Jump to:

RJ Reynolds

Gauthier, Et Ux V. RJR, Et Al. Your File: 001127-17709.

Date: 19721101; 19990524
Length: 105 pages
520818223-520818327
Jump To Images
spider_rjr 520818223_8327

Fields

Type
LETTER
REPORT
Referenced Document
List of Footnotes. Nicotine and Addiction. The Brown and Williamson Documents, by Slade J, Bero La, Hanauer P, Barnes De, Glantz Sa, Journal of the Ama, 19950719. List of Documents Regarding Smoking and Health Research.
Copied
Rouen, D.
Nieset, J.
Copley, S.
Recipient
Bertaut, C.
Chaffe Mccall
Date Loaded
05 Mar 2002
Request
US
Comprehensive
Request
124
US
Comprehensive
Request
80
US
Comprehensive
Request
140
US
Comprehensive
Request
47
US
Comprehensive
Request
61
US
Comprehensive
Request
61
US
Comprehensive
Request
181
US
Comprehensive
Request
220
US
Comprehensive
Request
241
US
Comprehensive
Request
201
Box
Na
Characteristic
Marginalia
Site
Law
Litigation
Mckim Tf
Asst Gen Counsel
Named Person
B&W
Pate, J.
Saint Francis Cabrini
Bertaut, C.
Chaffe Mccall
Gauthier, J.
Jeansonne, M.A.
Grace Paint
Chaudoir, H.J.
Gordon, C.
I Brgh
Smith, W.
Gauthier, J.N.
Neal, S.
Whiddon, P.D.
Drummer, E.D.
Rouen, D.
Nieset, J.
Copley, S.
Domingue, B.
Gauthier, D.J.
Hj Chadoir Acoustics
Shivers, R.
Laborde, A. Jr
Ailand, J.
Hessmer High School
Ferriday High School
Kaufman, H.
Charity Hospital
Baton Rouge General Hospital
List, O.F. Doctors
Lafayette Charity
Bunkie General Hospital
I Bgh
Rapides General
Rapides Regional
Childress, J.
List, O.F. Relatives
Security Industrial
Commonwealth Life
Gainne, G.
Catha, K.
Liberty Mutual
Brookshire, L.
Ryland, D.
American Lung
Lemoine
Tisdale
Koya, R.K.
Social Security Administration
Seligman, R.B.
Dunn, W.L.
Philip Morris
Abood, L.
Fda
Hoel, D.
Jacobs, E.
Berntson, G.
Osdene, T.S.
Wakeham, H.
Fagan, R.
Brudny, J.
Levy, R.
Bellevue Hospital
Columbia Univ
Weinstock
Resnik, F.
List, O.F. Tobacco, C.O.
Freedman Memorial Cardiology Assoc
Shaw, D.
F Mark
Drerup, M.L.
Texada, R.P.
Tisdale, C.
Hair, J.G.
Jordan, R.B.
I Jlw
Jeansonne, K.J.
Mansour, A.
Ule, U.J.
Jordan, R.E.
Wal Mart Pahrmacy
Tassin, P.
Lemoine, J.E.
Wilkes, V.
Author
Jeansonne, M.A.
UCSF Legacy ID
zme50d00

Document Images

Text Control

Highlight Text:

OCR Text Alignment:

Image Control

Image Rotation:

Image Size:

