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1; ol. 33l \o. 2 SOCNDI`G HOARD • 123 I I I I 1 I I ESTABLISHING A NICOTINE THRESHOLD FOR ADDICTION The Implications for Tobacco Regulation ON February 25, 1994, the Food and Drug Adminis- tration (FDA) released a letter to the Coalition on Smoking or Health announcing its intention to consid- er regulating cigarettes. The agency's premises were that the vast majority of tobacco users self-administer the product for the drug effects of nicotine and to sustain addiction and that cigarette manufacturers control the levels of nicotine in cigarettes to maintain this addiction. The FDA further raised the possibility of regulating cigarettes on the basis of their nicotine content to prevent addiction. On February 28, 1994, the ABC news program Dav One presented evidence that tobacco manufacturers manipulate the nicotine content of cigarettes. One way thev do this is by removing nicotine from tobacco and then adding it back in controlled amounts, using tobacco extracts containing nicotine. It was suggested on the news program that the amount of nicotine in tobacco was controlled to ensure that the level was adequate to maintain nicotine addiction. In support of this idea the program quoted an internal memoran- dum from a Philip Morris Tobacco Company scientist that had been discovered in recent litigation: "The cigarette should be conceived not as a product but as a package. The product is nicotine. . . . Smoke is be- yond question the most optimized vehicle of nicotine and the cigarette the most optimized dispenser of smoke." ' That the pharmacologic actions of nicotine are important determinants of why people smoke is supported by studies conducted by the tobacco indus- try2-3 and by nonindustry researchers.} That nicotine addiction sustains tobacco use for most smokers is well established.' Once a person is addicted to nicotine, quitting smoking is difficult, and more than 90 percent of the smokers who try to quit each year fail.' An important, if not the most impor- tant, component of a policy to reduce tobacco use in the population is to prevent the development of nico- tine addiction in young people.6 Young people do not start to smoke because they are addicted, but rather because of psychosocial and environmental influ- ences, particularly peer influences, psychological fac- tors, and advertising. Young people generally under- estimate the addictiveness of nicotine, and most of them at first intend to smoke only for a few years.6 However, once they begin to smoke, many become addicted to nicotine, and this addiction sustains the self-injurious behavior into adulthood. The result of nicotine addiction is a 40 percent probability of pre- mature death from illness caused by tobacco.7 It is difficult to prevent adolescents from experimenting with cigarettes. However, by regulating the availabil- ity of nicotine in tobacco products, it may be possible to prevent the transition from experimental or ocr,a- sional smoking to addiction. This paper examines the proposition that the level of nicotine likely to produce addiction can be estimated and that mandating a nico- tine content below that level is a feasible approach to tobacco regulation. Is THERE A THRESHOLD LEVEL OF NICOTINE INTAKE ASSOCIATED wITH ADDICTION? We define addiction according to the Surgeon Gen- eral's 1988 Report on Nicotine Addiction: it is the compulsive use of a drug that has psychoactivity and that may be associated with tolerance and physical dependence (i.e., may be associated with withdrawal symptoms after the cessation of drug use).' For smok- ers, addiction is assumed to involve daily smoking of I I I I I I I I I I I I

