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Ci`arettr Smoking Phannacokinetics Trble V. BrandsmoKrg senedtiN used in the studjr by Prxi and Lynch (tse31. a.spo«aants,wrare rq,.ad fnom fmacers a,ut- trabw dsliv.ryixands for a perod ot'at Nast 3 mtxths. They smoked mae; iran a,Wcic of oqanns per day. Ttte average aaity consumption was 30 c+9#retta Weeks 1• 24 3 .i S 6 7' A 8' A 8 8 A 8 A li A C C C C a flespondengs' drstanary bnM. The sequence ii -wewtk .rcerxaK. of smokets who are free of most experimental in- }luences on their smoking behaviour in that they smoked lover 7 weeks in their natural environment Thus, this matched-paindd design study with cigarettes that am very similar in tfieir, yields, and . with smokers who did not alter their smoking be- haviourwith ~brand change, provided evidence that a minimal increase in nicotine y]eld will be accom- panied by a proportional I increase in i nicotine up. take. Table IV shows the results of a regression analysis for the datai obtained by'Gori and' L.yneh ('1983): [These investigators supplied, the weekly plasma cotinine values obtained during,their stud-, ies.] Table V illustrates the 7-week caossover and' switch design empibyed,, and figures 2 and 3 illus- trate the shill in the plasma cotinine concentration curves which occurred withi the change from one brand to another, during the 7' weeks of the study. Determinations of plasma cotinine concentra- tion as a marker for nicotine uptake has received acceptance by, a number of investigators (Benowitz et al.. 1983b: Goriiand Lynch. 1'98'3; Russell et al.. 1982: Surgeon General. 1979',_ "Further, attempts havc been made to correlate' average uptake of ni- cotine with tar uptake using;ttte tar to nicotine ratio denved from the standard smoking machine re- svlts for that brand. For a given indiviidual. plasma cotinine concentration is directlM1 related to dail% nicotine intake under reasoii stead,-starte con- dttnons: Howe.cri studiescompanng plasma coan- inr.onccnirauons among tnda%tduals -,th dtlTrr- 445 ent smoking behaviour should take into accounti the many factors which would alter, the plasma co- tinine concentration obtained from a given daily, uptake of nicotine. Table IiI presents the equations which relate plasma eoanine concentration to up- take of nicotine,,tJonversion of nicotine to aotinine. and dearance of cotinine. The relationship between tar and nicotine yield of the cigarette in the smoking machine test is al- tered! by changes in puff volume, puff frcquency,. as well as many other factors ('Wyndtr and Hofi mann, 1%7): Thereibre, it is unreasonable to at- tempt to relate smoke delivery of tar to piasmalCo» tinine concentration measurements. 100 eo 60 r I I Btana 8 smdcers 0 1U 100 1000 tnog;pturna ooto+ne cancennauon (nglrtr) Fiy. 2 Fi.erlysncy Ci!stnDutlon plot , for the loq', pasma oowtine cancenmration of 1be:206 responaents!a the stuCy by Gon and Lynch p19881. The loq plasma oohnwre eoncentraaon for each subpct,was pbaed!tor each w..k o1 the stuCy, TtThe lerna/bs anditne mates inttus qrapn,were smokers of brand 8': tfrere- tore truey smohed itr>ar own brand (stanOard'srtakng machine re1d. o.10my nwcotmee and, 1.Ortg i tarl for 2weeks: Tttey. 1Mn switched to brand "A'. which ts ramcer! as a 0" 18mg ruconne and t.Ortgitarbra/W..lor.3 weeks. This awrton,rs accomparnea1 byan increase in plasma . cotMUnie Ior 75% ot, the smohers. TAe i rncrease n plasma coonme was' essentially paraNN: therefore tf1esmolier did not change peruntAe rankw.g" n thehequency aistnbutiOn The 3, curvesstahe0 to, a+e.rqnt* representmq a"her pasma counine concentration at eaen percentiN tevet wnqn~was oGta,nea during ttw" period ol.smokiryibrand 'A' After 3 , weeks the smoRers changed to i brand "C which had smokmqimacrnne ratings ol'O~tmq ni¢oune and 1.0'nq~tar. Tne ~, pWasma~cotinme~.concentrabon~.r,elmuceG to~.nearo trN va,ues.OD:~ ca.inea toa orano 8i IV W,