Page 91: zme50d00
V r ) r Nicotine Dlagrxmmatic Representation of Ihe fllfecls ol Nicotine and ol Reserpine on Hypolhafamopituitary Funclions ~ - _ Brain 1lighar Regions Release " I Cnlecholammes ] .-- ~- No El/ecl ~ Seiolon,n ]-I DeplClion ol --- Ihe Slores $Iimulalion . vasoprecsm OrytoSn _.._,.; ... ... __. , Adrenoo corlicoirepm Reserpino I ., . _ -: ... .. _. _. _.. _.._....,....._t _..._ aecpuwlary Gondnnopin Thyrolropin Somalolropin Peripheral Targets -- Increaced Blootl Pressure (Vasoconslriclion) `- Anlirllt.retic Elfncl - - Melanoslimulaling Hormone (9) - Fat-Mobilizmg Ellect=Appelile - Cortir,oslmoids Stress Reaclion Blockade ol All Pituitary Funclions asked lhal the repLn-l be given tlo teider ell'Cl11atIUl1 t/nlll lhe Hippo reports hnd received. He noted: IThe Iroporlf is an account of work wllich Imx been carried nut_ in assncLdion a'iLh lh(- nlhor teseachec which were sent la you lecc•ollr unrlcl the lllle of II II'P(7 I feel sureynu rcill agree th,)t n knaclndge of lhe Llte uf nicot inr iu the body is a necessary acconrpaninrrnt tn slorlying the )lII}'siningit•al effects lhal nicntine can )n'urluce. 112(lg.1f) 'I'he documenLS du not include tul}' acknoteledglnent from Cutchins, bul Lhe nlan tvho would shortly replace him as prc,atclent, Ed P'inch, receiled the report along with an accurale sununo-uN of the research prepau ed by the RrllS' t•ice presitlent of research,'1'. M. Watle. Jr j1200.00J. A Tentative Hypothesis on Nicotine Addiction The 13attclle scientists who cuncluctetl the Hippo projects also wrote a specu- lative essay about the mechanism un- derlying nicotine addiction. "A Tenta- tive Hypothesis on Nicotine Arldict.ion" (1Z00.011 suught to explain nicotine tol- eranee, withdrateat, and addiction in terms of nem•oendocrinolog,y. The hyputhlllamn-pituil.ary stinmlatinn nf nicotine is the beneficial mechanism rehich makes people smoke; in olher lemds, nicntine helps people to cope with stress. In the be- ginning of nicoline consumption, relnticel~' small doses can perfm-ln the desired ae'tien. Clunvtic iutake of vicofine fends In r,e..slnrr the uorntat ph,rtsinlopicnl fiu+cltnuirry nf the endocrine system, so llmi ever•-incrcasiup dose levels of uicotiue are ueceasnry tn rnaivrtuin the des'irrd arlion. lhtlike oflwr dopinps, such as rrzorpkine. the dentand (nr iuu•edsing dose levels is relntivelft slulo for nicofirte. In a chronic smoker tbe nornml equi I i brium in the corticotropin-releasing system can be maintained only by continuous nicotine in- take. It secros that those individuals are bul slightl,y different in their' aptiturle to nore with etress in compatison with a non-smuker. If nic•utine intalke, hnwever, Is pirohibitcd to chrnnic snlokers, the ccnticotropin-releasinA ability or tire Ilypothalalilus is greatly re- duced, so lhat these Individuals tu-e Iefl u'ith an unbaLmced enduerine svstem. A hndY left in lhis unbalanced status crares for reneuvd drug intake in m•der lo restore the pMsinloki c•at equilibliunl. 7'kis /urcmrscious desirr, r.r+ plrtiv.s the addic.tion nfthrindinidnnl to rriratiueo jmnphasis added) 112(10.01, pp 121 Pharmacological research at 13attelle sponsored by L3AT in the early 1960s was based on a paratligm of addictiun. I t sought to clucit3aLe "beneficial" effects of nicotine, speci6ca Ily stress reduction and weight loss. The wom•k included fundamental pharmacokinetic sludies with an eye toward itd.m•e protluct dc-' Dl velopment. tj 9 DO Brown and Williamson (B&W) had a sophislirUlletl understanding ol how nicotine acls on the nervous sys- tem In 1962, when il was conduGing Ilre Prnjora Hippo research. CRF indicates corlioolropin-releasing lac- tor: GRF, gonadolropin-roleasing Iactor; T RF. Inyrolropimreleasing laclor; antl SRF. somalolropin-releasing laclor. (Typeset from a manuscript page ol a B8W documenl 11212.03, p 51 wilh corroclion or spelling and typographical errors.) . . . . dratcn into their muuths lchile rnost ol' thuse x'hu inh;ded absorbed bellreen iU:4and 411'hnf lhe ingesleLl dose. Thc lteo sfib,jecls Tvho "ejectjed] Ihe snlulte intmedialely after inhalntioli" Ilall nico- liue absorPtion rates in the 4LIC5 to G0% range. Daily consmnption of nicotine among these auh,jee•ts was fotmd to range 6•om 10 to 91 mg 1121'3.f11, p 8). These dala tlemonstraLe lhe impnrlancc of inhalation for nicotine absorpl.ion from cigarette sntoke Inhnlation is un- rclated to ltute and Ilavot'; it is unl,v irn- portanl for nicotine absnrOtion into tho blood stt•cam.P1 '1'he repurt alsn discucses rn'lier nrork on nicotine absarpl.iun, lchicll hlul demonslratetl I.haL 6•cebase nicnlinc is ahsorbed more rapidly than nicntinc salts. Nicotine exists in lhr• frecbase form nt nn :dlcalinc pH. In ac•idic enci- rnnlnr'nls, nicnliuo esis(s as a.all.'fhc more rapid the absorption, the grrnier llu' impacl nicotine has on the ln•ain.u 'I'he reporl concludec with a disrus- sion of nicotine metabnlism in the cun- lext (if tulerance and addictiun. IL u•as Imaun lhat tnlerance c:ul develnp cither fruul metabolizing n <hug faster with repcateLl exposure (met.abnlic toler- nnce) or frorn arhtptation to thc drug at thc Iecel uf the target tiscue (ec•Ilular JAMA. July 19. 1995--Vol 2)n. No. s No Enecl Ilypolhalamus ~ ... .........._.1~.=:::.:'._:._._.~._...:1.._.. Cnl ' GRF TRF SnF lolerance). I L was also clear at the timc that there is an important relationship betwcen the development of tolerance and tlle potential a drug has to cause atllliction. Although tote•ance to sonle drugs nlay de- pend tm accelerated enaynuttic break<bwn, prrulonged consumptiou of others,inclutling Innrphino, appearP to Illduce ceIllllar• adap- tinns. In any case, the present results offer no conclusive evidence for any particular mechanism involvetl in tolerance to nicotine, nor do they indicate a lead to the phenotn- ennn of addiction, II'e believe that both foGrr- rnrrr arxf atfdict-iou are irrli+nalely com nrr,fnd, tntd tlmt it tumdd he rroo.st usriid to iw:ealiyrde the lrun ptunrouteun mitlt'reyard fn relhdar nda7rRtGinn, csl)eciuAtg itt !ar'yrt orumes nf the crll{I'fll rn'r•UU1/fi sf/.YteB. lelll- phasis nddedl (1213.01, p 271 'I'he authurs cle:u ly understootl nico- tine ph.u luaculog;v in terms of tolerance mld adrliction. Indeed, at about this Lime, they tw•ote Sir Charles Ellis a thoughtful, brief essay on a possible mechanism for nicotine addiction (see below). WiLhin a few weells of the transmis- siun nf "'1'he Fate of Nicotine in the ltudy" to 13AT, Sir Charles sent a copy to William S. CuLchins, president of I3&W. In his cover letter, Sir Charles The Brown and Williamson Documonls--Slade el al 227 F ~ N .1`1 E:1
Page 92: zme50d00
Y _ ..~.. .~ ~.../:i U .. , ~. .. ~ . i. :. o..i:.,.t.. ~..: ...~.. ~.... ~..: ...~. ~,.... ....~. ..:, 7 t ~ o..'__._'.~ ....t . ~.. . p. 7 _ .. C.. .. .-N 0..~_.~. H: ......:.~. . .....~ a. '~ m W,. -.y. ....V....~.. f GN; i~. C.:y..C... ::.d..:. .... ... '. DLi~ C- . 00 ... V...) 'SH; .... .: . :. .. a'... .., .-~ V...V.~.4 ~ . .C.4._~.Fa.....,_ . r .. ~. Y.., y'....L.. I. .. .. 7 • i _... .. .. ~ U .U U i-- 'M~ . ~ ~...y ~.N .... ~.....i.. O. C JW C ' ' ..,....I~._.......: . J Ri .~ Y 0 . ~ , : . ti O F aq U~ _I .: V . , . .~~z O' d...;~...:i.... V 7 ' ..1....... .;. ~... .^ . . .L...L:..7: . ~ ~ , I^ ^ .:. ...:....!.. . .N.M.C~..h .:. ~....'~ ~.... :::+ ~.,. y ~ I I'N h N NiV' 60 L ...:..;.. V' ..~:.:.~.. » h ~ 1 +~ I.M 111 • . L...../. .~ .. f' ... 6 , U!~ ..( I
Page 93: zme50d00
I :C:=r HX ~ . _.. . ,,.. .--~---• ... -t a n 7 a ry -~--- -Y ~-- ... o . o n . 1~.~..~...~.q. . _ ~ ;.. <: Y .'I0 C p ~-• 3I' I'~ t 9 C p i Y p ... .~,..~. ...i... . - _. _. .a...,.....c ,_- ..c ..,, . . . : .h.... ....ico.-;_._....^.__i. ....._ ..
Page 94: zme50d00
II Nr,ls aXrveA thld insnfficicul wnrh il~ bciu); dnnr nn (husn cenefi6a I,rrc•aived I%V Iho eo,r rrynmer. amd thul ps,1'chuingical anJ ph:n•mn- c•uingieal stndics shnld4 hc inili;ded, bolh al imlustrp and group Ioccl, lu idanlil;r Ihe run€umcr: nrrds. 11170.01, p !II 'I'hc• impurUmcc• of phncnmcul,)iical resenrc•h tu idenlifv cnnsumor noerls il- lustratles lho uuderI)•ing inlent uf' I3A'I' an(I Rt@W sls rcllecled ill lhe appru,lc•h laken In• lhe c•ompauicc IrsJiu,g Scicu- li~ls. Studies on Cenlral Nervous System Effects of Nicotine The ducuntenLs include , ~unmriries uf I'ctrral rcl~carch rrllnrls th,d cxnnlinc thc effects nl'nicot ine un I he ccul ral ner- tuus s-vstrrn. 'fuu clc[•trncncrIrhnlo- ~taphic ( I;I~,( ~ I snl~lics uf smolcin)., ~rcre rel,nrletl in I'/7d (120F.61, 1'llla,l:,l.'I'he lirst. frunl I3RW in Luuiscillo, lit', wns uudettakeu tu facilitate prudnet devhl- upment. 'I'hr ducehqnncul of neaprodurls Imd thc n,uliliratiuu nf ecisling omne requirrs Ihnt wr h:n'e sumv knooicdy;r uf Ihr v,m,kcr Iii. ,c:ud :ch„m lht•..,• eflhcls m•c dir'orto,l.'I'hv ccork described in lhis repnrl is fucused nu lhe avul, nr iumrvdi:de phvsiningic:tl rc_ spuuse uf smukci:c. (1'l(Li.ll, p II In saying Lhat producl dcsiym cun be guidcll by phau Inaclrln} ical stndics suoh as lhis, Lhe authors rel•eal tm intention tn affect lhe slructure Or hnicLiun af thc hrnll'. '1'he rehulls were inlerprate l as shud'in}; bulh pslychnlot~ic:d aud phar- macolnf;ic:d effucts of ,Inul[iu};. FVr pn•.:entl}' interprcl lhcce rr•.y,anses nf Ihe smuker, to lha lt"n c•igarrlten iu hnlh ps)'c•hnh,Kical aml phm•Inncuingic:d ternis. 'I'he:dpha ahunJauc•(• reOerLin{t a sub,joctico ur, eundilioned respnnee to smuke and tdpha amplilutle intlicaling pharwacologi,atl re- spunsc to nicutinc. 11205.11, p bl The scconll EEG study aas con- dttc•ted by A. li. (;unler tmd It. E. 'I'hurntun al ISA'1"c Suuthumplun Inbu- ratury {12115.1G/. 