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Statement of John Slade, M.u. Department of Medicine St,. Peter's Medical Center New Brunswick, New Jersey before the Subcommittee on Health and the Environment Houee Energy and Commerce Committee FDA Jurisdiction Over Tobacco Products . March 25, 1994 Washington, 1).C. TI]V.IN 0046847

Harch 25, -994 ?age 2 Mr. Chaia rran, mecr:blrp of the Subcommittee, my name is John Slade. I am a:-, internist gperializing in addiction medicine. 2 8m & me:nber of the Department of MPdicine at the Robert Wood Joh"eon Medical. 8chool of the UniverAity of Medicine and Deaal.ietry ©f N=:w Jcraey and am the chairman nf the Committee on Nicctiija Depe:z-lence of thc American Society of Aric3i r.tior_ Medicine. My -,profesaional work largely involvea thp nllnical and public health -x.bpects of addictiono, eapecially addiction to nicotine. Cigarettee cause mct~a i1.lneds and death in the t3nited States than anything else (U9DHHS, 1989). The nicotine in cigarzttee makes cigarettes addicti.ve. Cigaretc.m manufacturers know their customers want nicotine, and their productu are deeigned to deliver nicotine. The evidence presented here will show that ciQarette rnan+_,facturere intend to affect the Zunction of Lhcir custotr,era' bo~.dLes. This, in turn, provides a basis for regulatiorn of cigarettes as drugs under the rlood, Drug and Cosmetic Act. Moreover, they intend to sustairn addiction to nir.otine in ctiatomers dependent on the drug. 0 What cau-see cigarette smoking? The cause ot emok:ng is not advertising, it is not low price, it is not widespread availability_ zf ._the-product, .t it is. not amoks.ngu_by_family.. members, and it ia not peer pressure. These things (among the others described as riak factors in the 1994 Surgeon General's Report (vSDxxs, 1994)) 4:acilitate the development of smoking, but they arc not thsm-_.elvee r.augal. The fundamental cauae of cigarette ~'IMN 0046548

March 25, 1994 Page 3 snoking is nic•:)tir.e, and ad.dicticn to nicotine largely sustains the practice (~JSDHHS, 1988). W<thout nicotine, adolescent tobacco use wouid all but vanish. Nicotine Addiction The 1994 Surgeon General's Report tells us that it is not the first cign-rette that produces addiction. It is the second, the third, azr-1 those that follow. Most adolescents who have ever smoked as few ae half a carton of cigarettes have a very difficult t.i:n-, stoppi ng. What do 1' mean by the t-Prm "addiction" ? The standard clinical dsfia6ition for a drug addici-i nn - also called a drug depcndence -4,s lops of contro]l over use of the suhAt-ance plus its coxLtinueid uae despite problems. This definition is embodied in the approa.h takcn to the addictions in the current editien of the Dia=o-a-ti•: and Qtati tical Manua (DSM) of the American Psychiatric A-ssociation, publishod in 1987 (American Psyahiatric Asuvc:iaLion, t987) . The D8M is the standard autlaority for diagnosing adiic:Lions in this country. Nicotine fits thin deiinition very well. Nicotine also fully satisfies the rese3rCh-ori~nted C~iteiia, emp~.uye~1 by the Public Health yervicc the 1988 surgsoa•-Ger.erai's •Report,--T-i•-•x 1±-h-Cna€,~~r-Ms ._f Smokina: Nicotiri Addiction, (USDHI3S, 1987) . " I Spoke=;men for cigarette makers have taken issue with whether or nCt nicotine is addicting. While questioning the interpretatirn of some of the data on which this conclusion is based, they L,ave mostly questioned the deiil-iition of addiction. TIMN 0046849

.March 25, 1994 Page 4 Nicotine, a centrai nervous system stimulant, produces effects in the zrain that are reinforcing. The consumer becomes addicted as he Dr she seeks the sensatior.is nicotine provides again and again, and the individual gradually requires an increasing dose to obtain the desired effects. Suddenly stopping nir_otine use often produces a characteristic withdrawal syndrome charar..t-Arized Iry such central nervous system effects as irritab'_lity, cifficulty concentrating, headache, trouble sleeping, chan,=*s in appoltite, and feelings of anxiety or depression. Tl:ese symptoms can perxist for weeks unless nicot'-ne is ingeated on:e again, either in the f.orm rlf a cigarette or some ~ other tobacco -oroduct or in the torm of a nic.atine rPpl ar.r?ment product auch a-i nicotine gum or a nicotine patch. The Public HeaLtr. Service uses a different definition of dddic:tion from that preferred by tho cigarette makers. The data strongly support the conclusion that nicotine regularly cauees addic:L,ian in a very high proportion of uscr®. The government's policies towards tobacco products should be based on its best underatandiaig •,~L the process, ae reflected in its undcratandiz~g of addictive processes and the entire range of relevant data. Spokesmen for cigarette makers frequently draw attentior_ to the large number of people whc have stopped amoking as evidence that nicotine is not addictive, While a large number of people have managed to stop smoking, the coricluwion is false. It ignores the fact that more than two-thirds of those who continue to arnoke wa.n_L to quit but feel Lhey cannot. IL i9~zorGs the fact that a third cf smokers-txy to atop each year. zt ignores the fact that the overwhelmizYg -ma-3-ors.ty- -of , quit_ .a,t.te4nYL..d ._t!XL~i in failure. it ignores the fact that spontaneous recovery is a well-known fe=,ture of 3_U addictions. (Ir. faca;, ulinicians and public health officials have long used general advice to stop using drugs Vi take advantage of this well-known phel.ouYeYlon. ) it ignores the f;_,ct that people who have addictions to more than one drug, such as heroin, cocaine, alcohol and nicotine, often rmydzd their addiction to nicotine as the most difficult addiction to stop. Millioiis ot people smoke and are also addicted to alcotivl. TIMN 0046850

March 25, 1994 Page 5 Nicotine Abeoy pta.on and Basic Cigarette Design Nicotine from tobacco products is absorbed in the mouth in the case of moist snuff, chewing tobacco, and cigar smoke, while nicotine is absorbed f.rom the lungs in the case of cigarettes (Gori , 198&; TLSDHHS, 1988) . The reason for t.his is a maj cr differerr.e in the degree of acidity or alkalinity, or pH, o= the nicotine fn,.m, - in thee~e various products. Nicotine at an alkaline pH i-_, reada 1 y absorbed in the mouth while '_t is not absorbed ther--: at all if the pN is acidic. Cigarette smoke is acidic while ~aioot other tobacco products p.r.etxArt_ nicotine in alkaline form to the oral membranes. A1kalin.e nicotinP i R harsh and irritatin-r to the throat (Faitelowitz, 1930: VSDmHS, 1988), so it is hard and unpleaaant to inhale cigar smoke. The acidic smoke from a.:igarette is readily inhaled, hokrever. . in f actc , unleso ci34rei:te smoke is inhaled, nicotine is not absorbcd (3ori, 1986). With inh-Llation, ac:idic nicotine is absorbed and transported to the brain lar more rapidly sud alL higher corlcentration than alkaline nico:ine absc+rbed in the mouth (Heauxingfield et al, 1990). The differenee: is like the difference between ca-nc;k cocaine, whichh is smoked by inhalation, and-powdered_cocaiiie, - which is sniffed 1nto the. ..noses. .',1he .fD.rmerx.ia. more..potent mg Lor mg and gives a more intense experience. it is also moz-e addictive. The cigxrette is the most efficient r.icotine delivery device on the market today (USDHHS, l9es). its complex balance of TIMN 0046851 -