Cigarette SmmkinZ,Pharrnacokinetics fml Brard A vnokers, oih- ~ I ~ ~ 10 1oo t Log piasma oomuu oona+maoion (nyrrh Fis.3. frsqo.nc~/ Qistrtuh'on plott for the respondenta who smok'eo brand 'A' (aN fq. 2'INyenil N,tlrs Case they smokad n*0 own brand for 2.eeks2 rne toq,a the ptasma cor:,i,e oonceraraoon for tnis puiod , is seen in ttw 2' plots which aie stwfted to thergtu: anaoaorg,a ttiynsrpasma toteww aorxen- trati«, a,r.g w: pa w. turiny tne l weeks of, smil the brands wtn tne tow.r nicotine rauny, the ptasmr a>orrrr ool centraoons were rea,oed. In both tne asa plot of rqura 2 and in ws oat: the urft in'rne paama,cobnne ooneMaaoon at per- cenMe bvels,wnic~ are 1 standard deviation eacA sitle of the mean an snwar to ane change one wal fxeacs'easee upon the raoo ot'tne uanoara smoking ratings for tnesebranCs. The pas frwa fiyurea 2'ana 3!snow eacsa«x'oomparaor, in tnat the vak'ues am vnCrn 10% tor each peraentile Mvel'for the 2 groups of smokers: The slopes of the regression rr,es given in table IV and the data trom these fgures provide evidemce that smok+ng: machine yislds are inportant to human uptake. 6. Conclusions Since the early 1950s. two important changes have occurred in the manufacture of cigarettes in the United States. Firstly, the length of the cigar- ette has increased to at least 85mm; thus there is greater tobacco ffltratimn of mainstream smoke - the smoke which is taken into the mouth. Sce- ondly. filters have been added to the tobacco rod which h'a.e'reducedlnomtal tar, yie111s from 30mg to 17mg. according to results obtained with the standard smoking machine test. The low tar cig- aretac's share of the market has increased. The viclllx oC,:garcttcs considered to be 'how tar' rance 446 from 1 Sntg down to 110mg tar. Remttly; cigarette brands which incorporate air dilution into the'filter ha ve been introduced onto the marketplace. These filters dilute the mainstream smoke by up to 85%: This procedure markedly reduces the standand' smoking machine: yields of the ingredients of smoke. The particulate represents approximately 8% of the mass of smoke. Even when puff volumee is largethemariaed dilution obtained'with the highly ventilated cigarettes greatly reduces the concentta- tion of the particulate in l smoke, , and while an in- creased puff volume and puff fnequency, by the smoker may increase the intake from 1 the ulttalow cigarettes~L the'redueed concentration of tar in the smoke may be very'important to lung irritation and other health considerations. 6.1 Difficulties in Rrlating, Reduced Cigarette Yields to Improved' Health Status While there is dose-response evidence that the reduction in cigarette deliveries from, 30mg tar to around 15mg tar has been accompanied by a de- crease in the incidettce' of those distases reported to be increased in the smoking population over non- smokers (Kattnel. 1981;'Kramer et aL, 1983): bene- fits which may be deri ved! from further reduction in cigarette yields to lmg tar havenot'been eval- uated. Both the time required for development of any changes in the health status of smokers related to the reduced measured cigarette machine ,vield, and the difficulty of determining specific risk fac- tors (given the variety of'hazardk in the human environment) have prevented adequate evaluation of this change. The percentage of' the population who smoke the ultralow delivery, cigarettes is also very small. However, when yields of cigarettes are reducedlto theseverM1 low valuesm it is obvious that the ,measurement 'techniques used to assess human uptake will neeid' to become more sensitive. The simple practice of the recording of smoker or non- smoker., number of packs smoked per dan, and possibly the labelled tar and nicotine content will not be'suffictenr in epidemiolop studies which at- tempc to dKtcrmone the intliieatce of reduction in smoking machine test vicJds on changcs in thr