7'he slud,q fuund that smuking increases the brain wave ac- tivity being roeasured iu sunc suh,jects but decreases it in olhers. In lhe llis- cussion, the authorc noLe that uicutine. "has heen assunu•d to bc•e the Inain phiu'nntculukiclJly active cunll,um•nl ill smulm: "fhey speculatc lhal t hc dispal•- ule Icsults Inly be exI,l:tined br Ihc hy- polhesis"Ihal smukiul; tnay t sSki. sutnc peuple tonptimise lhe level uf aclicily in lhe brain." Research Conference, 1974 Ity the 1117(ls, diluliun uf nminsllram cigarette stnuke with ruum nir had be- cume a nta,jor Lechniync for reducing utac•hine-meastn•ed Lar and nicolinc•. de- licorie t °'O'n'Termed "eenLilaLiun;' di- 230 JAMA. July 19, 1995-Vol274.No.3 Illtllnl was ilcc(/111OII511(1/l with ft Vi1r9Cty of techniqucs, includinl; Lhc usc of po- rous cigarette paper and the [h'illing of holes around the filLel' tip. The 13A'P 1•esearch cmtfercncc in•lanual:V IJ74 dis- cussed research at lhe RA'I' IabaraLol;v in Germany, which ahowed lhal slnuk- crs ad•Itlst Utc way thc;v snwke to con- lrul the Icvels of nicotine iu their blood. An apparent replicaLiun uf the Ger- nr,m tvnrlc was completed in the fullmv- ingyl•lu' ill Gnarle,'I'hc "Chrnnaluf±y of RtF W's Smuking und I le;tl(h Itesc;u•c•h" includc:e thc follaltiul; item fur 1!17u: ('unipcu<,dinn stud.V cunduclyd b}. Inlpcrinl 'I'nharco a IIA'I'Cu:d'liliatv, Irhutcs th:n a smrikerl ad,lusts his smnking hnhits whcu smaking cigarettev wilh Inunicnliur and 'I'I't<l Itntal parlicuhdc InnLlerl to dupliculr his nncnutl c•igm•el.t.c nicutine intake. (lmpe- rial Tuh:mca 1'rqjecl T-R1177) 11(IUG III, p 271 RA'I' scienlisls c•unLinucd to sludv cmnpensaLion. Ry 1984, the cunsc•nsus aroong theln lvas thatconslnners a[I- justed tJteir- smul[ing lrehavior tu acltieve specific nicotino (losing. '3'he inmm.diatc signal consumers );'ott tu {;auge uicuLine dunn was Lhe "impact" of the pllff on the throat.''he impacl., in ttmn, was a signal to l he consu mer about lhe dose thaL would be ahsorbed. This was stnntnarize(1 at a,joint R&1)/ umrketirlg cunference in 1984 as ful- lulcs: "it is accepted tltat uicutine is both lhe driving force and the signal (as tln- pacl) fur compensaLion in htiman smull- ing behaviotn:" (122/i(Il, p 561 '1'he i nhatabil ity uf tobaccu slnutce was discucsed at the 1974 reseau•ch confa'- cncc tmd led to two summary conclu- siona. The frsL dealt with cig'ars: 'I'hc policy uf tliscoucaging iuh:dable cigara ,cu" questiuncd, On lhc one hand, it ceas su);gc•sted that nmre behaviom•nl infurlna- lien was neceSlEo-u•y before a judKment cuuld he made and, on the other, that our present pnlicy of cautiun ic currccl. (1125.01, I) 4) 'I'he second was about cigarettes: Althuugh lhe Cnnference hatl cunc•lutlc•[I ill lhc past that the non-inhalable cigacetle was a tt•m'lhsehile cuncept., no scnrk had bren ilone in this Geld and the upernling cumpa- nies represcnted did nut feel that it presenl- cd a rc•alislic approach. It was agreed to re- cocd a difference uf vietr nn this suh•iec•t. I11Lb.n1, n 41 'I'hc tapid albsurptiun nf nicotine fl'oln inh:ded smulce ill the lungs is the chief ndv:mlage cigtu•e1Les have over cigars, the snlolm hmrn which is ucually not in- haled, in pt•uducing Lhe [Iesired phlu•- mnculog'ical effecls.10 Research Conference, 1978 'l'he phlu maculegy of nicotinc was fca- Llu•etl in [liscussions at the 1978 rosearch conference:• 'fhc two Lhentcs being conlclnpIal(•d (nr fu• Ltme wnrk by I hr Vvrh:wd f in I:ermnqc I ar•- lhe bene0c•iad effects uf nicutine aS a druft, and aatudy of hlnoJ and urinc leccls ~,f npeeified eunslituunln uo e.plore the ilt•Frra of coinpensalion hy cigarette s,noker=. 11174111, p 21 At unuther poinl, lhe inlpur'lanre nl' impcuFing lhe rlnsing of nicutiuv frnm cigarettes At as e ln j lh as i zetl: 1','ilh conrenLion:d eigarelles, thr trau4er,1f nieulinc• to Ihr smnlmr from Ihc tuhan~n ha, cet;c luuvl'licirnc~'. I',deulialic. I hcrefmr. appnrl.auilirv eXiFl Gn' rrl'y hig nacin}is in lubnc~if lhis low effcicet;r t•un hc );crtdl,,- increa~cd. I117•I.01, p 41 'I'his cotrune.nt rclates to lhe Glcl llca. in general, a smoker absorbs nnl,r n6aul 10^/0 of Lhe nicoline found in a c•igaurtlcr' This cau hee inc•reased to a maXimmn ill about 4054, with inlensite smnking tech. niques. 'l'he comment is m[•aninytlcss il' lhc mnntdacLturer's intent is Lhc dcli% ol;e of nicotine for (,•tsle.'I'he commeld nulV has meaning in lhe conlc'st tuf nic•ntino absorption. Research Conference, 1980 W hile Lhe doc•uments do not includr u stlnunary repm•t ou the 1980 rese.nrh cunferenco, they in(lude a seL of notrs made by llr It. A. Sanford, vice presi- [Icnt of It& 1) at MW, ill response ta a [lueslionnail'e circulated Ir,v Or /lhln Heard of RA'I' RF U about I hc• pruposoI agenda fol• this confcrence (1 I:.3'L.ll1 j.'f hr document is sometvhat cryptic: since it only supplics answers, it is nul clo:u' ahaL lhe questiuns lverc. Iu lighl uf lht• work BAT had previuusly (lone ml smokercumpensation,lhotll*h,onenf hr Sxufol•d's responses deseraes nlentimn. On a pcnposed discussiun af"compeu- satiun/sinoker behal•iour;' t)r Sanfurd indicated that MW Itall "definite in- Lerest" in Lhe area, but he also nule•d that this arca of t'esev'ch was "[Innker- ol1F" 11132.01.1) 31. The•obt-ious [lanl;cr, G'om 13&W's perspe•ctive, ceuuhl haco been that the c•ornpensatiun phenomc•non demonsWated the customers' desire for nicotine in a way that undernlined thv contpany's implie(I clatemeuts about I he health benefits of swilchiu/; to lort'-vicld cigarettes and its public slatrntenta abotlL snmking Lcinfg a malter of fn•c. choice. Uata on this phemmnenun Ilvnv the cmnpany could be embarrassing. Research Conference, 1982 Phe fu•st entry in the ntinule.c for lha Se.ptembm• 141R2 research conferencc•, un- der the headinX "Subjecls of \laior Group hnportanc•c;' is "Ilum;ut Snlulc- Illg Re11av10111:" Nicotine reee.u•ch nn4 psychologic[ll slu[ties of cunswncls fol m the bulk of this section. One coltclusinn wns: The Brown and Williamson Documenls--5lacfe el al j 52081 8243
Page 95: zme50d00
llrr 11 is mlv lnn cu.y ln d•, wlllt .b•op. • In4 pill<lqy.i'Lapx.lhrlc(ureI in Iliu mil:l ul' all Ihis c,msidoratirm uf Ihr pus.+ible Inu•mliil effre't• of z;nmking cnu triIl br pleasc•d tn hvm' lll;d'I'. D1 S,('. i< snppnrI.i n)! lvork t n clm•i~ lal e the rffrclsof nicutiue ns n Irrnt•fieenI odkadnid rhve. If 'inphasis adJvdl 111112.01, pp I!i-161 BATTELLE'S NICOTINE RESEARCH PROGRAM Nnt dimbscd in tiir Chnrlc>; ISh~.'. <preclt lcas cnnUncl rc e:urh nn nicn- I.iue th:rt was bcinyt cnnduc•Ird fur ItA'I' bc lhc knllellc 1lcmuri:ll mLil ute Iaho- rntarc in (~enc•t'n, Swit•r,ct1und.'I'ha ul- lim,lte purpn.ce uf the prnjncl llo. t•r dcl'elnpn nuvel nicutine dt•licel;v devicc that ll'!nlld acoitl the ltixicily nf cunvrn- lirnlnl cig:u•etteF. Ilntlellc luldcrlnnk xcvcral projcilF Gn• RAT oul nic•utinc fronl llo• Inle 1:151k Ihroup,h nhoul I:IG7. I'rqjrci I lippu I im cuI vc~ I a ninnt l ex peri mcnls e. p lnri i l1~ t h t~ efl'eclsnf uic•oline uu slre>I, tveil;hL);ain, tc,der Iralance, and horm,mal rngulaLion. I'roject I lippo I I exlendcd this work on lbc hppothahunic• el'1'ects of nicotinc• by explut ing tchether nicuti ne aetetl i n laty. similar ln t m\jor tranqu iliziu~ rh•ugs, suell as roscrpine. A separate series of ux- perimenls wm'Iced out Lhe pharntacoki- netic's of nicotine (absorption, disLribu- linn, and fate). Finall.y, 1'I'o.ject aricl was a pl o•jecL to develop em allerndive nicotine tleliver;y device: n producl lhat would provide lhe ceinsumer lvith nico- line whilee dolivcring negligible anlntmis of the other, tuxius fnund in lohacco smoke. Project Hippo I Ih'oject Hippo I esplomtlnic•otine's roic in several areas incolving hyputhalannc' Ilmcliotls, incluclink reduction of sLfess, iuhibiliun uf u'eighl gain, utainlenance nf ll'ater bahulce (hormonally couLrolled ltrough lhe hyputhxlatnus), auul reguhl- tion of gonatlob'opic hurnlones. 'I'he ro- sldts of N'o,ject Hippo I(u'e describetl in a•lmluat;v 1962 re)xn't frout 13ulLOlle Lo RA'I' 11212.011. 'I'Ite reparl oxplicilly ac- lutmcledges the centraV iulpartlmce of nicotine ill tobacco use: It is nn evel;vdltv experionce lo nach smnkec thnt smnkinK a cignrrtle holpr mn'U•rinp thn' numerous speavful st.irouli of moJern lifc. 'I•his effect is pn.~sihl•v onr nf lhr mcst poleel4al reasons lehich make one smnkc. lina' does nicotine esert this nction? 11212,01. P fil I n these experilnents. Iial lclle test'~d snnte. af the most adrancetl neuruendo- c•rine theories of Lhe day. 5ince Lhe mid 195(k, neuroendocrinulugisls hnll been c•urning tuunderstantl Lhe t•enLrnl rnlc nf the h•epothalamus in the rrgulation uf pilnilauy gland function'" Among (lie pharmnculugit•al phenonlena studietl by 226 JAMA. July 19, t99S-Vol 274, No. 3 R:dtcllc was tolerance to nicntine.'I'hc ceport nuted that tolerance cuul4 be in- duced in lQl rals sLudiell. I'rujec4 Hippo I included an elegant series uf experiments on weight control in rats using nicotine. Nic'otine inhibited I'rnrd inl•ldcc in hoth tolernnt ®td nonlol- cl•ant animals. lieserpine ditl not motlify I his action of nicotine. Nicotine rapidl,y Flinnllutetl the mobilizldion uf lipid de- posits ;wtl stimtdaletl the deg'ratlulinn uf fcce fatly nci/ls, Each of Lhese actions was in the directiml expocted I'nr a drug IhaL would he of benc'IiL in controlling n6esily (1'L12.(I1,p:31.ThelintLelleworic an lceighl, control Ineceled published :u•counts of these phenontena by 20 vears.!" The Grst scie.ntist to publish l%ork in this area (in 1Sh3'L) hac indicated that tile Glct thnt thecu data were not published scrioltsly dt:la,1'etl progl•csF in this area (Neil E. Crnnherg. writton cnnroumirdion, l)ecetnber!), I9J4).'I'he tlippo 1 repnrt concludes with the fol- lowing observations: I'rom all nm• Jata it secnis that the effect of nicotine in the "stress reaclinn" is a cc•r.9 prominent nnd :t rer}' campiic•xted one. 'f he untlel'sLaml i ng and lhoruugh investiga- Lion uf this effect secros of tht' {,meatesl inqxrr- uwce: it is by this very effect t41at nicotine acts as a "h'anquilliser." (1212.01, p 481 Project Hippo II f3attelle extended its research on the Iiypothalamic actions of nicoLine in l'ruject l lippo 11. 