March 25, :994 ?age 6 various tobacco-derived components and additives includinc sugars, as well as its paper, filter, and tipping paper are precisely desiqned to work.as a unit ta produce controlled dcses of an acidic, Aicotine-lader_ smoke for inhalation into the lungs. The cigarette Ls engineered to deliver carefully controlled doses of nicotine to the smoker's brain. The 9'TC Method Test and Sales Weighted Nicotine Deliveries In the mid-1960s, the Federal Trade Commission began to test cigarettes offared for sale in the United States with rnachine- based measurem.nts. The test parameters, codified :,n 1969, were derived from some first used in the 1930s by workers at the American Tobac:o Company (Slade, 1993). In the standard test, a 35 m1 puff is taken over 2 seconds once a minute until the cigarette is reduced to a certain specified butt length. The results are ekpressed (in milligrams) as the amounts of nicotine, particulate matter minus nicotine and water ("tar"), and (recently) carbon monoxide that appear in the mainstream smoke generated by the series of 35 ml puffs.l The test has been done consigtently on all cigarette brands ;.n wi cip Ai atri huti nn since 1968, initially by the FTC and recently througis. the- Tobacc.o Inst:tt.u.te.. Th.#.4+sm_ rfa.au.l r,R.,. c-omhinPC3 with brand apscific sales data f.or, ear-h year, havo pPrmi t-i-Pd t-np 2 The teat results are not enforceable standards. That is, there is no r, . qui rpmAnt- r.har r.i garai-tAa brands ar.tually prnvide the tar, nicotine and carbon monoxide deliveries measured in the samples of th= products tested. TIMN 0046852

March 25, 1994 Page 7 calcujation of sales weighted average nicotine deliveries, as depicted in Figure 1.3 Figure : shows a decline in sales weighted nicotine delivery from around 1.4 mg per cigarette to about 0.94 mg in the period 1968-1991.. However, nearly all the decline occurzed between 1972 and 1980. Since 1980, there has been no changr. Cigarett-. manufacturers rely on comparisons based on smcking machine tests to help sell their products. Enclosed with this statement is =, recent (1993) advertising insert from the American Tobacco CompaILV for its Carlton brand. The leaflet makes explicit comp.Lrisons of various versions of '-arlr.on with brands made by compe'~;itors. The FTC D4.tho-L T.®t is a Frgud. Despite ;.!he r..;garette companies' reliance on FTC method test results for c.garette brand prnmot:i nna, the FTC method test doeo not provide c-)nsumors3 with a re].iable index of the amount nf sraoko they in-;est from a particular cigarette. Unlike all other test results :a.ma.liar to consumers that are included in the ' The r=,port of sales weighted nicotine delivery prior to a,968 relied u:Pon by Mr. Johnston in hio 2/a8/9. letter to Dr. Kessler is un-available to me. The source referenced in the 1989 Surgeon Ganer al' s Report (LTSDF~I3 ,~~~ ~, pagc..8 8}.. .•~ca~s . a private communication from Helmut Wakeham of Philip Morris to another investigai:cr in 1976. Neither the 1988 Report nor the chart it references in:lude the actual numerica]l values being plotted, vnless the az?3lytic methods used are ahowrn to be comparable to those employed for the period 1968-1991, and unless the actual values aru available fcr replotting and ar.alya_a, the numbers taken off these charts prior to 1968 ehould not be used in comparisons with tLlYe later time period. TIMN 0046853

March 25, 1994 Page a labe=ing for other ingested items such as foods or dxugs, F^C method test results do not accurately reflect the bioavaa.labilicy of the meaaured components. The test is, therefore, a fraud. Ne:.l Benowitz and his colleagues at the University of California at =an Francisco have shown that nicotine yields as measured with +-he FTC method do not significantly correlate with blood levels oc cotinine, the major metabolite of nicotine (Benowitz et aT, 1983). This work has been confirmed by Gio Gori of the Frankl1=s Institute Policy Analysis Center and his colleagues (1906) as well as by David Coultas and his colleagues at the Universiyo of New Mexico School of Medicine (Coulcas et al, 1993). Thare is, however, a marked correlation between the number of ciga.vettes smoked and cotinine levels. In two de;,ailed studies, smokers ingested substantially more nicotine from .ndividual cigarettes and from an alternate nicotine deliv=:ry device than predicted by the FTC test. The first study, by Dr. Benowitz's group (Benowitz et al., 1991), found that smacers who inhaled absorbed an average of 2.49 mg of nic:otine from .i cigarette, when only 1.1 mg was predicted by the machine test. This is a 127% increase over the machine-based result. The eaconc3 atudy, by the biobehavioral research group at the R. J. Rayx±aldse Tcabacr_o. Company .1R. J.. Rey.nal.ds, .1,988a) , found that smokers who i.nhAl.ed absorbed an average of 1.0 mg of niaotino from a cigarette retec3 at 0.66 mg (51% inc_ease), ar.d the same subj ects absorbed an avarage of 0.7 mg of nicotine from TIMN 0046854

March 25, 1394 Page 9 a prototype of Premier that was rated at 0.34 mg ;106% increase) .4 People doa't smoke like the machi.ne, As detailed in the ., .988 Surgeon Ga-neral' s Report (T7SDHHS, 1958 ), they generally take larger puffs t nan 35 ml and do so in a shorter amount of time than 2 seconds. Robinson, Pr-tchard and Davis of R. J. 3eynolds also found that smokers take :arger puffs (mean 51 ml) (Robinson et al, 1992).§ Shorter, larger puffs, like those most smokers actually take, move air at a higher velocity through the cigarette. This may permit prcximal parts of the cigarette to reach higher temperatures rharn those reached under FTC test conditions. This effect would ~-ie expected to release more volatile components such as nicotine iLLto the smoke. This, in turn, predicts that, puff by puff, the -imoke ingested by smokers who draw in air through t-he cigarette at higher velocities than that used by the machine will hevoa hig=ier concentrations of nicotine than those taken by ® 4 1n all., three of 22 subjects in these two studies had atrikingly loaer nicotine lavels than the other 19. Tn interpreting their data, both teams of investigators assumed that a low nicotine .l.ua1.. maasit .that.. thee aubj.ert inhalPr.3,., very 1; r.ttP smoke. The RJR team did not even include the two non-inhaling Oubjects in its study in their final analyses. 'rh^ RTR t_aam was only interested in the data from the ten subjects who inhaled. 5 Their paper, "Psychopharmaco].ogical effects of smoking a cigarcttc wi*h typical "tar" and carbon monoxide yields hut-t minimal nico*ine,° is included as an attachment to this gtatomcnt. TIMN 0046855

