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in til.. :1' ~ r r ~tk'' ,~ , arat;... ! t. ~ , thit srcd ! ri?!\ir:i ~ :;bon r, in~ r..:. 4 I Ntp•. ~~ erc ; to parts nt ol )r tht sc , I a .14.The analysis of smoking parameters: inhalation and absorption of tobacco smoke in studies of human smoking behaviour ROGER G RAyVgONE. K MURPHY. M E TATE AND S J KANE fatroduction Marlier conference on Smoking Behaviour, held in 1972, dealt exclusively with the question 'what arc the motivational mechanisms sustaining cigarette smoking be}ariour?', considering this from both the psychological and pharmacological poiats of view. During that conference it was suggested by Armitage (1973), however, thatan important question, frequently inadequately cottsidered, was that of (nicotine) dogge, Ashton and Watson had shown in 1970 that the human smoker can and does adjst the dose (of nicotine) he takes into the mouth by adjusting the size of his puffs and the rate at which he puffs when smoking. Furthermore, as Armitage stated, the smolce can be inhaled very decply, moderately deeply, slightly or not at all. Since tld time many reports have considered questions which relate to how people smoke and to the smoke uptake and retention, but, apart from a study by Guillerm and Radaszewski (1975), there have been no published studies exploring the range of teebmiques available and their appliation in the study of such questions. '[his paper will descnbe techniques which may be used to answer the questions 'l;ow do people smoke?' and 'What is the sinoke uptake and retention?'; it will expiore some of the relationships between iinoke uptake and smoke rctcntion and finslty describe the results of exper{ments to study differences between habitual middk tar and habitual low tar smokers and to study the effects of switching _ between middle and low tar products. 'How do people srnoke?' In the analysis of this question we are concerned with the physical smoking profile. 'Ibe dose of tobacco smoke constituents available to the smoker will depend upon the cigarette specification (Table 14.1). However, for any given cigarette, it is the,. stnoking profile which will affect how much of the dose is delivered to the smoker and how much is absorbed. Table 14.1 Factors detetminin f the characteristia of a citaretta Produet' Cigarette Specifrcation i) Filter - Tobacco based ' Additives Diluents J Substitutes ii) Confit;uration iii) Wrapper ir) Filter - Type Vcntiiation .tise. - Pressure drop.... r) % 171 t

„ . , .... ~......... ...... t t.M 4vuruurc. I1rr/l duratiurr, number of puffs and irncr-puff interval) and the inhaiatiun p Itterr•.. 'IVliar is rJre saurkc uptake anil.Lcrritliun?' C',t~YJ,t,lb~ b,ll~ntify thc antoke uplqkp:and.doaaobsorbec!•nra roa ~,the snrtiking;p~4fii4ir fNost approafhcs to'ylhis;qyGslion.atl m"N~iv~s L~J ' 1doso•oFtobaCCO~It>6KoGriin an ~analysrs of'ycrtain. smoke oomponc, nt' oi4 t)skt : ,,, qurkcrs~wmrrtonly c~rbon iriQnaxide ~r~rllcotins,; It~shoulc~_.nA1Ea c ' S~rbifn;h~ond~ttitctls.a ;mcaltitre ,orfthf,g~s/vnpour•phas~ol,.thttimta l(y,,WIf iisCnlit'iii , is < rcAc ctloFr of p llculatc d it i osslbl ia hb ' h fr s - ~ , ~: . ., ~an ar .n r p e t t c lt l e tw~rplri.1v sris ttQ ~,R `tubrr.co smoke beha.cdifferentl~ln termi oC~helr.pu(monary.distjlbytjqn~tld ,.:. , "•_~ t.. ~ a.r...........J.J..~..a~.~...w~.... .~. 71)SOrplli)rl~ Carbp"nymoFiqs; c,may _c;mcq{uty jm thcs4lp, ,orr, n:ex ia e rp r~whll~ st:~i jii ,cn: usalY-'QlGas.tt[tsLJrLtbey)o.Qd-otln_the-urlne.-A-somtyrhat,:differen l:app~narh~= ._ •.is thc estlmttlbll'l1f`nl'cotln!<'IHtake fronLtFia~,i'etp(Alotlln.the.clgrarctto~sutt~ 61-^curensent of puff parameters diL..rod Puff parameters can be obtained from measurements of the pressure drop arruu a small resistance inserted between the cigarette and the smoker. In Ihis sitoatMont when thcrc is air flow during puffing, the pressure drop created across tise resisrm.e .vill be related to the gas flow. The relationship will depend upon whether ehc airflow is turbulent, when the flow rate will be proportional to the square raot f+t the pressure drop, or laminar, when the flow will be directly proportional ep the pressurc drop. In either case puff volume can be derived by Intcgration of ehe th•1 signal against lime and puff and interpuff Intervals can be measured directly. . Specialiscd cigar_tte holders have been designed incorporattng devices to tsrnducc a pressure drop with either turbulent flow (orifice plate) or, as used In the pscscnt cxperirrsents, laminar fiow (filter insert). Both types of device have their advanr,tx, and disadvantages but it is not appropriate to discuss these In detail in this parcr It is necessary, however, to outline some of lhe problems associated with the filtca InseEt type of holder as employed in the studies to be described. The holder is slt"' i in Fig. 14.1. It contains a replaceable 6mtn cellulose acetate filter a.ront which (he pressure drop can be measured using a differential pressure guage. Thc assumption is that this pressure drop Is linearly related to the flow of gas thruuch it. i.e. that the flow is laminar and Q°Kp •(1) where Q is nce flow rate, p is thc pressure drop and K Is a constant. Fig. IJ.: shows thc pressurc drop vcrsus flow rclationship of the holder for air over the rrnt;c uf flows found during normal smoking. It can be seen that lhc rciauomslnr is curvilinear indicating that the basic assuntption regarding flow derivation is not c,srrect. Neverlhclcss.. the degice of curval tire is relatively slight and tise avcrrll crrur intruduccd in computing puff volumc from lhe flow signal is accordinglv small. :rhis relal ionship between pressure and the flow has been obtained by drawing iir thrt>ugh thc lilter iwlder at room tcmpcrntures. The exact rclationslsip hclMrrn 0 . tsrI 14.1 The filter inrert cigarette holder wtth tr king-size fiiter tipped cigarette. r.o off the 6mm celtutose acetate fitter inserts, across which the pressure drop is eeesrred during amokina, are shown alongside the holder. . I . s s 1000 2M 3000 FLON eml / mtnl I 4000 I rs. 14.2 The relationship between pressure drop across the filter Insert and rlow .t ru through the holder over a range of rtows found during normal smoking. I A V.z~,~~sEzoz