124 THE NEW ENGI i\D JOL;R-\AL OF %IEDICINE cigarettes. difficulty in not smoking every day, and a high likelihood of withdrawal symptoms after cessa- tion of smoking. Most American smokers are believed to be addicted according to these criteria.8 However, approximately 10 percent of current smokers (a group sometimes called tobacco "chippers") regularly smoke five or fewer cigarettes per day and appear not to be addict- ed.9 Most do not have withdrawal symptoms when they stop. Typically, such people smoke in specific situations, can skip smoking for one or more days, and can quit smoking without great personal distress. The daily intake of nicotine from tobacco can be estimated from the level of cotinine, the principal me- tabolite of nicotine, in blood or saliva.!0 The average blood cotinine concentration in addicted smokers is about 300 ng per milliliter.",12 Smokers of 5 or fewer cigarettes per day have average serum cotinine levels of 54 ng per milliliter and an average consumption of 3.9 cigarettes per day." The cotinine level normalized for cigarette consumption is 14 ng per milliliter per cigarette, or 70 ng per milliliter for a person who smokes five cigarettes per day. Thus, it is reasonable to estimate a level of 50 to 70 ng of cotinine per millili- ter as a cutoff point for the addictive threshold. Of course, there is no sharply demarcated threshold level, and there are some people who smoke fewer than five cigarettes per day and have great difficulty in quitting and others who can smoke more than five cigarettes per day and quit with ease. Studies involving the infusion of nicotine and coti- nine into smokers indicate that the daily intake of nicotine can be estimated as 0.08 times the blood coti- nine concentration. `0 A level of 50 to 70 ng of cotinine per milliliter corresponds to a daily intake of 4 to 6 mg of nicotine. Thus, 5 mg of nicotine per day is proposed as a threshold level that can readilv establish and sus- tain addiction. DELIVERY OF NICOTINE FROM CIGARETTES On average, an American cigarette contains 8 to 9 mg of nicotine." The concentration of nicotine in tobacco ranges from 1.5 to 2.5 percent. Typically, the cigarette delivers about 1 mg of nico- tine to the circulation of the smoker,'{ representing an absolute bioavailability of about 12 percent. The vari- ation in intake per cigarette is considerable, how- ever, ranging from 0.3 to 3.2 mg, representing a bio- availability of 3 to 40 percent, depending on how the cigarette is smoked.'t.1S The daily intake of nico- tine is poorly correlated with machine-determined yields."•1z36 This is because smoking machines smoke cigarettes in a standardized way, whereas people can take more puffs, puff more intensively, and occlude ventilation holes in the filter or on the cigarette in order to obtain the desired dose of nicotine from most cigarettes. When the number of cigarettes available to an individual smoker is reduced from an average of 38 July 14, 1994 I to 5 per day, the intake of nicotine per cigarette in- creases an average of threefold," a figure consistent with the maximal absolute bioavailability cited, 40 percent. N`'e emphasize that this absolute bioavailabil- ity is the percentage of the nicotine contained in the cigarette that can be absorbed systemically by the smoker; it is unrelated to the smoking-machine yield. If the design of cigarettes were to change, bioavaila- bility would need to be reassessed in people smoking the redesigned cigarettes. THRESHOLD T.EVEIS OF IVICOTINE IN CIGAItETrFS AS A WAY TO AVERT ADDICTION Although machine-measured cigarette yields are not useful in predicting a smoker's intake of nicotine, the absolute level of nicotine in a cigarette could be regulated to limit the maximal obtainable dose. Stud- ies using cigarettes developed for research purposes to be low in nicotine have demonstrated that intake can be limited by restricting the amount of nicotine in the tobacco.