March 25, 1994 Page 10 the machine wikh the ider.tical cigarette, g In actual use, the cigarettes most people smoke provide them with similar amounts of nicotine over the course of a day regardless of Ae FTC test-rated yield. This is a function of both the numbey of cigaret_es smoked and the way those cigarettes are smoked. The FTC test does not provide consumers with reliable infonvation about what they can expect to ingest when smoking cigare;:tes of a particular brand. The Coatrol of Nicotine in Cigarettes In 1952, Oha Food and Drug Administration found thar cigarette tobacco from the five leading brands contained an average of froa 1.58 to 1.82 percent nicotine on a dry weight basis (Wright, 1952). These values may be compared to the 1.5 to 2.5k nicotine 'tRr. Johnston reported for finished cigarettes in 1994 in his re•.ent letter to Dr. Kessler. If anything, cigarettes on the market forty years ago appear to have contained Iggg nicotine than many do now. This suggests that the losses of nir.cr_ina durinj manufacture from raw leaf bo finished product may have been moro prcnouncad than than now. Howevar., thA whrld nf cigarette manuEacture was vastly different four decades ago. In 1950,-Zha-Fade.ral .x'.rad.a-••fiommias3.an fouazd, s Groate- heating of the proximal part of the tobacco rod and of the filter by increased velocity of the draw would be expected to release even more nicotine from these potentially nicotine-enriched regions. The jeck.nology for a:nAching these regions with nicotine irs discussed in the next section. TIMN 0046856

March 25, 1994 Page 11 Becai.:se oE the large amount of tobacco leaves used in the manufactLCe U cayarettes and the extreme var:ability in nicotine content of the =eaves, it is not practically possible Cor respondent [P. Lorilla,nci Colupany] , or ai:y of the other manufacturers of leading brands of cigarettes, to maintain a constancy of nicotine in the finiehed 4igaLeLte. (Federal Trade Commission, 195C, page 6) This is na longer the case. Innovations in materials processing and cigarette design since the 1950a have made it possible for cigarette manufacturers zo make products that are uniform despite the variability inherent in their chief raw material. The Appendix summarizes some patents _hat illustrate major ways ciqarette manufacturers can use modern technology to assure a uniform product, a product that performs as intended, as a nicotine delivery device. The patents demonstrate a concern with providiny predictable, controlled doses of nicotine to the r..nnmummr, engineering that makes it easier for the consumer to titrate his nrhAr nicotine Level. This overarching concern is especially c1-ar in patent rn. 1,584,930 from Philip Morris. Reconstituted toba.cao (paper sheets made fror Pt:Pma, finas and trash) ha= an inherently lower nicotine level than does tobacco loaf. fiimilarly, etems themselves, which are often finely cut an.l rollcd ao that they can be incorporated into c:igarette ble=tda, have a far lower nicotine- aonAnt than the leafy pdrt Uf t1~ bvba~ce-ledf -(laat-inal.. ~hcr~c._de£icianaiee, as well ae LtiG v4riabili.ty inherent in different batchec, can be compenwa4ed Mr with the wide variety of techniques illustrated TIMN 0046857

Mesrch 25, 1994 Page 12 in the Appendi: ;.' Nicotine i,s lost during processing, and it can be (and is; readded at muli:iple steps. Unlike the cigare-.te of 1950, the f ir.al result i~ s a product that is urifarr.t and consistent. The custotr,e= is th-.reby assured o= ea predictable subjective efrect f rom a ga.ven b~.-and atyle. The added nicotine can be recycled within the factory or it can be purchas=:d from outside suppliers. The Bureau of Alcohol, Tobacco and Fi-rearms ®icenses Special Denatured.Alcohol Num:.er 4 (SDA 4) exclusLvely for use in the manufacture of tobacco products. SDA 4 is 1 gallon of nicotine in 100 gallons of ethanol. Toba--.co extracts, designed for specific applications and with varyilq nicotine content, are available from 32 different suppLiers in 10 different countriea (Table 1). Nineteen extract suppliers are either based in the U. S. or have subsidiaries here. The existence of so many suppliers sugqests that° there is a relatively substantial market for these materials. ' LTR. Ta.duntria.Q, ,.a, subaidiary .of .,KimberLy., 0'1_ark, makae reconstituted sheet with nicotine content that varies from 0.7 to 3.5 pereent.~; eiiberat®isa, 1985) An advert isement f_cr T,TR 'e sheet tobacco emphasizes this property. Another advertisement attempts to p-Arsuade cigarette manuFacturers to use AhPArt instead of cut, rolled i stems. It offers to process stems from a factory into sheet an,I so reduce the overhead required to npprarp R stem processing fa,;ility. Copies of both ads are included with the statament. TIMN 0046858

March 25, 1994 Page 13 Alternative Nicotine Delivery Devices Table 2 lists many of the novel devices shat have been patented which imitate the function of cigarettes. Figure 2 is an i11u$tration taken from one of the patents for these devices assigned to PLilip Morris. The provision of heat, from electricity,'ns in the device illustrated in F'igure 2, or from =hustion, a.i in Premier, (needed to volatilize pharmaco].ogi rA11y effective doses of nicotine) is a common feature_ The individual patents and the body of work taken as a whole domonrat cata a core cor_r_exnn wi th delivering material to aoneumers tha: is at least relatively free of most if not a11 toxins other rha.n nicotine. Some patents mention nicotine, some "tobacco flav=,H and some only "flavor." The pair from B.A.T. and Sror+rn & Williamson are noteworthy since the- Sritiah version explicitly discusses nicotine, while thc very cimilar invention pdt,eiil.ed by its U. S. subsidiary at the same time makos no mention of nic:ol,ins or of tobacco. 2t only discusses "flavor. « The 2mperial Wup patent explicitly mentions the inhalation of nicotine as a goal auuyht by consumers of cigarettes. tndustry RWArch on Nicotine The CoL=_lcii •t:or•••Tobacco .k+tesearch, MOrris f and R. J. Reynolds hav e each funded auksstantial programs of rawedruh on the pharmacology ot nicotir.e. :n addition to a program K extramural research, R. J. Reynolds has supported an intramural "icotine laboratory since at least the early 1980s. Funded research Wa TIMN 0046859