. V ~'(p r" 8 nl whcrc r is lhc radius of thc dcvicc, I is lite lenglh of lite device and•n is the viscosity of lite gas. Although tltercfore flow may bc proportional to pressure drop the constant In equ•rtion (I) is dependent upon (lie viscosity of the gas which in Its turn will be influenced by temperature. In the prescnt situation thcrefore any calibrations of the filter holder should be carried out using tobacco smoke at the temperatures found in mainstream smoke. Measurement of lite temperature within the frher Insert during normal smoking is not constant, rising during puffing and failing between puffs. An overall rise of about 6°C has been recorded smoking to approximately 8mm from the cigarette filter, after which the temperature rises steeply. An evaluatinn off the characteristics of the filter insert holder using tobacco smoke at a temperature 3-5°C above that of ambient air was found to give results within 3% of those using air. There is one further question which has to be considered when using the filter insert holdcr - does the deposition of tobacco smoke condensate within lite filter insert, which inevitably occurs during smoking, affect its characteristics? In practice no diffrrences could be detected in the pressure drop versus fiow relationships or filter inserts studied before and after the smoking of a cigarette through the holder. It should be noted that when performing butt nicotine analysis (vide brfra) the filter insert should be Included to take Into account the condensate (nicotine) deposited within it. The analyses described Indicate that the iliter-insert holder, calibrated with air at room temperature, gives an approximation of the flow rate and hence lite volume of tobacco smoke passing through it as a cigarette is smoked. The filter inscrt requires renewing for each cigarette smoked and the calibration should thus be pcrformcd before each study. As the derived flow signal is only being used to calculate the puff volume, calibration can more readily be carried out by passing a series of known volumes through the holder and recording the appropriate signal. As a final check of the system a volume calibration of the filter holder was performcd using both air and tobacco smoke when, over a range of volumes (10•60m1), the results were within 595of each other. This technical evaluation enables lhe limitations of the calibration procedures and lite precision of our measurements to be known. *kiowever, one lrlust then considcr thc effect on the puff parameters of smoking with such a holder. There is the intrw duclion of thc holder changing the weight and feel of lhe cigarette; the added dead , space (1.6m1) with stagnation of smoke between puffs affecting taste; and the added draw resistance caused by tihe filter Insert. The latter is In fact relatively small when compared to an unventilated king size filter-tipped product as shown in Fig. 14.3 but may become of importance with different product designs. In addition to these factors there are the differences In smoking pattern which may result from a subject being studied In an experimental situation. This Is discussed by Corner and Creighton (1978) but our own observations, relating to butt analyses (vidc infrv), would confirm signllicant diffcrcnccs In the smoking profile between individuais smoking without the cigarette holder in a relaxed atmosphcre to smoking , m 60 ~. s e ~ 9o b a 0 ~ ~ N K 30 . 70 iD 1001t ~OOD 7000 4000 SoOlt FIOW twtl/wtint I ip. 14.3 The relationship between pressure drop and air flow across a king size lilrcr-tippcd cigarette and across the cigarette plus filter tnsert. The relationship for Ihr filter Insert (see Fig. 14.2) and the ci`arotle minus 50mm tobacco rod are also .hown for comparison. C'umpaiison of measured puff parameters witli standard machine smoking parameters Ikspite the limitations of the modified cigarette holder described in measuring puff vodumc, direct measurements of puff duration and interpuff interval can be accurately nadc. We have measured all these parameters in twenty subjects during the smoking uf 100 cigarattes covering a range of product types. Analysis of the average result fur each cigarette gives an overall mean puff volume of 47.5nt1( standard deviation (S.D.) ± 6.42m1), mean puff duration of 2.28 sec (S.D. 0.3 sec) and mean interpuff interval of 35 sec (S.D. 9.2 aec). The 95% confidence Intervals for the means of our data arc puff volume 44.96,50.04m1; puff duration 2.16-2.40 sec and interpuff interva : . 31.27,38.53 sec and for each of these parameters the mean result Is thus significantly - diffcrent from the standard (T.R.C.) machine smoking parameters of one 35ml puff of 2 sec duration with an Interpuff interval of 58 secs. It is not only possible, using the modified cigarette holder, to make quantitative nrcasuremcnts of puff parameters but one may also observe the puff flow profile. In any individual, this profile tends to remain constant and a classification of smokers ' tin the basis of their puff flow profile has been proposed (Adams, 1966). Ncasttrcntent of Inhalation ,th•thrxl lapth or inhalation Itas been measured by recording movements of the chest wall using a mercury strain gauge chest pneumogram. This consists of a thin, ciastic•walled tube containing mercury which Is held under tension across thc trpper part of the 0 ,eAA4.*&.

