco smoke which may be responsible for the development of arteriat disease. in this paper we review these aspects of CO and consider some of the implicatiors of modi- fying cigarettes in order to n•take them safer. Thc association between smoking and,coronary heart disease (CHD) is now well established (DoYLE et aL, 1964: MMORRIS Cf QL, 1966; K,ANN-tt, et a1., 196s; STkatt.ZV- et al., 1969) and many prospec:ive studies have shown that middle•a_ed men who smoke 20 cigarettes a day have 2-3 times a non-smoker's risk of d;•in; of CHD (Dott and Htu.,,)964; BEST, 1966; 1Gxrt, 1966; HawtoKO, 1973), making CHD numerically one of the most important discases associa:ed Mtlk smaking. C.IRIIOM MONOXIDE AS A M.1RKER OF TOBACCO SMOKE ADSORPTION 1 wiarr uexposcd to CO irom many sources, and thu-sc ha*:c been .vel1 reviewed (GOuDUttnt and Lt».aAw, 1963; U.S. Da:PaRrML%T OF 1IE+6m, Lst:C.+r1oV & '.Vetr•nRr, 1972). CO is absorticti throu;f: the lungs to tonn ar5ox;aa:r..oglobin (COHb) and Table I suaimariscs thc approximate levels of COHb that various sources of exposure cn produce. Data in this table rc!ating to cnvironmcntzl and oceupationri cxposurr were obtained ;rom non-smokers. .-•.. n::! ~. ....:. +i . 1 `.. -. .

. i 2 .1. W.ctD end S. liowwnls t 1 TASU 1. TyrGL GAlON sfO"7aDt A:M GA7t0oaYNAL%:oGWtitz+ LtvEU wssOGwTtD wtTx vAuot,'S SOUaCfS Ot t'C70St.'a[ TO GRSON lfO7`O'tiDt ~ Source of CO Approx. tttcan Apptox• maa Co (ppm) COHb (',Z Source of COHb data Metabolism o-3 S,tSzrtu.vo (1949) ) Environment (non-smokers) Los Ansdes coaunuters . 30 2-3 DE,wc and PEar;i.Y (Unpub.) London taxi drivas O=aasion (non-smokers) 22 14 Jo.rs d al. (1972) • ~ Motor car repair shops ZCanada) Parkuti stundanls s0 S Bt7CS+wAt.D (1965) so 7 Rx.+snr (1967) Border inspectors (`fexieo-U.S.) Blast furnace wor3:ets 114 4 Coxrxsrol.(1971) - 4 3vii er al. (1974) Satolinr Pitcs (Gfelons U.S. 8 U.Y..) Cigaretta 15.000 2 Gotssxtrx and L.A.aw (1969) 40.000 6 WAt.a (unpublished) ~ CjG= (rrelong U.S. & cJ.1c•) 70.000 2 Ctisruacr and Cotl (1973) ~ lYipiSTetgSrs (exil~i(ette smokers) - S Cowtc er e1. (1973) { I (i) CO in tobacco smo; e Smoking as a source of exposure to CO dsarfs all others. For most types of cigarette the conantrstion of CO in the smoke averigcs about 4; by volume. C.igaretta deliver about 12 ml CO per a, re:te when tested on a smoking machine under standard conditions as sDeeil;ed by the Tobacco Rescarch Council (RotawEu and Gxww, 1972) (35m1 puffs of 2 sM duration at a rate of I puff per minute smoked to a standard butt length). As a cigarette is smoked and becomes shorter, the quantity oir air entcring through thaporous cigarette paper is reduced, and so the CO concentration increases with each puit Since the paper surrounding the filter of filter-:ipped ciprettes is relatively non porous less air can entcr to dilute the CO. prc+duc:n; a higher CO yield in a filter- tipped cigarette than in a plain one. Tlus surprising ;uit has been cenf;rtnrl on several brands of cigarette (Evm~zs, personal communieation). Fgure 1 which shows the CO concentration per pu1T of four brands of cigarette illustrates this. Two of these, Senior Sertirice Filter and Pla.•en , f,. 6 Filter, have non-porous filter tips, and one is a typical 'piain cigarette, Senior Sersice Plain•, The fourtit, Siik Cut Extra 1 : t 1 -H.T.f.4:1R11N -i.pd.r. Tw.ia PI.i• ~ _ = r t 341 .. t 1 T 1s Ii„ rwr %G. Fte. 1. Carbon monoxide yidds ;+er puff of four btands of cigsrctta. Silk Cut Fxta Mild has a ventilstcd itlter. a Fh~ :#