March 25, 1994 Page 14 encompassed th.: entire spectrum of subjects relevant to nicotine pharmacology. Studies have ranged from basic work on nicotine receptors and iiicotine analogues to human psychopharmacology studi.es. The =:xistence of these research programs means that the cigarette :ndu-;try is knowledgeable about all aspects of the pharmacology o-: r.icotine. While the~;e is a very large body of published research on the pharmac®logy of nicotine, there is remarkably little on the contribution nLcotine makes to the taste and flavor of tobacco products. In .2act, apart from a few patents in which experimental cLgarettes were assessed for flavor, taste, harshness and :he like, I cannot recall a single published study since the 1930-3 in which this aspect was a central focus of the research.° - Cigiretto am;k. SnhaistiQn is Intended by the Manu,factttrers. Cigaretteo are designed to f.ar..i 1 i f°ai-P inhalation, and nicotine from =igarettea can only be absorbed blr ' inhalati on . This is doli.berat• and intentional on the part of the manuf acturers . 8 The e~La~tasc© . of• Ncxt., . tha..deniao.tiniz.fad..c3.gar®t.t© . from Philip Morris, suggests that substantial quantities of nicotine are not necessary for the achievement of characteristic tobacco taste and flavor. Philip Morris ofdered this product in three & di_ferent packaginga: aa Next, aa M®rit da-Nic and as Benson Hedges de-Nic. it is inconceivable that a company as careful about its prc~lucta aa Philip Morris would have done this unless it knew from Lareful premarket testing that these products provided the ta©te aeneatione of convontional cigarettes. TIMN 0046860

March 25, 1994 Page 15 • Both the R.J. Reynolds Tobacco Company and the American Toba,.co Company referred to inhalation as part of the smokLng process in their advertising in the 1930s (Tye, 1986). The text of a Lucky Strike ad from 1932 tAmerican Tobacco Co., 1932; read in part, Do you inhale? What's there to be afraid of? 7 out of 10 inhale knowingly ® the other 3 do so unknowingly. ... Do you inhale? Of course you inhale: Every smoker breathes in some part ot the smoke re or she drs.wa out of a cigarette.' • Until such claims were banned by the FTC in 1955, cigarette advertising often featured claims of reduced thrcat irritation. Table 3 provides an example of this phe_r-om&non from each of the six major cigarette marn_faaturers circa 1952. Throat irritation is only an iagi.Q if the r.nnsumer inhales. If a puff of smoke is tak--.n in and then Axpwlled from the mouth without inh-Ll.ation, there is no ; mpAct on the throat. The=,e£ore, claims of reduced irr; tAt_ion are the equ.valent of claims for ea®s of inhe.Iat; nn _ e If nhalation were a misuse of the product, the ab+l,idant evidencc of harm from inhalation should have led tha.-aoutipan.i*a- to .tak.e, firat ste~+s ..to, .wa._rn its cus:cmera against inhalation and to change ciga.r.Pt-te dcaign to discourage the practice. Nothing of the anrt I A cop•r of another ad from this series is included with this sLatemenG. I TIMN 0046861 -

March 25, 1994 Page 1,0 has h4ppened in f orty years. ® Racher than discourage inha®ation by product design and by consumer warnings, the industry has conducted elaborate animal studies cf tobacco smoke inhalation. For instance, the Council for Tobacco Research, throug'rh its Special Projects operation, funded a $10 millicn moua° study under a contract titled "Smoke inhalation studies in mice." (Henry and Kouri, 1984; Colby, 1992) e Willjam L. Duain, Jr., of the Philip Morris Research Centar, speaking at a C®RSSTA-TCRC sympcs'_um in 1972, repe-.tedly referred to the fact that smokers inhale and cons=;quently absorb nicotine. The thesis of his paper is that absorption of nicotine produces effects that the imoker has sought (Dur}n. 1972). ® Tt,w A. j. Reynolds Tobacco Company treats inhalatiorn as a ma j mr feature of intended cigarette uee. When the comp-.kny sougrt to show the scientific ccmmunity how ciga:ette-like Premier was, it did not publish taste teata. Ir.stead, it published a detailPri6 sttidy of the phaa;•=cokinetics of nicotin®, comparing nicotine absorption from a cigarette with that from prototypes of Prcmier.. W..A,aynolci.a. Tobacco Comg.art3r., 1.9:9.a) • An Imperial Croup Limited patent for a nov1 nicotine delivery system notee, "Among the raasonra why most peorle smoke convcntional cigarettes is that they wish to inhale an aerosol cOnt3ining nicotine." (Imperial TIMN 0046862

March 25, 1994 Page 17 Grottp Limited, 1982) The inhalacion of mainstream cigarette smoke, with its resultant obligatory absorption of nicotine, is an integral, foreseen, and intended part or c:garette smoking. 8ome intendad Ph.rmaeologic Effects During t'Ae segment about cigaretree on the February 28, 1994 broadcast of !)ay Oa.e on ABC, J. Donald deBethizy, Director of Research and oevelopment for R. J. Reynolds, declared that peopr.e smoke because they are "looking for a pleasing sensory experience with mild pha rmacoloqy.'1 What is "mild pha: -acology?" Advertising for Camel brand cigarettes in the 1930s emphasized th: ability of smoking to give the customer a lift and to calm the cuetomer down (Tye, ~986). Similarly, Lucky Strike adverti.sing once included the claim, Smoke a Lucky to feel yn»r IAva1 besti Luckias, fine tobacco picksi you up when you're low...calmFa you down when you're tense. (Walsh, 1952) In a eourt filing, attorneys for Lorillard have noted the benefits of dmoking as follows: ® Lorillaz~d contends that smokers do derive benefits from smoking cigarettos. Theae benefits presumably vary from individ,_.al to individual, are personal, and cannot be put in a univ^---sal or comprehens3ve.l~t•. -Some •-o.£ _•t.he bene: ita that ar=-i commonly reported by various smokers are: enjoymei:t; pleaeure from tasto; Qme11; relaxationr relief of anxiety and stress; reduction of boredom; increased alertne-_is; improvement in concantrationj and enhancement of social '.nteractions. (Reply to interrogatories, Covert v Lo__r'i7.1 a ~~d) SimilarLy, attorneys for R. J. Reynol-da hava dcacribed the TIMN 0046863

March 25, 1994 page 1; benefits of smoking for its customers in the =ollowing way: Among the benefits cf cigarette smoking which have been trequeant+y mentioned by amokera or which have beern noted in the literature are the following: pleasing taste and aroma; satisfac:G ton; stress reduction; relaxation; stimula=ion; aided concentration; increased memory retention; alleviation of boredo«, aiid fatigue; avoidance of loses of vigilance in repetitivn or sustained tasks; and facilitation of social interaction. (Reply tc .iiit.rsrrogatories, 4ilhov v R.-1, RQVnol1) The biobaiiaviora'_ research laboratory at R. J. Reyr.olds has proven that sex,er,a1 of these effects are caused by nicotine acting in the Orain. A paper by Dxs. Robinson, ?ritchard and Davis (1992), copies of which have been provided to the Subcommittee, show that cigarettes which do not deliver nicotine (presumably Ne:ct brand cigarettes from Philip Morris) fail _o change the EEG of smokers irn ways characteristic of the relaxing and the atimulAtinq effects of smoking. Conventional cigarettes do cause these EEG changes. The paper proves that it is the nicotine in c'larette smoke, and the nicotine alone, which causes theeP deaired affects of smoking. Throughout the article, the authors emphasLze that these are important phar:nacolcgic effectg of smoking and r.hat the achievement of these effectg are among the reasons pe-aple Amnka cigarettes. Cigarette companies often aay 1'hay design and market their products in .reapoziee .to.,.cr~asumex.,dema~d~..,au~. t:h.~.. ~xpl,ieit eff.ects mentioned by cigarette companies and di.ar..unnAd in this section are among the effects amokers expect frnm r{garettes. eince cigarette cnan~-?.facturers are market driven r.nmpaniee, they intend that their proaucta provide these effects. TIMN 0046864

