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d'NT7ALS OF CCCLRPATIONAL:, ffEDIDCINE, V.18', 1975. `1; ~ -w. HY,P: VoL IlI. pp. 1,14. Perganson a 1993. .^rincM in Grcit' Britnin, SMOKING, CARBON MONOXIDE ANti7 A RTERIAL . . . DISEASE N. 11VAr:D! and S. HOWARD t -~....---...,r, DHSS Cancer Epidctniology and' Clinical Trials Unit, Department of the Regius Professor of Medicine, Radcliffe In6r.aary,, Oxford O?CZ 6HE A'bstraet-This paper reviews the role of carbon monoxide (CO) as a measure of, tobacco smoke absorption, and as a possible cause of'arterial'disea,se in man. Smoking is the most important'sinS'lcsource of'ex'posure: to CO; and freiquently lead's t'o carboxyhaemoglobin (COHh) lcvels above 8%: Most filter-tipped cigarettes' produce more CO''than plain' cigarettes. The main factors alTccting the uptake and elimination of CO aree eonsidered and itis shown'thata single COY.b measurement combined with a recent smoking andlex'ereise history can beused'to estimate the COf;ib derived from each cigarette. !n a cross-seetional stttdy COI•Ib lbvels weremore eloselyassociated with the preva:cnce of'eoronaryf heart disease (CHD)'than was smoking hutory. CO exposure from smoioing has been shown to be harndul in persons who aitx~ady have CHD or intermittent' claudication. The evidence that CO is also harmful in persors without arterial disease is inconclusive, but animal dzta suggest:t'hat this may be the case. Some implications reiating to the uae of 'Smoking Tables' and the modification of.cigarettes are considered. I'NTR 0DU!CTION RECENTLY,, considerable interest has been fucused on carbon monoxide (CO)' as a measu're of tobacco smoke absorption and also as a toxic constilcucnt in tobacco smoke which may be responsible for the development of arterial disease. In this paper we review these aspects of Cb and consider some of tlte imrntpiicatiars of modi- fying cigarettes in order to make them safer. . The association between smol:ing and coronary heart' disease (CHD) is now well established (DoYLE et af, 1964, Mottms et ah„ L'9C6; Kir:-,NEL et al:, 1968; STAstLt:aR er al.,, 1968) and many prospective studaes have shown that middle-aged men who smoke 20 cigarettes al day have 2'-3' times a non-smoker's' risk of'd3•iio; of CHID (DOLt, and HILL, 19641; BEST, I'9Cc6; 1C.n'rtN, 1966; HAa0,toNlD; 1972), making CHD nurrteriaaily' one of the most, important diseases associated with smoking. CARBON MONOXIDE AS AM.1RfiER' OF' TOII'A'CCO S.MOI:E ABS©RPTION . II!tar, is exposed .o' CO from many sources, and t:hese have been wcll revicwed (GOLDSMITti and L1:.wt)AW, 1968; U.S. DEPARTIIENT OF 1`MGa LT!kfi, 1:DUCATIOI & WELrAttl:, 1972). CO is absorlied tdirouglh the lungs t'o form carbo:C,ilaelTog'lobin (COHb) and'' Table I summarises' the approximate levels of COHb that various sources of exposurc can pr'odtice. Data in this table r'e'ating to environmenta: and occupaticunaC exposure were obtained from non-smokers. TlpYnI~ / R~ l~,.~aJ1 ~,1~Y7 ~, "'-•..4Y. _II' 1'I

. 1 2 A1: VfhLc and S. HowMRa TABt.B 1. T1GP!cA7: CARBON MOt.OxtIDE Arm CARBOACYHAEmOll, LEtisELS AS50C•7a1'ED wl:H,vAR1OUII'. SOURCES OF' EXPOSURE TO CARBON NIOltiOkInE - Approx.mean Approx. mean. Source of'CO' CO (ppm) COHb (iZ Source of COHb dam Metabolism - Environment (non-smokers) Los Angeles commuters London taxi dnvers Occupation (non-smokers) Motor car repair shops (Canada) Parking attendants Border inspectors QvIexico-U.S.). Blast furnace workers Smoking 22 80 80 1'14 0-3 S36sTw+.w (1949) 2-5 DEANE and PERtctVS~(Unpub:). 1-6' - Jo.rFS et a!. (1972) S BUCHWALD (1963) 7 RAmslar (1967), 4 Cbttl:rF,et al. (197'1) 4 BtttT, er'al. (1974). 