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John Slade, MD, FACP Potential Public Health Dangers From the RJR Nicotine Inhaler 1. The RJR inhaler may be the most addictve form of nicotine ever devised. The abstracts presented by RJR at the Society of Toxicology describe several experiments in which rats were exposed to cigarette smoke and to an aerosol from inhalers at various concentrations. Figure 1 shows how rats exposed to cigarette smoke shut down their breathing because because they find smoke profoundly irritating. In marked contrast, rats breathing the glycerin-nicotine aerosol only reduced their breathing pattern a trifling amount; the same reduction was seen in animals placed on the inhalation apparatus but only exosed to room air. In other words, the rats found the aerosol generated by the nicotine inhaler far easier to breath in than cigarette smoke, as easy, in fact, as room air. Figure 2 shows the nicotine concentrations achieved in the blood of rats exposed to either smoke or aerosol. Probably be- cause of the irritating effects of smoke, the animals breathing the aerosol achieved nicotine levels in the blood which were nearly three to five times that seen in the rats which breathed cigarette smoke. _ Novice smokers usually have some difficulty learning to in- hale because of the irritating effects of cigarette smoke. The aerosol produced by this device does not appear to cause any ir- ritation to laboratory rats, and so it is likely that teenagers would find it easy to inhale fully and achieve high blood levels of nicotine more easily than with any tobacco product available. Since the inhalation route is the most likely to cause addiction, Page 10 TIMN 0025651

John Slade, MD, FACP this pair of experiments reported by RJR suggests that the RJR nicotine inhaler is the most addictive form of nicotine ever developed. 2. The inhaler will be attractive to novice smokers. Children and teenagers commonly experiment with tobacco products, and this is how most adult nicotine addiction begins., The RJR inhaler will unquestionably be marketed as a product which reduces the risk of.using the most dangerous consumer product on the market while still providing all the pleasure and enjoyment of "the'real thing." Such a combination will have great appeal to those seeking to experiment with nicotine. Since it is so easy to use, it is likely that it will also more readily produce addiction in these same young people. 3. The inhaler will make abstinence seem a less attractive option to smokers. More than two-thirds of those who smoke want to quit, and their relative interest in quitting is in constant flux, in competition with what are perceived as the positive aspects of smoking. The mechanisms of denial and rationalization are ready-made to take advantage of the RJR nicotine inhaler. Since it will be perceived as lowering the risk of lung cancer (although not of other major categories of disease caused by smoking), many smokers will be fooled into thinking that they can continue to smoke and not suffer any consequences. This will retard the tendency to quit of the majority of those who smoke. Just as filter cigarettes and low tar cigarettes were marketed to meet consumer "concerns" about lung cancer, so, too, with this product. The tobacco industry piously pretends that Page 11 TIMN 0025652

John Slade, MD, FACP its product advertising is only aimed at helping committed smokers choose which brand of cigarettes to smoke. Two adver- tisements for another RJR 'product, Vantage, tell a different tale. Their headlines read, "To smoke or not to smoke." and "How many times have you decided to give up smoking?" The choice offered to consumers is not among various cigarettes. Rather, the choice is between continuing to smoke and abstinence. It would be exactly the same with this product. Consumers would be asked to choose between using cigarettes, the RJR in- haler, or abstinence from nicotine. There would be no explicit discussion of the substantial dangers posed by the inhaler, however (see below). A tobacco industry analyst, quoted in World Tobacco, notes that the RJR inhaler might lead to increased per capita. consump- tion among existing smokers, as well as a return to smoking among former smokers and the initiation of new use among never smokers (Appendix D). 4. The inhaler may be used where smoking is prohibited. Clean indoor air policies and laws are designed to protect the nonsmoking majority from the harmful effects of tobacco smoke pollution. While such policies are not intended to force people who smoke to quit smoking, they often help those who are inclined to quit anyway to do so. (This effect contributes to the great popularity of such policies and laws.) The Favor Smokeless Cigarette was marketed for use by people who found themselves in places where they could not smoke: it promised nicotine by in- Page 12 TIMN 0025653