March 25, 19•94 Page 19 Cther effects many customers expect are relief from withdrawal sy-,,ptcma and help with weight control. The next two sections explore two particular industry terms in more detail,. These terms, "satisfaction" and "physiologic activity," su~~gest relief of nicotine withdrawal and maintenance of nicotine a~_ldiction more than they suggest the relaxation and stimulation ei`fects so emphasized by Robinson, Pritchard and Davis.10 CiQaratte Man+tfacturQre Intend to Provide Tohaaco Satisfaction Tobacco -iatiafaction is a technical term in the tobacco trade that de-lotes a quality separate and apart from taste and flavor. Ite uaage indicates that the term describes certain pha.r.maanlogic effects of nicotine. Table 4 iixta a$ew examples of the term in advertisementse that clearly 3iatinguiah tho r_nncept of "satisfaction'f from that of "tamte." The introduction of Premier in 1987-88 wau acanmpanied by a variety of descriptions of the product in ternns of and similar sounding terma. - -----prom a patent application : - 8rn_king-articlee .of the .iavention.. . ..are cap.ablv of pr<<viding the user with the sensal'-ions and benerits of lo Dr. cleaethi$y'a term, "mild pharmecology," can readily include nico,-ine addiction since the R. J. Reynolds team has tried to mak--, ouch a strong diotinetion between nicotine and other addicti.ng drugs based on the fact that nicotine in usual doses does n~~t cause intoxication (Robinoon and Pritchard, 1992). TjMN

Marcki 25, 1994 Page 20 c-iaax,ette smokina. (emphasis added) (Clearmar et al, 1988) hrom a cc-LUpany prese rclcaac : The •:igarette ie based on t%ew tecr.azalogy that heats racr::r thann burns tobacco to provide smokers with ~~Y~g~:c~ ta te and aat_~~~ctic~. (e;nphad8ia added) (R. u. Reynolds, 1987) F'rom the tlonograph, Chem'_cal and Biolggical S9udiee... c - R.J. Reynolds' Product Development Objectives for deve.oping the NEW CIOARETTE were as follows t '1'o provide the tobacco taste and smoking p1ea_sure of other cigarettes, as demanded by smokers... , (emphasie added) (x.~. xeynolds, 1~88a, page 35) The ~W CIGARETTE is based on a concept that allows a smok-3r to receive the tobacco ta te. sensations and e_nio en of cigarettes without burning tobacco. (empaaeis added) (R.J. Reynolds, 1988a, page 43) From a magazine ad in a test market area: - 3moks that satisfies, yet dissipates almost the moment you exhale. (emphasis added)lI (R.J. Reynolds, 1988b) In none of these five descriptions does "taste" or "sensation" stand alone as a sufficient description of the benefit R. J. Reynolds promises consumers from smoking Premier. Additional promises are made for "benefits of cigarette smoking," "tobacco aatiafaction," "smoking pleasure," and "tobacco enjoyment." Additidn.-.l illuminatiorn of the meaning of the term "satisfaction.. can be found in two patents, copies of which have been submitte~l to the Subcomatittee. li One must have first inhaled the smoke in order to be able to cxhal=i it. TIMN 0046866

March 25, _994 Page 21 These are patents held by R. J. Reynolds, number 4,830,028 issued May 16, 1989, and nucr,ber 4,836,224, issued June 6, 1989, The problem these patents set about solving is how to make cigarettes that have low "tar" delivery but which still delive: "a desirable tobacco taste, flavor and satisfaction to the smoker." The patents make repeated reference to Usatisfacticni, as a quaZity =,istinct from "taste." In establishing the need for the present i~,vention, the patents no:.e that simply adding nicotine to l.~;w "tar" cigarettes in an effort to so_ve the problem at haj,d "generally yields mainstream smoke which may be perceived as i~arsh or irritating to the mouth, nose and throat of the user." The solu;,ion disclosed in the patents is the use of an organic acid oalt of nicotine, especially nicotine _evulinate, as an additive to cigarettes having low "tar" deliveries. The patents provi~le detailed instructions for the synthesis of this salt from nicotine which is 95 to 99 percent pure. The firsi: patent gives as examples experiments with a 99 mm cigarette havLng an FTC "tar" delivery of 4.6 mg and with a king size cigarett;a having an FTC "tar" delivery of 1.8 mg. The desired smokizQ characteristics, increased nicotine delivery with smoother smok ing,,.. wer.e achiaved mith:.the...add.ition_: of about 3 7 mg of nicotine 1?vulinate to the first experimental cigarette and about 36 mg of nic:ntine levulinate to the second (Table 5). The patent Pmphasi.7es r.hat t_he achievement of the desired effect was associated with a rec3urec3 pt; of the smoke in the treated TIMN 0046867

., March 25, 1994 I'age 22 cigarettes. Ao.igarette spiked with nicotine alone, without the levu=inic acid, had a much higher pH than even the control and was felt to be "extremely harsh" and nnot palatable." These pateats show that the addition of nicotine in a form that lowers the pH of the smoke increases nicotine delivery not without raising "tar" delivery and does so in a way that ist harsh. The pat~nt indicates that the use of nicotine levulinate as an additive is a solution to the problem of making a cigarette with a low "tar" delivery produce desired levels of taste, strenqth and satisgfaction to a consumer. R. J. Reynolds intends to provide its customers with tobacco satisfaction, and tobacco satisfaction has to do with the delivery of inhalable nicotine. Moreover, the term +'Rar_.isfaation" suQgests a state of comfort, of well-beinq, that can only be mum-rained by someone already addicted to nicotine by the ingestion cf sufficient amounts of the drug to at least alleviate or f,-~xestall wita.drawal symptoms. Since nearly all of R. J. Reynolds more than 10 million U. S. customera amnka chronically, t%$ir actual attainment of natisfaction neceRRari } y involves tho mm-Lintenanca of the addiction to nicotine that movr.o of them have. in ir.ter_ding to provide its customers with "tobacco nAti.ai:act.ion.r..t' R.. ..: .- .lkeyxiolde .intenda. . to,, maintain addictiorn tc n.cotine in thooe addicted to the drug. TIMN 0046868