`'a Assuming that the estimated target daily dose of nicotine should be 5 mg or less to avert addiction and that a young person may smoke up to 30 cigarettes per day, one can conclude that a maximal available (i.e., systemic) dose of 0.17 mg of nicotine per cigarette is the threshold level for a less-addictive cigarette. As- suming a maximal bioavailability of 40 percent with intensive smoking, an absolute limit of 0.4 to 0.5 mg of nicotine per cigarette should be adequate to prevent or limit the development of addiction in most young peo- ple. At the same time. it mav provide enough nicotine for taste and sen59_r-ystimulation. A POSSIBLE STRATEGY FOR REGULATION The rationale behind the strategy for regulating the nicotine content of cigarettes is to prevent the develop- ment of nicotine addiction in young people. To mini- mize the hardship to already addicted adult smokers, the level of nicotine in tobacco could be reduced gradually, with a goal of reaching a target nicotine level over perhaps 10 to 15 years. The intended result of such a strategy would be that cigarettes cr,uld stiU be sold, but the number of addicted smokers would be markedly reduced. In the absence of addiction, levels of tobacco consumption should decline sharply, caus- ing a substantial reduction in the rates of tobacco- caused illnesses. There are, of course, a number of caveats. A thresh- old level for nicotine addiction is a theoretical concept based on observations in current smokers and studies of the bioavailability of nicotine during smoking r0- striction. That restricting levels of nicotine would pre- vent addiction needs to be verified empirically. There is concern that for already addicted adult smokers, reducing the nicotine level in tobacco might result in more intensive compensatory smoking, with increased exposure to toxic combustion products such as carbon I I I I I I I 1 I I I I I I I 2046398998 I

I . Vol. 331 No. 2 SOUNDING BOARD 125 monoxide and tar. Switching from higher-yield to lower-yield cigarettes has been shown to result in smoking more cigarettes or smoking more intensive- ly, both of which are associated with increased ex- posure to carbon monoxide and other toxins.18•!9 Overcompensation (i.e., inhaling more smoke from low-nicotine cigarettes than from higher-yield brands) appears, however, to persist only for days or weeks. In long-term studies of carbon monoxide exposure after subjects switched to low-yield cigarettes, compensa- tory oversmoking appears not to persist.20,1t It is also conceivable that cigarettes could be manufactured to reduce the delivery of tar and carbon monoxide as well as the nicotine content. Even if there is some element of overcompensation and smokers are ex- posed to increased levels of toxins, their short-term (10 year) risk may be offset by the long-term benefit of a greater likelihood that they will stop smoking (as cigarettes become less satisfying) and by the enormous benefit of preventing nicotine addiction in future gen- erations. It should be noted that other researchers have pro- posed the introduction of "safer" cigarettes that are enriched with nicotine in order to reduce the ratio of tar to nicotine.' The rationale for such cigarettes is that smokers would need to inhale less smoke to obtain the desired dose of nicotine, and exposure to toxins would thus be reduced. A strategy involving nicotine- enriched cigarettes might reduce morbidity and mor- tality from cigarette smoking, but the reduction would probably be limited, because even at reduced doses, tobacco smoke is highly toxic. The goal of that ap- proach - producing a safer cigarette for those who cannot stop smoking - is the diametric opposite of ours. Our goal is the prevention of nicotine addiction and a reduction in the prevalence of cigarette smok- ing, which in the long term would eliminate exposure to the toxins in tobacco smoke and reduce tobacco- induced morbidity and mortality much more. The measures described in this proposal may seem drastic to some. However, the problem of one quarter of a billion premature deaths caused by tobacco use in developed countries' calls for drastic action. Tobacco use is motivated by nicotine addiction. We offer a strategy for the prevention of nicotine addiction based on recent scientific data. This approach deserves study by the regulatory authorities. University of California, San Ftaneiseo San Francisco, CA 964110 NEAL L. BE,rowrrz, M.D. National