79te plinuil;y ptnlrose of Pro•ject ilippo 11 wa.stodetermine wheLher nico- tinc s effecls on the 6rnin were sintilur Lo the effects of tl•wnuil izi rig dnrgs, particu- hu•I,y reserpine.'Che findiugs are desclibed in an inlerint ceport (ID(i2) (121`L.02) and a final reporL (1PC>:3)11212.p3). The interim report discusses the thinking behind IToject Hippo 11. is it possible to perceive an,y simihtrities be- twcen these effects of the new drugs called "q•anryuilizetx" and Lhe feeling of comfort experienced by a smoker? Some of these similw'ities appear at fu•st sightand are cerlainly wm'Lh lehile studyiug: I. Nic•oline, like rosel•pine itscif, releases norndrenaline fcom its atore.e; it acenl.e also lo release serotonine stores from the btoin. 2. 'I'he athninistration uf one (lose of nico- tine enh:mces the h>•Irerpra4ncLinn of cortico- stcroids in the mh•ennl concecutive Iffcl bo u >:Lress, as tioes resarpine itsclf. 1121'L.02, p 151 'l'he linal report on Project Hippo II indicates why I3AT was interested in cumpar•ing nicertine and reserpint•: there was concern that tile then new tran- quilizing agents woukl compele with cigarettes as stre;s reduc.ers. In Lhis t'e};tu•cl, the results of 13ntteVlc's re- scarch mnst have been 1'eassul'tllg to 13A7', since the experiments demon- straled that nicotine had far fewer nd- verse effecLs than reserpine. The report notcd two benc•ficial ef- fecLs of nicutine: The so-calletl "beneficial" effects of nicotine nrc of two kinds: I• Enhancing effect on lhe pituitm;v- adronnl respancc to atress; 2. Itogulnlion of budy lt'eighl. 1121'L fla, p 21 The reporL asstuned that tolernnce• withch'awal, ancl MddicLion to nicotine were rcal phenqmena: A quanliUtlive incextig:dinn nf the relntiuuc lcith time nf nirnline .md nf sonro Pt~~0hle Lrain nleQiators--un aih•enmcorticnlruphic activity cnuliKil'ee us the kec tn the expla- nal ion of bnlh phenomrna nf tolrra ncc znd nf nddiction• in xhou•iny+the st'mploms of lrilhdraual. (1'112.11:3, p 41 'I'he hypothe.scs gui lint± I lippn I I au'e slnnmarized in u di:tgranl rcla•orluccd in the Figure (1212.(13, p GI. In lhis ntodel. nicotine ac'ls in the brain and at lhe Iel c•t of the hypothahnntts to affect appclilc. stl'f!sg 1•cact7o115 mediated thl'ollf!h thr ath'enal gland, snd changes in blood pressure and in water balnnce (anlidi- lu'etic effect). The experimenlal tlnUt gathered by the Battelle scientists in Hippo I antl Hippo It provided direct enrpiric stlpport for this mudel. The Fate oi Nicotine in the Body' In addition to contlucLing the llippo prqjects for BAT, Battelle also studied how nicotine is absorbed into, tlictrib- uted within, and eliminated from the body. 'Phis work seems to have been parL of the overxll development process for Ariel, the code name for HA'1':s al- ternative nicotine delivery device. '1'u propet'ty design such a product, liA'I' needed basic pharmacokinetic data. The resulLS ofthese pioneering experiments are described in a A1a,y 1JG3 report en- title/l "'Phc Fate of Nicotine in the Body" (1218.t)J J• The report begins: There is ixcreasing eeidenreOmt uicofise is Ute key fac(or in confralfirrg,' fhrnnglr lho cr-nA'nf veruans strs(enl, n rurrrlbrr• u(bmie•fi- cial effec(s of (obacco sumkn, inchrdiug i/s acfion inUlepresrvcanlxh'u.qs sihrafinns, hl nddifion, tlie afknfoid fnicofirrr/ npprru•.c In be in(inta.fely coroeec(ed u•ilk (1re Irheaowein of tobacco habifttntion (fofmrunt•r) nudlnr (ddic(iox. Detailed knoll9edge of these c•f- fects of nicotine in the bodc nf a snloker is therefore of cital impnrtUnce to the tobaecn iudustry, not only in connection Avilh thrir present standard prndnctc, but alco l~ilh n•- gard tn future putential uses of tobaccu alka- luids, lemlrhasis added) 11213.01.11 I I Inhalalion is essential fm• nicotine absorption front a cigaretle.' 'I'o sludy lhe absorption of nic'otine., Rnttelle used nicotine labeled with carbun 14 to men- stu'e Lhe amount of nicotine absorbed hy different types of smokers. The two subjectsdescribedas"non-inhalers"ab- ' N sorbed 22% and 42% of (lie nicotine ' e m t, The Brown and Williamson DocVnSents-Slacte el al 0) l. W to
Page 96: zme50d00
Reaction to Battelle Research at a&W 'I'he dncunmots include intern:J dk- eucsir,ns uccr tehc•lht•r lo chnrr the rc- =ull>' nf Illo Ratlr•Ihv I'rcenrch t+ilh Ihe llti I'ul,lic Il,allh Srrcice, u0hich +rll Ihr•n cmldut•Iing thc rct'ielc lh:d umrdrl 6rcrnne the 196 1 .sufFeml }:euer,ll's rc- pm'1 11200.10, 12u(1.1'L. IKtrZ.(1l. I~nY.(11) . Isu?.n5). 'I'he oschangc; dc!unn<trntc lh,d li+l'•\1';tnll ItA'I'escrl«itt:~rc.Lj,:u'(1ed lhrse sludicc ac rclinLlr. ('I'ht• rcp,,rts ceere nnl shnred.) As p;+rt uf lhic internal discusniuu of u'hether ill chare the I4tdlelle repurtl: w'it.h the lIS I'uhlic lir•:dlh scr+'icc, RrFI\"c gencrd ruuu.cl. Addi:on Yen- nr,m. `mnnru'izo/l his vir•tci, nbrt« nicn- linr ill n Inelnur:tntltnn dntc(I Jul) 17, ISlcta (I8n'L(I51. 1'rantan s;+sv tho 1{;d- tcl It• wurk mi n it•nt inc as n tvay I o,lnxti fy smnhing hcc•uu.c• of iL~ pnsitirc hcurl ilx. If ItR W cnuhl remove Inu mful cnnslil II- ents from timokc, it could then, n•ilh a c'lt•;u• co» scienc,e. prumolc cig;lt•ettei as uicntine deliverl' devices I'ol' people un- drr slress.'I'he memo ol,cue: 'I'hc delc•rmin:rtinn hy linltvlle uf lhe'9r:ur quiliziul;' funclinn nf niculine, ns rr•reived by tht• hnnuni svslrnr iu Ihe delicered <Inul:c r,f cig:u'ctle.C tnytether w'ith uiculine'x possible effect un obesily. drlirclx to Ihn iuduslr,v what well tuay he its first effaclice inslrn- ment of prop.+gnnclx cuurder to that uf the Americnn Cnncer Sucietp, et ed, damming cig:u'ettes as h;tving;t caucal ydatinnship lo c•nnccr af the lung. IISU2.u5, p 11 1•e;mcm x;nc nicotinc ns bciny; iml,m'- laut fin• its "Ir:mquilir,in}%" el'fectS. mrt for its tuste. In fuc•L, Ile even mentions taste and nicutine ceparalely in the document, indicating that these quali- tiec,n•e dislinet.'fntv;u•d the end of Lhe memo, lie noted: rllnrrnrrr, rrir•ufiue r, qddir•lict. IPr•rtrr, lhen. iu Ihc bnxiues.< ,(rrlling nirofiur, rur nddir'lirr dr'o,ry rl('crlicc iu fltr' crfrn.se of slrasx nrcr•brurisnrs. Icntph;+As nddctl I I the?.(15. 1, -I I Project Arlel 'I'he hnsie phanuacningy emLullicll ill the Rnllr•Ile prqjoctx +cn, fonnded on lht• 1'ealiz;dion that cikal'cltc's aro nicu- linc delively s>stems. In thee proeess af delicering nicotine, how ever, cit*;u etles alcn deliver numye:nrinogcnsnnd uthcr toxins. 1iA'I', svith help froln Battelle, developed ;m allernntive dcliver,l' sys- lvm to adulinister uicutinr. I'rcc• of lhc tuxins 6'om tohnc•co slnuke:'I'he rlecign goal tca+s a snfe ciplretle. 'I'he dceice srnc cudc-numed Arinl. 'I'sco palenls cvefv issucrl l013allrlle un Arid, but RAT's Sil• Chnrle, Flllis is listed in buth as lhe leacl invv.utnr.l-'I' A 147(1 letler G'um IiAT to Addison Yea- nuul at IItF,W notes that "lhe p:dents 228 JAMA. July 19. I{I95-'Jol274. M,,. 3 teerc pul ill Bnllelle's name rather thun Ii.Aa':s for suc•tu•ity rt+nsuns".(1'LU'l.ll1. II 11. N'icl relied on burning tahncco to he:d ncenU'rdly:u'1';lnl;od Lubucontaining nicoLiue smd;ln aerotul fTnerntor, u lu.r Iorinl >;uch nc wnler that w'utdd furro nn aerusul tnc(•n hc;dell ;md thcn cooled. '1'he conLMwner tvuuld inhalo through Ihew cenlral c•oro and avoid fnI(Irllj 111 tobacco 1molro. Nicotine diccoh ed in the eh•oplels t'uuld he inh:ded as Irm•L of' lhe nerosul. 'I'he pntcntv for Ariel emphasize the impurtnnce ol' nicotine fur the smoking crcpcriencc•:md indicate Lluttil.sact.iun is phsu'rnacoingicnL One uf the Iralents I1rJteF: A U,td :md utisf,rillp "sInnke" can hc oh- lainod a'ith a high nicotine to L•u• r«i„ ar, ns sumotiltiea expresxed, :+ lo+v rntiu uf total pnrl iculalc m~«lcr fl'.P.M.) ln nicnlinc.'I'his kdtcr I'alio con readil,y be reduced tn une- qmu{cr ur Icss uf l.he rdut:s nurnmlly ex- pr•cled af xlnoke frrnn cignretlt:s Lnviug un spcciul provision for rcducing the t'atiu. lf rfrsired, tlrr nicnfine cnrrlerd mng be rnnrle rrurwrd, brdt rrilh IilHr u(fhe nor•ruul pru'- lirufrdr• nurl nryrur phnsr... 'fhu>:, rrlren IIm srnuking rGa'ir:r' i.r uurnh,rd Ihe xnmhra'reil( drrur iufu Iri.c rnunUr a xrrmll mrrnrud nf xmnke ndrqrmle In enlisfjl I)rr losle of Wu xrnnhc'r rdmrY milh llrr, niculirm rurNniuing rterusnl. Although thc inventinn lhus sceks pri- marily lo furnish a smnkhrp decice refrick will Iield tdcoliae irF aurn arceplabte fnrm, 6nfkh psJckoloyicnlllJ nr!d frklJxiologicaflp, btd withottt the necessity for tnking into the sysLem sq much of the pt'uducls of combus- liun o+s is usual when srnoking a conventional t•igweLle, it mn+y nlxu he used Inninly or pam- tinlly tes n mcans fur nchieving grenter hre- dum for inllua+cing the taste uf thc smoke, for introducing fluvurs xnd so fm'th.t It'nr pMtsis ndde4l 'l'his patentdclnonsl.rates the pharma- culogic•;d rule nicotine plays in cigal'ettes. It shou:c that the esscnce (if a conven- tiunal cigu•eLte, sl.rippcd of ita undesiirv alde elernents, is "u smuking device w'h ich will ,yie1J nicotincc in an acceptable furm, both psycholugdcall,y and physiologically;' While the product w'ns never Lrought to marl(et its cleslgll and conceptiun dem- onstr:+te whnL BAT and 13&W thought scns the mosL in+portsmt part of their tu- hucco products: nicotine. Aricl continucs to live on at B&W. 'Phe company h«s received three addi- tional patents based on the Ariel con- cept., moct recently in 1994,+a-0i BAT'S INTERNAL WORK ON NICOTINE I3A'I' also conducted sLuclics on nico- tine at its own k+borattol'y in South;mip- Lnn and aL other company Inbut•o-dorics I neler¢nce 13. ['.olumn 2 I~nec 3p$6. SL 55, antl 66. a,tl r.oWrnn 3.11,10, 3 :u'ouwl the w m Id. Sonlc uf lhesc t't :crarch activities arc tlescrihcd iu repnrts nf fSA'f's nnnunl rescarc•h canferenct:s. OLher resenrch nc'tivitic~ on nicutine wr described in site t'isitt re.ports nnd in rese:u•ch reports. Those documentii im dieale that lhe ceutr;d intportxncc• nl' nicotine wac recnl!nired thrnughout lhe cnml rany oecl~i+n cxlended pcri od ol'ti mr• and Lhat nicotine was uttful fur ill; ph.u- Inuculugicnl I+rupcrl i es. In Seplember 1969, I). J. 1Vood h nm R+&.DI's at ItA'1' gave a present.;+tion fim companVexecutives about lhe Hr@I) eork llie contpany n•ac (luin(!. The nutos nf his talk, whic'h sulmn.n'ir.e lhc w'urlc being donc on nicnline. prnvidc mmmcr- otls detuils about thic systemntic Im„- gfsmt of phnrmaculugicad resc:u'ch: 'I'he presenc'e of nic'uUnt• is the reuson wlq' thc lnhacco plLU+l scns singled nul from :dl other pL•mts for consumplinn in this n«hrr unusual tv:+y. Nicotine hxs trell tloeumentud pharwacr,Ingic:d ncliun. It is claimed lo hnee u duul e6 ftrt, nctiug Loth xx nslimuhwl und a lr:rnquilliser, Il is hclicved In lir respunciI,lr Dn' lhe „~nlixfncliari' uf s,nnkin/;, u~ing lhis lrnn in lhe physiulagiral rnthm' lhan Ihe ps,rehu- lugic':d sense. Inveslignlions at It.