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, THIS REPORT IS CONFIDENTIAL TO THE BUSINESS OF THE CCtWf'ANY: IT SHOULD BE CAREFULLY HANDLED, IS NOT TRANSFERABLE TO ANOTHER INOIYIDUAL, AND IS NOT TO BE PHOTOCOPIED. If the report has served Its purposa and Is no longer needed, please return It Icresed(ately to the Central Ffle at the Research C®n qr for record keeping purposes and destruct(on. I u1 ~ll C. E(-Lt5 Accession Number: 82-295 Copy tlumber: Issued.To: C - 6 LL+s PHILIP M ORRIS U•S.A• RESEARCH CENTER RICHMGND, VIRGINIA t 0 COMPLETION Q SPECIAL REPORT TITLE: THE EFFECT OF CIG:aRETTE NICOTINE CONTEXT ON SMOKER PUFF PARA:N!ETERS AND DELIVERIES CHARGE NO• & TITLE: 4009, SMOKE STUDIES TYPE REPORT: Q ANNUAL U SEMIANNUAL DATE: \ovenber 29, 1982 PERIOD COVERED: BY SUPERVISED BY APPROVED BY DISTRIBUTION:' KATHLEEN GUNST PAUL \ . GAUVTN Mr. L. Dr. W. Dr. R. F. Meyer A. Farone Fagan ,r. W. T' Mr. W. Dr. R. Dr. W. L. E. M. A. Dunn, Jr. Claflin Ikeda Geis:ler Jir. 4t. Mr. F. Dr D G. J. M Houck, .1t•. Ryan Ennis N O G1 . . .%ir. M. Nis. J. . F. A. riellev Jones O C!I ~ Central File KEYYlORDS: Nicotine, Pui:f Duration, Human Smokina Si:7u:ator, Flow Rate, Puff Parameters, Puff Intervai, Puff Vo I ur.te t fua d~;.;uir..ecrr bulon,~s ta Phalrp tv?orns U.S.A. it sannut be photocop}ed. It cannot be t t - ;uet c: r<aetrrr'r.d to R&C'i'a raR~f tt,u r.r Ccn[tai File js so,~f~dS yau have rta F,lrit:cer ~r:,t, t-

iu.~ S"_'F.AC;' Cicarettes ~ti ltf: variable tevE'ls of i:icot ln@ an.u similar tar C.ellveriC-s were stuokeG bv human smokers ldhil e t}?eir Pufi nur.iber, puff volumes, puff c.uratloi.s, ilow rates anG nllff intervals were recorded. Deliveries were obtained by s,;,oi:ing these cigarettes on the simulator usinc tre mean purr varar.,eters of the total panel. t•ihile smokers generally tencec to decrease puff auration, puff number and puff •e oi une anc. increase • auf,` interval as t:^.e nicotine level of the cic,arette incre`sec;, these differences, based on the mean _r.uff r.a.rameters for ten smokers, ,tiere not large enouch to show sicnificantlv different ratios of nicotine for the t'r,ree ciaarette models from those expected based on C. I. deliveries. to Pkui p fvtexris U.S.A. It cLinttcttt be photrr:upicd. It r,annor ba transt~rred t, o c jliau ~t e tt n:uro tw i: t"rn„-,i to R?4U's Cmtrof rsir is buc,n n> you have no #urtt4cr uso tosr it.