Maruh 25, 1994 Page 23 Tobacco Manufa:turers Intend to Provide "Desirad Physiological Activity" In patent no. 3,584,630 ;issued June 15, 1971), PY.ilip Morris declares, It has long been known in the tobacco industry that is order to provide a satistying smoke, it is desirable to maintain the nicotine content of tobacco products at a unifortr level. However, it is difficult to accomplish this result since the nicotine content of tobacco varies widely, depending on the type of tobacco and the conditions under which the tobacco is grown. ... Maintai_ning the nicotine content at a sufficiently high level to provide the desired physiological activity, taste, and odor which this material imparts to the smoke, without raising ~,he nicotine content to an undesirably high level, can thus be seen to be a significant problem in the tobacco art. Th=! addition of nicotine to tobacco in such a way that it remai!Ls inert and stable in the product and yet is released in a controlled amount into the smoke aerosol when thR i-nYsaoco ia pyrolyzed, is a result which is greatly desirabl-:. The pres.:nt invention provides a solution to this longstanding problem Anc3 rpsti1.ta in accurate control of the nicotine which is released in tobacco stftokt. For Phillp Morris, providing a satisfying smoke involves controlling t'ie nicotine delivery in a precise manner so that its customers rec-.ive the "desired physiological activity, taste and odor." The ":~hysiological activity" of nicotine can only be understood to mean some of its bharmacoloaic actions on the brain. The term "physiology," though, suggests the maintenance of homeostasis, of a state of normalcy, irn the body, in contrast to the term "pharmacology," which more suggests a change in the body brought about by a drug. In individuals tolerant to the actions TIMN 0046869

March 25, 1994 Page 34 of a drug such as nicotine, though, the sudden withdrawal o: that drug can produ~_e a dis-ease, an illness, which is experienced as a disturbance ~f homeostasis. The ingestion of the drug, in alleviating th-: withdrs.wall syndrome, is then experienced as a restoration of normalcy. Philip Morris, choice of the term "physiolgical activity," then, implies that the particular pharmacologic Actions of nicotine intended in this patent are those associatLad with the relief of withdrawal symptoms. The term i'satisfying smoke" also suggests this,' as discussed in the previou-; section. Similarly, Gallahers Limited, a subsidiary of American ~ Brands, refers to nicotine as "a physiologically active agent" in its 1980 paten;, number 4,236,532. Taken tog=ather, the two patents on tobacco satisfaction and the two on physiological activity demonstrate that major cigarette manufacturers intend to provide tobacco satisfaction and a restoration of physiological balance to their customers. This is accomplished by the delivery of nicotine to the brair_, enc3 nnr_h terme refer to the maintenance of an addiction to nic.ot ine. a7ieatia• and _t-'&f f.iime.. Cigar®tt=: industry spokesme'n frer_;uently compa-re amnk= ng cigarette$ to the drinkinr.~ of coff@e, tea and caffPi nar.Pd bavorages. T=iey $peak of smoking as a rabi t-. ,1 i kA c-nf=r?A drinking. In doing so, they concede that smoking is nf.r..Pn at. I TIMN 0046870

March 3S, 1994 Page 28 least regular, repetitive and compulsive (habitual), and that it a.s engaged in ;--o achieve a range of effects, incsuding the suppression of withdrawal symptoms (headache in the case of caf f e ine ). 3o:•iever, the analogy s hou_d not be pushed too f ar . it by no means "proves" that nicotine is not addictive. • An e:cpert group :ev:ewed the.clinical and basic science lite^ature on caffeine and, concluded that, while it would be important to include the diagnosis "caffeine withdrawal" in standard classificaticns (DS.M zy and 'Co 12), the data did not support the inclusion of a rubric for "caffeine dependence," that is, for addiction to caff eine. (Hughes et al, 1992) in contrast, the = has had a diagr~ostic category for tobacco dependence or nicotine dependence since 1980. • The potential occurrence of harmful consequences because of drug use is acn important clinical criterion for addiction. Harm consequent to use is a maior pro'EiIem with nicotine but not with caffeine. a ThP-rp are virtually no systematic data on how difficult m it -.s to st.np r.affPine use, while there are abar.dant dat-i or. the difficulty penp1iz. enanunter in becoming abei:inont from nicotine. Stcpging mmnk.in.q is often v®s ( difficult to do. Decaf r.offepa and sodas are popilar, but denicotinized tohar..nn prnductB are not. More than two-thirda of people who smokP cigarettes want to stop but find this a difficul= thing to dc. There ;A no evidence TIMN 0046871

March 23, 1994 Page 26 that people who use caf=eine face similar ditficulties. Caffeine withdrawal is a real phenomenon, as is nicotine withdrawal. Unlike caffeine ingestion, however, chronic nicotine ingestion usua:ly producea loss of control over use and continued use despite consea_usnces, the defining features of other drug addictions such as those produced by cocaine, heroin and alcohol. Moreover, from a regulatory perspective, to the degree that the ana;.ogy is at all valid, '_t only supports the conclusiorn that cigarettes should be regulated as drugs. • Caffeine is already regulated as a drug by the FDA.when it is sold in tablets as a stay-awake drug or as a compcnent of a pain relieving medication. Beverages that contain caffeine are already regulated as foods by the rDA. Since these beverages are regulated as fcods, they avoid being subject to the requlations that govern c3rug-,: The part of the definition of a drug in the Food, nrug & Coametic Act that refers to affecting the stru,-!ture or f.tmr_tion of the body explicitly excludes food-i. Tobacco produr..t_e have never been regulated as food-j, and the tobacco industry hae never suggested that they shou:d be. To the e-x:.ont •. that. tobacco- prcduc.ta,, ara to he,!-hnught of as affecting =hc ~itruature or function of the body in ways that are similar to caf feine, r.hey ehou].d be regulated aR drugs. The argum-tnt that emoking cigarettes is like drinking coffee or l,tta and tha: amoking cigarettee ie-therafore not addictivA is TIIVIN 0046872

T March 25, 1994 Page 2 7 false. While there are similarities betweern nicotine and caffeine, there are important differences. Nicotine is highly addictive while caffeine is not. All caffeine-containing products intended for human consumption already~are regulated by the Food and Drug Administration. Cigarettes are not. Nicotizim Addi--tion is iratend®d ie nicotl_ne addiction intended? It is. Dr. deBet-hizy's reference to "mild pharmacology" is imprecise, bur, it evokes the often subtle and varied effects of nicotine on tl-.e central nervous system. it is compatible with the conclusio,~ that the cigarette companies intend to create and sustain an-ad~lietion to nicotine in many of their customers. The "mildness" th_~t Dr. deBethizy may have had in mind has been discussed in freat detail by two of his colleagues at R. J. Reynolds; at the doses usually consumed, nicotine does not produce the h-trsh, intoxicating changes commonly associa=ed with many cther addicting drugs (Robinsorn and Pritchard, 1992). Th=s, however, is not evidence against regarding nicotine as addicting. The creation )f intoxication under common conditions of use is hardly a defiaing feature of addicting drugs. nMildn.pAV" .e is.,.also.,.ac_.ieved in anQther -saxid'e :.. :Unlike street drugs, t.hA potencies of which can vary enormously from baq to bag, a ga.vrn brand style of cigarette produces a very predictable puff profile ng nicotine delivery because of advances in cigarette enginarering. The cigarette smoker has a far more .TIIVIN 0046873 ~`.