2 Gownwrrtt and U',DAhv '(1968) 61 WALD (unpublished) 2 CAvtnEr andCot•E (1'973) S': CowtE'er a!. (1973) Pipes (difelong; U.S. & U.K.) I6;000 Cigarettes 40.000! Cigars (lifelong US. & U.K.): 70,000 Pipa+cigars (ex-cigarette smokers) - (i) CO 1 irt tobacco smoke Smoking as a source of exposure to CO dtivarfs all others. For most types of cigarette the concentration of CO in the smoke averages about 4°,; by voliume. Cigarettes deliver about 12 ml CO percigarette when: tested on al smoking machine under standard cond"at'ions as,specified by the Tob'acep: Research Council (P(oTHwfit.L andGtaA, T;,1'972),(35m1 puffsof 2~ sec dtuationatarate of I puff per minuta smolked'1 to: a stan8rd butt length). As ~a cigarette is smoked andi becomes shorter, the quantity of air enterir•.g through the porous cigarette paper is reduced, and so the CO concentration increases with each puff. Since the paper surrounding the filiter of filter-tipped cigarettes is relatively non-porous less air can enter to dilute the CO, producinm a high'er'CO yield in a, filter- tipped cigarette than in a plain one. Thi's surprising, result has been conflnmed on, several brands: ciQarette (EVANS, personal communication). Figure 1 which shows the CO concentration per putT ~ of four brands of cia rette illt:strates this. Two o'F these, °aenior Service Filter and Players i`!a. 6 Filter, have non-porous filter tips, an& one is a typical plain cigarette, Senior Service Plain. The fourth, Silk Cut Extra, i I 1 t'. 3 J)1!{. ~10 llRUFF M.. Fta. 1. Carbon monoxide yields per puff of four brands of cigarotte: Silk Cut Extra Mild has a ventilated filter. ^--.~•--• Ilay.rs rp_6Fil4.r~{'-Seni.r S.rHce-.PI+in -SYnier f.nicr~~Riiter~ N ~ s i ~ 0 ` 'r s .,....-.~-. ,.,.. . :--~...-- . ,._ ~ . .. ~ -~. , r, ~ .._._.. _. . _.. t

I', rH vAwoUS s a t t!)I tb data ~ ttys~~') :d t`rr--ava (Unpub ) rl. (11,', 2)) e(1~;:c) t7it7) at: (l • 7'l) t. (11971 :) ' ti'an4' t.AtvnAw (1968) tpabG- hcd)' v and I ;:otE(1!973) al: (l'.1731 C For most typcs of , ::t 4by voDumr. :Il s'tnok-ing machine :ouncil (R'OTFtwELL per minute srnoked' air en!tcring through t inc;r-es si'th each :arcll~___ is' relatively Cn!yic!d in a filter- bccn confirmed on, xure I which shows -rates chis. Two o'f.' cous lilter tips, and' rtl~, Silk Cut' Extra k Ci:t Extrs hlild& has a 1 Stttoking, carbon monoxide and arterial'disease. Mild, has a"ventils!ted" filter, which differs fronl, conventional filters in' having perforations in the paper surrounding, the filter tip. With this last type of cigarette, air entierin'g,through the perforations dilutes the sm!oke, thereby reducing the quantity of Cb' per puff, and'' this can result in a CO yield even lower than that, of plain cigarettes. When the perforations are artificia'lly'sealed the CO }ieldi of the cigarette increases to levels which are more typical of conventional filter-tipped cigarettes (W/ALD and S,%tm-l, 1973). ' (ii) Uptake and loss o~ CO by smokers Thcuptake of CO from tobacco smoke and the rate of elimination of'COHb frotni the'body depend on several factors which are listed in Tablr2': Apart from'the type' and! quantity of'tobacco smoked, the main factor affiectin!g, CO uptake is the method TASIz 2. TEIE PRINCIPAL FrAE'rOttS INFLUENCtNCu THE'RATES OF, UPTAKE AND EiINQNATIONi OF CARBON MoNoX1IDE BY SMOKERS - CO Uptake Concentration of CO in tobacco smoke No. puffs, puff volume,,puff ftbw rate Depth of inhalation Pulmonary transfer factor for CO' Total haemoglobin+myoglobin mass CO Loss Initial COHb icvel!and!ambient CO levels Alveolar ventilation (physical exercise) Pulmonary transfer factor for CO Total: haernoglobin+myoglbbin, mass Cardiac output . of smoking-that is, the'size and frequency of the'puffs as well as how, deeply each puff is inhaled! The rate of loss of'CO is determined chiefly by alveolar ventilation, which is itself dependknt on physiaal'~ exercise. Figure 2, derived'' from' data published 144 vao ua w u pAERING! SIeM/lY FqatrAEt' 1 I I l ~ tt 16, t? Zu i! YENEILATIq'N RIRi~6 I 11a{el~ FIG.Z. Half-life of,CO'Hb in relationtoalveo,larven'tilation rate. This SFurcwas produced from data published by ConUev er at. (19651. Adjustment has beenrn.zde for the increase in trnsfcr factor for CO with activity, taking avadua firomJ0 mt nrin-' nvi l!1;-' at rost to .0inT1!min- TTuTO FII,;-' with Strem.tous exercise such as foutball. Thc energy expenditure for each activity sh'o:%n'was taken from PxssMoxE and DuRszrr (1955), aud converted into alveolar ventilation rates using 3-4'5 mI oxygen per calorie (Boon<tart et at., 1936), a respiratory quotient of 0•82 and a mean alveolar CA, concentration ofl5•6%. It has been assumedithat the inspired air contains nb CO. sutG/r1RG. STUDMING~ TYRING'