Institute on Drug Abuse Balumotc. MD 21224 JACK E. HENNINGFIELD, PH.D. We are indebted to Dr. Charles R. Schuster, former director of the National Institute on Drug Abuse, and Dr. John Slade, Univer- sity of Medicine and Dentistry of New Jersey, Robert Wood John- son Medical School, for their helpful comments; and to Nis. Kaye Welch for assistance in the preparation of the manuscript. Address reprint requests to Dr. Benowitz at San Francisco Gener- al Hospital, Bldg. 30, Rm. 3220, 1001 Potrero Ave., San Francisco, CA 94110. Supported in part by grants (DA02277 and DA01696) from the National Institute on Drug Abuse. REFERENCEs l. Dunn WL. Motives and incentives in cigarette smoking. PlainuH's exhibit P-5171. Cipollone v. Liggen. L'uigation documents 3.4'IPLR 3.362 (inter- nal tttenanndum. Philip Mortis Tobacco Company). 2. Robinson JH. Pritchard WS, Davis RA. Psychophannacologieal effects of smoking a cigarette wlth typical "tsr" and carbon monoxide yields but minimal nicotine. Psychopharmacology (Beri) 1992:108:46(r72. 3. Robinson JH. Pritchard WS. The role of ttieotine in tobacco use. Psyetto- pharmacology (Ber)) 1992:108:397-407. 4. Department of Health and Human Services, Public Health Setvice. The health consequences of smoking: nicotine addiction: a report of the Surgeon General. Washington. D.C.: Government Printing Office, 1988., (DHHS publication no. (CDC) 884406.) 5. Fioce MC. Trends in cigarette smoking in the United Sntes: the epidemiol- ogy of tobacco use. Med Clin North Am 1992:76:289-303. 6. Department of Health and Human Serviees. PubGc Health Service. Ptevent- ing tobacco use among young people: a repon of the Surgeon General. Washington, D.C.: Goremntent Printing Office. 1994. 7. Pem R. Lopez AD, Boreham 1, Thun M. Heath C Jr. Mortality fmm tobaoco in developed countties: indirect eatitnuion ftom nauonal vital statistics. I.aacet 1992:339:1268-78. 8. Henningfield JE. Clayton R, Pollin W. Involvement of tobaeeo in alcohol- ism and illicit drug use. Br 1 Addict 1990:85:279-91. 9. Shiffutan S. Tobacco "chippen" - individual ditfertnees in tob.ecro de. poidatee• Psychophaimaoology (Berl) 1989:97:539-47. 10. Benowitz NL, Jacob Pl. Metabolism of nicotine to cotinine studied by a dual stable isotope method, Clin Phamtxol Ther (in press). 11. Benowitz NL, Hall SM. Heming RI. Jacob P fII, Jones RT, Osman A-L Smokers of low-yield cigarettes do not consume less nicotine. N Eng) J Med 1983309:139-42. 12. Goci GB, Lynch CJ. Analytical cigarette yields as predictors of smoke bioavailabiliry. Regul Toxicol Pharnucol 1985:3:314-26. 13. Shiffmut S. F'ucher LB. Zettler-Segal M. Benowitz NL. Nicotine expostne among nondependent smokers. Arch Gen Psychiaay 1990:47333-6. 14. Bettowitz NL. Jacob P III. Daily intake of nicoune during dgatette smoio- ing. Clin Phattnaeol Ther 1984;35:499-504. 15. Benowitz NL, Jacob P III. Denaro C, Jenkins R. Stable isotope studies of nicotine kinetics and bioavailabiliry. Clin Phumacol Tber 1991:49: 27(Y7. 16. Coultas DB, Stidley CA. Sarnet JM. Cigarette yields of tar and nieotine and nwke:s of exposure to tobacco smoke. Am Rev Respir Dis 1993:148:435- 40. 17. Benowitz NL. Jacob P III, Kozlowski LT. Yu L Influence of smoking fewerciguenes on exposure to tar, nicotine, and carbon monoaide. N Engi 1 Med 1986:315:1310-3. 18. Beaowitz NL. Kuyt F, Jacob P III. Circadian blood nicotine eoneataatioas during cigarette smoking. Clin Pharrttaeol Ther 1982:32:758-64. 19. Stepney R. Consumption of cigarettes of reduced nr and tueodne delivery. Br J Addict 1980;75:81-8. 20. Guyan AR. Kirkham AJ. Mariner DC. Baldry AG. Cummiag G. Loog-eerm effeeu of switchirtg to cigarettes with lower tar and nieotitx yields. Psyc3to- p6arasaealogy (Berl) 1989:99:846. 21. Rusaell MA. Sutton SR, lyer R, Feyerabend C, Ve,ey CJ. Loog-term swioehiag to low-tar low-nieotine cigarettes. Br J Addict 1982:77:145-58. 22. Rttssell MA. Low-tar medium-nicotine cigarettes: a new appeo.eh to safer smoking. BMJ 1976:1:1430•3. 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