176 SwKINC ut'11AV10WR ' INIIALATIUN ANI) A,ISU1tITIUN UI:'t•U11AtY'US%IUKIi 177 . ~ . . ~ . • anterior chest wall by a strap passing around the subject. As the chest expands with inhalatiuri the mercury-filled tube is stretched, thus changing Its length and cross- .. sectional area, and hence its electrical resistance. This change in electrical resistance wn bc displayed on a recording device. In order to rciate the change In resistance to a change in lung volume a'calibration must be performed simultaneously measuring the chest pncumogram deflection and lung volume changes. The lung volume changes can conveniently be recorded at the mouth using a spirometer. It will be apparent that this calibration must be carried out each time the chest pneumogram is applied to or adjusted on a subject and must therefore be performed at the beginning of each smoking study. A typical calibration for one subject study Is shown.in Fig. 14.4 where the linear regression line for volume change versus pncumogrnn deflection is shown both over a hr(* Aume range (0-S litres) and a smaller volume range (0-2litres) as might be cxfmctcd in smoking studies. Comparison of ntcasurcd inlrolarlon with o subject's srrbjectivc assessnrcnr This technique for evaluating inhaiation may be used to investigate whether a persun' subjective analysis of his inhalation correlates with the volume of gas which be actual inlurles. In a prciiminary study, 15 subjects have becn presented with a'140mm analogue scale with the extremes'do not inhale' to'inhalc maximally'. They were asked 'tu place a mark along the line in a position between the two extremes which curresp~pm as closely as possible to the way in which you smoke. As a validity check subjects . answered this question on two occasions with an Intervening period of at least 24 hours. Anaiysis of the date usint; a paired t test Pave a mean difference of -I mm wttl"-.: a standard deviation of the difference of 19mm (p=0.9, N.S.). Subjccts; thert sntuked a cigarctte with thc chest pncumngram in position and the mean smoke inhalation volume ror that cigarette calculated. The results uf thc relationship bctwcen thc analogue scale recording and the mearr inlralcd vulumc are shown in Fig. 14.5. Moshnal 140 d = 4 0 ti0 x x Z x ,1 1 r~ r r r 10 20 30 40 50 PNEUMOGRAM DEFLECTION (mm) r•0.91 (v0l 0-2 1ItreS) t 60 . Fia. 14.4 The chest pneumogram calibration from one subject study. Correlations between the pneumotram defiectlon and simultaneous measurement of lung volume chanaes as measured by splrometry at the mouth. The correlation eoefflcients and linear regression linet are shown over the lotal (0-S litre) volume range and a smaller '(0-I litre) volume range as might be found In smoking studies. In all expL- ntai studies we have performcd, the correlation coefficient, over the ~ rant•e t1-7 li/re,(or the cniihratinq nrocednre. has )en Rreatcr than t j90. J NR x O. S 1.0 1.5 2.0 MEAN INSPIRED YOLUME Oltrest FIg. 14.5 Compartson between a subjeetlve measurement of inhalatton as recorded on en analogue scae, and an objective measurement of inhalation • the mean inhalco volume as measured from the chest pncumogram. The linear regression line for the data (ra0.63, p<0.01) ls shown with Its extrapolatlon. IndicatinC that the Intercept is not zero. An apparent linear relationship exists over the range of inhalation studied (r=0.G5, p<0.0i). There are however few observations over the lowr -%ge of subjective Inhalation and the linear regression line for the data does rx> slwwn, cxtrapuiatc towards ihe orir•in. It would thercfore sccrn likv(v Ihat n linear relnl imnehb, ,t„e.

inlralatioo, nul coverod In tLis experhuent, that much interest lics-do people who ; siutc that they are non•Inhaters really not inhale when smoking? It may be argued that the actual Inhalation volume should not be expected to eorrelate with a measure of subjective inlralation because what is regarded as a minimal inhalation In a 'large'subject may be regarded as a maximal (nlulation In a'small' subject. In order to correct for this the mean Inhaled-smoke volume or each subject has been related to their vital npacity, this being used as a measure of lung 'size'. The result was surprising arid Is open to speculation for it was found that In all cases the mean Inhaled volume was approximately 25% of the vital capacity (2696± 3 (S.D.)), Smoke exFosrue Indcx As in the case of tile puff flow profile the chest pneumogram trace will give a qual- itative indication of the form of the Inhalation. Two examples are shown In Fig. 14.6; In tire first or these the subject has taken a deep Inhalation with immediate exhalation whilst In the second example a more shallow Inhalation Is followed by a period of breathholding prior to subsequent exhalation. ( Secs 1111II1IlII11IiII1IIII1IIIIIIIII11111111I1jj11111II111i11111II111I11 Pneumogram Trace I PneumoQram Trace i ~ 1 Ilt(e 1 lltra ~ ~ Fit. 14.6 Two examples of the chest pneurnogram tracing ehhowin`differentpatterns ~~ df Inh'dlitidn.' Id each example the Inhatation of tobacco smoke Is Indlcated by the arrows and, for one Inhalation, the area from which the smoke exposure Index Is caleulated has been shaded. The exposure of the lungs to tobacco smoke during smoking will thus not only depend upon the depth of Inhalation of the smoke but also on the time which this smoke remains In the lungs. In order to take this Into account a smoke exposure Indox has been deilved froin the chest pneumogram traco by summing tile area under the curve for each Inhalation of smoke. The areas were measured by planimetry and representative examples are Indicated In the traces shown In FIg..14.6. . szA a- ~sizo~ . 4 I Derivation of the puff flow profilo and }ItRlnhqlation profile have been described separately but useful Informatlon may be gained by. combining these techniques. Fi 147h Ing.. are sown two examples. Secs 11111, 111 I I I I I 1 I MI I I I I l 1111 I I 11 I 111 Pneumogram Trace I Puff Prollle k 1111111111111111111t1:1I111I 11! 1 N Fig. 14.7 The pneumoaram tractnj.and the purr flow profile from two ampkers during normal smoking to Illustrate: O the relationship of the puff to rhe Inhalatlon and II) the pattern of chest wall movement during puffing and prececdlng the Inhalat of smoke. The time relationships of puffing from the cigarette and Inhalation of the smoke can be studied when It is observed that the puff is taken Into the mouth from the cigaret before being inhaled Into the lungs. This has Important implications In terms of dosr exposure for It means that the whole of the smoke bolus is potentially available to be taken deeply Into the lungs at the beginning of Inhalation rather than being distributed throughout the total inhaled volume of air. ':, Recording both puff and Inhalation profiles it is also possible to note any gross movements of the chest wall during puffing. In the majority of subjects studied the pattern shown In the first example of Fig. 14.7 Is observed where virtually no movement of lhe chest wall takes place. llowever. In a few subjects, most notably smokers of high tar products, there is an apparent active exhalation following the puff prior to the subsequent Inhalation. This is shown In example 2 Fig. 14.7. The impliation of this pattern of smoking Is that' the bolus of tobacco smoke has been blown from the mouth and very Iit11e, ir any. is available at thc subicqucnt' inhalation (presumably this is also the pattern in cigar smokers). Measurement of carbon monoxide Method Tobacco smoke contains carbon monoxide and studies have shown that the venous arboxyhecmoglobin saturation (IIbCO%) of'bshuling cigarette smukcrs Is slµnil: i~wntly highcr than thul of nun•snrukers. Mcasurcment al'vcuaus caibuxylraamuglu with the necessity of obtaining a blood sample by finger prick or vcnepunctturc. was not considered satisfactory for (large sale) studies in a'norrital' Iwptdalfon. 11 was therefore decided to measure carbon monoxide In mixed expired air and to derive the partial pressure of carbon monoxide In alveolar air using tlte Bohr equation.

statcs th:N thc voiuntc of carbon monoxide in any cxpircd breath (Fractionai conccn- tratiun uf carbon monoxide x tidal volumc) equals the volume coming from the alveoli pius thc vohlmc coming from tlle dead spacc. Substituting and-rcarranging the equation will give the fractional concentration of carbon monoxide In alveolar air (f ACO):- F CO VT.Fc CO - VD.Fi CO ~3) A 6 " VT'VD where FeCO is the fractional concentration of carbon monoxide In mixed expired gas, FiCO is tite fractional concentration of carbon monoxide In inspired gas, VT Is the tidal volume and VD is the dead space. The details of the method have been published in detail elsewhere (Rawbone. Coppin and Guz, 1976) where It is also shown that the results for alveolar carbon monoxide partial pressure obtained correlate with the simultaneous measurement of venous HbrO76 (I IbCO%= 240 PACO (mml Ig)- 0.26; r- 0.96; p(0.001). A( .rrparison ojalveolar carbon monixde between smokers and non-smokers and the changes in alveolar carbon monoxide occurring during llre day with smokind As an initial evaluation of the technique the alveolar carbon monoxide partial pressure (PACO) was measured at random times throughout the day In 35 non-smokers and 35 smokers. The smokers, who had not smoked for at least twenty minutes prior to study, were unselected on the basis of cigarette consumption or tar yield of their regular brand. The results are shown in Fig. 14.8 as a simple histogram. % 0.:~ V/. :: R I Q1 Q g S ~ OQ O ~ `8' ~'S O N Q 0-4 O O a~~~gg~~99, 69 G Cci C O C C O O d O O O O O O O C O 9Z&VZOStZ0Z Alveolar Fto mm Hg Fig. 14.8 /- •`raln showing the distribution or alveolar carbon monoxide partial pressure in. Rerr and In non-smukers. v.w& /1u/u%) w6ulx lllv 18/16L' /V_ 1 i111UK1:1>t Wil? II/UCII 8Ic:I1Cl t/11G:111 "nI,V U.UI U mmlig; S.D. 0.008 rnmi•Ig). The two Qopuiations are significantly differcnt (unpaira t tcst, p<0.001). In order to evaluate the suitability of lhe technique for more detailed studies of smoking behaviour the changes in PACO with smoking were followed over a i 2-houl period In two volunteer, regular smokers of ten to twenty middle tar cigarettes per day. Neither subject had smoked for at least 12 hours prior to the commencement of the study period during which they were allowed to smoke without restriction. Both smoked the same brand of cigarette which yielded 25mg carbon monoxide/ cigarette under standard (TRC) machine smoking conditions. Before smoking each cigarette and exactly 1 S minutes after, measurements of PACO were obtained and tl results, from both subjects are shown in Fig. 14.9. It can be seen that the PACO inaases with each cigarette smoked (mean increase 0.0036 mrntlg, subject A; mean increase 0.0027 mmHg, subject B) and fell between smoking. The overall pattern in both subjects is a rise In PACO during the early part of the day with a tendency for the level to plateau after 14.00 hours. In subject L', who was asked to chain-smoke four cigarettes at the end of the study period, there was a further inerase in the level of PACO. The characteristics of a tliter cigarette can, by machine smoking the product using standard (TRC) smoking parameters, be defined in terms of the measured mainstrea smoke nicotine and a derived filter retention efficiency. The filter retention efficiet is calculated from measurements of the mainstream smoke nicotine and the filter nicotine: NR Filter retention efficiency (F) - - (4) Ns+NR where N is t ~„~,f,g nL ,,,,_~ R,,.,h~lqt;riicOtlqC,an is the mainst a, srtloketnicotinC ~,assu!n4dAtiitc,thlpL[CislIIt[2U-8jilS C11fLtLA.ce.Mtant..for_any,girc.p 1 f~a~~ifj~ttlon:~henowing the.amount of nicotine retained in tite filter af't'er' t~u `man smoking, it is possible to estimate the amount of nicotine presented to the smoker (mainstream smoke niootine). NR(1,F) Ns = -(5) Once the amount of nicotine presented to the smoker has been determined, an index of the way in which the cigarette has been smoked may be obtained by calculating the ratio of the smoker's ntai,lstrcam smoke nicotine valuc 10 tite ntain- stream sntoke nicotine measured on machine snwking. We have called Ihis the nicotine compensation ratio whicit, because it relates the srttokers value to tlre standard ntacltine smoking figure, may be compared butlt bctwccn subjects and across product types. )

* Venout lIbCO Saturation G t C a~-,ots~sm?ras¢ew~a~ ~~7a~.m~am.._-~-'xax;-+?~car. +c~s.!~:.~wq e- e d . a. a d d d a d d d ~ 611 ew e>J Jelooslv Vnrl.llur-IIn .Iventar cathr+ reennxldr nertl-/ nrre+err wtlh cl.-.,rette UIM&sTzm INI IALATION ANt) AIISOttt'TION OI' TOOACCO SbIOK1i 183 ., , ".\'comparisots between Ilre (ncremcnt in alveolar carbon monoxide and hull nicotine aualysis 'fwr indicalurs or a suhjCcl's'doae or tubaccer snwke' have now been described - mcasuremenl or the increment in alveolar carbon momrade from smoking a single cig.hrelle rcllects lhe'dose' absarbed wirilst Ihe derivatiun or mainslrcant srnukc nicotine reflects thc'dosc' presented to the subject. It is of interest to compare Ihese two measurements. Fortyseven subjects look paa In a study where each was asked to chain-smoke five cigaretles. Carbon monoxide measurements were made befure and 15 mirurtes aflcr Ihe snwking prrieni 'and cach subject's cigarette butts were collected and pooled for nicotine analysis. In lMs way minitnising errors due la analytic technique. 1)oth tbe increntenl in carbon munoxide and Ihe nicotinc presented to the srtwkcr have been related to nachine snxoked values tu allow inter- subject and inter-prnduct comparisons and the results are shown in Fig. 14.10 as a sWltergram. 1.0 c°a . W Z '. . s . .. . dC 0 f 0 .• 0 • ~ 0 u . . . , z . . . . : . fJ . . 0 . . 0 0 . . . e . ' - - --I- - - -1 1 0 0.5 1.0 1.5 7.0 NICOTINE pRESENTEO TO SMOKER I MIACHINE NICOTINE P1g. 14.10 A scatterRram or the inerement In siveolar earbon monoxide partial pressure/machine smoked carbon monoxide yield versus the derived '-tine presenled tn the smokcrJmachine smoked nicotine value (nicotine c nsatton rallo) In 4e subJects (r-0.2t, p)0.05).

......Jh.. . I hc°`dnsowf ltinaCCvTlftrlk . pr scn c, u l reM'smokor_ (as mcusNrcd by.butJ.,Ricqlino~ • i :~ It niil tlic~~flyVct~~~11~~~,}Itr 4rf (~/bnCr~yuslnuhQ•1l~ISnrbcil . hy~1ho_ ~mtitkcr.(r~strllo;istir~tf hy,lTl-to parbSrlt•.naYWc,lncreiiiotit) anrl llic ,najoi"^ /aclar llt;lclcrmining Ifirdlllcr^neeq I~proliubJy~{;~r~crl~Iti. ~~~IK1allon Ah'lI~S/LZ ~ ,.--..- .. ..«..•_..... v~ .....u e.r ]um}1iF,;pwuth In(o~h ~Sngs~s~ A The relationship between the alveolar carbon monoxide increment and the smoke eaposure inder. if inhatation is the major determinant of differences between the 'dose' of tobacco smoke presented to a subject during the smoking of a cigarette and the 'dose' absorbed during smoking, then a relationship might be expected between the smoke exposure Index (reflecting the depth of inhalation of smoke and the time which this smoke remains In the lungs) and the increment in alveolar carbon rltonoxide (rellecling the 'dose' of smoke absorbed). IlaLkual middle tar sntokers .n Fig. 14.11 the carbon monoxide increment has been plotted against the smoke exposure Index for ten habitual middle tar smokers smoking one cigarette of their usual brand. 0.001 ( E 0.006 i 0.005 e °u 0.004 ~ rL ~ ~ a u 0.003 , 0.001 (K 10 - 20 30 40 50 60 Sz~~4sTzoz EXPOSURE INDEX hltre secl ® Fig. 14.11 The relationship between the Increment In alveolar carbon monoxide partial pressure and the smoke exposure Index In habitual middle tar smoketa. x, normal smoking; m; deflned smoking either with maximal (nhelation and breathholdlng or no Ir tion. The linear regression line for ell measurements (s shown (rs0.96 p < O.OI z 0.00? . p(U.U3). I11 oruer tl/ UCIIIrC 111C Iclallu/mltlr /ullllul llla I.anbc u/ uum1.1uvil ..".. hhu' extended by InsttuctingAne subje4Sl.to smoke with deep Inhalatlon wnJ t rreat and thrcc subjects tu sn,oke wilhuut inhalation. When Ihcse Jcfincd,smnking measurements nre added to ihe measurements obtained on normal smuking tlw linear rcgressiun line is as shown In Fig. 14.11 anJ ihc corrclaliun cs,cPlicicnt for data is 0.96 (p <0.001). It should be noted that when there Is no Inhalation there is no measurahle incn in carbon monoxide suggesting no significant buccal absorptfon; this Is diffcrent the situation found with nicotine when absorption through the buccal mucosa ca be readily demonstrated. Habitual lo w far smokers A similar linear relationship between the increment in alveolar carbon monoxide and the smoke exposure index to that fcund in middle tar smokers has been dclr atrated in frve habitual low tar smokers (r=0.94, p <0.05). The linear regression Is shown with the data in Fig. 14.12. Fig. 14.12 The relationship between the increment in alveolar carbon monoxld partial pressure and the smoke exposure :ndex in habitual low tar smukers. 0 , normal rmoking;(1, defined smoking without Inhalatlon. The linear retlros.lon line for the measurements Is shown (r-0.94, p <0.03) together with the predlct- regrerslon llne - see text. ('ot comp: rlson the linear regression line of lntddle ta smokers Is shown. r .. . '. 0.. ...

l lnfruhUJrrn ... Fig. 14.12 shuws, lo 111141111011 to the linear regression line for low tar smokers, the wt;ressiun linc fnr Ihc udddlc tar smokers previously discusscd andshuwn In Fig. 14.11. Thcse Iwo Iinas are significantly different at the S961evel. The sigoificanl rclalioruldps between the incremenl In carbon monoxide and the sruukc expusruc Indcx for buth rnlddlo and low 1ar snsuken Is perhaps surprising, fur within e•rch t•rr gruup lhere is a range of products of differing carbon monoxide yield. More hnpurtanl'however, Is Ihc implication of the demonstrated relallonshlp, , that all smokers of Ihe saote product type inhale an amount of carbon monoxide which falls within relatively narrow limits, such that the inhalation pattern is the major determinant of the carbon monoxide Incremcnl. Although the 'dose' of tob•rccu smoke presented to smokers differs widely from subject to subject, the 'dusc' inhaled and available for absorption tends towards a constant. If, In Fig. 14.12, the slope of the middle tar regression line Is set to represent the relationships between Inlsalation pattern and rise In alveolar carbon monoxide for -rn average middle tar product containing 20mg carbon monoxide per clgarette, .hen Ilre relationship for an average low tar product, which contains 10mg carbon nsonoxidc, can be predicted. The predicted line for such a product Is as shown In Fig. 14.12 and it is not signiflcanlly differenl from llse actual line obtalned from habitual low tar smokers (p )0.05). Furthermore, is can be seen from Figs. 14.11 and 14.12, the values for tlte smoke exposure Index of the middle tar smokers overlap the values for Ilse low lar smokers and statistically there Is no difference between Ihe two groups (p )0.05). One must Iherefore conclude that there Is no difference between the Inlalallon patterns of habitual middle tar and habitual low tar smokers, and, at any given level of smoke exposure Index, differences 11) carbon monoxide increment can be accounted for by the differences in carbon monoxide content of the different product types. illveolar carbon ntonoxide Jncremenrs In tise previous studies Invesligating Ihe relationships of alveolar carbon monoxide increments with the smoke exposure Index, subjects were studied at tandom times during tlre working day. II Is possible that llse Increments In carbon monoxide 0111s smoking may show a changing pallern, ollser tltan randorn varlallon, during Jse day. In order to Investigale between-product differences therefore, measure-' ments of carbon monoxide were made In relallon to llie first dgarette of llte day. Nine middle and nine low tar smokers were studied before and after their first cigarette of the day on three separate days over a period of three weeks. The results • are slrown In Table 14.2 as 1he mean group levels. T•rble 14.2 The mean elreolar carbon nronoxide partial presaurea bofore and after smoking Ilro fbrt elaurelle of rho day In groups of habitual mlddle and low Iar unokers. I s~~.~~ stzoz Middle Tar Group Cow Tar Group Lerel of Slanificenoe ' Pre srnoklng .0063 t .0068 t NS Icvel (mmlls), .000669 .001045 Post smoklng. .0094 * .00g6 t N$ __ level (mmlls) .000840 .0010gS Increm• .0031 t .0017 i p 4.01 (mmllj, .0003Zg .000371 +.% . . .• - .-. 1.: . - highcr Ilran tilal for Ihe gruuii ul• low lur smokers lp <O. I); Ihc nragniluJe uI Ilus difference Is approxInrrlciy two-fold-whlch•Is as prcdiclcd frunt Ihc average carbur . munoxidc deliveries of tha twn pruduct groups. More Inleresting however Is the obscrvrtiur. that thc pre-sruuking level of carbnn monoxlde ln lhe two groups of subjects is the same. This might he •rccounled fur Ilrc uppruximation uf initially different values tu wlthin thc limits of rnc•rsurcrncni capability as tlre levels of carbon monoxide decay exponentially during the night (period of no smoking). The other possibility to be considcred is th•rl, despite tb. fact that middle and low tar smokers appear to smoke on average In an idenlical %% they eventually plateau at ehe same average level of carbon monoxide. This may a reflection of differences In cigarette consumption or pattern of sumking, nsodifi of smoking parameters during ehe day or the hsfluencc of carbon monoxide back pressure from tlte blood which Increases-as Ihe day progresses. ' Smoking naranrerers As a separate study of habitual middle tar and habitual low tar srnokers, cigarette length, butt nicotine and puff parameters were measured. Seven middle tar and five low tar smokers entered the study and response paran were recorded twice In each subject wllls an Intervening period of seven days. Pu parameters, butt lenglh and filter nicotine values were all derived from the smoki of a single cigarette on each of the two occasions. For tlse present analysis tlre nr value from tlse duplicate measurements In each subject have been used to calculal Ilse group statistics on wldcls analyses have been performed using tlte unpaired 1 t The results are shown In Table 14.3 Table 14.3 Puff parameterr, butt nlcoline and bult lenath In groups of habitual middle and ' lar smokers. Tett Low Tar Smokers t,tid_ dle Tar Smoker+ Levcl of N- 5 N - 7 Significance Puff duration sees 1.74 t 0.028 1.92 ± 0.203 NS Puff Interval sees 43.6 ± 3.430 3e.e ~4.e73 NS Number of puffs • 9.8 * 1.07 10.9 ~ 0.77 NS Nkotlne to tmoker malcls 0.53 ~ 0.033 0.76 * 0.032 p(.001' Nicotine compensallon ratio 0.70 ± 0.043 0.70 ± 0.047 NS Tobacco butt lenalh mm 12.1 ;_ 2.081 10.2 ~ 0.