Cigarette Smoking Pliarmacokinctics smokers' health status either on an individual or population basis. The classic 't' test and calculations of p values with large standard deviation for the population can cause sampling errors to appear as significant results. Care must be taken to define the' popula- tion and the distribution, especially since many distributions are not 'normal' (bell-shaped). Like- wise: regression analysis has many pitfalls. Mouth delivery of smoke has little meaning in terms of human uptake of smoke ingredients. The acid pH of cigarette smoke, the amount of'nicotine iw the smoke and' the limited absorptive surface area prevent absorption of nicotine in the mouth. Thus: puff volume has very limited meaning, es- pecially when one considers the differences in, ex - haled volumes. lke amount of smoke inhaled is more important, but here air dilution, breath hold- . ing, physical and! chemical considerations of the product used, and! indiiridit,al' factors such ~ as tidai' volume and vital capacity all have substantial-ef- fects on uptake of the ingredients of smoke_ While nicotine accounts for only a small amount of the mass of smoke;, it~ represents approximately 10% of the particulate mass. Nicotine is a major biologically active compound and~has been exten• siwely studied, both as aphartnacoletgial!agent and as an ingredient of'smoke. However, when one re- views, the literature related to cigarette smoking;, many of the experiments are disappointing in, thar considerations of pharmacokinetic parameters were not included in either the experimental design or the conclusions. Many of the experiments compare single blbtDdl levels obtained a few minutes after smoking a cigarette. With a compound like nico- tine. where tissue distribution is rapid and half-life is short. naturalls•, the blood level is more depend- enu upon rate of uptake and clearance than it is to amount of nicotine taken up. Steady-state condi- tions such as those obtained through continuous infusion are nou reached. Carbon monosidr has been used as ai measure of uptake of the gaseous phase of smoke (Surgeon General. 1'0'9)i Since the particulate iscontaincd wuthun thu gasoous phase. this would seem to bc a satistuczon measure of uptat.c oLsmol.c. HuNr% rr. 4477 physiological factors such as exercise and environ-, mental factors such as automobile exhaust can al- ter individual carbon monoxide values. While car- bon monoxide values appear to correlate well with individual plasma cotinine concentrations, this correlation reduces as corrections are made in the analysis for common factors in both measure- ments. such as bodirwright and ~ number of cigar. ettes smoked per day. Population studies using av- eraging techniques suffer from the wide variations in: background kvels of carbon: monoxide and in- dividual activity patterns as well as' differences in other parameters that can affect carbon monoxide values. 