~ 'll 4 eoqe% by COBURN er a!. (1965), shows the considerable eRut that level' of physical activity has on the half-life or COHb, ranging,from 4 hr during sleep to 1 hr dUring vigorous exercise. COHb levels in, smokers normally show a diurttaL rhythm witlt ltvels rising durin,g, the day, and' declining during sleep. The Wye diurnat' variation in CO'I=Ibb level makes a"random"'level difficult to interpret. Figure 3 shows how the pattern of .~ t fr _F IA'CKGt011'N'0 OLOf N. Watm and S. HnwARD i-- . xee ttML'tlrJ ' - FtG. 3. Examples of COHb patterns in'2 smokers. Both sttxtke 20 cigarettes daily but at different times: ney both eliminate COHb atthe'same rate (half-life of4 hrwhile aslecp from OD 00 to 08 09 hr and a half-life of 2 hr while awake from oB-0D to 24 0o hr). Vertical fines represent the increase in. COHb level produced' by each cigarette; this COHb "boou" has been taken as l% COHib ,xr cigarette for both smokers. For simplicity, each cigarette has been shown to have been smokcd instantaneously. The "background" COHb leveUdue to endog=ous CO production and atmospheric CO exposuro has been taken as t;;, recent smoking can affect the daily COHb levels of two hypotli~tetical 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, inhale to the same extent (that is, produce the same rise in COHb level per cigarctte), eliminate CO' at the same rate.but smoke their cigarettes at different times of the day. Thus ':4' and 'B' have thersame exposure to tobacco smoke but their COHb levels are the same only at 09.00 and' 119:4©, and at any other time their COHb' levels would be misleading inn suggesting that one smoker was bcing,esposed to more CO than the other. However, if instead of simply comparing COHb level's, the CO uptaAe were measured from cach cigarctte smoked by each of the two persons. it would be demenstraued .hat the two were, in fact, being exposed to the same tota.l quantity of CO. On^ problem of this approach is that the CI0' uptake, and henc: the amount of CO'lib derived ftom'a single cigarette (the COHb 'boost' per cigarette), is likely to vary considerably frotrr cigarette to cigarette according to the circumstances of smoking, even for a,ivtin individual. However, it is reasonable to 'suppose that a smoker's acera;e COHb boost per cigarette is likely to be a characteristic of'that particular person. In fact, this measure can be estimated' from a single CO'idb measurement and a smol;ing and exercise history covering thc previous 24 hr (N1YAtrD et aJ.,,in press). Such estimates have been shown to vary much less within an individual smoker from one day to another than bc;t%scen ditTerent smokers. A smoker's COHb pattern can be I+iott:d as in Fig. 3, and the mean daily COMb can be calcultitedl Figure 4 shows the csti- mated mean COHh levels on sevcral diiTerent days for each of S suojeccs who smoke 15 25' cigcrcttes dhily„ and one (P'H)who smoi-es 40 a day. Alt;iouglr th:.re is a day-to-day variability, somc subjects are consis>,ently and' substataiadly different from others. • ,. +wrsww~.+~^o'.~"'. -- . . ,