March 25, 1994 Page 28 reliable drug delivery device than does the person who obtains drugs of widely varying potency from street dealers. This feature lets the cigarette smoker avoid unexpectedly high or low doses of nicotine, a benefit the user of cocaine or heroin does not have. The cigarette smoker will reliably receive the expected dose, a dose known to the smoker as one that will produce the de;_ired effect. The user of heroin or cocaine does not have this ~ssurance. The tobacno companies are familiar with the scientific literature on =acotine and know that smoking is a hard thing for most of their ouatcmers to atop. They intend to provide their customers with "satisfaction" and to sustain in them a phya;nlogic state of normal feeling. The industry's repeated comparison to oaffeine is valid to the extent that caffeine, l:.ke •nicotine, hac A variety nf pharmacologic ef fects, including stimulation, talerance and withdrawal. KnwevPr, nicotine is a more potent drug than caffeine : consumers of ni cat-lnA fiO it hardcr to atop, and 4xporte have concluded that addiction to nicozine in a rogular consequence of nicotine ingestion while adda.ction to caffeine sooms ao unucual that it has not baen . . c3esrsmsd neceenary-0o -izicTude thie diagnoaie in comprehensive lia Llngs of inedicad,l...canditione_ ... . . . . _. . . _ In their intention to providc cuotomero with tobacco eal.lsfaction, in their intention to provide cuatomers with pt,.yaiol.oyic e yfectn , and in their intontion to provide customers wilkx a c3rug t;.at induces tolerance and withdrawal, cigarette TIMN 0046874

March 25, 1994 Page 29 manufacturers r~eveal their intention to sustain addiction to nicotine in th=ar nicotine dependent customers. Diaaus©ion Cigarette13 are intended to affect the structure or _unction of the body. The manufacturers have developed technolcgies which permit them to precisely control the dose of nicotine so it is predictable, neither too much nor too little, from cigarette to cigarette. Tha intended use of cigarettes involves inhaling the cigarette smoke. :nhalation has nothing to do with taste and flavor; inhalation has everything co do with the rapid delivery of nicotine to the central nervous system. The intended effects of ciqarette smoking include relaxation, stimulation, the provision of satisfaction, and the promotion of physiologic equilibrium. Any one of these intended effects is sufficient to trigger application of the Food, Drug and Cosmetic Law to cigarettes, bl:t in fact, all four effects, as well as others, are intone3aad_ In other wordm, a1 t-hrnigh t-ha cigarette makers do intend to su$tain nicot.ne addiction among many of their mast-omers, t°rArP are also othe-~ intended pharmacologic effects of smoking which aloo chould r=iieu1~-- in • the . Food and..Drug..Adminiatration_ exerting ite regulatQrf authority over this induatry. Objections from cigarette makers that sales~ weighted nicotine deliveriee have be.n falling over the years are not pcrouaaive that cigarettes are not intended to affect the TIMN 0046875

March 25, 1994 Pace 30 structure or f"llction of the body. The sales weighted average nicotine level 'zas been level for more than a decade, and the , actual nicotine taken in by smokers is substantially higher than this curve woull suggest. Moreover, the decline came as a consequence of an unprecedented marketing campaign that was designed at least in large part to persuade smckers to switch to low tar cigarettes instead of to stop smoking altogether (Warner and Slade, 1992). objections from cigarette makers that their finished products conta4n less nicotine than are in the raw materials are not persuasive that cigarettes are not intendgd to affect the structure or f±,nction of the body. The average nicotine content of finished ci~_-arette tobacco today appears, orn average, to actually be mo_•:l than it was in 1952. After processing, cigarettes stil,l contain enouah nicotine to easily sustain addiction to n',cotine. A major a~:complishment of the many'advances in cigarette engineering ov:r the last 40 years has been the achievement of prer_ise controL and uniformity over nicotine delivery. This achiwvmmwr,t wa-i not even conceived of as possible by the federal governtnent in 19FA. This achieved consistency of nicotine delivery prcba'oly enbanr.wea thn addictiv_enes.a,..of aigs,rettest since cuatorners are able tn more confidently obtain the Drecisely daeired incake of nicoti nn fresm moment to moment. Tn 1973, only a few yAmrA after his employer had been granted the patent on spi.ki ng r.i garette f i1 ters with nicotine TIMN 0046876

March 25, 1994 Page 31 adsorbed onto c-arbon black (pat. no. 3,584,630), the patent that spoke frankly o: the need the industry had to carefully control nicotine delive:y to achieve optimally satisfying smoke and the desired physiol,)gical activity, William Dunn described the cigarette in th=a following lyrical manner: ...the cig-arette is in fact among the most awe-inspiring examples oE the ingenuity of man. Let me explain my conviction. The cigare:te should be conceived not as a product but as a package. The product is nicotine. The cigarette is but one of many pa.:kage layers. There is the carton, which contains the pack, ~which contains the cigarette, which contains the smoke. Th-a smoke is the final package. The smoker must strip off all these package layers to get to that which he seeks. But considar for a moment what 200 years of trial and error designing has brought in the way of nicotine packaging: Think of t':ie cigarette pack as a storage container for a day' ssupp Ly of nicotine : 1) It is unobtrusively portable. 2) its contents are instantly accessible. Think of the cigarette as a dispenser for a dose unit of nicotine: 1,) rt is readily prepped for dispensing nicotine. 2) Its rate of combustion meters the dispensing rate, setting an upper safe limit for a substance that can be toxic in large doses. 3) Dispensing is unobtrusive to most ongoing -behavior.. _ s . . .... __ ._ .. _ . . Think of a puff of smoke as the vehicle of nicotine: 1) A convenien.t 35 cc mouthful contains approximately the right amount of nicotine. 2) The smoker has wide latitude in further calibration: puff volume, puff interval, depth TIMN 0046877

March 25, 1994 Page 32 and duration of inhalation. We have recorded wide variability in intake among smokers. Among a group of pack-a-day smokers, some will take in less than the average half-pack smoker, some will take in more than the average two-pack-a-day smoker. 3) Highly absorbable: 97V nicotine retention. 4) R;~pid transfer: nicotine delivered'to blood s'-ream in 1 to 3 minutea.la 5 ) . N~ n-noxioue administration [sic]. Smoke is beyond question the most optimized vehicle of nicotine an-~- the cigarette the most optimized dispenser of smoke.(Dunb ., 1973, pages 5 and. 6) Conclusi.ons • Nieoti=ie is the cause of cigarette smoking. • Nicotl<<e has important psychoactive effects, including addicti.on. • Cigare!etes are designed to promote inhalation of cigarel:te smoke and thereby the rapid abeorption of nicotiiie into the body. • Cigarel:tes are engineered to deliver optimal doses of nicoti=_ie. A wide range of technologies, including the additi.;n of nicotine in various forms, can be employed to acc~;mplish this. • Cigarette•..companies .d intend that their cust_ome.ra experience a variety of pharmacologic effects from the nicotirie absorbed from cigarette smoke. Among these 12 Actually, delivery is in a matter of a few seconds. TIMN 0046878