~'l•D.41 .uc aimrd nl ISn<ling outmme xbu+rt the fuclms eontrnb ling nicotine nbsarplion in lhc lum+an rcrpi- relory systent. Extractable and Non-extrnctuble nicotine (Jefine). Ibssibility of getting satisfaction fnm+ fairly low• nicutine cigarettes, provided suff- cient nicutine is in (lie extractable form. Cel•tniu metlic•al studies would seck in blame nicotine fur ctudiu-cnmulur disca~c, sn high levels or total nicotine are not likely to be f;eshiunnble in heallh-conscious c•ottntrics in the fulw'e. Mt+ntiuu absm'pliun uf nicotine cil+ thc moulh, e.g. c•igar sntokers. 11184.0'l, p 71 BAT Research on Nicotine RobcrL J. Johnson• n senior scicnti<tt with 13tGW re,ecat•ch an(I develupment., sunintarizetl n June 1967 meeting tu dic- cuss pnst and pt•esent research on nico- line. Sir Ch;u Ics Ellis sttu•ted the Inent- ing by remincling those precent "lh;+t hc had first in'ought out the ccrncept l.hnt w'e !tl'e ill a Illcotlne 1'ath('1' 1.111111 a t0- bacco industry' 112(11.t11. p 101. DrJohnson describeti si>: meus of re seal•ch on nicotine that the RA'1' R+EI) I,a'oup had on its ngenda at the time.'t'he.w included Project Ariel, studies on "es- tractnble tlnd non-exLracLable." niculiuc. the pli of tobacco cmoke (relaled tn lho work on cxtractable nicetinc), nik:Jinc lil tel• addilivc•s "w'hich seleclivel,v incrclsr uicutinc dcliccrthc ~ynthcais nl'rnrlir, labeled nicotine, nnd studies on lhc al'- gannleptic propertics of nicoti nc 1120 )! I I, pp 1(I-I1)•'I'he pl•oportion of nicotine thxt was eXteactnblc w•ilh chloruform ~c,+s rrc- Tne Brown and Williamson Docuntents--Slatle cl al 52081 8241
Page 97: zme50d00
I 0 : o{tnizr.d ln bo :t hc't tet' yiaul;o ul"k!.ronlt~ll I" nf luhllec•u pmtluck Ihau Ihc lolnl nil'n- liuo Ic•\'el. ll \cas lhnught lhnL eslruel- n6O 'nit'utiuc rvnc•hcd lhe In'mn nlnl'e ,plirkly' Ih;ul ultexlractablc uic'nlinc 11'1n5/111. KNlrnctablc niadinr \\ns. cs- icnli:dly, frcc'e uiroline, lho I'urtn Ihnt is uv,rv casil,r nlc.urhed :ee•rosc hiuluy;ic utenlbrmcs.' Thr I't;"r:urh pl'uy!rnm t\'als c,mrcl'ned aith lllc rlelivery uf uicntitta in smnke. :mJ its ans,n'Irlinu. 'I'hv orp:lnnlol,lic m,rk r„Inr.. closer l hvl :mvi llingolsr in lllt• dncumrnls ln sugit!esliujt an iulrroct in Iho laae anil Ilat'urnf nicnliuc, lnl(. it 8t•111:1111' Reellri lq hat't• hecn IIIUI'e rull- cerned \c'ilh lhe irrilaling prupcrl ies of nicntine nn nlucnus ntenlhratlo.ti.'fhix is un impul'UUn ivrohlcnl ill ci,eamttc dc- si}tn s'mrr niknline nicntinr, aillt'h is readil~' ulisnrhed in Ihe nwulh, is ;tlso it'I'ilatinK tor the llirnal.", A fih(-l' additicc /pnl~'cllpitvlciniine I I'I':I I) thal honstecl llle deli\'ery uf "ex- U'actablc nicutiuc" llr alkaliniziug ci}ta- rctlc• smoke wus uscd ill a serie.~ uf hu- lunn lt•sl pancl experimcnLs IISLI5.qal, blcraasetl levels uf "e-strnct,'Ible nico- line" increased the "inlpact of inhnling" tvhile producinq a"smoJl inc•rease" in thrnal. auld uosc irrilatiun. Mouth irrl- pact :uld moutb irrilatiun wcrr, umd- fcc'lc•d. Research Conference,1967 .'I'he 1907 RtCU conference was Itelcl /ltnring a 1,-d.;Y pel'iod ill Octobel' /1lttb.01, 1165.02, II(35.0'I. Antonq the tutderly'ingassumlltions llle parLicip:mis cxplieitl,V agt'ee4 nn wcre the I'olluw•ing havin}g to do tvith uiculino: 'fhrrc ic a minimmn Ic•t'el nf nirnline. ,clno/;. iug i.v un ndJirfirr bnLil alfrihnla6te tn nir,dnrr nurl ILr lnrnl n( uirnfixr' a,(Irrlx fler fqlv q('ahxnrp/iun hp flu• surolrnr. 1/ ILrrr ic rlrr iulrrdiuq. fAr're. i+' nrl Ittuq ,a,urrr rn' rrrpinrlonl Jisrns,•. Smnkinet has lmlh physiuingitrd and p.ep- c6odr,l.ic:d cffcc'ts. 'I'here trill hu sutne grrcennneuli in\'olre. ntent ill lhv ln6accn imlustcv ill lhe fulto'e. Iclnpha<is ndJedl 11165.01. p 21 A handx't'ittun etlil in tho dnc'tnncnt changes the phrn~e "an addiclivc h;Jtit" "a habil." 'I'he eteelinl,• nntes rellect a cuncern tcillt the inrcitnbilitl' nf fulm'e gu\ern- ntent Iegulaliun. It \\a= uglcrd th:rt sntukinti is likeh' lo Lc associated uilh hcnllh c'onlinuunsla in Ihr Nlurc•tutd Ih;d it \cns nut a pucSin.p Plias,•. 1t ervr..' lidrfq. mnrcurn,l 0lnt fuLnrrn runufd br iqrnlrrtl in Grlix6efinn u% a Irnrt! annl rL-hq nrlu•i,,../rvlliqU unfru'r !v rrrcprr'1 I~nld "l' y~•rrhnl nu,t nl rrrrrudhrhn'r. Irniph;lsi,. :~ddcdl II Ir:inl. p ol -I'hnl, thc lap IIA9' scicnl.lsts reco};- uized th:tt health cnnc'el'll. \t'ere nevet' JAMA. Jtnv 19, 1995 -VOt 274, No. 3 g(ling to disappe:u' (ie, hc dislu'oven). Pm'lhormure, they felt that FDA•styIe pruducl regulaliun cntdd be,justi0ed by the public health cnutuuutily. Aricl wus discussed, ns \a'ets "n c•i);n- rollc aimed to be pleacautl,V non- inh;dablc" ( I In6.n2, Ir G). I\'loroover, "I ill. Was noted ill passing Lhat tho trcucl lutt'artls making cigu'IeLs IlitUc ci)!al•sj milder and Lhcrcl'orc nwre easily inlntl- :tble \vas tmdesirablo on heullh I,n'ow14s" I116u.u21, p 5/.'I'hecc two cnnmiculs cnt- phusiae the inlporlance of inhalation to tile uormnl ftnlctiuning of cil;aralies os \tcJl as Lhc fundnvmnl;d pl•ubleut lh;d this poise ill the prollucLiun of diro;tse. 'I'he impurl:mce uf nic•uline was enr phnsired elsett'hcrc ill the cunference notes as \vell: A}tenclal di.cussiun fnllmmd au haxir' nss sumplinns tvhieh 1;uiJrd Ihinkinp ill tho lii•Id „f au„I:iny; nn,l hr:dtl~. \V6ile recn}!nizinp: tLe impnrl:mcc uf p.yc'huingicnl fzclol:= insniolc- ing aud lhe poccsibiliLy that sonlc snlokcrs tYOtlltl :ecce)It I10t1-ItICUlllle cigal@Ltes, it u'ns fe~f61Jm1 vir'aline i.c impurfnuf (nr flre vmjnr- ilq r f s'woker.e rutrf fhn/ t6rt frrrru rrf nit'uliurt crnr br si/ptilicnnf. It \cus ;dsa eonside.red t.hlel nieotine \eill bre iuc•reaingly subject to ntlne'k. It \cas agreetl qud Ihere will be inceeasing governmenL im'ulvelnent in lhe indusl.t;v. lenephasis uJQedl I11(15.e2, 1? lll In Ute cuntext of Lhe laboratol;V worlc these scientists were doing on nicotine at the time, these contments enephasize the importanceof nicotine as a pharma- colugical agent in tobacco products. Research Conference, 1968 A major conclusion of Lhe RAT re- searcL conference in 1968 c'uncet'ned the nectl to lauk for subsLwlces thaL wot)d havee the actions of uicutine ill the brain buL that would not be toxic Ur Lhe circu- latm;v systeme rl'he intended effects werc "bi nin stimulation ancl stl'ess-t'elief": lu victn of iLv pre-entirtrref irrrfurrfrrutre, fhe pknrrrntcnloqqnfuicufiucsltoulrf rontivrcr tn 6n krfrt ttnrlrr renietn mret rtlfetdfnu pnir/ lo the possible rfi.scucrsy qf oUtr.r' xuGsfnveces 7m.vsrss'fng t/ae rlesit'rd fuuGU'es rf braix sfiutldelinu nud sh'r.v.v-re(ief ruFUrnrddir•eel r;(firefs ou !kr cimrdnlnrf/ ag.vfcnr. 9'ho pussi- i6ilitl' that nic•ulina and nLhet'substances tu- gc•Lhur rnay exert effects I:u'ger lhan either veparatel,4 (s.\'nergisn) should be stutliett and if nec•essau',v the aUcnlinn of A1nrkct.ing peparnnenls should be Jraa'n lo these pns- sihililies. lemphasic adtled111112.01. p 8) 'I'hus, the pharmaculogical effects of nicaline vvere of 'pre-eminenl impm'- Lance," and it was helieved Lhal, other subsLancex that could do the sanm thing withouL adversc•.ly ;tffvc•tiug lhc circ'ula- Lul;v spstcut shnulQ he snttghl. 'I'his cuncluciun nulY have led to tvurh thnl \eould be eepnl'Lcd inlet'nadl,v :tL ltA'I"s h\Q U laburalorius et few ,yeal's later uu nicnline analogues. Research Conference,1969 'I'he minutes of lhci06P researt•h c'nn- ference inc•Iur1c several salient conunents relaLed to nicuLino II1li9.1111. Ill tliscussing 1'P.I-Lrcalell Glle.ls ( I'I;I is an atldiLive that buosts exll'aclablv nicotine delivet',v).I he nliuulez nutc lhmd a sul;gestetl, upper lintil fur l'I:I is ar7, nf the filter b)' \vs•ight because uf cuncrrn abuut a(lvc•lxcY•ffects nn biuacsq' (lusi- culng)') tests I11fit1.01, p 81. Nicotine came up in lhe tlisc'usciom of nouLobacco materials for smoking: 'I'hrce w;ts_a genrral rlistussinn nn rn,utubacc'o nln cl'ials ;md, lolrgul+' dut• lu lhc difGculties fureseen teilh Ihe addiliun ,d' nir,- liuq lhc• Conference did nol enckage at proseul the likely snrrrss nf a lnLJly mnr LplIJt'CU l'ig:lPVLIt'. IItRCVCPr. 11 I1MC SVt9np quilc lilcelr lhal nnolakwcu ncetcri;ds \\'ill br socce.ayGdl,e incurpnrnLrd intrn ei>;:urltr'= as IJend l'tmvtilttontn, pv'lirul:u'Ic in hrn11L uric•ided produc6•. .l fm'qr' nsnpr nl rn,u- fubnrro rmrtrrirrl.e mo¢td be lil;c•Iq hi int 'r'rv.\. Ifte drnunrd,frn• hi,qlladrotn+e fofult'eo.v. Ient- phasis added] I116t1.e1, 1181 TIIe provision tlf a cOtell)It'Lely Irnbac- co-free protiuct wac seen as tutlikelr because in such a case, nicoline a'atdd have to be aclded. It is doubtful lhat t.hi~ represented !t technical obstuclc•, wllich su9gests thaL lhis judgmenL retlecled a perceived regulatory barrier. Were nicotine to be added to a tobacco sub- stitute material, it might not have been a lxlge'step for a(Irug t•egulatnrv au- thoriLy, sucb as thc M'llA, to raise qac•s- tions about whether the nicotine in this instance was a drug. Research Conference, 1970 A research conferenc•e was hcld in Nu- vombel° 1970 (1170.01j. As had been dis- cussed Llte previous year, pure nicotine was nott to be used as an additive in a tobacco product, btdt a high-nicotine to- bacco extract was permissible. '1'hee addition of nicolinc to SM Isubslilute materialsl was considereJ, aud it \cae rec- ouunendel Lhat nicotine per ac, t:huulti nol be used insitle any tuUacro fxclut;c. Ro\eecvr. high uicutine conlent tobacco cxlracl mighl be adJetl. So Inng as SM rc•mains a blentl constituent, it wotdd nnt be cnnsidc•re1l tlesiraLle ftn'the supplier to inc•Inde nicolinc ill the fnrmulaliun. Ncverlheless. fut'-Pln'- poses of laboratol;v ezperimentation tnldrr suitable c•onU'ols, nicolinc-cuntaining tn;ue- ri;ds uffered hy supplicrs may be used. 17l 7u.o1, p 41 Once again, this conclusiun seentS to renecL it ergulatol'y', ralher Lhan a lc•ch- nicul, concern. '1'he Catladinn subsidiarv t\'as encom- a);ed to explore the development of rr- c'onstitutecl tobacco with high-nicntiue tobaccos 1117(1,111, p 5). Cunsumer needs . were to be addressed: lhe nrown antl Williamson popumenls--Sletle el el 229 '