John Slade, MD, FACP halation without lighting up. In February 1987, FDA declared that Favor was a drug and could not be sold without FDA approval (Appendix E). As with Favor, so, too, with the RJR inhaler: if the in- haler is used where smoking is prohibited, this product may un- dermine thoughts about quitting smoking brought into focus by clean indoor air policies. In this way, the nicotine inhaler represents a form of nicotine abuse in just the same way that a heroin addict may abuse methadone on the street to tide him or her over until the drug of choice is again available. 5. The inhaler may promote relapse to active nicotine de- pendence. Many who have stopped smoking are not stably committed to abstinence for some months to years. Relapse remains a threat for a long time.- This new product may be regarded as safe enough to use even among former smokers, even though such use .would in fact be.hazardous. The industry analyst cited above noted, "[Y]ou might bring back some smokers who stopped smoking... . m While this analyst may approve of such a prospect, this pos- sibility is genuinely alarming to those concerned with health. Unfortunately, there is no way to predict how much of a problem this would be short of unleashing it onto the market for several years. 6. The inhaler will be directly toxic in several important ways. While use of the inhaler may well be associated with a lower risk of lung cancer than smoking cigarettes, the product is far from safe. Smoking causes more deaths from heart disease than from lung cancer, and this product contains both of the Page 13 TIMN 0025654

John Slade, MD, FACP poisons from cigarettes, in similar concentrations found in cigarettes, considered to cause- heart disease: -carbon monoxide and nicotine. These same chemicals are also implicated in the damage which cigarettes cause the fetus. A detailed considera- tion of the toxic long-term effects of nicotine alone is found in Appendix B of the Surgeon General's Report. Thus, while one may predict that the inhaler will cause less lung cancer than cigarettes, it would have substantial associated morbidity and mortality. Considered by itself, it would be dif- ficult to justify marketing such a product at all for this reason alone. 7. The inhaler may be user-modifiable for use with other drugs. The RJR patent on the device speaks of the possible use of this invention as a delivery system for a variety of medically useful drugs. While speculative (because no samples are avail- able for testing), it is easily conceivable that this device may be modified by the user to deliver inhaled doses of other drugs of abuse, such as heroin. Injecting a drug in or near the aluminum chamber may be possible, and the user could then heat it up and inhale the drug without pyrolysis in the same manner as the device delivers the nicotine provided by the manufacturer. Summary Nicotine addiction is a major disease which usually begins •in childhood and adolescence. Since it involves more than a quarter of all adults and directly leads to more than 1000 deaths per day, it is by far the most common serious medical condition Page 14 TIMN 0025655

John Slade, MD, FACP in the United States. The recent Surgeon General's Report makes an essential contribution to the public discourse on tobacco by bringing the addictive nature of nicotine into sharp relief for all to see and understand. This report will be of equal impor- tance in shaping public policy about tobacco as the landmark report issued in 1964 by the expert committee appointed by Sur- geon General Luther Terry has been. The medical profession and most who are addicted to tobacco already know and accept the major conclusion of this report. We now face the task of sorting out its implications and acting on them. The RJR nicotine inhaler is a major challenge to public health efforts aimed at controlling the enormous epidemic which tobacco has caused in this country. The Surgeon General's Report concludes that "new nicotine delivery systems should be evaluated for their toxic and addictive effects.". The RJR inhaler is such a product, and the responsibility for conducting or supervising such an evaluation on behalf of the Federal Government rests with FDA. The World Health organization has called on its member na- tions to ban the importation or local manufacture of smokeless tobacco where there is no historical market for this product be- cause it makes no sense to complicate epidemic control with the introduction of new tobacco products. In exactly the same way, the RJR nicotine inhaler is a novel nicotine delivery system which would likely seduce large numbers of current, former and novice smokers by its appearance of high- tech and safety. The novices would be children and teenagers. The sad reality, though, is that this product is not safe, and it Page 15 TIMN 0025656

John Slade,, MD, FACP will sustain and thus prolong addiction to nicotine. In short, the introduction of this product would needlessly complicate the major gains public health officials have achieved in recent years. If introduced, the RJR inhaler will be a major setback to achieving control of the tobacco epidemic. Thank you. Page 16 TIMN 0025657

Fl Minute Ventilation Rats Exposed to Cigarette Smoke or to Aerosol from Nicotine Inhaler % of Baseline out of Apparatus 100 75 50 25 Inhaler 0 Lou Medium Test Group High Plasma Nicotine Rats Exposed to Cigarette- Smoke or to Aerosol from Nicotine Inhaler Plasma Nicotine (ng/ml) 250 200 150 100 50 MCigarette Inhal.er =Cigaret te 5 ugil 15 ugil 30 ugil Atmospheric Nicotine TIMN 0025658

Appendices A Curriculum Vitae B Nicotine Addiction C The RJ Reynolds Nicotine ]:nhaler: Company Documents D The RJ Reynolds Nicotine Inhaler: Analysis and Reaction E Related Alternative Nicotine Delivery Systems TIMN 0025659