Page 2 TABLE OF CONTENTS ABSTRACT SUMMARY ............................................. LIST OF TABLES ...................................... 3 4 DESCRIPTION OF GRAPHS ............................... 5 I. INTRODUCTION .................................. 7 II. L_TTE....:URE REVIEW ............................. 7 iII. EX.PEP.:1•tEi:TAL DESIGN AND }•tETHODS ............... 1 `) IV. RESULTS APdi DISCUSSION ...............••••.•...10 V. COtdCLUSIOMS ................................... 15 VI. REFERENCES ....................................47 Th;n d z,;umoru bci, n_4,; to Phrfip Prlorns U.S.A. i[ cunnot be phowcopre.~'.• It cannot be transferred to i coliadj:re 11 n_: Ar c;t: r,;turt,r.d ,;. R&D s G.;ntrul rrl® us soc,rt as you 'nave ro further use tor t. -

Page 3 SU I it•if; n .-r Cigarette models were made with nicotine levels of .11 r-,.g, .36 mg, a;1C .95 ":g, with sii:ilar tar and CO deliver4es and identiCal "TD. Three cigarettes of each model were smoked on the human smoking profile recor•~ers to get the mean puff parameters of puff number, puff volume, puff duration, uraXlulGr:• flow rate and puff interval. SiG:ulator comr:?and tapes were 'made from the totai panel mean puff para,;.eters and the puff parameters of one smoker who showed remarkable nicotine regulation. The deliveries for TPM, nicotine and water wera analyzed for or those si;•.Llator smokings. Nicotine residue ' n the butts was analyzed ?.n both human and s:.s:ulator sr:,oked cigarettes. Sibni °'_c:ant differences between dlf : erent nicotine levels irn the cigarette were found for puf f duratiot:, puff interval, and mean ;moke volume, with puff volumes being significantly different at the .07 probability level. A rise in nicotine level in the filler was associated with an increase in puff interval, and decreases in puff number, puff volume, and puff duration. Sictulai:or deliveries, based on the mean smoker auff pa'rameters for ten smor.ers, did not show significantly different ratios of nicotine f rom those expected based on C. I . deliveries. However, for the one smoker whose puff volumes dropped the most, and whose puff paramet~rs were also used to drive the simulator, delivery increased by only 54A in going from the r^ediur, to the high nicotine cigarette compared with a 62a increase in C. I. nicotine deliveries based on ec;ual puf f volumes. '.~'ie'livery changes associated with puf f volume changes in response to nicotine levels in the cigarette appear to be very minimal. It is not possible to say f rom this study if the changes in p;:ff parar.teters are a pharmacological response to nicotine or a response to the taste or strength differences in the cigarette. t,, PYr;hp P.1<xrts U.S,A- Ii :ur;not ba pt.otncoprecl, it c:annor _ b.: r; nsf, rr J rr, i colI'_ ..~,3 e C or,rr,i Fi/e a5 sor~tt an you ir:we n~ fr,rttsar

Page ~ LIST OF TASLE'S Table 1 Delivery -Variable Nicotine Cigarettes Simulator Study ..15 Table 2 Ten Srokers' i•Sean Puff Parameters or. Three Cigarette Models ...................................................1; Table 3 Mean Puff Parameters for Ten Sr-okers on Variable Nicotine Cigarettes ...............................................1~ Table 4 Total Mean Smoke Volume Per Cigarette .................... 19 Table 5 Nicotine Residue in Cigarette Filter Compared with Nicotine Simulator Deliveries .....................................20 Table 6 Puff by Puff Smoking Parameter and Simulator Deliverie~- for Total Panel and Smoker 9 .... ......................... 21 Table 7 CU^1L'latlV elatlVe SimUlator Deliveries for Total Panel ( i) and Smoker 9 (t•i) ..............................................2L Pttili,) M• rris li.S.A. I[ • anrt •t tiO phoiocclPrcd. It c;ann3r Y b, t ~ t,3n5f:;C J r„ 7C,~-'iirili FiIC 36 oGC4ft ..,i you l13vv r]!) Ir1rtGY Ulit'~ fiur ij. t

Page 5 DESCR IPTIOP. 07 G RAPES GRAPH 1: C. !. i::.coti ne De" ivery vs h{ean Number of Puffs for en Smokers ........................................ 25 GRAPH 2: C. I. iJicotine Delivery vs i•iean Puf f Volume f or Te.n. Smokers ............................................ 26 GRAPH 3: C. I. Nicotine Delivery vs Individual Mean Puff Volumes for Ten Smokers ............................ 26 GRAPH 4: C. I. ,:icotine ilelivery vs t•tean Puff Durations for Ten Smokers ........................................ 27 GRAPH ~: C. I. tlicotine Delivery vs Individual hiean Puff Durations for Ten Smokers .......................... 27 GRAPH 6: C. I. Nicotine Delivery vs Mean Puff interval for Ten Smokers ........................................ 28 GRAPF: 7: C. I. Nlicoti ne Delivery vs Individual Mean Puff Intervals for Ten Smokers .......................... 28 GRAPH 8: C. I. Nicotine Delivery vs Mean Maximum Flow Rate for Ten Smokers .................................... 29 GRAPH 9: Mean N'icotine Residue for Human Smoked Butts vs Mean Nicotine Delivery for 20 Cigarettes Smoked on Si,.ulator by the Total Panel Mean Puff Parameter Tape ........:... .................................. 30 GRAPH 10: t•tean Nicotine RF ;idue for Human Smoked Butts (n-3) for Smoker 0. vs Mean iti i cotine Deliv ery for 20 Cigarettes Smo~:d on Simulator by the Smoker 9 Mean Puff Parameter Tape ........................... 30 GRAPH 11 : Mean Cumulative interval on Rod vs hiean Puff Volume Across the Rod for the Total Panel ................. 31 GRAPH 12: h:ean Cumulative Interval on Rod vs Mean Puff Duration Across the rod for the Total Panel ................. 31 GRAPH 13: Mean Cumulative Interval on Rod vs Mean Naximum Flow Rate across the Rod for the Total Panel ............ 32 GRAPH 1 4: Mean Cumul ativ e interval on Rod vs Plicotine per Puff for Total Par,el .................................... 32 GRAPH 15: idPan Cumulative interval on Rod vs Tar per Puf` for Total Panel ........................................ 33 GRAPH 16: Mean Cumulative interval on P.od vs G:ater per Puff for Tot;-~l Panel ........................................ 33 GRAPH 17: Mean Cumulative Interv:~l or, Rou vs I:icotfne to Tar Ratio for Total Panel .............................. 34 Thr: ,! ,c,rn,r nr brar,nris tr, Pn,l,p kiurns U.S.A. It cannot be pFEC,coc:opeed. It cormot be rranaferred t u <i coli~:ifj,;~ , n,u ~r br: r~turr~e:~i i, R&a`, C,;nirai FrIe a; ooan is you havs no turttrer usj fir rt.

PaEe 6 GRAPH 18: C. I. Nicotine Dey ivery vs Product of t•;ean Pu1 f i:umber and Mean Puff Volume for Smoker 9........... 35 GR APH 19: C. I. tJicotin, Delivery vs Mean Puff Volume for _ Smoker 9 ........................................... s6 GRAPH 20: C. I. tlicotina Delivery vz Mean Puff Duration for Smoker 9 ........................................... 36 GRAPH 21 : C. I. Nicotine De.livery vs i•tean '-l aximum Flow Rate for Smoker 9 ....................................... ;7 GRAPH 22: C. I. flicotine Delivery vs Mean Puff int7rval for Smoker 9 ............................................. 37 GRAPH 23: Mean Cumulative interval on Rod vs i•:ean Puff Volume Across Rod for Smoker 9 .............................. 39 GRAPH 24: Mean Cumulative Interval on Rod vs Mean Puff Duraticn Across Rod for Smoker 9 .............................. 38 Graph 25: Hean Cumulative interval on Rod vs IMean Maximum Flow Rate Across Rod for Smoker 9 ........................ 39 GRAPH 26: Mean Cumulative Interval on Rod vs Mean Nicotine per Puff Across Rod for Smoker 9 ........................ 40 GRAPH 27: Mean Cumulative Interval on Rod vs N~ean Tar per Puff Across Rod for Smoker 9 ............................. :?0 GRAPH 28: Lit Rod Flow Rate vs TP'M to Nicotine ?atio (I:Gws and Nepomuceno) ........................................ 41 GRAPH 29: Mean Cumulative interval on Rod vs Hicotine to Tar Ratio for Smoker 9 ................................. 42 GRAPH 30: I•Sean Cumulative Interval vs Idean Puff Valume vs ,arette iYicotine per Puff for Medium i+1COtlne Cigg for the Total Panel Data .......................... 13 GRAPH 31: Mean Cumulative interval vs Mean Puff Volume vs Tar per Puff for Medium Nicotine Cigarette fcr the Total Panel Data .............................. A3 GP,APH 32: t:ear. Cumulative interval vs 'r,ean Puff Volume vs i;icotine per Puff f or Qdium iJicotine Cigarette ......................... .. for Smoker 9 44 ......... .. N 0 GRAPH 33: Mean Cumulative interval vs F:ean Puff Volume vs C1 Tar per Puf f for Medium Nicotine Cigarette ~ for Smoker 9 ...................................... Q ~ .(~ GRAPH 34: Maximum Flow Rate vs Nicotine per cc of Mean Puf f Volume (micrograms) ............................... 45 1<«,a +j,~.:wns~n.t fta Pt;d: b,tui;; P 11.S.A. !F cunnot be pt:utocop.ed. I> cunnm bn r.ransfurzJ M a c_:tf<;.t,;a- { '' ' i: .yt f:r: rr_turrie:a [" F;&D ; Cwitr,4 Fae as suo:5 ~.:5 yuu have rto Fiir{tser use t':r :t. - f ~.~

Page 7 Ii;T30DUCTIOt: It has been shown by previous studies that smokers ^ake changes in puff parameters that affect dellverJ' in response to physical parameters of the cigarette such as RTD, dilution and flavor. Additionally, there is a wealth of literature concerning the•effect- of nicotine on the smoking behavior of people. The purpose of this study was to hold as constant as possible all the physical parameters ar~ machine smoked standard deliveries of the three cigarette model' with the exception of nicotine, ?.n order to examine the effect of r.. :.tine content on smoker puff parameters and resulting smoke deli:-r; ,. II. LITERATURE REVIEW Some researchers have expressed concern that the desired effect of low delivery cigarettes on the actual deliveries that smokers are getting may be overestimated due to changes in cigarette consumption and the puffing and inhalation parameters. Dunn, Schori and Duggins (1973) surveyed smokers in 1962 and 1972 collecting butts for nicotine snalysis and calculating tar deliveries. They concluded that cigarettes in 1972 were delivering less tar, but that smokers were smoking more cigarettes and more rod length on each cigarette. Those smokers w ho had switched to a higher delivery cigarette were smoking less. There is evidence that some smokers may alter their puffing and inhalation parameters in response to changes in nicotine and tar levels. Many of studies used cigarettes that have variations in botcl 'ar and nicotine making it impossible to tell to which delivery component the smoker is responding. I:` the intake of smoke were being decreased by the smoker in response to higher nicotine levels, tar delivery to the smoker might be greatly reduced by increasing the nicotine to tar ratio. Jones, Houck and Martin in a 1975 study found that a .95 mg nicotine, 10 ::g tar cigarette was not significantly di fferent in acceptability from the Marlboro control ; and that an 1 1 mg tar model with 1.31 mg of nicotine was judged subjectively higher in strength than the 18mg tar t~tarlboro. These findings would seem to suggest that smokers are subjectively more influenced by the nicotine content of the cigarette than hy the tar delivery. The degree to which smokers smoke for r.icoti ne is difficult to assess. Many researchers have hypothesized that some smokers smoke to maintain a steady level of plasma nicotine while other less addicted smokers smoke to get the peak effects in plasma nicotine derived fror occasional smoking. A number of studies have been conducted administering nicotine by some route other than smoking to assess whether this preloading would affect cigarette consumption or the manner in which cigarettes were puffed or inhaled. Russell et a (1976) reported that administering 2 mg of nicotine in gum once every hour reduced cigarette consumption only sl7.gCltly more than did admini sterin- placebo gum. However, the carboxyhemoglobin levels in smokers were lower on the nicotine gum, perhaps indicating that the cigarettes were being smoked less intensively when gum was administered. A 4 r.:g nicotine gum per hour produced plasma nicotine concentrations comparable to heavy :,;,oking, but the degree of satisfaction in the subjects seemed unrelated to the -plasr a nYcct:;ne c2t:.o^ ~T~owevei'c~:i=as'~~-41c7" h rr ~, . ..•., . „ .,.,•<,:. u ~t-a %oun ~ t..a t 11 On,~., u:: rt. t.r,irai r,> R&D , CunV.il FTe is t~cc~n a~ you na~.e no turthr.r usd t„r it.

Page 8 high nicotine gum decreased the intake of nicotine as measured by total puff t i m e (tire for which the coal of the cigarette glowed) cornpared with low nicotine gum. !umar et a2- (1977) reported that intravenous doses of nicotine failed to alter subsequent smoking as measured by volumes puffed. However, controlled doses of inhaled tobacco smoke reduced subsequent puffing in a dose related manner. Schachter reported that acidification of the urine, which increases the excretion of nicotine, caused an increase in the number of cigarettes smoked. He also tested the urine of subjects under stress and found it to be more acidic than normal, which would agree with the common observation that ceople smoke more when under stress. In general, these studies seem to indicate some effect of body r,icotine level in the smoker on cigarette consumption or the intensity with which the cigarettes are smoked. The effect of the level of nicotine in a cigarette on the degree of smoke inhalation has been studied indirectly by measuring changes in carboxyt:emoglobin levels or nicotine blood levels. Wald (1981) reported that carboxyhemoglobin levels indicate that men who smoked low nicotine cigarettes inhaled 33% more than the mean, and those smoking high nicotine cigareFtes inhaled 17; less than the mean. A similar ;•Tald Study t 1980) sho'.:ed that ventilated filter smokers inhaled 82% more than nonfilter smokers, and unventilated filter smokers inhaled 369~ more than nonfilter smokers. Russell et 31, (1980) found no relation between blood nicotine concentration and the nicotine level of the brand t'r.e person smoked in spite of similar cigarette consumption.. The authors suggested that increased inhalation might be responsible for these results. Dunn et P. (1978) showed that a cigarette 3010 higher in nicotine produced significantly lower alveolar resting levels of CO, but they did not show significantly altered cigarette consumption, puff numbers, intervals, durations or butt lengths. Assuming that an increase in carboxyhemoglobin is proportional to the degree of inhalation, Russell (1976) reported that on switching to high nicotine cigarettes the subjects took less smoke into their lungs and carbox.yhemoglobin levels decreased. They also reported a 38% decrease in cigarette consumption on switching to a high nicotine brand and a 17A increase in consumption when switching to a lcw nicotine brand. The literature most pertinent to our present study involves the effect •of varying nicotine content in the cigarettes on the puff parameters; or the effect of varying nicotine content on the mouth nicotine delivery, as calculated by nicotine in the butts. Studies by Creig'.lton and Lewis, Levy and Lieser, Ashton g= al., Russell ;j gj~, and Fsattig et a?, address this effect, but are confounded by the fact that tar deliveries in the cigarettes varied along ..ith nicotine deliveries. Ashton's 1979 study used cir,arettes with nicoti;ie levels of .6 1.u mg and 1.8 ,:,, and reported that plasma nicotine values and blood carbcxyhemoglcbin levels showed that smokers changea smoker parameters to compensate for approxirately two-thirds of the standard yields of the cigarettes. Analysis of nicotine in the butts showed that, althouEh delivery c:as greatest for the high nicotine cigarette and least for the low nic7otine cigarette, the s~;cker compensated some t,, i'nri,p 41:,rrti; U.S,A. lt colr,not ba phutracuprE=d It rar,not b•: rr,,nafr:rro:j ec -I c•>ile av:,e 0 ,:yr ur: r,,turned t„ R&i3', C..rrtre,i File <ts br,:~rs t; you have nc, tt:rthar use i;,r ,t. j