6.2 Recommendations !br Future Studies Measurement'of'daily uptake of nicotine by in- dividuals smoking in their ouvn~ naturall environ- ment is best'accomplished'by use of measurements of plasma cotinine concentration. The better esti- mates of'cotinine li.alf4ifa of'near 15 ' hours from the previously repotted'. value of 30 hours (Surgeon GeneraL 1979) increases the need for care to en• sure that as near steady-state conditions as possible are reached'at the time the blood samples are ob. tained for determination of plasma cotinine con- centration. If' comparisons of brand' yields are to be made. a matched-paired design should be used, and the study should be carried out over saveral' weeks. Daily consumption of cigarettes should be obtained: this can be done by req}tiring a diary or cigarette butt collectionl While these procedures will unduli inform the smokers, of their cigarette con- sumption and hence may affcct smmking, behav- iour: in a matched-paired design with proper cross- over experiments this factor should be constant for the individual. Where there are marked differences in weck-to-week plasma cooinine values or where there are marked differences in the dailg• con- sumption data w•ithout' corresponding changes in plasma cotinine concentrotion. the dhta should be suspect. Data comparnsons should'be made undcr, rclattcei% sumilar, cconditions for the individual. Naturall%, diQfcrcnccs in smoking bcha% tour, that acaompa m a brandl change arc meautingttill but'

Cig,arotte,Smokin` Phamucokinetics changes in smoking behaviour while smoking a single brand should be carefully evaluated if the intent of the study is to make brand comparisons. Plasma cotinine concentrations can be used to compare standard smoking machine yield with hu- man uptake. as was done by Benowitz et al. (l9g3a). These experiments are more di fficult to control since major differences in btands ean affect uptake by the individuali and thus affect clearance and metabolic conversion of nicotine to cotlnitle: Brands, with very similar standard smoking ma- chine'yields of nicotine and tar - where air dilution characteristics and smoke pH are'similar - would be! expected to have' similar uptakes of nicotine. Therefore, plasma cotinine concentration would serve as a marker for average daily intake ~ of ni - cotine (Gori and' Lynch, 1983). Where there anr differences in numbers of cigarettes' smoked dailyfor a given individual, this would' naturally alterr determinations of individual cigarette delivery. Changes in daily consumption ane important' in compensatiow considerations. Similarlit, individ- ual metabolic differences, as reponed i by' Benowitz el' al. (1982a) and Hertung et al. (I983) also need' to be taken into account in the individual differ- ences in plasma cotinine concentration following a given daily dose of nicotine. It appears that about 50% of the'difl'erences in plasma cotinine concen- trations among smokers can be explained by' dif-ferences in metabolism and 50% due to smoking betiaM17our difFenences, incltiding' brand selection. Smokers of the ultralow yield brands have average plasma cotinine concentrations that are about31J9b below those ofithe more popular brands: These in- dividtrals would also benefit from a marked re- duction in'particulate concentration in'the inhaled s'm oke: References alticrs. R-E.. Pcterson Jr. H.T:. Bohnmg- D E. and L,opmann. %1.: Shun•torm etTc,-ts of etgaronr.smoktn(,on ~bronchul i.lcaranuc. in humans, k.rmnevoi En.uonmcnut Hnlth 3G 3di1-36'- ttV-st armimgc: a'i:. Bl.wd Ic.-ds'.o(mcotma and .-ountnc achtc•lcd dunncsmut<mc. in C.ntrdl i1a1 tEdta \.cnunc N.wknh.rp Bcr. t:uer'ru* f~rvrr,cvnunr'> :>n 448 Arrmtage. !CK:: Dolkm. C_T.:,('seofse: C:F::' Housrnun. T.H!: tkwsPJ. and'Tumer. D.M_:Abwrytron'and metabolism of' nicoune ftom,esprettes. Bntnh Medical Journall4: 3'13-316 (t97s1.'. Austin. E`_ lirock. l. and Wisskr. E: A model for deposition of stable and unstable aerosols in i the human resprratornr tran. .