March 25, 1994 Page 33 intended effects is the sustaining of addiction to nicotine among those dependent on the drug. • Cigarettes are articles intended by their manufacturers to affect the structure or function of the body and therefore are subject to regulation under the Food, Drug 3nd Cosmetic Act. m TIMN 0046879

March 25, 1994 References Page 34 American Peychiai_,ric Association. Diacmostic and Statiat'ca1, Manual_,-Thir7d Eda, icn, R vised. Washington, D. C.: American Paychiatric Association, 1987. American Tobacco Company. "Do you inhale?" Time, back cover, July 25, 19-l2. Benowitz, N. L., Hall, S. M., Herning, R. I., et al. Smokers of 1ow-yield cLgarettes do not consume less nicotine. New Envland_Jou:nal of Me-dieine 309:139-42, -983. Benowitz, N. L., Jacob, P., Denaro, C., Jenkins, R. Stable isotope studiee of nicotine kinetics and bioavailability. Clinical--P~'?-&rmacoloay anSLTherapeuticg49:270-277, 1991. Clearman, J. F., Gentry, T. L., Shelar, G. R. Smoking article with tobacco jacket. U. S. Patent Number 4,756,318. Assigned to the R. J. Reynolds Tobacco Company. Filed October 28, 1985, ieeued July 12, 1988. Colby, F. Personal Communication, New York City, February 27, 1992. Coultas, D. B., Stidley, C. A., Samet, J. M. Cigarette yields of tar and ni~-otine and markers of exposure to tobacco emoke. Ameri,can___g=v-ie.w, ~Z. 2egca_ratory. D aeaa ...14,Q,:435-.440, 1993. Dunn, W. L., Jr. Motives and incentives in cigarette smoking. Preaented =-Lt the CORESTA-TCRC Symposium, October 25, 1972, Willi.amsbt? r.,g, Virginia. Dunn, W. L., Jr, Motives and incentives in cigarette smoking.

March 25, 1994 r Page 35 Typescript. Richmond, VA: Philip Morris Research Center, 1973. Faitelowitz, A. tberr die Bedeutung der AciditAt des Tabaks fiir seine hygieaische Beurteilung. Zeitgchr. f. Unte suchunct der Lebensmj"gj 60:518-a23, 1930. Federal Trade Commission. In the Matter af P. Lorillard Companv, a__car=oratigZ. Findings as to the facts and conclusion. Docket No. 4922. May 24, 1950, page 6. Gori, G. B., Berowitz, N. L., Lynch, C. J. Mouth versus deep airways absorption of nicotine in cigarette smokers. Pharm-acoloUv Bio hemi.stry a Behavior 25:1180-1184, 1986. Henningfield, J. E., London, E. D., Benowitz, N. L. Arterial- venous dif==erenees in plasma concentrations of nicotine after cigA=,ette smoking. J~ 263:2049--2050., 1990. Henry, C. J. a*±-'. Kouri, R. E. TobacCo-Re=iea:_rc - tT.S.A.. T c. Contrac CTR-0e30; ir moke Final Report : The Council for inhalation Stu ies in Mice." New York: Field, Rich & Aesocatea, 1984. Hughes, J. R., clliv©to, A. H., Helzer, J. E., Higging, S. T., Bickel, '-W: K. -Should cafeine abuse, dependence or withdrawal be added to DS_M-IV and ICD-1Q? Am J Psvch atry 149 :33-40,.. 199G2,-.. Imperial Group "Jimited. U. S. Patent 4,340,072, iseued in 1982. R. J. Reynolds Tobacco Company. R. J. Reynolds Tobacco Co. developing new cigarette. Press release. New York: R. J. Reynolds T.Dbacco Company, September 14, 1987. TIMN 0046881 -

March 25, 1994 Page 36 R. J. Reynolds Tol7acco Company. CheM'caI a d ~,ological Studies ~w Cj.~=3tte Prototvr~ee that YHeat Instead of SVrn Tobacco. Wiaston-Salem, NC: R.J. Reynolds Tobacco Company, 1.988a . R. J. Reynolds TcDacco Company. Sntroducing Premier. Better Homeg and__4Ardens (St. Louis area edition). November 1988 (1988b) Robinson, J. H. and Pritchard, W. S. The role of nicotine in tobacco use. Psychonh rmacoloav 108:397-407, 1992. RRobinson, J. H., Pritchard, W. S., Davis, R. A. Psychopharmacological effects of smoking a cigarette with typical "tar" and carbon monoxide yields but minimal nicotine. Peychooha aco1oav 1®8:466-172, 1998. Silberstein, D. A. Flavouring reconstituted tobacco. Tobacco Journa1 _Int_ern t~ ionaL. #1 for 1985, pages 24-29. Slade, J. Nicotine delivery devices. In Orleans, C. T. and. Slade, J., Ade. Nicotine Ad iction: P_ringioYe.~ end Management,. New York: Oxford tTniversity Press, 1993. pages 3-23. 'I'ye.,_ . J-.. . Sixtv_. Y= a'*s of De_cegt ion • an .Analygis and omnilat i on o_f CiszaK*-t-t---: Ad in Time MaSgaaine. 1925 to 1985. Palo Alto, CA: Health-Advocacy .Center,• -9.986.. _•,,. _ _. .. . . ...._. U. S. Department of Health and Human Services. The Health Conseauence-i of Smokina • Nicotine Ad iction Renort of the_ SqrcreorL General. U. S. Department of Health and Human services, p+iblic Health Service, Centers for Disease TIMN 0046882

March 25, 1994 Page 37 Control, center for Health Promotion and Education, Office on Smokiny and Health. DHHS Publication No. (CDC) 88-8406, 1988. U. S. Departmert of Health and Human Services. Redcing the H_e_al_th-ConsecZUences of SmokYna ^ 28 Y®a;rB ot Progrege A Beuo_°t of the e Sur,aeon General. U.. S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Health Promotion and Education, Office on Smoking and Health. DbIIi9 Publication No. (CDC) 89-8411, 1989. U. S. Department of Health and Human Services. Prev ntinc TQbacc4 LTse Among Xoun,a People. A Reflort of the Suraeon General. Atlanta, Georgia: U. S. Department of Health and Human Services, Public Health Service, Centers for Disease Contro3l and Prevention, National Center for Chronic Disease 'Prevention and Health Promotion, Office on Smoking and Health, 1994. Walsh, F. H. Affadavit. FTC v Liggett & M3rers. November 19, 1952. Warner, K. E. nad Slade, J. Low tar, high toll. American Journal Qf Public Health 82:17-18, 1992. Wright, C. D.. -- Af fadaari t . • • In . the.. Matter ...of...Ligget.t & ~MYers Tobacco Co=anv. Washington, D. C.: Federal Trade Commission, October 9, 1952. TIMN 0046883