SmoL•inf, carbon monoside and arterial diseax 3 1 -Zw.v (1968) V__ (1973) (ii) Uptake and loss ojCO by anokers Mild, has i"ventilated" filter, which differs from conventional filters in having perforations in the paper surrounding the filter tip. With this last type of cigarette, air entcring through the perforations dilutes the smoke, thereby reducing the quantity of CO per pu1f, and this can result in a CO yield even lower than that of ptain tdgarettes. When the perforztions are artificially sealed the CO }ieid of the ci;arettc increases to levels which are more typical of conventional filter-tipped cigarettes , (WAtD and SmtTH, 1973). . smo e _.~.~ ¢ihe body. depeAd'gzs>severai:facsoi~r3t:it:lt ur I'isted 'ut Table~ Apart frocii c ..- .... .. . .~ - • • _ ~te of elirtunation cf 0 rom l~e aad the t ke fCt~f om ~'h . r ~....; . . . , • . . . .~+ ~2. . eciing .. .cuantity.cftobacto smoked; the aiain faEtor atT C_0 upiake ts; ;. TAac.tt i Tst rturarAL rActotu uaLUa+cr.n: ittt Iuirs or UrrAtts at.a tzuatawao:r or catnote "0roxtac rr saartss CO Uptalte . CO Loss .;TFroush ,•: uth eaelt ;~ V ely :1 .cr- :ir.,.;d on L Txc of rt:,:,and' ' CuL F•[tra Concentra:ion of CO in tobxco smoke Initial COHb level and ambient CO terels No. puffs, ;atC arolume, puff flow rate Alveolar ventilation (ph) sial'eaercise) Depth of inhaL•.tion Pulmottary transfer factor for CO Pulmonary transfer factor fortO ' Totat haemotlobinTmyog-lobin mass Total haemot?obin+m•oalobin msss Cardiae output ~'smo)ang~ - h ii: uen~i'of t]•,e :. u wVd1 as.,Jiow drpl~ea_ ,^rT a e... . A uff ,s t~thale 1',atq~ oss of C_ 0 rs det~aty,ned~htraly'~ ` veolar „e~ntil~~o ~ i te~"i ~ fdepe~3ent.'on pl[ysictt acerase.~ ~gnre-2,.dsrived from data~ubi_i~f.c~ :+@ r 1 Iltt7fK I tn vAtcluiSlOWtT m FaottAtt ! ~, 1 / 1 ~ ~ 1 It t~ rO 7t rf 7tattttallO~ Matl, I NNU t ii1d has i 1 flo. 2. 14alf-lirc of COHb in relation to al.eotar.rnu'lation rat& This 5gurewas produced from data published by Couus:y et oi. (19651. Adjustment has been ntade for lhe inereas¢ in trsnsfer factor for CO eith 3ctivity, tal:int a valua from 30 ml min-s tswa 11g-' at rest to SO mi n+in-s nun )I; ' aich strenuous eacrcise suca4 as fontbaq. The enerty e.c,xn'e.itute for each activity shown was taF en frtmt PAssa+olut and DuR»rI (1933), aud convened ir.to alveolar ventilation rates usinr 3•4S ml oaygen per calorie (Boo•rtuY er al 1936). a respiratory quotient of 0,52 and a mean alveolar CO, concentration of 3-6 J,. It has bmt assumed that the inspired air ecatains no CO. -- . --- :.r..r`..:....-~,•-t~:,,,_. z

4 N. tV..ta and S. Howam i .1 ) t Dr.4~v.tr:a1. I 6iLsltows tWc'*iinside~r,~hrabie~c+at that Ie eI ot~hysicaI utivi y tgo rhas oa tlte.~talf-1•.ft of COHb,: i aa~'tn fg rom 4 dunag"~ecp to I]ir durin'g v rous eze COb Ievels in smokcrs normally sho a diurna~T-Ir ty lf-iiri •vr i leveTs -rtstng. during the day and declining during dcep. The Iarie diurnal variation in CO'ib' level makes a"random° level diffit.ttlt to interpret: Figttre 3 shows how the pattern of q.M 1 tr"i. xr n.K ad Fta 3. Etampta of COHb patterns in 2 srnokers. Both smoke 20 eiprenes d:.t7y but at ditTerent timesr They both eli®inate COHb at the same rate (half-life of 4 hr while asleep from CA-00 to 6S-t'.I) hr and a half-tifao(2 hr.hile awake from OS-00 to 24•00 hr). Vertical &nes represent the incraise in COHb level produced by each ci;arene; this COHb "boosi has been taken as t'; COHb per aprette for both smokers. For simplieity, each cftarette ha been shown to hamm been smoked instaataoeousir The "badcrrotutd" COHb level due to etdogaous CO production and atmospheric CO exposttre has beea tal:en as t~;I recent smoking can affetx the daily COHb levels of two hypothetical cigarette smokers, 'A' who smokes mainly in the evening and'B' who smokes steadily through- out the day. Both 'A' and 'B' smoke 20 cigarettes a day, inhaie to the same extent (that is, produce the same rise in COHb level per cigarette), e:iminate CO at the same tate.but smoke their cigarettes at diflcrent times of the day. Thus `A' and 'B' have the same ezposutt to tobacco smoke but their COEib levels are the same cnly at 09.00 and 19.00, and at any other time their COIib levels would be misleading in suggesting that one smoker was being exposed to more CO than thc other. However, if instead of simply comparing COIIb levels, the CO upta' ke were measurcd from each cigarctte smoked by each of the t.to persons, it would be demenstrated ;hat the two were, in fact, being exposed to the same totr.i quantity of CO. On: problem of this approach is that the CO uptake, and hentr the amount of COi'b dcrived' from a single cigarette (the COHb 'boost' per cigarette), is like:y to vary considerably from eipre:Ie to eigarette according to the circutnstz.ecs of smokino, even for a a-ivcn individual. However, it is •reasonabie to suppose that a smokei s arerage COE,'b boost per cigarette is likely to be a characteristic of that particular person. In fact, this measure can be estimated from a sin;ie COI-1b measureatrnt and a smoking and exercise history covering the prcviotts 24 hr (NVAt.D rt aL, in press). Such estimates have been shown to vary much less within an in.ividual smoker from onc day to another than bet%v.en difTerent smokers. A smol;rr's COHb pattern can be piotWd as in Fig. 3, and the mean daily CO1•{b = be calculated. Fzv-e :I sl:cws the esti= tnated mean COHb Icvels on sevtral ditTcrcnt days for caeh of S sabjecu who smokc_ 15-25 cigcrcttes daily, and one (PH) who smokes :0 a day. Alt7touSh thcrc is a day-to-day variability, some subjects are consistently and substar.:ially ditTcrent from others. ' ~~....~^..t.- . .... ....r. . . N .