#meriran Industna! H.yene Association Journal 40: 1055- 1066Yi19991.i 9tnowitz NiL:~ HaA S.M.: Herain4 tLt.: Jacob. P:(II1): Jones. R.T: and Osma>L A.-[..: Smokers of tow-.ietd~ ciprettes do not constune kss nicotine. New'England Jourml of 1Ml+dicine. JO(r 139-1K2 (i19iDat. Beno•ritz,N.L: J.oob. PJ(ttth Jones. R.T'. and Rosenber. J:: Intaindividual .ariabitity in the metabolism,and cardio.•as• cular effecu of iaicocine'in iman. Joumat of Phannaootogy'and Exqecimental Thesapeuties' 221: 3153:372 (19M1. lienovntg N S Kiryr F. and Jaaob P.tlllt Cireadian blood' ni- cotine eonoenuations durinZ cigarette smokin4 Clinical Pharmaoology and Thenpeutia 32: 758=76i{ (t9b2aL tte,wWita. NeL; Kuyt. F.; Jacob. P:(Itlt: Jones. R:T, and Ounan. A.-L: Coanincdispositioa and klktts, Ctinin! IPharmaeology and Therapcuucs 34' 604-611 (19d3b1. Brain. l.D: and vafber6. P_#: Di!posttion of aerosol in the res+ piracory tract. American Roriew ofRespintory Disease 12P 1325••'•t373 (1979/. Breimer: D.D.: tnuxindi.iduat variations in drug dispositioa. Clinical impliouons and nMethods'of'inrestigatlon. Clinical Pliarmaeoktneacs 8: 371-377 p1983). Cohrn. #1. and Roe. F:J.: Monograph on the pharmacology and toxicotugy of n><ounc: tkcasional Paper No. 4 (Tobacco Ad- visorrCounciL London 19H11. tDarb..,T.Dw Phannacologic considerations in the design of'toaf iaology experiments. Clinicat Toaieotop I:.• ="9-238 (197b):., Doll- R: and Peto. R.: Cigarette smoking and' bronchial carai- noma: Dose and time trlationships among regular smokerss and lifiilortg non-smokers- American Journal of E.ptdcaniolaty and Community Health 32' 303-3t3 (1978)• Garfink'cL L:,Chanpcs in number of cig;rettes smoked compared to changes in tar and nicoune content over a 1}vear'pcnod: in Gon and Boek (Edst ASak Cigareste'..,pp.19-.4 (iBanbunRepon /31. Cold Spnng Harbor Laboratory. Cold Spring Har- boc vl" 198tC1. GuWborg. LS and Smith. R:B.:.SetUmg,and'ddTustoniofaerosol panu+les tn, small atrrvau-s dunng breath holdrng. Annals of Bromadtcal'.Enp.ncenng,,9; 557-535 i I1V811. Gu/dstnn, i:L and i:apman. S.M.: Prnncipks'.ofdrug',actton: the basis ofpharmacoingg . _'nd ed. (J' N-tk% and.Sons: :+1hw .S-nrl' 19141 . Gun. G IB'. and Lrnih ('J_: SmoFcr rntai.e from ctgarenes in the 1-mg Ftdcral Tra.fe'Fummtsston tar elass. .ccgulir Tutueol- ogp and Rharmacul.rg% 7.. n ltt•J'Q q I V33t G..nod. I'N Th'ae es.Troon andd mctafw4Wsm n1 imcotmr and somc min.tr taEucco.all,afotda in man..&+araNC.tur. Tatvll2xshunR. t..u,rr•n \1 k t hcm.ull.,omN••ru.>n.•t:iNa•ttc.m..kc'tnr~...n

Cigarette Smoking Pfiarmarokinetics and BocktEds) a,Sak CiBarene?. pp.19(-203 (Banburx Re- pon t 31. CokllSpnng Harbor (aboratorv. Cold'SprtnB Harbor: YY 1980L Harns.1.E: Cigarette smoking among sucerssrve'birtL cnhorts of men and .omen in the Umted',States during 1900-80. Jourtnl of the N'luonal Cancrr Instttute,71:,a73-479 (A983). HennmB„R.L:Jotas. R'.T.: Birttotritz N.L and IMines.A:H.: How a cnptetse',u'smokedidtlerrnines,blopd nicotine k+rt(a Clinid Phamucolosy and Therapeuties 33: 849A ()983ti H)ern. L: Ciprene stnoke. tarand nicotine kve(s in S..eden dur- ing the decade 1964-1975. Pnoeeadingt of tMe 3rd Wor1d Con- krence on Smoking and Halth: Modifwin8 the Risk for the Smoker. p,p.97.1021DHEW Publieation No. (NIH176•t221. 19,76L Hoficker. C.F.: Abuse of uatistioi paeka8es: Theease ofUie Ben- eral Ilinar'tnodd. .