:al activity :u t'tttring vigorous ar.dith levels risin'g, ariation itt COHb how the pattern of X:aUKn%ar=.=a Smoking, carbon rnouoxide and arterial distase 5 .y' •. ts r . 9 / r . . / f ~. / /!./o u dlt,,,, but at difTerent' c.•p from 00•00 to 08!00 rarescnt t.he increase in +kcn as 1'„ COi{b per ' I to, have bcen' smokcd tuction and'atmospheric •pothctical cigarettc :es stcadily through- : to tt~e same ettent nat( ) at the sam.e +.•h `V and' `ii' have •c tlic same only at •'tl N- misleading in •he ot•nr: Iloo•erer, -c-. n-cn,urcti, from • d,::noastratcd that ~~. Onc problem ~•r4.~~ CO1'Ib dcrivcd to s•ary cans'id:rably kintg, cvvn for a given :er'scu•cra,e COE,Ib dr,r, p:rson. In fact, ~ and c, smoking and s). F-1ai cstirnates Cr' frctin one Lln)r to •+terni.-un inc plotted !r; 4 >.awti:s lt:c esti} <t.,i,;. + c Nk ho Sn1DiCe: AltltotIr,l1 tiicre is a, .ubsta'nti;ully diAcrcnC w 1005052~12 ,~.. ...._..- . •.,._._.. __-__..._.__~,.~..,.~... _.... ..T.~ _~~,.T_ .........,__.~......_..Y......,... I 4 I 3 _ / • /r Fl1 al WM~Yr MS~1C'~.w~.t6 ts. Fio. 4. Estimated mean daily COHIb levels (above the "background"' level due to endogenous CO production and atmospheric CO exposure) for nine smokers. For each subject, the points represent estimated! values for several ditTcrent days, based on a single CO'Hb messurement. ASSOCIATI~ON BETWEEN CARBOXYHi'AEN4OGLOBM AND THE' PREVALENCE OF ARTERIAL DISEASE The association between COHb' levels in smokers and'' the.prevalence of arterial disease has been studied in a factory population in Copeahagen (WAtD et at., 1973). Satisfactory data were obtained frotn1 950 subjects of whom 53 had either CHD or intermittent claudication: All the subjects were classified into four categories according to the estimated' weight of tobacco s'moked. Blood was taken for COHb measurement after lunch, the subjects having smoi:ed' as usual that day. The COHb level was not corrected for times of smoking or level! of physical activity. Table 3 shows that the proportion of subjects affected by at least one of these disorders increases not only with tobacco consumption (11 °; among heavy smokcrs) ; but al5c, with COHb levcli (13% among smokers with a COH'b lev.et of S"/, or more). A multiple regression analysis using a logistic model showcd tllat the only' factors found to be significantly associated with CHD or intermittent claudication TA'OI:F 3. YStOPORTIt9PIS OF StJB7F.Cf5 wIT't4, CORONARY HEART n15E'1SS' AND/OR nNTERMITrENr CLAUDtIGCTION: GROUt"EID BY'COHb t_ENt1.,ADtD SMOKING CATEGORY. PsRCEtvrAGts IN PARI:vMFSts (TAxla« FwK WAt.D ct aL', 1973) • Smoking COHb % category' 0- 4- ST Totat Nil 21,180 (1) - - 2JQS0 (1) Lighr 0j90 (0) 1127 (4) 0iA (O) 111112111 (I1J~ iVtoderate 4a06~ (2) 15117,3(B) 13j5Q(25)321u35(7) Heavy 5160 (8) 10/95 (1'1'): 8/59 (14) 23,1214 (UI). Total 1,11536 (2) 2K;t3001 (9) 2U1114 (18) 55;950 (6) Definition of smoking ;categories:: Light: 1-14g tobacco per day: Miodarate: 15-24t_ tobacco per day; hte3vv: 25g or more tobacco per day (assuming that each cigarette providcd l g of tobaceo, and each cigar 3g): :

..ni.~r..L... ` 1' N. tiWA'Lo and S. HowAxn - .~-...+-..!`.a~.~,.,.r . were COHb level, age and serum cholesterol (iP<0!00I for each). After allowing for these factors there was no significanc association with the other factors investigated, namely sex, years of past smoking, amount smoked and type of tobacco smoked. Similar results were obtained' among persons who smoked only cigarettess or only cigars. After matching for sex, age and' smoking, history tlie relative risk of having CHD or intermittent claudication with a COHb level of 5 ja, or more was about 20 times that of a person with a COHb level less than 3'y(lower 95 % confidence limit 3-3). The data from this study demonstrated that the COHb level' was correlated with the prevalence of arterial disease independently'of the amount smoked, and suggest that COHb may, in prospective studies, predict such disease more preciseiy than the smoking history. Moreover, the magnutude of the risk associated with an increased! COHb level' indicates the importance of the COHb level as a risk factor for CHD and must at least raise the possibility of a causal relationship. - Two points should be borne ini mind in interpreting these findings. Firstdy, there is the possibility that as a result of'having these diseases persons ini the study al'tered their exercise or smoking habits so as to leadi to higher COHb levels for a given cigarette consumption. This might occur, for example, if