>!S6 NS Mean levet t standard error NS not significant No significant differences are apparent between llte middle and low tar smokers puff pararneters, butt length or Iha way In which iho cigarettes have been smuki judged from the nicotine compensation ratlos. There Is a signHicant difference the amount of nicotine presented to the smokers but thls is merely a ref)ection

2021574730 1 INIIALATION AND AIISOItI'TION OI:'1'OUACCI) SNIUKIE IK`) l)t:1NC IIIi1IA'VIOUR .,S : . lenccs In nicotine yield of lhe two product groups. rniddle mr and ba6Jnral low tar snrokers studics of inhalslion patterns and smoking parameters presented would t suggcst that there are no differences between habitual middle and low tar iu thc way lit which they snsoki; and inhale their respective products. :cs in carbon tnunoxide, nicotine and presulnably tar presented to smokers ly a reflection of Ihe differences between Ihe products and not modified by This concluskln would appear to be contrary to a lot of publislsed experience studies are predondnantly switching studies where middle tar smokers are moking low tar products and vice rersa, comparisons being made between :cqucntial smoking periods. switching studies parm crs rinsent to examine the effects on smoking parameters of subjects switching Idlc to low tar clgarcUes was conducted lit nlne habitual middle tar smokers. inal experimental design was for the subjects to smoke their own middle tar for Ihe first two weeks of the study and then switch to a defined low tar (or four weeks. Following this second period, on a low tar product, subjects iected to switch back to their middle lsr product for the third study period ould last a further four weeks. During the study however, at the completion cuud period, five subjects declined to switch back to their original middle Icl, electing lo remain at lhe low tar level. This is presumably a reflection as of subjects volunteering for such smoking studiest As a consequence, the audy popuiation consists of two potentially different groups snd for the presented here these groups have been treated separately. Group A are )jects who, In lhe third period, switched back to their original middle tar (n=4) whilst group D are those subjects who elected to remain on the low 1Cl (rV nse m't...arements were obtained weekly during the ten week study period. ; parameters were recorded from the smoking of a single cigarette, butt id butt nicotine analyses were Ihe average from a 24 hour butt collection rclte consumption was the rnean daily eonsumption from a weekly record. swnmary results presented lite mean response for all subjects In each of'lhe ips is given for each of ihe three smoking periods. Examination for differences Ihe groups has been carried out using the unpaired t test. 14.4 presents lllc results from Group A where subjects have switched back iddic tar product fur Ihe final smoking period. There are no significant :cs I'or any puraolclcr bctwecn Ibe first end third smoking periods when subjects uking Ihc middle tar pruducts. The nicotine cumpensrtion ratio would Indicate that lho low tar pruducl Is bcinR slgnificunlly'uvcrsntuked' when compared idLlle tar pruducl aad fruln lhe puff paramctors this would seem to be the laking•largcr pufl'volunrcs. Despite tlds'oversmoking of ihe low tar product, raliun. In terms ;utinc, is nul cuntpiete. Although lha decrease In plcscnlcd tu tlit .,,nokcr Is nut slgniFicont whcn switching to lhe low tar t a a 0 u ~ C © v+ o w > O V O V O v u 6 0. 0. Y A N r Y w © ~ ` 0 ~ ~ Y = .C. i V N O V1 N 0 0 ~ Y > V V Y J a 0. Y M .~ .. • w O .+ M M O a ,.g O a O 0 M b O M N O O O O O r: O N Y Y 66 s .1 *1 .1 41 il •1 +1 .. R • O r ~ O q n O e. ~ N M A • • O I~ N A V .~ ~ o% n 0 d . p p O O O ~ ~ N H M1 O I4 O O b ..+ M Y a 0 O Y Yf 1- N +1 ..~ +1 M al w1 •1 M tI O •t .0 w ~ ~ 4 o e: p c .1 .. A M r1 0 ^' n n a 0 u W .. q ~ N a O o• O O N w o~ 0. .-. ..i O O , N M ~ t^ O fl ia •1 tl al O +1 n y O q .+v FI V O o - 4 V O~ al J .P~ ~ N M • O O ~0 fV M 0 r Yl ~w ~ ~ Y .~ ~ e Y V ~ a Y ..~, u E a o V G V E 4Y u R Y C C 93 ~ C N +1 < N Y Y 0 y O f O ~ .0 R .. . Y j1 V Y • A ~ u E ..~. Y Y o .,Y. r = a C ~ a ~ > C ~ v V ~ C Y V , C ~ 4 4 ~ V a v w 0 z Y z ~ 2 0 F M u V