#metion Journal of PAysiolo{y 245 (SuppL Regulatory lntepau.e'Camp.,Phsiol 1Kk R249-R302 (1983)., Holmbc% R.w':: Deternumtionof partick size intoEacco smoke inhalation expowee dtvioes,usia8 meehykyanoaerylate 6ica- tion and scanning rttieroseopln in Guerin and Griffith (Eds1 Tobacco Smoke Inhalation Bioassay Chemiury, pp:11D3-118 (ORNL-Ss_#. Oak Ridge National LaboratorN„Oak RidBe. Tennessec 1979). Kannel K.B_ l'pdiue on the rok otciprctte smoking in ear- onarr, artorv disease. American Heart, Journa( I 101: 319:3r8 (19811 Keith. C.HJ: Eapenmenta( and' theoretical aspects of'oi8aroae smoke filtration: in Deitx 4Ed.) Removal of Traa Conumi- nants from the >tr: pp:79-90I(ACS S)znposium Series No. 17. 1975).', Keith_ C.H.. Phyucaf mctlwds for the modification of tobacco smoke: in Gon and'Bock (Eds) A Safe Cigarette?. pp:•?5:237 (Banburn,Repon (31.' Cold Spring Harbor Laboratory. Cold Spnna Harbor. Y'1- 1980). Knmer_ 1.11: F:ita:ume. H.: Proudfit: W'L: Matsuda: Y:: Wi1- liams. G.wW and'Sones 1r„F.N.: ProBression and regression ofcoronarn atherosakrwsts Relauon tonskfactors A'menican Heart loumal',105 1JJL1•W (i1983).1 Kunre. M- and.Vutuo. C.:. Threshold oftar eaposure: Analysts ofsmokmE htstoryof mafc lung cancer cases andlcontrolt: in Gurn and Bock.UEdst.1. Safe CiBarette. pp_'9-3J (Banbury. Rbpon (I1. Cold'Spnng Harbor Labontory,, Cold SpnnB,Har- bor: \}'I`7901: L.nch: G.1 andiGon. G.B.: vondctectablr nskieveli in cigarette smokanE- in Gon and Bock 1Eds1 i Safe Cijarente" pp.37-i3 t Banburc Rcpont)). Cold . Spring ~ Harbor Uaboratorn, Cold SpnnE,Harbor, `l' 19801. 4G9' McKcnnts Jr. H.: Eapenmenul considbrauons of some alternate toutn ia the mammalian metabolism of eicotine. Beitrape aur,TabakforsAunB 8: 388-=89 (i1976'L Ro.dand M. and Toaer, T:N.: Clinical Pharmacoluaetics Con- cepts and,Applicatrons (Lea and Febiar.,Philade(phia 1980). RussNL M1A H; Suttoa SR.:,Iyer: R::,Fe.erabend. C and!Vaey, CJ::,LotK term switching to low ur b.., ttieotine ci8atettes. Bnush Journal IofiAddtction 77: 145-1'S8'(i198B): Schrovelbeia , H:: A'bsorytqn of' nieotino under various condi- tions. Beitra8e aw Tabakforshung 8: :86_87 (II9761,' Schmeltz L(Ed.Ic Chemistry of'Tobaeoo and Tobacco Smoke (Pkaum Piess Ne+. York 19721. Sdke: W.Ak and Mlthe.z J.H_ TAe :permcabiHty ofci8areae p- pers and cigamtte ventilation. Beitra8e :ur Tabak'forsaNunB lattrnational!9:' 193-200(19781. Suryeon Goneral:, Stnokin8,attd Hwlth: A,rt:port of'the Surgeon General U.S: Depastment~of'HealtL. Education and We(farr Publication No. (PH5) 79-5006'6' (1979): Tobin. MJ1 and Sackner- Mi.l: Monitorine smokitt8,patterns of low and high tar ciprettes with induaive pledi.smograpfoy. Americoa Rbvie.rof Resptratory, Disease 126: 25E-26A (19821 Turnrr. , D.M.: The use of a radiocbomia( method to study the metabolism iof nieotiiro in experimenul,animafs. Bcitra8e zur Tabaktacachun8 Bi 391 i (19761. VescdL ES: and Pimtp, M.B: Auessment,of,rnetbods to identify sources of iiuerindividual pharmacokineuc'variauotts: Clinical I Phamuaokinetia 8: 378-409'(19831. M'aW. N,': Doll. RL and Copeland. G.: Trrndt in tar. atcotine: and i carbon ~monoxide yields of UK ciganettes tnanu6ctured since 1934. British Medical Journal 28"_- 76'3-765 (19811: Wrodor. EL Some concepts of the,kss Aarmfu( ciprette: m Gori and Bock (Edsl A Safe C4xrette?. pp.3-1= (Banbury Rbport' (31: Cold Spring Harbor; Laboratory: Cold Spring Harbor: PtY 19801. Wynder. EL and' HoRman. D` Tobacco and Tobacco Smoke, tAodcmic Press. New York 1%71. Yeh. H C.: Phakn. R.F. and IRaabe. OiG.: Factors influencing the deposition of inhaled particks: Environmental Ha1th Per- specuves Ii: 1a7-156 (I19761 Yu. C.P.: A two component theory of aerosol',deposvuonin luna, au..ayi Bulletin of \tathemaucal Bwlbap a0: 693:706 (1I978): addtrss for eorrespondence and re+pmms: Dr T D: DarM•. Dc- panment of Pharma¢olo(t., School of Sted.ctnec.. l4m.rorsnyofSouth Carolini Columbia. SC 29208 t1'S>I