cigarettes were inhaled more deeply to compensate for a reduction prompted! by medical advice, althoug' this is unlikely to account for the magttitude of'the observed effect. Secondly, the study cannot incriminate CO as a cause of atherosclerotic disease, as CO'Hb may merely reflect' more accurately than the smoking history the absorption of other constituents of tobacco smoke such as nicotine, which themselves may cause the disease. CARDIOVASCULAR EFFECTS' OF CO In considering the toxic eflfects~ of CO in relation to arterial disease it is helpfull to distinguish the effects of CO in, patients who already have vascular disorders from the effects in subjects who are free of disease. (~ i E,Q"ects of CO on patients with artzrial'disease There is evidence that it is harmful for subjects with coronary heart disease to bee exposed to CO at ia:v levels notl yet shown to be toxic to healthy pco,t:;.. Angina pectoris is aggravated by exposure to CO at concentrations which result in COHb : levels of 3-4 */;, as has bcan, shown by two studies ( ANMttsoN et al:, 11973 ; ARow©uv attd LsnELt, 1973). In each study 10 patients were exposed to air andi CO on different days without either paticnts or investigators being aware of which gas was being administered. Table 4 shows data from these two studies demonstrating that patients with CHD who are exposed to 50ppm and 100ppn} CO for 2-4 hr, have significantly reduacdi exercise tolerance and increased duration, of'ansinai pain as coripared! withl the control group„ althoughi there was almost no, difference in exercise tolerance between ilae two levels of CO exposure. Electrocardiographic changes ;ug.gcstivc of' CHD (imcreasedi ST'ile7ression} were noted durino,CO exposure at rest i¢: one study (ANDexsoN ct al., 1'973), bur oniy during cxercise after CO exposure in the oaher. (f\uOtiow and' Isnraa, 1973). ARON©w dnd RoKAW (19'71) sltovecd' that these cardiac cfTccts were not, caused by nicotine, by investigating, Fatients •xith, CHD who had smoked'8 nicotine-free cigarettes in 4 hr and had, on average,, raistd'tCieir COhi'b levels by 6 %b. ' Ti. ti'. A• I`:' prt FI: dii alli . n:i ~ p C; in t i r u on• i Wr ex.c, ; ~ .. . . . . ...... ..,._._.. .. . ~.-..R,_.......•... •,~ • _ . ~ .. ...._.. ~_ . ~ ....._..,. . ~ . iwY :~

: Smoking, carbon monoxide and arterial disease After oUter factors and' iype of tobacco ~oked only cigarettes -,- thc relative risk of of 5°„ or morre was ower ?5 % conftdence I was correlatcd with -moF •d. and suggest ;re prt:ciseiy than the :d wi i h an increased' risk fictor for CHD r,diite-~. Firstly, there .. s in the stud1r altered c!s for a given S- tcs' were inhaled tcal advice, althoughi. afect: Secondly, the ,zasc, as COi11b may absorption of other •4lves tnay cause the ;e it is helpful' ~ctrla~ disorders from -Y' hcs ric disease to be 'th;v 1,•:ol+lc. Angina 3iicir result in COHb c , 1973;; ARONOw n d CO on ditTt:rent which gas was being 'itrati;tg that patients :' Itr ha c significantly ta as roniparcd with :a excixiFe tolcrancc sraucstive of r at re t in m.ne studyy ivl.ur,- iit thc other 'thm,: A t lt,1t these '~nu v iiih CHU who raisctl thcir CbHbi Air 50 ppm CO 1q0 1ppm CO Before After Before After Before After Andexsort er el. %,COHb (4-hr exposures) Mean 1F6 1-3 1-4 ?.-9 1-6 4+5 S:D. 0-6 0+4 017' 0•7 0.6 0'8'. see Timo to onset=of angina Mean 309 265• 26t'' Duration of angina Mean 242 285NS 3l'St' Aronow et a1 %COHb (2-hr exposures) Mean 1•t M ' 1 10 . 2-7 S.D. 0a3 0•2 0-3 0-2 sec Time to onset of angina Mean 223 188. •P<M5, tP<0-01, ;R<0-001. CO vs air. NS~=Not significant. Much work has been done on the physiolo;ical effects of'CO exposure and on the mechanisms by whic;v CO might aggravatie CHD (Ct3~tnltT~[- o~ EFFeCTS OF , ATMOSPttERIC' CONTAMINANTS ON HUMAN HEALTH & ' tiVELFARE, 1969 ;, COB(JRN 1970). Haemoglobiin combined with CO is not available for carrying, oxygen and the presence of COHb reduces the release of' oxygen carried by the remaining hacmo- globin to the tissues (DoLCt,.ts et aL, 1912; RQUtcEtroN'and DARLING, 1944). Under such circumstances a healthy heart can supply extra oxygen to the myocardium by dilatirtg,the coronary arteries and increasing coronary blood flow. However,,coronary, arteries occluded by atheroma may not be able to dilate sufficiently to prevent myocardial hypoxia. Evidence for this is somewhat inconclusive but AYRLS et al. ('1'970) have demonstrated that coronary blood flow increased' less in patients with Chi'U exposed to CO (10iD0ppm for S-1S mini producing a mean COHb of a%) than in' normai subjects similarly exposed. Whereas the role of CO in precipitating angina inpaticnts witltCHD is reasozably clear, the role of nicotine has not been demonstrated. 1it is kriown that nicotine stimulates the heart both' directly and by the release of catechula'mines Whicl: incrazse the heart rate and blood pressure (GtceEVSPAV et aL, 1969). Such effects increase the demand for oxygen bytlte heart and it is possible that in patients with, CHD coronary blobd flow cannot increase, with consequent myocardial ischacmia. In, addition there are theoretical grounds for expecting the catecholaniit:e-release produced by nicotine to cause cardiac arrhythmia, particularly in a disessed heart. Although these actions of nicotine might explain the cardiac effects of smoking there is little evidence to indicate that they are; in fact, responsible. Ncverthele;s it would be unwse to dismiss nicotine as harmless in people with coronary discase until more data are avai:able. CO has bcen shown tp, aggravate pcrir±heral arterial d'iscnse as well as CiTIU. ARONoW etal: (1974) performed "double-blir+d"CO exposure studh'es on, 10 patients with intermittent claudication rExposurc to S'0ppmi CO for 3!ir raised the rrcan COHb le%-ell from 1•1 °r;; to 2•8'"; and decreased the exercise tolerance before the onset of leg pain by 17,0 (P'.'0 COl) whereas thcrc was no corrasponding change in exercise tolerance after breathing,colnpressed air. ~ 1005052914 .~~.._., _.~...~-_ ~_...~:_.,.~.-...._,. TABIF 4. EkACLQaA7toN oF .1I:CrT.`iA IN PATIF`TT5 EXPOSED TO CARnON NONO)QDE' (TAi:Eti FRO2W1 ANDERSON et al., 1973; AROr'cow et cl., 1974) .. . . ...~~ .. .. ~ + _ . .. .~ . , . r..w.. ..-..IM....Y..-_.... i.... . _ ,__ _ _ . ._ .. .. .. . , _ . .. .. . . . ~ . . . . ..^+~.~~...r_...~.~.~..~„^nr.-..~.1..1w~.+~~~.~-+.r...-i. ~~._~'_

4 t I , 3 N. `Vatn and S. HowAM (ii)i Effects of CO on normal arteries ' The effects of CO or, normal, arteries are~ less clear than those: on a diseased arterial systernL There is good' evidence that exposure to CO encourages the develop- ment of atheroscltrosis in animals, but no dite~ct evidence that it has this effect in man. AsTRUrn ('1'973) has suggested a mechanism whereby CO causes atherosclerosis by reducing the delivery of'oxycen by the blood to the intimal and mediai layers of arterial walls cau.sing,hypoxic damage. This results in an increase in the permeability of the arterial walls to lipi ds, including cholesterol. The combined effect of hypoxia and increased cholesterol entry into the arterial wall initiates or promotesithe process of atherosclerosis. Increased serumi cholesterol and raised blood pressure„both well- established nisk factors ;n CHD; .vi1l obviously exacerbate this pat'hul'ogical process: (a) .4trima!' experinrents. Animal studies have shown th :t exposure to CO causes the deposition of cholesterol in the walll of the: aorta in rabbits and in the: coronary arteries of prirnates, withi electron-microscopic changes suggestive of, early atheroma. Because of the importance of'this work and because the experimental conditions need to be considered before interpreting.the results, it is usetul to consider the relevant experiments in some detail. In the early experiments by AsrxLP et al, (1'967) on cholesterol-fed rabbits exposed to CO (16-18%,COHb) for 8-10~wee.ks„therewas increased' depositiion of choiesteroi in the intima of'the aorCa, compared wit,h control' animals exposed to compressed airr and fed on the same diet and, kept under the san:e conditions. In later experiments (iK.tst:DSEN et al., 1968; 1969) the etFect was found to be greater with intermittent CO exposure than with continuous exposure; moreover, hypoxia (16 % oxygen) pro- dticed the same lesions andi these were reversed by exposure: to. 28%, oxygen. TIz7ss reversal of the atherosclerotic lesions may have useful therapeutic implications in man and suggests that regttlar, oxygen administration in the treatment of CHD might prof'itablw be investio ted. WAtasTxUP et al. (1969), exposed_rabbits fed on; a aormal diet to CO for 3 months, producin, COHb levels ofabout Thc rabbits;develbpcd cha'nges ir the aorta identified by light microscopy as atherosclerosis which were not seen in control animals. There were, howzver, no macroscopic intimal changes seen. KJELDSEN er a!. (1'972'; 1974), using the electron microscope, demonstrated lbca4l areas of partial or total necrosis of myofibrils, intirnal and subintiinal oe3cn;a and' fibrosis in rabbits fed oni a normal' diet exposcd to 180ppm CO (15-1'7 °; COHb) continuously for 2'weeks: Coaorol rabbits kept in atmospheric air did not show these: changes. WEBSTER et al: (1'968)i demonstrated that . CO could cause arterial dama,e in primates as well as in rabbits. Excessive lipid was deposited in the coronary arteries of choltsterol-fed squirrell monkeys exposed to CO (20„ COHb) for 7' months coniparedi to control animals on the same diet and breathing air. Electr©cardio- graphic changcs of right bundle branclr block and T wa.•e dc¢ressian Nvere noted in the CO-expos.:d nnanl:e.rs. Tiiosts,:` (1974) exposed munlecys fed: on normal diet tc CO (producing 21 '.' , COHlb), and found af:a.:mcs indicative of atheronia in the coronary arteries when exposure was continuous but only minor changes were seen v.•itli inuermittenC exposure to tfne sanne ini of'CO. lit is interesting to, note that in rabbits tlse lesions causcd by CO were fountd in the norta, whereas in priniates athcroma was restricted to the coronary artemes. The signi'.i+canuc of this difference between the two,species is not known. I . i ti ..r~.'-r-.+.. ~.*e}-...Y~;....~.- .R. .. .~ ..~.:.~-.~.: ~r ... .

n diseased thc devclbp- t~his : ~T1e~t in man.- Ithcroscicrosis by ntctiial lnyers of a the ;-crmcability, !.'ctio:+ of'hypoxia •;notr: the process essu:; -, both well- It:olopical~ process. •un: tti> CO causes 4' in the coronary ,*t'ca7:y athcroma. ;ncntsl conditions s1 ( onsider the ;-d rabbits exposed •:ion oCcholcsterol to conipressed'' air f later experiments !a intcrnti2tcnt CO~ t6°; oxy,bi:n) pro- _3 i, o:.ygen. This -.ic tmallications in ..nti( ;HD might ?:: •°cd-on a normal : raabi:3 devc!ol.^.ed •:ir.%Oira were not. :tit;tl1c%at:,,s se.en. •mntvrra'tcd lhcal •imal tvdcma' and -1 ! "; COH'b)) ntDt' Show, these :rtcrial damage in ^ caronary arteries fftr 7, months 'r. E'.-ctrccardio- -iott rt•:•rc notcd in •in ne;c Imal diet to : tltcrf,lna in the ~•Suznv-, n•cric scen CO wcrc found in •mary artcries. The •. n. SmokinY. carbon monoxide and arterial disease 9 (b) i Nu»ran studies. There is at present only indirect evidence that CO may be a cause of atheroma in man. It is difficult to test this hypothesis directly for two reasons. Smokers who have high COHb levels are also simultaneously exposed to other toxic substances in tobacco'smoke, making it difficult to identify a cause and effect relationsluip, while COHb values in occupationally exposed (non-smoking) groups rarely reach such high levels. However, certain data are at least consistent witlt the hypothesis that CO is atherogenic in man. StGGA.aRD-ANOE'RSEN ec aL (1'9G3)'have demonstrated a significant increase in leakage of plasma proteins, including lipoproteins, through the vascular wall during Cl'J~expoiure in both humans and dogs. The epidemiological study of' Danish factory workers described above demonstrated that atherosclerotic disease was better correlntedi with