Page 98: zme50d00
U -/6r• nrrluhnAsu, nf rrirnfirrr n'ill. nr 1fr,• bw dq. im'InrLrrll rnlrs ,urd ,~prdihrinru 'I~hv qrcrbqriuyl In'ugcnnml(• nf r•<o:n•rh nt \nlll lllllllldrnl IS'nP Slllrlml'I P,1. allroil (lrnl ry'r•rrlra~ rm(rlm.ci.c clmrrlrl Lr plnrrd uu rlifrYf fnn)nu „irulirs rnl6rr' Ihrru nrr wriural.a..-- pru'fir'qlnrly iu rirn' nl rvrntl nmjr.r rnf~ rrnrrrs iu hruin /,harnrnr,Jngp. It is ~mcism agr•d llnll ulnch ul' sarll tn•li, sclll I,o underlakru mlder cunlricl. Il sca~ I,rnl,n.eq I6:11 :1 .rnior pvi'niol a 6nu1 haniplnu .Lnnll l Lr r,•sl~,msildo Gnr- „mlinnling Idl 11m rol~ rniul InlrrvSl nWl tlnrlr Ihruu}ihuul Iho t Imup.'I'haro i, uu urt;rnl necd Ill prrpw'o It slatu. I'eciesa nn nll majuc aepct•ll nl' Lllr- ph:u~luar,d„):icul inllnrnrr•s r,f nlrntinr in Ilu- sin„kin)± prnrrs<. I rinpha•is ,rJd~ ~il I I I IFIL115, pp 1R 141 Nicotine is impnrL•tnL hc•t:ul>c of il-e phacmncolugicnl prnllcrlic".'I~hr rcl'ce- enec• ln lhc:n'linn (if nicol iu(' 1 ui Iho luu,L~ nup' hc a I'et•u);uilinn of Lhtr fncl I h:d I hc lunj! h:IS an exlt•Osice nPIU'n/'I~:. (if ncI'Pe endings lhat [•lul resllund Ln uicntine and dircclh' stinwlutc lhe hr;lin.l 'I'hn enl- Ilhnsi. nn nicoline in lht•se crmferrnce minules c•nu nnly htn ca•ruu<c nl' nn inlenlion lu havt• n pnl4uet that Ilelivel :5 a reliahle tmd predictahle tlase ol' nico- liue lo lhe consumel'. i.r'. ;1 sInoktv' Ims Icau'ul by cxporience, lllal if ho perceis'es II p:u'li(•uLu' Ievol al'inlpacl, Ilc tcill subselltlenll,y receive lul ncceptnhle de- til i•o of satisfaction. h) IfscearelamekebrtlecusciuprotlucL lorms of Lhe levels of nicutine in wunlm cur- I•rntlv urailnble-and rren nlol•e so if tre src fured to m:u'kcl cie:u'olles ail.h 1•e(luc'erl Ies'ek trf nit•oline-lhen it is impnrlanl ln si)•niGraull,r inc'rea.e um' unJerstmlding ul' imp;lcllsalisL•IClion.'I'here is lul urgenl nocd fur esprrimentnl ci)!arellns in tehich Llle les•- ol, af nicntine in smnkc (:md unulcc PII) are c;nrl'ull,v cnnn'nllerl. /1181071 ISA'I' scicnLists had a snphisl.icrde[I und ulrto-date Iuldm:sLantling of nic•n- line mld its rnle iu lonmkin/, behnviol•. 'I'he impurtlmc'e of anul[e pFl in tlesign- inl; mt effective prudue't at lutrer nico- Line deliveries is npplu•cnL. fintisGlction is descrihe[1 as bcing relaled to ihe ef- fvch of uicol.iue on lhe hude, espec•inlly' • cuo the brnin, nnd l.hc itnporl+mcc of in- h:1lat.ion is emphnsi•r•ed.'I'his is Lho firnl plllce ta'here';mlisfnclion" is clelu'1,1' de- ftnecl t>.v the stnffof n tobacco comptuty. 'I'he discussions held nt this technie•ul exchange were vhtu'ed wil.h diviviuus outside of R&f), at IiA'1"s jninl ft[CD! mau•keting cnuference in JuI,V 1984. Koth Lhe noLes summat•izin}; lhe techni- co-ll exchnng'e and Lhe ntinuLes of Ule Conclusions of Technical Exchange tliscussimt at that conference mention Meeting on Nicoline, 1984 the imj/a'Lance of consi[lering nicotine In June 1981, a R-day technic;tl ex- levelsihproductdesign/12'L6.01,ppGl- change nweling aminll; ItA'I' sc'ienLisls 071• The nlinutcs note: ` tvtiK hehl nlt ilicnl.ini. 111ti1.0ij.'I'hc en-. . ali inlpruvetnent in nur luulrl.tanding of lil'e suntnlal}' slated: . . nieotino action is of mnjnr inlpnrlnnee fnr fu- 'I'ho mnin cunrlusirm, reachod tl'ene ... ture In•odnel development. II'L'LG.tll, p G31 nl I'I;tPII1:111iCUlil1('/entillinC II1lOFlll'l'llll'lll8 '1'hls cttlllllletll is yet nlt[It.IICI' illtllcn- c';nl give•reliahle estitnn7esoflhe nicutine.Iql- tion of intent on the pal't of RA'1' to nf- lake6}•)!lYmpsufmurlccr.=,;Indtt'illlsuitaLle fecL the sLructure or functiun of the pm[•nuliunx, h}' wl iudicirhr.d xlnuluor. Mnny hod,y through tttu delit'el;V of nicoLine in smrrkrlx appe:u' tr, nhlnin 1'L-14 nll*. nf nieu- l' I'I'rtlll IhPll' ('IJ(al't'11"}, its tobacco pl'otltl«ts. flll[• IN9' (Ia , bl t'il!:n't•tle<tchichh;lct•:Idtdicel•)'nfless lh:m 0.7, m7e. of nicnline pci' cie:u'etl[• nc measm'ed an a slnoking nlachiue, rln ont . achiecc L•u'{m vuluule sode,, c) I'1•ncidingxnlakcivinhalrJ-cvenshal- Imc InhalAtlnll=l4~kof lhc nlcotllle is rc- lained. (1) Illlllltlt'el)' it IS fvlt that "nulis6icliau" must he rclalr'(I tu niculine. Alan)• pcoplc br- liovv it livl a"tchol(• hnd)' revpun.r" aud in- colcex lhr arliun nf uirnliue in lhe Innin. c•I Althou>!h Inan)• smulcrls appenr ln npI,runch a plnte,lu nr rnust:nli Ircrl of uiudiue in ihe hlno4, it is nol knnun: (i) It'helhor a sinuker feels Illt• nerd fnr :uv(ht'r cipnrutle a'hen his hhalJ letvl falls sil±uillr,mtl}' hclme lhic plalc+m leccl rm Iii) whelhcr lhe sinokor is seeking lht' Inorv• ll;msicut prJ( Icrels ulper- inqm,ed ullun lhe );currlll plaleau It•\ r•I. p If les'rl in lha hrnin is lhe ke)• G;durc, sce hace lilllc idce rd pre.Iont on Lhc reln- IiansLip bpllcer•u hbrr,d IcrclslpalU`I'n uutl Ihrr=r in Iho In':lin. AVOIDING MENTION OF NICOTINE While company sc.ientists woched on nicotine phal•macology, 13tCW avoided talking about nicotine in its mat'keting campaigns. One of the documents shows hoe' reference.s to nicotine nnd wilh- th'awal were ediLed out of un externally preptu•e[l pronpectus for a mat•keLing phutfm•alow-Qolivet;ycigarette.ln 1D78, I.isher & Co, at markeling management consulting fu•m in New Yurk, NY, sub- mitted a th'a1't pl•oposal fol' a low-[Ieliv- ery cigarotte to 13&W for review.'I'he gnal of the pro,ject was to develop ciga- rettes that mutched the parametols sug- };estod as desil•nblc by Lhe Nalional Can- cer Institute. A mm•ked-up copy of this drsdt nppe.u's in the docuntents• Befol'e editin}t', ouc pal•ngr:qlh 1'end: l;l Au inmlrJi:dr xrnsiny :dl'ecl I+6'I ;i:- (~Inrtnl mal'kel u'entls c•Ir:u•ly inQicrac :I snt'i:drd u'ilh nic„tinn is Ihc "iinp;lcl' nn in- tna,hn' tl'eml lowluvl luw-L;u' In'aotls, (d- hnlin{l. ln lhis sensotiun a{!rnuinrp;u•It nf the lhnuglr rlo'rrFf "ulOn" /otn /ru• brvattls knuc reseal'd a smuker is ceolein{l, ar il it a"eu('', bad finlidr:d n+rrros.c 6nrtnrse nflLeir ('rril'm'e Inrfrlirrr'xali.tJilrlinpbuninlnitr nl/ ndrrplydr• rtirufAle Icurl. An ancilLu•)• conce.l'n rrl:airv to nicnline drlivt•ry is thal (fn eali.cfgiultf lalo-rri['rrf itle r'ipq ref I e rcrr'e In bv (/rvvdnpr~l, if cmJ[f rrprexruf rul rllrc(ir'e rnr'rm,c of n-i/Adrrurnl rnifA seccre irnplirnllnn (n' lon,l. fra'nr wm'kr( grnlvllr. Iemphaxi. nrLlndl 112(13•lll, p 11 AfLecediting, it read: 9 Cul'1'enl nlarket U'enJs clau'Ir indicate al Imllnr n'en(I lmcnni k,sc"I:tr" branJ., >Il thnullh cm'ecnl "ultru" Ina''y;lr" hr:md.Iia~'r' hud lilnil[•II succcns 6rcaust• nf lhoir faihu'r l~~ deliver snlisfat'tiun. I/Dli.ltl, p 11 A,IL<poc•ific mention of nicutine n':1, excised. As(riginnll~• tt'riltcn, the Ilnrn- graph ncetu'alcly t'eflectecl a conecrn wilh provifling, a phafmac'oingicall)'suG ficienl (lose of nicotine to c'rrnsunu'rS. 'fhe etlitinl;' prnce.s concentrltcll all uf this metminy;' into Ihe lerln "anlinl'ac- lion•" "Satisfactinn" is a cul,hentisul that obsc•w'es lhe (;'enuine ph:u'In:u•n- lo};ic:d intent. 'I'he intent to Ilrm'ille satisfaction is, nc the scientists dis- cusced ntt the.ir canferonces, ;ul inlen- tinn to maintain au "atlcqu:rte niculinc level." CONCLU SIO N 'I'he tloctnnents shuw that Ule t•o1u of nieoLine in tobaoco pl•oQucts is thal of a phtu•nlacological agent: 13&W und I;A'I' value nicoLine not fom tchnt it does to tasle and olfaction but for what it tloes to the bfain. The nbsm'bed close of nicu- tine is a facttn'to be considered in prud- uctdesign. Nicoline isirrelevnntto taslc. '1'he sensel•1' pultels occ:IsionsJly de- seribed were not nslted Lo measm c ul.cle in i-elation to nicotine• Hathcr, ihey me+r sm'ed tlte irritation nicotine caused in diffel'ent forms, ot' a'hether nicotine hml a ccrtain "impact.." In conU•asl, inhuln- tion is essential to the core funclirm of a cigal'eLLe, which is to delivet• nicoline ln the brain. Inhalation is necesat;v for nicotine absm'plion. LSA'P's itlerdiu•II cigarette was embodied in thc Ariel cou- cept:aclevice designed to minimize toxic smoke components tuul deliver niculine. The contl'act work and the intel'nnl company research projects on nicolinc reviewed herein have not been Itublished in lhe scientific literntln'e. Often, lhc wm'lc was well ahead of its linle. 'tho Battelle work in Geneva was at the [alt- ting edge of nieoLine pharmncolog;f.'I'he wol'k on sntol[et' contpensalian in lhe 1970s prececletl the main published re- ports 6'om the genel'nl scientiflc conr mtmit,y by sevel'aI )rlu'sr2 'I'he public rel:ltions pnstnt•e of R.F11' diffel:~ nuirhedl,y fronl the intel•nnl ss'nrla- inl views expressed by R& W nnd IiA'I' (lul'ing thc last 8(1 yeals:' Whilc Lhe pull- lic posture is Ul.dt nicotine is not addict- ing,t' company i nternal writings 3(1ye;u'• 232 JAMA July 19. 1995-Vol 274, No 3 The Brown and Williamson Documenls-SiaUe el ar 52081 8245
Page 99: zme50d00