Page 9 so that differences were not as great as the standard machlne smoked value would predict. Creighton and Lewis (1978), using cigarettes with 1.0 mg, 1.4 sig and 1.8 mg nicotine, found that high nicotine resulted in lower puff vol umes pufF durations and puff numbers. For a .4 c~g increase in aicoti;. there was a 10", decrease in mean pufx volume. For a.U mg decrease in nicotine there was a 14n increase in mean puff volume. b:hen smokers were switched back to the medium nicotine cigarette they resumed approximately their original smoking parameters. Battig, Buzzi and Nil (1982) measured puff volume, puff duration, peak pressure. and interva.l on 110 smokers and also measured their pulse rate, blood pressure, pulmonary function and expired CO. For women ti.ey found a negative correlation between machine standard smoke yields and smoke volume. Vo1u;;e compensation for nicotine delivery was nearly dose dependent in cigarettes with less than 1 mg nicotine. The standard nicotine yield was positively correlated with puffing interval and negatively correlated with change in tidal CO and with inhalation efficiency, suggesting mechanisms of compensation. An in-house study by Levy and Lieser (1976) using cigarettes which varied in tar as well as nicotine reported that ni-cotine in the butts indicated that smokers obtained as much, if not more, nicotine from the low delivery product as the high one on a per cigarette basis. Puff volumes were higher on the low delivery cigarettes for all but one smoker. At least two studies have manipulated nicotine and tar delivery by having the smoker smoke only a portion of the rod. Ashton et LI, (1978) presented subjects with a two-thirds length cigarette. Over a 24 hour period smokers obtai ned 112.3% of the expected delivery, as they smoked the two-thirds cigarette more intensely by increasing puff ~ duration or lessening the interval between puffs. Russell -P-t- (1978) gave smokers cigareztes shortened to 75n and 50t of normal smokable length. Smokers significantly increased the number smoked and the rate of puffing on shorter cigarettes. Mouth level intake of nicotine was reduced less than would be predicted based on the length of cigarette rod smoked. The effect of nicotine content on puf.' parameters can be best assessed when tar delivery, RTD and physical attributes of the cigarette are controlled. This can be achieved by denicotinizing tobacco and then spraying filler with varying levels of nicotine citrate or by using a developed strain of low alkaloid tobacco and blending it with tobaccos of higher nicotine content. Flavor dif f erences result with both methods maki ng it iu^,possible to rule out the possibiiity of subjective response contributing to any of the observed effects. Gritz (1978) rreported that nicotine-free cigarettes made with a genetically low nicotine content strain of tobacco, were inhaled more sharply than cigarettes with nor:,ral nicotine levels. The puff volumes for the low nicotine cigarettes were larger for beth deprived and undeprived smokers, although not significantly Jarvik showed that subjects smoked more of a low nicotirle (.2 mr.) tan a nicot ne cigarette (2.0 mg) and took more puffs. These 2Cr',: change i- smokir.g ra te in r°_-spo:lse to a 10-f cld Titr .~.,rurr;e nr t, a,> to °iuhp h'lc,rn4 t}.S,A. it c,rnnot ba ~,hoio_or~red_ it canrtrJr bP +rarsf rred co a o((~a;j,: I r„r,sr tr, R&U - wntrtyt EiIe ~*auu{i ss you i,tsVe no h,rr}rvr usa rur ii. ~._ - - - ~