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, , 1 . i The Lancet.Saturday z9 September 1973 COMPARISON O'F INCREASES IN CARBO'XYHR.MOGLOBIh?' AFTER' SMOKING "EXTRA-MILD"' AI+TD "NOht-MILD" .'. Al Q1\7ARk=J' ' . M. A. M RvssELL C. WlrsoN Addiction Atrtcarch Unir, lnstiiute of Prycfiiatrq, London' SE3 8AP '' . P. V. C©LE' M: IDLE Anatthrric RbssarcA' Lab'oratory,, St. Bartholomew's Idospiial, London EC7 ` C. F'E1rERA:BEND' Poisons Uvtir,,I1lew Crou Ffotpital, Lottdon'SEl4' Summary A cross-over comparison' was made, in twent~two smokers, of iacreases in carboxyhaznoglo-6in (COHb)' after smoking " eatra~ anild ° and " non-mild "' cigarettes. The mean increase after smoking a single non-tuibdi cigarette' was 1'43'' o for the standard-size brand (ten puffs) ; andi 1-09'g'„ for the smald-siie brartd' (seven puffs), The mean increase after a single eatra-nlil& cigarette was 0-64 p for the standard and 0'75'°J,' for the smail brand. The low CO absorption from the standard. size mild', cigarette was less than half the' amount absorbed from the sitnilar=sized' non-mild'' agazet2e. ; This low CO btand' also' has a low' tar and nicotine yieid. COHb increases after smoking were greater in the women than in the men, and there was an inverse relation between COHb increase and hamo- g(obin leveL The health implications of variations ia CO yield of' cigarettes are probably as important as those: of differences in car and nicotine yield. It is suggeste& that the CO yield of cigarettes should' be . published together with their tar and nicotine yieldl Introduction MEAStntss to reduce the harmfulness of agarettes are directed mainly at decreasing their tar and~ nicotine yield: Many countries now publish " league tables " of' tar and' nicotine yields of different brandb of cigarette 1 Manufacturers are competing to pro- duce mild'' cigarettes with~ low tar and' nicotine yields, and' expert bodies have': advised those : smokers who cannot abstain to'sw'itch to tifie milder and supposedly safer brands.23 ' But is it only'the tar and nicotine yield of cigarettes that is cause for concern ? What about carbon monoxide ? Evidence is beginnittg to actxue that it is the carbon monoxide (CO) in tobacco smoke 7831 which may be implicated in the' increased risk to smokers of' arteriosclerosis, ischaemic heart-disease, and fetal damage.' ' Should we' not, therefore, be equally concerned about a' cigarette's CO yield ?' In 1922 Armstrong showed that the CO content of tobacco smoke varied with the brand of cigar or' cigarette and the rat'e at which it was smoked! We have' attempted to explore the variation' in carbon monoxide yield of four brands of manufat:tured, cigarette by comparing the rise in the carboxy- hasmoglobin (COH'b)' level' in venous blood before and after smoking a single cigarette. Materials and M'ethods Twenty-eight, students and hospital staff volunteered to take part in the experiment. All were tobacco smokers who said that they could inhale. The experiment was not restricted to heavy smokers, and the volunteers represented a fair aoas-section of smokers (see table t¢). Unfortunately, a few blood specimens were partially clotted an atffival' at the'laboratory and had to be discarded. This was possibly'due to a faulty vial of heparin. This happened with specimens from six of the volunteers, and the analysis was confined to the twenty-two for whom the data were complete. Each' volunteer was used as his own' control for' eom- parisml of' the COHb increase after smoking' an " extza- mild "' cigarette and'' a' popular brand, of "'non-mild "' cigarette. With half the volunteers the' eomparison was made, between two standard-sited cigaretttes, one " eattra- mild "' (A) the other "'non-mild "' (B): Wit'h! the other half the comparison was between two sma11-sized dgarettes, one extra-mild (C) and the other non-mild (D). A'll'' four brands were filter-tipped: details are giwea in table I. The two standard-siied'' brands were fairly well matched for' size, as were the two sma!I1Lsized braada' The volunteers each smoked two cigarettes of similar size, one extra-mild and one non-mild. To control for a possible' influence due to the order in which the two cigarettes ~ were smoked, half' smoked, the extra-mild cigarette first and the non-mil& cigarette second, while TABJ= t--DL+fA[t.l Os ffl[1a' aRD1ltt/s OF CtoAAEL7R sAto!® nT mamtUAMM ' V ~ Brand t3 ~' 6 e.... 41 B e. 4 x, w z ~ A' ' Silk Cut B:at Mild' " ' 4 c0;9' 0•0- ' i 7-00 ' 231 I B Hmbasy Filter 20 1-j' 1-n:' 709 2 SZ~ C "P1sye'a Mild Milfotd' e <0+9' ~h7o ' 649 ' 2-26' D 'Plnet. No. 6 Filtv' 20 I 1-2' 0•77 6•!7 2•3'7' N

688 for the' other half this order was reversed: To achieve this balanced' design, seven volimteers, were randomly assigned to each of four schedules (see table it), but the'e exclusion of six' of the twenty-eight volunteers resulted in some loss' of sytnaletry. The' laboratory workers responsible for the COHb analyses were not aware of' these smoking schedules. The volunteers did not smoke for at least 20 minutes before the start of the experiment. Venous blood- samples were collected before' and' precisely 1} minutes after the first cigarette and again before and precisely 1} minutes after the second,cigarette. Thus four samples were taken from each volunteer. Between the fust' and second cigarettes there was a' 20-minute interval which wsu' spent sitting quietly. Each agarette was smoked to instruction with a puff every 40 seconds to a~ total of tea puffs for standard-sized cigarettes and seven puffs for small-sized cigarettes. The volunteers were encouraged' to inhale every puff as deeply as possible.' The purpose of the 20-minute interval between cigarettes was' to allow the volunteer' sutEcient time to recover from the first cigarette to enable deep, inhalation of the second one. The venous blood-samples' were drawat, steadily over 30, seconds, with the scheduled' time, falling in the middle of the 30-second interval. They were collected' in heparinised' syringes which were capped and' stored, in ice. The analysis for, CO13b was done using an IL 182 "CD-Oumeter'. This is an accurate' method with reproducibility having 95a„ eonlfidentu limits within 0•1°'o CO13b! Statiatical'' analysis was by Student's r test. Results The' mean increase in CI"J'Hb level after smoking a single' cigarette was about 1%, the mean increase saau ut-trtatsAn rx Ct]Hb t:aveu Arreat sAtotttxo Dtrmtexr a!<AtJ'DS oF ctOAaarTl . 11tof of puRt increue in tncreue in' Brand of cia.rette to complcte COHb per COHb per' pprette cigarttte (me.n t s.a.) puff (mean x ua:) (~:d ( :I Extra mild A 10 0•64It0r40 0-064t0+040 Non-mild,8 10 143 sto-l7' 0•'143 t0+037. Extra mild C 7 0•73 t0J7' 0•108 t0i067 Non-ntild D 7 1•09 ±0.61 0. 136 t0+088 One grottp smok'ed en A and ie B while a dllrerent group smoked a'C and a D:,Tlhurthe eomp.riretts A a: 8 end'C'v: 0 ere.rithin.ubieaas whiteotheteomp.risons ue betveen subiecte. being much the same' for the first and second dgarettes (table li). There was, however, a signifi- cant tendency for the COHb to increase less after the milder cigarettes (table' tll, 6gs. I and 2). This was most striking in the Case of extra mild A, which caused less than half as' much' increase' in COHb as that produced by non-mild B(P<0•001). The difference between mild C and non-mild D is' not statistically significant, but mildi C produced signifi- cantly less elevation of COHb than non-mild B (P<0-01). When allowance is made for the difference ia cigarette size by calculating the rise in COHb per puff' (table tu), the difference' between C and B is no longer significant and' the difference between' A . and! D becomes sigaificant (le<0-01). None of the other differences between the brands' of cigarette are significant. , : , 7J1ffii t1-•C7iANGES~~.IN~~COFIb r39IQS IN 22 SMOt®Lt aat+ONE~AND AFrdA SMO[m0: A~SntGrJa aTOtA-MIt1D~AND:A'SntGli ttOH-MIIA~.QGA'7lallni ! vohmteer Blood,COHb le.el. ( ;) ~ No. ot' Ciaerette Hb Utud'daly, cigarettes stttoked'in i, First'dpretts, Cbanae efter Saeoedaaarette eeqaeryce' ~fo. Ses '~te (t Id00 to1)' ap~e consumpnon morning r 20 min. (Tr.) befon icter..l' i t between ezper mett Before After DiRereneei °garmO Before After I DilTercttee Bme mild A 1' ' M' 18 13-7 20 S 6-3 6-9 +04 I -0r3 7•8 +1-2 followed by 2 I F 22 11-2 10 4 1•6 1•9 +11 ' -0•8 2-L 4•3 +2-2 aeo-muld B 3 'i F 18 12 8 12 6 S•0 5-3 +OrJ', +0-2 S•7 7-6 +1•9 4 F' 50, 12•7 20 6 3•4 1r9: +0•1I -0-3 S•6 7•4 +1•8 s F' 24, 12-8 20 1 2•7 3•9: +1~2 -0•S 3•4 S•2 I+1•8 6 M 1 41 14.1 ' 00 0 0-9 1•. +04' -0-1 1•3 2-4 B tollowed by A 7 F' 21 12-9 30 S' !•2 7-0 +14 , -0 S 6 3 6,9 +0 4 8 F' 20 13-2 1.S 3 ' 0•7 1•7 +160 -0-2 1-5 2•0 '+Ws 9 E' 18I 12-0 10 4 2-5 4-4 +1•9: -0-5 3•9 S-0 +1•1 10 M 49 I 13•3 J 3' Od 1•3 +0•8 -0-3 1-0 1.0 +04 11 M 44 14-9 10 6 1-0 14 +0-4' +0•2 1-6 2'0 0,4 + Bztrrmild C 12 M ' 36: 13•3 18 3' !-0 6-0 +I•0 -1•0 1-0 6+7' +l•7' followed by 13 F 19 11•9 1S 2 2-9 4-0 +1•1! -0-3 3^7 4,9 +1,2 eoa-mild ID 14 F' 37' 11-4 20 1 2•3 44' +1•6 -1•L 3-0 4,3 +1,1 15 F' 19 13,8 3 0 0.7 1•3 +0•6 -0-1 1^2 1•7' +03' 16 M 31 14•7 17 10 3-3 +3 +1•0 -0-4 3,9 5,0 +i~l 17' M ZT 1J-4 10 7 0.8 o•a +04 +0-1 0-9 1-0 +0 1 D follow.d by Cl 18 F' 23 12•9 10 !' 4,4 5-7 +1-3 -0+6 7.1 6,3 +1-2' 19' 'F' 17 13,8 23 I3 816 10-9 '+2•3 -1-3 9-6 9+8 +0-2' 20 F' 23 14-6 20 12 6-3 7-1 ' a0•6 -0..3 6•8 7T3 +0;!' 21 M 22 15-0 31f 0 9+9 10•18 ''60.9 -1-1 9-7 10,.3 +0-.6 2II' M 34 aS-4 I! 12 $10 !-8 'I +0•8 -0-4 54 $19, +0.5 MenfiD 27-6 .. 15,It6,.S) 3+sf31/ 3-70 4,69 1 0-99 -0-46't 4•3S 5+23 0-98 +30+7 t2-66i f2-86' I t0•1! t0'38 f2,62 f'3'70 t0;6f • Rze.iotu ae.rette tmoker, no+w an oro.ionel atpr smoker. t'Oetaeiond'eiaerettes, reaular oiprsabout 6 per'di7r t'tbe thee..oiantats who rhowed en " inaase •• were aoonted r seta. S I Bsotudina tlte t+ro aaar tmotet.. i.

: ; / ~ i ~ M t.ANesr, SEPrEMasx :29, 1973 3 0 Standard Smclll A b C 0' ~ • C A I y ~ Ifl ~ • • y A A . ~. • .~ • ~ ~ A . I •• • A..@~~ A. ~ .• . . A A MWe • fenwle. Fig. 1-tacrease In CtD}tb levels after emoklns dUferent brande of 'elsaretto. 'hhe ! average initial COHb level for all volunteers was only 3.7%, confirming that as a group they were not unusually heavy smokers. The initial COIib level was relatedi to usual cigarette consumption (r=049; P<0-01) and to consumption on'the morning of' the experiment (r=0-SI8, P<0-01'). There was no relation between' the increase in COHb after one cigarette and usual, cigarette consumption (r=0-41, N.S.) or between increase in COHb and initaal' level of COHb (r=0-13, N.s.); but there was an: inverse relation between haxnoglobin level' andi increase in COHb1 after smoking (r=-0-69, P<0-01'). The average fall in CDRb % during the 20-minute interval between cigarettes was 0-46, (table II). As expected, this was reiated' to the level of COHb after smoking the flrst', cigarette (r=0-65, P<0•0l): :, Though there was a slight predominance of women among the.volunteers, the random assignment ensured that any sex differences would be reasonably balancedl The women were younger than the men (mean age 24 years v. 33' years, P<0-03'). They also showed a much greater' mean, increase in' COHb than the men after smoking the non-mild cigarette (1-32 ~, compared with 0-90 ;, P<0+02), but the difference after the extra-mild cigarette (0-82% ' compared' witlt 0+S'1'a,) was not statistically signifiiant. Discussion The average rise in the COHb % of'ven!ous blood after smoking a mild cigarette A was only 0-64 com- pared' with 1-43 after a non-mild cigarette B of'equiva- lent size. This comparison was made in the same individual, and each cigarette was smoked in an identical manner, one puff every 40 seconds to a total of' tew puffs per' dgarette. The difference in COHb increase produced by these two cigarettes is very consistent (fig. 2)! and highly' significant (P<0-001). This suggests : that the CO yield of A is very much~ less than B. Indeed it would' take two A cigarettes to produce as great an increase of COHb as one B cigarette. In addition, therefore, to its low tar and' nicotine! yield the remarkably low 689 3, ' Standard Q non-mild ( 81 n 0 mild (Al , 0 u:'r uar- I,t M Z n~ t l il' S 4 7' 1 0 0 1!0 11 Small Q non-mlld (!0) o mild (ic) ~ V 1 : I 't , r.. t: Q 19 12 14 1E 13 1e 21! 22, 20 15 17 Volunteer N! Plr. 7.-C'•omperleen of lnoresea In COHb lerels of indlridu•' eublectrafter senolilhe mild end non-mlld,eitllfeltt6 CO' yield woultd seem to indicate that extra mild cigarette A may, be an even Iess harmful cigarette than has previously been assumedi It' is not evident from this study whether the lower' CO yield is due to differences in the filter or in the tobacco, and we are inNestigating this aspect: With the two sma'il-sized cigarettes there was again a tendency for the COHb to increase less after the extra-mild cigarette, but the difference is not statistically significatu: CO yield per cigarette is determined by the CO yield per pu$' and the number of' puffs which it is possible to take from the dgarette: When a compari- son is' made between a11l four brands in terms: of increase in COHb per puff (table iu)' the differencee between C and B' loses its significance while thee difference between A and D gains significance. Thus ; the mild brand A is the only one of the ! four with a significantly lower CO yield per puff and lowez CO yield per cigarette. Furthermore, it seems thai the differences in CO yield are ! to some extent independent of tar and nicotine yield. Despite atternpts to' ensure that each' dgarette was smokedi in, a sim'slgr way it is possible that systematic differences did occur. Some volunteers may have inhaled the extra-mild cigarette more deeply. If, this were so, the finding of' reduced CO absorption from the exm-mild cigarettes is even more striking. Be- cause of'the exclusion of six volunteers (see above) thee symmetry of the design was slightly upset, and twveivee extra-mild cigarettes were smoked first compared with ten, non-mild. Some participants may have found the 20,minute interval between cigarettes too short, so that they inhaled less deeply at' their second cigarette. If'this were so, the imba'lance:of the cross- over would tend to: reduce rather than enhance the differences. In any case the order of smoking the cigarettes had! no effect on the amount of CO absorbed! The women showed a greater rise than the men in' CORb level after smoking; This happened after exara-mild and non-mild cigarettes. It cannqt' be explained by the fact that the women were younger, because age had no relation to the increase in COHb after smoking. In', view of the inverse relation i f+ 0 0 ~ 0 ~ ~ cc w N ~ f ~ ~ i !

between Hb level and increase in C0'Hb-after smoking, it is possible that' the lower Hb levels of' the women (mean 12•.8' g~ per 100 ml. compared with 144 g. per h i l r smad e tr 100 ml. for the men) together with t blood volume accounts for' their greater COHb increases after smoking. This' relation between sex, Hb level, and COHb uptake has not as far as we know been reported previously. It is certainly not generally appreciated. It may have especial implica- tions for those women who ismoke in pregnancy and who are anamic. 'I'he findings indicate that besides variation in tar and nicotine yield, commercial! brands of cigarette vary greatly in their CO yield. Direct measurement of the CO concentration of ' mainstream smoke presents no more of' a technical problem than the measurement of its nicotine or tar content. Indeed, it is likely that the tobacco manufacturers already know the CO yield of their agarettes~ and cigars. Because the health implications are' probably as important as is the case with~ tar and nicotine, the CO ~ yield of all commerciaily available' cigarettes should' be published' together with their tar and nicotine yield. Furthermore, this should be done' soon. We thank Upendna Patell of the Addiction Research Unit for checking the statistical calculations, Pauline Beattie for ' seeretarial' help, and the Medital Researeh Council, the Depar2ment of Health and' Social Security, and the Joint Research Board of I S6 Bartliolomaars liospital for financial support. Requests for reprints should be addressed to M. A. H. R. 1EPERENCES 1. fanctr„ 1473. ;. 974, 2' Wynder, B: L!w Seeoad World Conferenca on Smokiag and! Health (edited by R. G. Rich.rdson);'p. 197. London, 1971. 3. RoyR1! College of', Physicians. Stoobns aod Health Now; p. 134. Londonj 1971. {: Surgeon General. The Health CConsequenoes of Smoling. U.S: Departrnent of Health. Education and We1Lre, 1972. !. Astrup, P. Br. rnsd. ]. 1972, iv, 447. 4. Astrap. P., Tmlla,D , Olsen. H. NL, Kleldsm, K. Lancrr, 1972. il, 1220. 7. W.IdJ,1+t,,Howsrd, S., Smith, P. G., Kiddien,St. Br: n.d.1.197D; 1, 7at. 6. Atmsuong, H. E. ibid 1942, i, 992: 9. Rus.cll:,.ti1. A. H., Cole, P. V,, Btowo, H: Lewca,1973, l„37b. ° The Malrhusian nightmare, thatmaas storwtion,will be the ultimate population contr+ol, is only one, and that the most distant, of several specters. Beyond' the immediate question of whether, this year's aops willi produce enough food, to avoid major, price disturbances, poiititxl innrabiiitics, and' famines, therr is concern tbat the' present alarms and scarcities may teflect not just last year's badi weather, but a fundamental deterioration in the world food situation.. Already there are those who foresee a period of food sarcity,, in which those with food to sell will have a usr~fsil ptolitiaal weapon in their hands. Governments of developing countries will find this year that thee soaring prices of',food grains and freight rates have driven their imported food bills up by 60 percent or roughly $2 billion, a drain on foreign reseroea which, should it continue, threateans to retard economic development and make the gap between rich aations aad poor grow faster still. Much besides the threat of' famine,,therefore, hinges upon the ability of developing aountriea to make aop,yields grow futerthan people."-Ntt>losyas WAD., Soiatae, 1973, 181, 63+l. T118 IaMCBT, SEPTPJN'BER 29, 1973 DETECTION OF HEPATITIS•B ANTIGEN BY RADIOIMMUNOASSAY IN CHRONIC LIVER DISEASE' AND HEPATOCELLULAR CARCINOMA IN GREAT' BRITAIN W. D. REED A. L. W. F. EDDLESTON R. B. STERNi ROGER, W'ILLTAMS Liver Unit, King't Collegt Hospital assd'Mtdical'Sefi'ool; London SE5 A. J. ZUCXERMAN A. BoWES PAMELA M. EARL Hepatitis Research Unit, Department of Microbiology, Londtrn School of K'ygienr and Tropical Medicinr S„mrsary Itl, a series of 264 patients with chronic liver disease or hepatocellular car- cinoma, a sensitive radioiinmunoassay technique showed 37 cases to be positive for HBAg. 201of these 37patients were HBAg negative by immunodiffusion and electrophoresis. In active chronic hepatitis 1811,11 of the 94 patients were HBAg positive. Comparison of these cases witih HBAg.-negatdve cases showed' a higher frequency of HBAg, in males and those born overseas. There were no significant differences between HBAg positive an& negative patients for clinical maaifestations, immunoglobuiins, autoan'ti- bodies (after allowing for differences in sex ratio)+ cell-mediated immunity, or prognosis, and' in some cases the progression of tissue damage in this con- ditiom may,beunrelated to, the continued presence of circulatiilg, HBAg: HBAg, was found in only 1 of 45 patients with primary biliary cirrhosis, and coincidental infection following bloodLtcansiusion was a possibility in half of' the HBAg-positive cases of eryptogenic cirrhosis. However, blood-transfusions could be' implicate& in only two of the six HBAg- positive patients with alcoholic cirrhosis. In primary hepatoceilular carcinoma„23 °', of the 38 patients were' positive, the fsequenry'being higher in those born overseas (56 ; compared with 15 0), showing that thee reported' geographical variation, in this association cannot be due entirely to differences in technique for detecting HBAg. . Introduction AN association between:viral hepatitis and active chronic hepatitis' was recognised in one of the earlicst reports'of this syndtome, in which it was' called "aaive chronic infectious hepatitis " 1' However, the sub- sequentobservation of a,positiNe lupus.erythematosus (s,.E:) cell phenomenon; hypergamraaglobulin'a:mia,' and the presence of autoantibodies in the' senun ` led to the concept of a primary autoimmune patho- genesis.s More recently, the detection of' hepatitis-B'B antigen (HBAg) in the serum of some patients " has renewedi interest in a viral atiology. The pro- portion of HBAg.-positive cases varies from 51 % in Italy s to 3% in Australia.10i In Great Britain, HBAg was present irl 8% of patients with active chronic hepatitis but all of' the 6' positive cases had come from abroad." A pronounced geographical variation in the frequency of HBAg has also been reported in hepatocelluiar carcinoma.'&u t. l I