4 0 tly!'u Ilsyqnt'd addicliuu.'I'In'ulll;huul. lllt' 'L'L ye:u'n frunl theSrmlhllamptun lu D1un- ll'r:d ennforrnro:;, Ii&1\' and I{A'P hsd:l I((•t'n intta'l:sl in :dl :IRpt't•llt ol' lhl' phw'- m;Leulnp nf nicutinr.'I'ud;q'. Rtl'•\\' puh.l liel}' nrccpt, onc, uud mll ' unl'. cnnclu- sinn frtnu lhc 1961 Rm•/;cun };cncrd's mpnl't: thal Iliallinc is n hahillulli114,nnt nR ;Iddic'tiul; Qrul;r'I 1'rl hitt'h-Iot'cl eXrt•ulil'cs null RcirulislR nt h/nllh litl \G :utd BA'I', nl nuc limc;ll lcast, Ilriv:drl~' ;yqa:ur/l lnl,dtc AlWisnn 1'r;uu;ui. IPf ; rlllsrl'\'atiult In hc;IrL' lhl;V \el'Ir iu Ihr IIIL'rllllll• Itll,lnl•FF. rl 'iLi. e,.li: un, slq,p„rlr,l iu p.ul ly Fl:nt I':FrIlnl fr.nn Ihr f:;ni"m:J Ibuv„r In<I,Irb, n~ll I:IAItl. _h'1'.INIi2 all,l 11' I' 1111°5 Ilncr Iln~ 1116. 1. sily url:Jifnrnia'I'.b hrlaloJ Ilizrarrv I(r. .rw'rh IYnKr:ull. 1\'r :11.rr (hnrdt 1'hil linl' Id ll:o l'nict•rvit)' ul 1':Jifurui:l, Sall I'1'flnci>,u, mld Itnbiu h:u{h:d.nc :md'1'inl NuLm nf LjefG C:Jq'nsrr:wd Ilrlnl;unl. trhu pruvkled n+~irlunrr iu ind,•sinl% Ih•• ,I•r.v: rllrmx. aud Adriaua Alnrchi•urr /'oc a.si.l:mrr• in mNnu>nipt pl'r)mlalinn. I'inallp, in ml vl'a in tchirll puLlir juslil Iltiuns;u't• inrrrn~in>!ly held in d j~Jaiu, tcr truuld likl• l u I La uk . tLrllnicrrxilcufl;:difr,rninfurprucidinl!nncuvi- rl,nulrul cunmliltvd lu ,Iradrmic I'rrrJuw ,md ILr ptlblit' inlrco=l. It tclndd 6avo br:•u .impL•r-:nlll chv:qra-fnr Ihr univrrsit,r lr+.implc \cldk ;m':Ip frmn lln, prqjrcL Afba' tdl. lhr hi1tnr; uf :Lo Inbnccoissut•is unciu\chirlumml' inailuli„n=lrntr falluter,I I6t• palh uf It~:l5t rrzisl:mor :mrl hlRrll 1 u canfl+,ul lhe i.<uc< I'aisrJ in Ihete duclnnrnts. Nu nr6ninish:M1ul' ol' athrr nflirial rvvl' LnIJ ux lu xlop. Quile Ihc t•uulr:u;e, Irr tcri't' cucnul'npcrl ;unl Iq'u- Itt9ed in olu'tt nl'k.'Iltishollncior ist+'L:d ol:lltl•x thc l)nire;xil)' nf CuliGn'nia a ktvsl puhlir: iullilulion. Relerences I, (IR Ilrpl uf Ilr;dlL nml Iluln:nl Xt•rcjcr•t-. 1'Irr 71rrJ11, fuuanprvurrx n! Fnrr,tinll' ,\'irnl nn• .6Mir. linlr. A R•jrrni r416r Gnr,/rnn Crnrrul. \\'nxllink- lun. II(': UR Ih•pt of Ilr•nlUl nnd Ilnnnln M1m~cLa•I:, I'uhlic llr•allh Srrcicr. (.'rnlar, fur 11i<t•n.v t'rnl~ InrL Cvnlcr Gn' IIralLll I'rrunlllinll ;nIJ liduealinn. Offce an Smuking anll Ilealth; 1988. DIIIIS pulr licalinn CI/G R4.SIIM, 2. UF Ilrpl nf Ncxllh nod Ihloum Scrviere. /7r•~ dnriuq Ner !/rnlllr Cnuxrqrrrrrrna a( Srnn&iuy: !.' 1'rurx ef 1'ruqrr•ns. \1'nshiuglnn, U('; Il,l' Ilel't'If Ilrallh:wd Ihun:nl FI•rt'iers. Publio Ilo;dlh •u•r~ vitv. Crnlrlx fur llil:caxr Cunl r, Ik I knt rr fur('lu.rni•. Ili<rllsl• I'recenlion mld Ilv:dlll I'runlnliuu. (II'Rcr rrn Sluukinh nod Ilenllh; I!ly!I, I/1111R pnblie:rtiuu ('UC R!LN11 I. 11. Nlnntz BA, It:n'nr. Ilf„ Iton, I.A, Ilnnunrr I', Slndo.l. huultiug lllrnnph a krtinJo nt lh~ ~ I nL.l,~en iuduclrc: Ihc UI'mcn /uni \\'illi:nnson ,lurwnrld!. .l:0la, 197.'r,274:219-221. J. I'vxplor 17. $:IlOmrnl uv r•i•runl'Iinlut;,~iFx. Iv.r.: %'r,6urru ('unhnl. I'•q:::a.1~.15s. , 5. 16nl;mcr I', SIaA,•.I. liarm•. I l li, I ir•rn 1•A, Gl11A, l anrver runtrvI nf inl crnnl crlonl i lic rrnrareh lu pnrlt•ci ng:lin*1 in+llh;rls IjnLilil' V ~ Inlc<njt~. Ihrt Iirnn'o nnd Willianls,nl dnrmuenls../;l,llrl. I!r!li,; 21-12:11~2-1a. li. Rncalf~+llogrnfl'h}'?irianc}lun/ciuqnrdl6•d/L: :1 Nrp,:N r,f IJ,r 8n(pd ('n1Lpr ul' I'Inbr'n•rua rl,r $GUnkivy iu Hrhdnu la ('nln'rr rrl' Ilrr J.mN rlrr•I Ulfu.rlli.rr..rx. Lnndnn, Itn4l:md: I'ibuan ilvdie:d ISI6lishiu{; ('n IJd: 1!1112. 7. \I:nliui L,Il:mnugW,A'rnr,,,•ud,x~rimdnpg. Nom qurl:. N1': ACadrmir ISrss; 1964. R. -'•-dct•i V. 77rr llixlrn'g r f(7inirnl liurlmv innl. JAMA, July 19. I995-Vol 274. No. 3 r,yy. 1'rarl Iticvr, Nl'.'I'hv I`:u4hrnun I'uhlirhin~ urr,up: I!r)L!. !1, I:IVUherR N.'1'hv rflbclc nf nicalinr nnrl vigamilo xn;okjui; uu fmrd eauriunptiun nnll lnnlr prr4 rrvurrc, AdJir/ Hrhmv. U182;7;1174C11. Ill. Sladr.l. Niruljnr Jt•lirvlq Jericvv. In: Ulirnns (', Rludt•.I, rds. .\'irnl inr ,l ddic'linrr. 14'i nrilllr'x ruul r\lnuqyrnrrld. NI•u' 1'ul'k, NY: Ikfnid Ilnjcel:,ily press Inr: IuP7:8"a. 11. Ilrnniupfudd.I. I(rrllan It, Nivnlino drlit'ul')' kiro•t!c, uud nbllsr li;l6ilily. ,1 Gnr.euf/ ('liv 1'..'I/rlwl. 1'17Y9i I' i4:l4SU. 12. I:IIi, I I, Crharhnrr II. \Yillisul'lm U. SnmLiup dreim', llg Ir,Arul ;2L%nIL. Assignt•d tn IfallclIo, !Iffl. I:I. I! Iljs I', I I Ipglm= \\', Sno ddl l{; drrires: l IS Patrnt . ^faiual. In Ilnllrilr, IINR. Il..lulul=nn I(.'fonC.1Y. (IiRamllo: IIR pulrlll I!tr,:Cl7. h.,j(•nrJ In Ihmcn :md \\'illi;m;nlnl TuLuren I'n. I:Ihq. 15, I.itzingor I<. Cmuhink :n'lie!v: lIS p;LLanl .I!r'.IFerL AssiRnoJ la Ilmlen nnq 1Cillimn=an'fuL;lecn Cu. 191R1. Ill. 1'nrrnski II, I'lolnrr Ii. S;nul:inp urlirlr: US palrnl GR'Lif11G. Axsignr•41rr Iil'umn nnd Willinln- run'h+hnrcn 1},, 199 1. 17, I(- ~zlnw.kj I., I'upc DI. Lns.l, l'racnlrurr uf lhc n; isllcr uf Itltralmr-l;u'ri>;:u<'i lrc Iry' hlnt•kin(! 611v1' cl•nin. Anl .I l'nhlir Ih'nlUr. I!IR.4:7N:11!I•I-G!Ifr. 18, Kuzlotc.ki I.. IIr:11U;crlnn T, F•rec9tcr It, Nullr 11, SeIf-seleclrrl hlockiug of eenls un Imc-vjeld cignrollr.c 1'hnrrq RinrrLrur I/r/rnr. I11R!I,:fa:RIGRl9, IB. Uckt•ut•.I, Ilynnnvilv N, RI•alnn M, liruxtc S. Cnmparivl,n nf pnUCru. uf slnoking beh:n•inrchlul);e ;uuuul, xwnkcrl: in lhr tdulliple Itick Fnelen' Inirr- vl•ulluu Sludy (AIItPI'I'). I'r'rr: AIeJ. 1!IH2;IU:47f61N1. 21), Ilvuuwitz NL, Ilrnuill);6/4d.IIL Is4Jllixhiogn uiculinc lhrn=Lnld bn' uddirlinn: Lht• implit•nliunt frn' In6necu roguhtliun. N linyf J Afcd. IUU4:IR1: 121i-17b. 21. Fnnd, Ihug. xnd Cu<mrLic Acl. YI l1SC chnp!I. 2'2. Itusst•II Nl,.lart'is M, Iyrr It, I'eyra'ab:uld C, Itt-0ntinn of nianl!nr yL•Id nf ngu'rllux lo Llund nirrdine t•nuct'ul rnlinns iil nmulu•I:v. IhILL I!1%Il;2itk !li2 !/81. 2:1- Ilr'nriuf.c /frfrrr ILr llrul..r \uGrnuur:illrr uu llrnllh rnal f6r lirn'innuucnL rf 1Lr /irucrlp/ nmf Cunuut•rt•r ('umnliflee, (Ig Ilnuxr. n/ Ifrprcxeu/a- f irrx, 1QArr1 Cung. 2nd SexS (1994) (tcxlimmp' (.ff. .I. F;mdrhn'. Itrpul:ninu uf'fehat•eo R'uJuris). 21. LIS UrPt uf IIr:Jth, 6durnliun, nnJ WclLnt. Fnur6'iu,rk nnd llen f fh.: M'purl r fmc wfr'rxnr(/ Crrm - nril/er fn f]rr,Snrfleuu f7ournd nf UI214(6fic /lrrtlllt ,Srrrire. 1\';IShiu!;lun, DI): lIS I)tyll of Ilrnlth, l:du. cntiuu, nnd Wrlf:ve; 1!If,q, I'ublic IIc;Jth Sntvicc pu6licniuu 1103, ' Ciled Brown and Williamson Documents 100riIIL C6rnnulnpv nf Ipun'n & 1S911innlsun Smnking ImJ llv;dlh RercnfrL, IUSaI. I1112.11 L Nr(:ru'Inick A. Klnnkiug nnJ I IrldIJ,: I'olie,v nn Gr:=rurch. Aliunlrv. 11162, 1112JIL UI'ecn A, Itr•:cumL r,mfrirnav hnld,d Ililinn I Irnd IsLlml, S(:, pti;nllav, Sr•pte;nhm' E~I, 1!InF, 1125.111, rn•rn N. Nutrs un I l,e I;roup Itrrvr:nrh & I h.- rrlnpn;enl ('unfrrw;ce at Ilu<k Key, I'I:,.Jnna:ny 121u IN, 104. Nrer~=. II:K.n4 SznGml It. IArr,iJ "J:nlgrruus" rcxonrchl. I,rtlla tn A. Hl:nil. rlrymsl IR. 11,180 , 111;S.u1. Ib1T ItAlt (lnderonn•, Nwrirrul, Quvlme, I'rurcrdinFS.'I'urndn\',Ilqr,hrl'2~I,ItIn7.M1iimllrs,l!4iY. Ihi.•il@, RA'I' It4U (bnfrrrorc, Flnnlrc;ll, (turLer, I'r,rredin;:c, \VrJnrtdnc, Ilrlu6er 25, 1967. M1linulrx, 11u;7. III:S.mI. ILA'I' N,FII llunferm~n Mmllrral, Qur•Lrc, I'rnrorJiqRs, 9'hm.d:rp. /k91.Lrr Yf, 1!If2 Aliuulrr, I!x;i. 1lli!1.111. frrvn S. Itr=onrcL 6.runro helrl Id lu,ul- Irrr A, Grlwnng,.lnna 1 1.6, IBm;.I. AI inlnvx..hlue'L'1. I III 11711111. Fuuwl:u'y 4/',mrhnim;n: IIA'f Crnup 14•- =ralrh Cnnfcrrnee, No. oulLo ILIa, Illil), SL. Adrln, l(urLre. 1970. Prrnled aud FUhlrshetl:n Ihe Untled States of Anrenc& 1171.411. ' ~n S. Nu1. I r. nn I;rau I Itrpenrrh k . (;In. Ihvcrb al•mt•nl (+n;forent'e, fi•,Lug, Alt.bnlin. M1l:vrll 197R nlnrnlr~. Allm 0, nlns.' I17Y./1I. hlnokm;ulL.Ilesrul'r•hr.,nfrrrner,?I•~uh~l„-0I~~. (/nrhrq Auf!usL an.Rrplrmhrr:l. I!IAL. hlimnr.. F,~p. lewbrr 1(I, IP~t, 11811.07. IRuckmun I.. Ite+r:u'rll ('unfrrrnrr, Ilbl de ,lanelnl, Itrazil, August 2d.2f,, IpS9. Minml•., nvtrn,rr I:l I!lSi. IIN1.117. Nicalinq cunfrlrnrr.,l•uulhen,plnn.I:ngLrn,l. .Im;r 6,8. 1981. IIA'I' Rasr:nch lllv.l. 1191.112. \1'uud h, Ary1,4'ls nf Ihc 11kI1.F] funt'tom, nnt rs Gn' a lelk I,c 11, I. tl'ond gicrn nl ('br!wnwl. S,ik. Irwbcr I91'U. N,~IO., 19611 '. IriIILnI. Ihmrlhnch I', LiLrrl n.:l 9'r'urnb-r 1Lr1p," nn .'Yirnlme a,ldirlinn. Loud,nl, linglaod: liriti~:h Amrricnn'I'ulr.,crn ('n Idd: 194:1. I'tllll.ll6. \1'ndr'I'. IIII•: "'I'llc 15dr „f Ni(„linr iu Illr Ib,dg'.I. Mr;nn I'iurll,.hllc:ll. IPG:I. ILnll.lll. Nnlr fr Alr 1'ulAlh:c jroR:ndlnr Lvnonrl:J rffrrls uf niuntinvl. M1lr;nu b, \Y. I'ulchinr,.lvur 19. III21. . 12n/1.12. 1',~nnlun A.1)ul(;nin(! ru1J,~ IrrA:u11vle di-rb" xmr el rcarurch en nir„I Inr In vurRO,m q,ymr.J'r r„ur millrvl. Lrltrr tn A, Mr(',mnlrk, Auk A. 17,;4. Itllll,lf. lillis('.1'I'rnnslnillinF "'I'hv Fnlr „f Nir.,linr~ ill Ih> Itully"I. Lvllcr lu t\'. tlrirLiur,.hd) RI, 1'lm. 12ql.lll..lnlln.~all IL /'nn;nt;alls nn nirolin,•, \liulllrs. I?n2.aL M1leCormirk A. I Rr: Arir•IILcllrr In A. 1'r•a~ I¢m,.lnlg 2(1, 1970. 12118.111. I•icLcr ;md Cn. I'nqluzal fur Iua' dtd;n~ly prnjrel (or Brmcu mld \1'illinmcnn. 1205.01. RA'f II@U Saulh:unplon. Fl:r'll,rr II'nr(~ r: '8drnrlnLlv' Nirnfine Solllllnmplun, f:ug!aml'. I Il:\'I I Ilece:u'rh xud Ilecelopmrnl Rstnhlidhmeuh IOnG, I'uh- lirntiun IiU 4:S7~R. I'l11.'r.ll:l. N'trul p.l, I(rfnlinn Ilr4rrrv 'R!'rvur/nL/r A'irnliuP Cmtlenl rf ,l•ru„Ar nnd l'rluvl lhspnnnr. $rrtllhallll+lall, I'IIIgLIntI: I IIA'I' I IlC[rAl'fll nnrl I )vet'IVlr~ mrnt hsLahlichme;d; 1967. ISlblicatinn I,'l2ti~It. 12n5.11. Itrul.ege Itl~, Ncuurdy.IlS. fln m r Sn,u,k,,,q ,Sh:diea: Arnfr Fl('rI n% ('illnrdle Frm,4r r,n /(rrlirr IL'nrr AIpAn Rllplhul-Ficxf Ifrlpnrl. Loui•+'illn, h)". Itrua'n xnd SVillinnlsnn'fuhnrco Cu Itc•x•:ueh xnll Ur~ t'elup;nenl Ucp:ntlnenl; 1!171.l'uLlientiml 74~2n. 1205.15. (i,mcr AK, 'fhorntnn RE. Infanrlinv r,f Srnnkr: nr,d IOv Smnkm: l'mi.t:7'hr Efli'rl nf ('itplr;lir Snruking nn flrn Co,rl ivyrvl fiur 1`n rlniim,. Gmllr umlAuu, Unglxnll: IiA'f f;runp Rt•<rereh and Urvebq•, mrnl ('enlrr: 1974. I'uhlic:nir,n ItI1JIG611. 12117.111. Cuufelrnrc un Slnak!ng Itch;miow'. II6\'I'1 Olrrup Ilaxl•:u'eh nnd Ilrrc!r,p;nrnt UVnlyd, 19717. 12118.111. IIAT (uunp Rrcc:ucll Imd t)v+'ebqlmr•nl I:ru~ n'e. Alelllrrd /u' A'irrrlilrr' rnrd Cnfmine in IJllx,rl n,•d Rrirrr. 6oulhnlnplun. I:ngland: ISA'f Gruup Rrse;urll and Ue.elopnleot (Tnur; l!ISU.I'nhlicalinn Ilil,17:1i~f'. 