COHb than with smoking; history, and while it is nott possible to axclude any role nicotine, or any other absonbed' constituent mf'tobacco smoke, may have, the evidence is nonetheless consistent with thehypothesis that CO, is causative. Since exercise has a marked effect on the elimination of CO1 from the body, but probably only a slight effect on the elimination of most other constituents of'tobacco smoke, it might be expected that smokers who exercise vigorously have a smaller excess risk of CHD1 from smoking than those who do not: A study by Moxttts er a!. (1'973) demonstrated this effect (Fig. 5), althought the difference did not reach statistical significance. Nicotine may be involved in aggravating existing CHD but, there is. very littlee evidence to' suggest' that it'' causes atherosclerosis. Most experiments whiclv have investigated this have produced negative results and the few studics that haveshow'n a link between nicotine adniinistration and increased, atheroma only occurred in animals which were fed' on a cholesterol diet (US. DEPAttT'1vtfiD1T ©'F' HEALTH+ EDt1C:A- •rto*r,wt7 WEt.> ARE, 1'971), .~ ' YIIjOriOYf fiefCl6e Nelia0f0YS'.tiefGi3N' iaien nrem. Merntc.1491111, OetH ea.27i uf.svM N/ maltnet eentrUtl . Fio. 5. Relative risk of developing coronary heart disease in smokers and norr-,mokcrs in two exercise groups. Mtonsst'those who did not exercise vi;orously, smokers hnvc 2•5 tintes tite r'ssk of non-smokers; whereas in those who took vigorous cxcrcise the relative risk of smokers as compar~.-d to non-smokers was only 174. (Taken from ivtoaxis er al., 1973, based on 23S'cases and 476 controls.) -„6 . -_..,~,.,.-,-~..... ..,-.~-.-~...,.....,,,-.-«.. ,:. --r----- . •t.

10 N. wA't.n and S. HoavA,tm TRENDS IN MORTALITY FROM CHD AlY'D LUNG' CANCER Relating the changing, mortality from two smoking-associated diseases, lung cancer and CHD, to changes in the composition and!consumption of cigarettes r.;ay, provide some cl.ues to the aetioliogy of these two diseases. Since 1955 there has been a dramatic change in cigarette sales from the'plain to the filter-tipped' varitst-, ' (Fi& 6) which have lower tar and nicotine yselds. During Pleln~ uq+f@NU >r 31 .. L.. , fiiler~tipe!'. Ellilte/1ef: 10 10`~0 ID001O10 1924 1h30i 11148 11150 1964 . 1910 .j Fto.6. Cansumptionofplainand'filter-tippedcigarettes'intheU/.Kfrom1'890'tm1970i(TocD,1!972)n this period the number of cigarettes smo3ced- by men has not changed greatly, but there has been a clear increase in the numbers smoked by women (TooD, 1972). Lung cancer mortality, has been falling',arll'ong men aged less than 60 years but has in- creased in, women, while mortality from CHD has riser, in both men and woaten, (Table 5). Since conventional filter-tipped cigarettes have a higher CQ y,ield, than plain cigarettes, the increase in, CHD mortality is consistent with the hypothesis that Cp is a contributory cause of this disease, although tlte rise could'well be attributable to other factors. TABtB'S. PERCETiMTAGY CHANGES IN'DEATH RATES flROSS LUMG'.CA'NCER.AND CORONARY HEART D[S87SG' IN ENGLAND A.1M NWAt.es FROM :'956--60 To 1966-70 CHD Lung cancer Women Men Women s e .o: 90% i `. e/ e confidence confidence confidence confidence rl.ge % liniits % limits % lim,its % limits 23J- +17 -L18' +67 f52 -17' ±23' 01 1-43 30- +16 ~ 9 +29 ~ 16 -31 ±13 -21 f22. 35- +26 ~ 5 +93 118 . -20 = 8 0. -L1i6 40- +52 ~ 4! +72 s-1G S +35~ ~12 45- +44 = 2 + 42 = 7 -1l ~3 +51 = 9 50-- +26 -2 -L3l - 4 - 31 ~ 2 -6G 1 7 55- +20 ~ 1 + 16' = 3 -41 =2, -41L (4-4 +21 f 1 + 13 = 2' +13 ' ~ 2 +55 = 5 The figures fnr corouary heart disca;c are taken from Table I and Taole 17, of thc ;tqistrar Ctncra9's Sta'ristical Review Part 1, Tabics 'acdiaral; using ICD eoRics 420!and 422.1 until 1967, andl ICD codes 410-414 for 1968 onwards. The :a'tes for lung,tJncer are obt:tincdi from Case (personal communication), and from Table 17' of the R'ogisDtar Generai's Statistica! ILeview„ Part I, :'ables Medical, using DCD codes 162-3.