1209.115. fSAT (71nup Rellcart'k lald Ueerlirpment ('rm tl'c. Nim(ine SOrdirn: A Srrynd lfrpnrl: 8•flnrnliou nf II'hule Flrxl / Nirdine Uum 1V/ Urmru'rl A1r'nlle.• nnrl Cnlininc Alrrplurnrenl. Stluth;nnptun. F:n41unJ: RA'I' Orwql Ite.cuch and Uet'elopmrnt (,1enUr; i!151. I'rll•~ licnliun RkU-IA21-R1. 1210.111. Bestmrdl wnfrrence, IJn!Ied Kingdom 10.'tl. RA'I', 1984. 1212.111• fAbelt 0, F'ivnl Rryxuf (hl Prv,(vr9 llip/vl I. I Srp:m•d for llritish Amelirnn Tolmrra Cu Lhl., ttrnrce, Rtcits.v9;wJ: Ilatlelle Flemurl:J h+xtilltlr; 1!x'@, 1212,112. hibert (1. Repm1 Nr,, f l7vyunfinry 1'rqpvr 7liplln!!. Ih'clrarrd fol' Rriti.k Alnrrirrul Tuhutru 1'I, I•IdAcnct'n, fip'itr.erland: ISnIIeIL• A1 rtnnrinl I uslilulr: 91;8. IYI2.aa. IlaxolLneh (.:. Lihnq tl Fiu,J Mymvl rr,r pnrir'rl lFppr, IL 14oparrd 6n' Itrilich Annaicnn '11,Irzrru Cn IAA, (7enevn, Sa~j V.rrl:,nd'. R:I1lrllc M1icm„- dnt Institlnr; 1nfa. 121:LIIL Crissbuhll•.r 11, Il;lselha,~h C. 7'6r Fnh• ••/ A'in,liue iu llre Itmlry. Grnncn, Srcivn~r4lrld: Ih,wal,~ (butrc rlt, Itrchcrchr Jv I:rurcr, IBI!:i 122:L01.'fhnrnWn 1(. Romr 'UrurJi/.v' yl -~n'uku,q S,ulh:unlnan, Englxurl: Ila\'f Gn,nl, Rnlrnrch;unl Ul ~ erdtpmmul Cvnhe; 1977. ISI6livaljnn 110 11161. L undxc~ si0rll. 122/1.111. I'mercJings of Ihe SmekinQ Iirhaeimv~ I•I:ukclillg Con(rrcnce, Jul,y tl-IE, I!uRL xr,•.bm III. 19.a1. INII2.111. YemnnuA.l(IhjoriinAlul6vrnrllhn116dlldlr rrqx,rl exs nt•nl lr,'PIB/;l l,rtler tn A. \IrCormick. ,lunr 2N, I!li,l. IR112.e't. M1teCurmirk A. Inemning c::b!c. 1•rilrr b, :1. lbmnnn,.hlly 9, 1!M11, 19112,16. 1'n:unnuA.llnplit'nlinn, ofRnlb'llellilq,lI& I I nnd Lhc hrif(th Piller, nlGl. (n N O tXl (.. The Brown and Wlllomson Documenlc--Slade el at 233 0IR q1
Page 100: zme50d00
a Dlnrc must be knotrn :d/uut hou di0t•Ient ;mtl colinine levels in bluod and lu-ine 111HOA71,'Pheseincludellinhalationand cnnnmlerxsmukcdiffercutlnnduclsamld1•I,t•trvide e:duable insighlv into the im- nicotine itself. rile Ailfercut Ierelx nf sadixfaclirm ~rr IV•- 11or1anUnlellA'1'scientislsthuughl.nieu- 'I'he nlinules of the nleeting I'ocused ,:prmsc thcreGow. We ;nc cmumrnr•6 t,'Ilh tinrplayedinsnlukingbehaa•ior(121)R.(14, on the tension between delivering un I~cnnxlrrcts:L'aG•n~nli,rn.midrr•y,,rsr.n~ 17/14J)j).'fhefu'stsludyll'romMay1980, efl'eclictduseufnic•ulinetothccunvunler Ihr• mnulh Ircrl-tl~hirk inllnrncr iuilinl suIccliunamlbr:undl,r}nlty.d,l'I'h,•I,h:nu~ar,l slnl.cs: andmiuintizinglhedcliverCUfLuluthc b.t;nA n.sidl ,rf SnuJ.c ulrLdu•. II IT!1ol.l' 1' Ill Snirlo InFl:nlt'rY, lh0 ,II:11'111:ItYrlngicnl m- Imlgc•'I'hese tPel'e lliecURS[•d nltQel' (he Thr minulrs nldliur ttnrk luulc•' teuy uf smoJ;ecs lu nicnlinr is 6t•lict[•d tu c:degmvnl"'luhnlutiun tuld 1'rolluct In1- ht• rc>prmsibIc for ;tn indicidwJ:s slnnkin); I•ovenleoL.". in /Lrrmauc nn Irr[•t•ise nicnlinc Ilu.r rrocidin1, r lhc mutiv~diun fnrand •~ Inraxtu'elnenLs in rr~ic:nnl(•rs. iu I l:ulniln hrhaciumt I 'I'hcre ure teru pulenti;d a';n's if mndifyin)t un ruff du rlicatinu Irchni, ucs to nm,l- thr degrae of sulisfactiun retplired by l6c the eigarette fnr pruJucl inlprnccmenL lil I I 1 stnr sntnkel• hchnc ior tcilh prrr vmukt•c. 112U3.U1, p 21 retluccd retenlion of smulte iu lhe lun4 lantl I iinn. i)incre•aseoflhelet'elufirrilaliuntureducr ;md a'nclt phuutod in lho I'nilell Sl:ttrs 'Phe aecond repurL describes a tech- :d R.F\\' nn surrrptiliuus cillcutnpiun ln niquo fur i•slinlaling the "whole body depth of inhalaliun. Allhuufilyll'lenx;lppreciatetlthnt irrital.inn rnrastur smuking in nnlur;d srllinys. niculinedoveluthet'aLfollowinginLra- nmy6ech;mtiodtu{livenpruduc•l:rdr:wl;t4r. \\'hilc Ihr IfA•I' ruse:urh Ircny;r:ml :n venous ntlntinish'ulion:' The nuthors' it ttns agrred lhal the rvsearch shnuld crm. iix tiuuth:tnllrinn lilcililyu'ns aiwrrl nl inleresL in tlsin}C knowledge uf' Lhe ab- eenlr:de nn L1Le first route, ie the nrudiGc:r- idrulil\'in{t nnn'kct so);unmis h:o-rd nn snrbed (lose of njcotine as an aid in timl of the smoke :u•rosul to rlecrexsc thc ",Innl(ing hch;tciuurd ehJu'actcI i ° cigarelle design is revealetl in l.he re- mmounl of S~nloke relxincd in tlir lun)!. An italwtvaclwy'ingnttunlionln"lLol,in- purL's (Iescrilrtiun uf the value uf I.he impurtanterileriuuisth:dxncchangesmado ['lIDI11iFt1;C:11nII111HP111:1[•n10p 'BriFqc'llllr•d nl•\1• leelllllrlne: Ilr Lhe product nitlSl Ilnt ,18nraJ!r .nlola9' u'ilh lh[• inhnlaliun uf nrl,j,n' Snluko acroplnbilily'-indecrl lht• nitn musl he tn in- "I'his tc•chni,pic Ints:m inmu•dinlc nnd dircc•t cirn.c it. cumpunenli' II17!l.tll, IrP'1-:31. ralet':uleeforfi)animalloxicilysUldiesinthe 't'he basic assunlPliun is lhxl nicrdine. A desi)%n objeclive fur netlImuducls culnp:u:dice assessumnl (if c•igarelles. (ii) tchieh is alnlost cerlainly lhe key smnke n'ns hunlan behuvintu•al sUltlies in the assess- cutnponenl fot• satisfaction, is fully rclcased 1u irrhnurr• ac wuxiwisr .cu,urp) rwd pP,lr'- ment of an intlivitluals' nicoliue lloseC in to Lhe body systenm before exhalation takes r,rnrnbqliral .ccrrsrdinux• i.r. l,r "rra•7r,. rLr• . 1'rspon=c Lu mudifeaLinn in cigarcllW design. place. IL is [•asenlial.lhereforc, loaltempt to >rnrd;r rrnrdtrnrdrr" xu a< In achit. n, mn.i- 112nS•116, p 11 quanlify the ch;m}te in chcmicatl curnpnsiti„n nmm SeuSatinn :it a siaru qrdic,•rc I-•rrl lrcttc(•en inllaled and [•xhaleJ mmnke under \cilhullt ounnnarinl; lhr• smokr-c tn c nnp.•n- 'I'huv, the xbsot'bed rlose af niculine differeut condiLinns of smokinf!. ie sh:dtr,w. xate•Irnlpkasil:ndJeJlllli!UII,p:t' tcasregal'dedJt5.u1 impol'lantconsttl- nlediuln;mddecpiuhakttion."fhc•absorpti,m eratiou in cigaretLe tlesign• Cig<tretLes of nicotine via lhe nasal cavity should also lre In this statelneul, the It&U st:dks ul' tur which the delivered nicotine dose is imestigated. (1180.07, p lo) If!1'1`, tuld l3tCW ahotve l Ihcir unrler- a(Iesign parameter would seem to fall Nicotine absorbell throttgh the lungs st.miling uf the purposo of a cif;aretle: sqtsu•ely un(ler the definiLioil of a drug tt,;ts essential for the novisiun of "sat- "Irhxi•macological s(;nsations" xre not in the Food, 1)rug, and Cosmetic Act•.`t , isfacLion" to the consumer, that is, for onl,v inlenrled but are to lle inanipuklLed One of the definitions of "(b ugs" in the the nm'nlal functioning of a cigarette. sothidthecnnsuntertcun'thavelrl:J(c..ac•t is "articles.(oLher Lhan food) in- 'fhe noninhalable cigarette lrts nott a in milre stdnl(e th:ut inLenlred to e• `ho Ir nderl to affect the sl.ructtn'e (rr' any rcalistic alternative, so to re(lucc tar righl d[ise of nicutine. I'!r .• lion uf the budy of lnan ui• other ,tbsarption, the sntolce shottld be ex- :r •vaals" [21 USC fi321 (g)(1)J. . haled as quickly as possible. This, in Miscellaneous Studies and A sinlilar concern with the relation- turn, suggested a series of experilnents StalemenlsRelaledloNicotine shjpofnjcotjnedoseatn(Iprolluctdesign to nle,asure nicotine absorption as a SercraluLhm•cunfcrcncepreseuultions is evident jn a paper (lescribing the flmctjonoflungrcLentiuntjute.lVhileil by ItA'I' ac'ientists in 1976 and 1977 ctn- conclusions of a rese:unc conference is not known if these studies were done, Irhasi•r•erl the impnrLane•e of nicolinc. At at setting priorities for the R&U gruttp at the quoted passage clearly shotvs that conference on smoking behavinr, A. K. SouUtantpton in 1A,44 (1210.01)• Unllcr the absorption of nicotine is nec•essary Cnnlergaveapresentatinnentitlod"'I•ho the category "Smuker Behaviour;' a fm• the intended functioning of a ciga- FulukingNabil:SonleCurrent Vietcson series of studies was planned, w•hich, t•cLte. lhe Role of Nicotine;' lict• re.t'iru indi- amnngotherlhings,tvnuldexplore"the The 1!)ii;, mceLing d(rvclulleil a re- cated that nicotine's offeclS nn lhe hrnin efOciant use of smol(e nicotine thruugh seacch agenllu on nicoline itsclf. 'I'lie :urantnng lhe inlpurLlnt rl•ason.e Ilenpl[• pli modification" (121(I.O1, p 21. notes on niculine are: sInalte 11'L1PL(I1). I:. H,.'lhrnrntim, in a L•dk 'Phe•se sludics will itlentify thc rclationship 'fhe grow•ing cv,ucern xbnut cumpensatiun is entitlell "Sonte 'lienelils' uf Stnol(ing;" betaeemi nicotino Jnse and niculinc-reInletl foc•ussing attention un the rule of nic•oline in recietts ilnprot•entenls in pel'fca'nvlnce subjeclive improeeroent. 'Pllis VciII furlher the smol(ing procesc It tvas ngree4 lhat +cc fntrt»snlukingandl+sychulugical'benefit.c" help tn identify the relxtionnhip between nlust lalow as nwch a. pmSible about: 112`L'3.111, p 11, relnle(I mainly U) pltainta- product acceptability and cmoker xatisQtc- - factors thxl Idfect the trunsfer of nicu. e•ologic;tleffect.eufnicutineI1223.011-'fhcy tiun. 11210.01, p 21 linc 6om leaf to snlnltc ncrosal includcimprovudpclfurncuurofti~il:uue 'PhisconunenLlicsLugethcrtheLet'ms fectorslhalinllucncelherateol'lrltn fer utsks, pleasure frmn sntol[ing be('ause uf satisJactiort, rricofiae do.se, all(1 7liC0finC- of nicotine from pnrtictdale mnlter tn ihe slinmlatiun of thc liulbic syslom of thc relrrtr'd srrL,jectiue inrpr•ouenderd. 77tis, `'a1'mu• phase Inain, ameliul'ntiun of the s%t•luI rLnuii nf - lhe contcibttLion of nicoline to snlrrkc too, is ahout affecting tlte sLt•ucLul'e and sell ol;y CIIRI'actel'IstlCs (111(•ltl(IIIrK 11111'FIIneFs nlcnt:d ilhless, tvcight crmLrol. cuwdcr- function of the I>ody, not about'sitnply ;tll[I irrilation) acting lhe (•ffecLs of olhc.r tlrugs, sucli as using nicotine as a flavoring agent. - tpcsi/caud uu•rtmuiarn.q(rrLsmphon u/ nlari,ju:ula. nrnl a reduc•tinn in the Sy'IUP- ultv/iur• ®ilhili fpr 4wurur ..nx/eol lunls of P;u-I:insoli s disense.. Research Conlerence, 1983 • Nre 11'n1J rNCU/ine lfinndulCx hnNr Ilrr I'tcu R:` 1 R&U (S[lutlmmplunl re- I'hel!1R31'CSeal'chcunfet'eltcecuvcl'eQ certtlvd 1IP14'nrtR Fyc/PG/ nnd (lir prv'itJrrra! :Ln purtsofu.- •dsforrncnsuringnicutine n varicLy of Lupics rehned to nicotine nrguns(rfllusn'loudtuulr) to DD JAMA. Joly Vol 774. tJo 3 Tho Brown and Wilhamson Docun"!nls--Slacle el ai 231 t'' W IJ it-

Text Control

Highlight Text:

OCR Text Alignment:

Image Control

Image Rotation:

Image Size: