Chapter 3
Addiction and Cigarettes as Nicotine Delivery Devices
Moreover, nicotine is addictive. We are, then, in the business of selling nicotine, an addictive drug effective in the release of stress mechanisms.
Addison Yeaman, B&W general counsel, 1963 {1802.05, p.4}
Introduction
Of the thousands of chemicals in tobacco smoke, nicotine is the most important. Nicotine makes tobacco addictive. The addictiveness of tobacco keeps people smoking long enough and heavily enough for the other chemicals in tobacco to cause heart disease, cancer, and other diseases. The documents reveal that B&W and BAT had a sophisticated and scientifically accurate understanding of nicotine pharmacology, including an explicit recognition of nicotine's addictiveness, more than thirty years ago. By 1963 B&W and BAT scientists and executives were internally acknowledging that nicotine is an addictive drug and that tobacco companies are essentially in the business of "selling nicotine." Nevertheless, the tobacco industry has publicly maintained over the years that nicotine is not addictive, and that the alkaloid merely adds "taste and flavor" to tobacco.
Addiction to a drug, also called dependence on a drug, is a condition in which an individual has lost control over the use of the drug and continues to use it despite adverse consequences. This conception is the basis for the diagnostic criteria for addiction found in the Diagnostic and Statistical Manual of the American Psychiatric Association (1). Although it has long been recognized that people cannot readily stop using tobacco products (2), the modern scientific basis for classifying nicotine as addictive was not highlighted until the 1988 Surgeon General's report, Nicotine Addiction (3).
There are several reasons why the tobacco industry has maintained so staunchly that nicotine is not addictive. First, the tobacco industry has argued in products liability lawsuits that smoking is a matter of "personal choice," and that tobacco companies should not, therefore, be held responsible for adverse health effects attributed to smoking. If the industry were to admit that nicotine is addictive, it would have a much harder time arguing that people can choose to quit smoking any time they want. In addition, if the industry were to admit that nicotine is addictive, it would open itself up to increased regulation. Under the Food, Drug and Cosmetic Act, an article (other than a food) is a drug or a device subject to regulation by the Food and Drug Administration (FDA) if its manufacturer intends that it affect the structure of function of the body when used. An intent to cause addiction would clearly qualify nicotine in tobacco products as a drug and the products themselves as drugs or devices and therefore subject to FDA regulation, just as the agency regulates nicotine chewing gum and patches. Intent to cause pharmacological effects besides addiction, such as effects on mood or weight control, would also qualify the nicotine in tobacco products as a drug. The FDA examined this question in 1994 (4, 5) and concluded that cigarettes and smokeless tobacco are, in fact, devices for the drug nicotine (6). On August 10, 1995, the agency proposed regulations under the Food, Drug and Cosmetic Act to protect children from nicotine addiction (7).
Nicotine's addictiveness also has implications for policy regarding tobacco advertising and promotion. Virtually all tobacco use begins in childhood and adolescence. Half of those who smoke cigarettes as adults have started by age 14, and most of those who will smoke as adults are already smoking every day by age 17 (8). Among young people (12–17 years old) who smoke at least twenty cigarettes daily, 84 percent reported that they "needed" or were "dependent" on cigarettes (8). Three out of four adult smokers say that they are addicted. By some estimates, as many as 74 to 90 percent are addicted. Seventeen million Americans (more than a third of all smokers) try to quit each year, but fewer than one out of ten succeeds. For every smoker who quits, nine try but fail (4). Since addiction develops insidiously, those affected only gradually come to appreciate that they cannot stop despite their intentions to do so.
Although the tobacco industry accepted the current series of rotating warnings on cigarette packages in 1984—which mention lung cancer, heart disease, prenatal problems, carbon monoxide exposure, and improved health from stopping smoking—it successfully lobbied against
having the word "addiction" appear in any warning (Matthew Myers, personal communication, January 30, 1995).
This chapter discusses what the documents reveal about the tobacco industry's knowledge of nicotine—namely, that both B&W and BAT clearly recognized that nicotine is pharmacologically active, that it is addictive, and that cigarettes are essentially nicotine delivery devices.
Southampton Research Conference, 1962
BAT held periodic research conferences so that scientists and executives from its subsidiaries around the world could share the results of their research and discuss various issues affecting the industry. The 1962 BAT research conference was held in Southampton, England, and was attended by twenty-nine BAT representatives from five countries. The United States and Canada sent four delegates each. The report from the conference is fifty-five pages long and discusses a wide range of topics related to smoking and health. In this chapter we limit our discussion to the portions of the Southampton conference that are relevant to nicotine. (Chapter 4 examines the smoking and health dimensions of this conference.)
The keynote address for the Southampton meeting was delivered by Sir Charles Ellis, an executive in the Research and Development Establishment at BAT's Millbank headquarters in London. In his keynote address, Sir Charles attempts to explain the conclusions of the British Royal College of Physicians' (RCP) first report on smoking and health, which had been released a few months earlier (9). The RCP report concluded that smoking causes lung cancer and that the British government should take "decisive steps" to control the rising consumption of cigarettes in the United Kingdom. According to Sir Charles, the authors of this report were predisposed to believing that cigarettes are harmful. One reason for this belief:
... smoking is a habit of addiction that is pleasurable; many people, therefore, find themselves sub-consciously prepared to believe that it must be wrong [emphasis added]. {1102.01, p. 4}
Later during his address, Sir Charles acknowledges that nicotine is the substance responsible for the addictiveness of smoking. However, he also appears to believe that nicotine has beneficial properties, which studies supported by the Tobacco Manufacturers' Standing Committee (TMSC, see chapter 2) are now investigating.
One result of the recent public discussions on smoking and health must have been to make each of us examine whether smoking is just a habit of addiction or has any positive benefits. It is my conviction that nicotine is a very remarkable beneficent drug that both helps the body to resist external stress and also can as a result show a pronounced tranquillising effect. You are all aware of the very great increase in the use of artificial controls, stimulants, tranquillisers, sleeping pills, and it is a fact that under modern conditions of life people find that they cannot depend just on their subconscious reactions to meet the various environmental strains with which they are confronted: they must have drugs available which they can take when they feel the need. Nicotine is not only a very fine drug, but the technique of administration by smoking has considerable psychological advantages and a built-in control against excessive absorption. It is almost impossible to take an overdose of nicotine in the way it is only too easy to do with sleeping pills. Perhaps, therefore, in the midst of all this consideration of the possible harmful effects of smoking you will be pleased to hear that T.M.S.C. is supporting work to elucidate the effects of nicotine as a beneficent alkaloid drug.
We have almost completed arrangements to support Dr. M. J. Rand at the London School of Pharmacy to investigate whether cigarette smoke produces effects on the central nervous system characteristic of tranquillising or stimulating drugs and, if so, to see if such activity is due solely to nicotine. The cost is likely to be about £13,000 in three years.
We attach so much importance to this aspect of our research that we are proposing to start active work at Harrogate with our own permanent staff. Arrangements are practically completed with Dr. [A. K.] Armitage to start at Harrogate to work on the pharmacology of smoke, and we are fortunate in having the distinguished Dr. [J. H.] Burn to act as consultant and advise us on the direction of this work [emphasis added]. {1102.01, pp. 15–16}
The Southampton conference report includes a detailed summary of the discussion following Sir Charles's keynote address. While there was a brisk debate over the directions BAT research should take (discussed in chapter 4), there was no apparent disagreement with Sir Charles's characterization of nicotine as addictive, with his comments on its other pharmacological properties, or with his characterization of nicotine as a drug.
Battelle's Nicotine Research Program
Not disclosed in Sir Charles's 1962 speech was contract research on nicotine that BAT was already having done by the Battelle Memorial Institute laboratory in Geneva, Switzerland. The project was headed by Sir Charles, and its ultimate purpose was to develop a novel nicotine delivery device that would avoid the toxicity of conventional cigarettes.
Battelle undertook several projects for BAT on nicotine from the late 1950s through about 1967. Project Mad Hatter was a comprehensive literature review. Project Hippo I involved animal experiments exploring the effects of nicotine on stress, weight gain, water balance, and hormonal regulation. The investigators regarded each of these diverse phenomena as related to the action of nicotine on the hypothalamus, a part of the brain that was then the focus of intense scientific interest because of its apparent control over the pituitary gland, the so-called "master gland" of the body. Project Hippo II extended this work on the hypothalamic effects of nicotine by exploring whether nicotine acts in ways similar to major tranquilizing drugs such as reserpine. A separate series of experiments traced the basic pharmacokinetics (absorption, distribution, and fate) of nicotine. Finally, Project Ariel sought to develop an alternative nicotine delivery system: a device that would provide the consumer with nicotine while delivering negligible amounts of the other toxins found in tobacco smoke.
Project Hippo I
Project Hippo I was designed to explore nicotine's role in several areas the investigators thought involved hypothalamic functions, including reduction of stress, inhibition of weight gain, maintenance of water balance (hormonally controlled through the hypothalamus), and regulation of gonadotrophic (sex) hormones. The results of Project Hippo I are described in a January 1962 report from Battelle to BAT {1211.01}. The introduction to this forty-eight-page report describes the background and goals of Project Hippo I:
It is an everyday experience to each smoker that smoking a cigarette helps mastering the numerous stressful stimuli of modern life.
This effect is possibly one of the most powerful reasons which make one smoke.
How does nicotine exert this action? The normal defence mechanism against stressful agents is a nearly immediate release of those hormones synthesized by the adrenal cortex which act upon the cell metabolisms: they are called "corticosteroids" and play the cardinal role in the defence of the organism against stress. Their release from the gland is mediated through a very complicated system involving the stimulation of hypothalamus and pituitary function. ...
As a working hypothesis we assumed the idea that nicotine could help to master the stressful stimuli by way of enhancing (or facilitating) the normal defence mechanism.
If this were true, it would be easier to understand another very important effect of smoking: it is well known that stopping to smoke has an immediate
effect on body weight. As body weight is regulated by the hypothalamo-pituitary system, our working hypothesis could be enlarged in order to assume the idea of an interference of nicotine in the hypothalamic regulation of body weight as well as in the defence against stress. {1212.01, pp. 6–7}
By conducting these experiments, Battelle was testing some of the most advanced neuroendocrine theories of the day. The adrenal corticosteroids had been introduced as wonder drugs into clinical medicine about a decade before this, and since the mid-1950s neuroendocrinologists had been gradually coming to understand the central role of the hypothalamus in the regulation of pituitary gland function (10, 11).
The report also discusses experiments that Battelle's scientists conducted on nicotine tolerance in rats. Tolerance to a drug is said to have developed when an animal requires a larger dose to achieve the same effect as that previously produced by a smaller dose. Tolerance is a common feature of addicting drugs. It need not be present for addiction to exist, but it usually is. Addiction, or dependence, is a clinical syndrome that includes loss of control over use of a psychoactive drug, withdrawal symptoms when the drug is no longer taken, and continued use despite problems caused by the drug. The report notes that tolerance could be induced in all rats, although some required several months to achieve this state.
The report describes in detail the effects of nicotine on rats in the various experiments. Of interest here is the importance the authors attached to nicotine's ability to influence the response to stress. For these scientists, this response helped explain the tranquilizing effect of nicotine and provided a direct link to the subsequent project, Hippo II.
Project Hippo I also included an elegant series of experiments on weight control in rats using nicotine. Nicotine was shown to inhibit food intake in both tolerant and nontolerant animals. Reserpine did not modify this action of nicotine. Nicotine rapidly stimulated the mobilization of lipid deposits (fat) and the degradation of free fatty acids. Each of these actions was in the direction expected for a drug that would be of benefit in controlling obesity {1211.01, p. 3}. The work Battelle conducted for BAT under Project Hippo I on weight control preceded published accounts of these phenomena by twenty years (3, 12).
Project Hippo II
Battelle extended its research on the hypothalamic actions of nicotine in Project Hippo II. Battelle's final report on Project Hippo II, in 1963, spells out why the tobacco industry was interested in comparing nicotine and
reserpine: it was concerned that the new tranquilizing agents would compete with cigarettes as stress reducers. The results of Battelle's research must have been reassuring to BAT, since the experiments demonstrated that nicotine had far fewer side effects than the tranquilizer reserpine.
The aim of the whole research "HIPPO " was to understand some of the activities of nicotine—those activities that could explain why cigarette smokers are so fond of their habit. It was also our purpose to compare these effects with those of the new drugs called "tranquillizers", which might supersede tobacco habits in the near future. We studied mainly the drug called reserpine.
Why does one smoke? It is certainly not because of nicotine's cardiovascular activities, which are so well-known to pharmacologists. The reasons for the "pleasure of smoking" must be found partly in the relief of anxiety that cigarette smoking brings so constantly, and in such a very short time.
This sedative—or soothing—effect of cigarette smoking and of nicotine is however very different from the "tranquillizing" effect as it was defined by pharmacologists after the discovery of the Rauwolfia alkaloids. [Rauwolfia is the plant group in which reserpine is found.] Tranquillizers are highly effective in the management of overactive psychotic patients and, as such, are largely used in psychiatry; nicotine is certainly devoid of such effects.
However, as the new drugs are used increasingly by "the members of our so-called normal population who are subjected to intolerable stress" (see our First Report on HIPPO II , p. 3), they might, from this point of view, supersede tobacco habits.
Our investigation definitely shows that both kinds of drugs act quite differently, and that nicotine may be considered (its cardio-vascular effects not being contemplated here) as more "beneficial"—or less noxious—than the new tranquillizers, from some very important points of view.
The so-called "beneficial" effects of nicotine are of two kinds:
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These effects do not seem to be shared by reserpine, which on the contrary shows undesirable side-actions that are not given by nicotine, i.e. a nearly complete blockade of gonadic and thyroid activities, reflecting most probably a general blockade of the hypothalamo-pituitary system, which normally controls all the endocrine activities. {1211.03, pp. 1–2}
Two pages later, the report indicates that one of the hypotheses under study might explain the phenomena of tolerance, withdrawal, and addiction to nicotine.
A quantitative investigation of the relations with time of nicotine—and of some possible brain mediators—on adreno-corticotrophic activity could give us the key to the explanation of both phenomena of tolerance and of addiction, in showing the symptoms of withdrawal. {1211.03, p. 4}
So, addiction to nicotine is real. The hypotheses guiding Hippo II were summarized in a diagram, which is reproduced as figure 3.1 {1211.03, p. 5}. In this model nicotine acts in the brain and at the level of the hypothalamus to affect appetite, stress reactions mediated through the adrenal gland, and changes in blood pressure and in water balance (antidiuretic effect). The experimental data gathered by the Battelle scientists in Hippo I and Hippo II provided direct empirical support for this model.
"Fate Of Nicotine" Study
In addition to conducting the Hippo projects, Battelle also studied how nicotine is absorbed into, distributed within, and eliminated from the body. This work seems to have been part of the overall development process for Project Ariel, an alternative nicotine delivery system discussed later in this chapter. To properly design this delivery system, BAT needed basic pharmacological data on how nicotine was absorbed, distributed, and eliminated from the body. The results of these pioneering experiments are described in a report titled The Fate of Nicotine in the Body , dated May 1963 {1213.01}. The report begins,
There is increasing evidence that nicotine is the key factor in controlling, through the central nervous system, a number of beneficial effects of tobacco smoke, including its action in the presence of stress situations. (Larsen, Haag & Silvette (1960)) In addition, the alkaloid [nicotine] appears to be intimately connected with the phenomena of tobacco habituation (tolerance) and/or addiction. (Larsen et al. (1960)) Detailed knowledge of these effects of nicotine in the body of a smoker is therefore of vital importance to the tobacco industry, not only in connection with their present standard products, but also with regard to future potential uses of tobacco alkaloids.
The numerous effects of nicotine in the body may, at first, be conveniently measured by various physiological and pharmacological experiments. However, the elucidation of the mode(s) of action of nicotine will ultimately depend on biochemical analyses dealing with the behavior of the nicotine molecule on, and its interactions with, the surface of physiologically active, macromolecular cell constituents (enzymes, receptors, etc.). The success of such analyses depends, in turn, on a detailed knowledge of the fate of nicotine in the body, i.e. of the various mechanisms which control the type and the rate of (a) absorption, (b) distribution, (c) breakdown or transformation, and (d) elimination [emphasis added]. {1213.01, pp. 1–2}
Battelle's 1963 report describes a comprehensive series of animal and human experiments on the absorption, distribution, metabolism, and elimination of nicotine.
To study the absorption of nicotine, Battelle used nicotine labeled with radioactive carbon (C14 ) to measure the amount of nicotine absorbed by
Figure 3.1. By 1962, when it was conducting the Project Hippo research, B&W had a
sophisticated understanding of how nicotine acts on the nervous system. Source: {1211.03, p. 5}
different types of smokers. The two subjects described as "non-inhalers" absorbed 22 percent and 42 percent of the nicotine drawn into their mouths, while most of those who inhaled absorbed between 70 and 90 percent of the ingested dose. The two subjects who "eject[ed] the smoke immediately after inhalation" had nicotine absorption rates in the 40 to 50 percent range. Daily consumption of nicotine among all the subjects in this experiment was found to range from 10 to 91 mg {1213.01, p. 8}. These data demonstrate the importance of inhalation for nicotine absorption from cigarette smoke. Inhalation is unrelated to taste or flavor; it is only important for nicotine absorption into the bloodstream (13). Similar work with C14 -labeled nicotine was not reported in the general scientific literature until a dozen years later (14).
The Fate of Nicotine in the Body also describes Battelle's animal work on nicotine absorption. Using C14 -labeled nicotine in rabbits, the Battelle scientists compared gastric absorption with pulmonary absorption. Gastric absorption was slow, and first pass removal of nicotine by the liver (which transforms nicotine into inactive metabolites) was demonstrated following gastric administration, with consequently low systemic nicotine levels. In contrast, absorption from the lungs was rapid and led to widespread distribution. These results show that nicotine absorbed from the stomach is largely metabolized by the liver before it has a chance to get to the brain. That is why tobacco products have to be puffed, smoked or sucked on, or absorbed directly into the bloodstream (i.e., via a nicotine patch). A nicotine pill would not work because the nicotine would be inactivated before it reached the brain.
Battelle's report also discusses earlier work on nicotine absorption, which had demonstrated that free-base nicotine is absorbed more rapidly than nicotine salts. Nicotine exists in the free-base form at an alkaline pH. In acidic environments nicotine exists as a salt. The more rapid the absorption, the greater the impact nicotine has on the brain. Work such as this on nicotine absorption has nothing to do with taste and flavor.
The Fate of Nicotine report concludes with a discussion of the work on nicotine metabolism in the context of tolerance and addiction. Pharmacologists had recognized that tolerance could develop either from breaking down a drug faster with repeated exposure (metabolic tolerance) or from adaptations to the drug at the level of the target tissue (cellular tolerance). They also recognized that there is an important relationship between the development of tolerance and the potential for a drug to cause addiction.
Although tolerance to some drugs may depend on accelerated enzymatic breakdown, prolonged consumption of others, including morphine, appears to induce cellular adaptions. (Axelrod (1956); Shuster (1961); Takemori (1961) (1962)) In any case, the present results offer no conclusive evidence for any particular mechanism involved in tolerance to nicotine, nor do they indicate a lead to the phenomenon of addiction. We believe that both tolerance and addiction are intimately connected, and that it would be most useful to investigate the two phenomena with regard to cellular adaptation, especially in target organs of the central nervous system [emphasis added]. {1213.01, p. 27}
Within a few weeks of completion of The Fate of Nicotine in the Body , Sir Charles Ellis sent a copy to William S. Cutchins, the president of B&W at the time. In his cover letter, Sir Charles asks that the report be given no wider circulation than the Hippo reports had received.
[The report] is an account of work which has been carried out in association with the other researches which were sent to you recently under the title of HIPPO . I feel sure you will agree that a knowledge of the fate of nicotine in the body is a necessary accompaniment to studying the physiological effects that nicotine can produce. ...
Would you please treat this as confidential document under the same conditions as I described for the report HIPPO . {1200.16}
The documents do not include any acknowledgment from Cutchins, but the person who would shortly replace him as president, E. P. Finch, received the report along with a summary by the B&W vice president of research, T. M. Wade, Jr. {1200.07, 1200.16}
A Tentative Hypothesis On Nicotine Addiction
The Battelle scientists who conducted the Hippo projects for BAT also wrote a speculative essay about the mechanism underlying nicotine addiction. The essay, marked "Confidential" and titled "A Tentative Hypothesis on Nicotine Addiction" {1200.01}, sought to explain nicotine tolerance, withdrawal, and addiction in the context of what was then cutting-edge neuroendocrinology.
The hypothalamo-pituitary stimulation of nicotine is the beneficial mechanism which makes people smoke; in other words, nicotine helps people to cope with stress. In the beginning of nicotine consumption, relatively small doses can perform the desired action. Chronic intake of nicotine tends to restore the normal physiological functioning of the endocrine system, so that ever-increasing dose levels of nicotine are necessary to maintain the desired action. Unlike other dopings, such as morphine, the demand for increasing dose levels is relatively slow for nicotine.
In a chronic smoker the normal equilibrium in the corticotropin-releasing system can be maintained only by continuous nicotine intake. It seems that those individuals are but slightly different in their aptitude to cope with stress in comparison with a non-smoker. If nicotine intake, however, is prohibited to chronic smokers, the corticotropin-releasing ability of the hypothalamus is greatly reduced, so that these individuals are left with an unbalanced endocrine system. A body left in this unbalanced status craves for renewed drug intake in order to restore the physiological equilibrium. This unconscious desire explains the addiction of the individual to nicotine [emphasis added]. {1200.01, pp. 1–2}
The short essay includes a review of the effects of nicotine on appetite and weight control, based on experiments using animals.
It is a well-known fact that fresh smokers show loss of appetite, and therefore loss of weight. Chronic smokers gradually turn to normal food intake. If nicotine is withdrawn from these individuals, the low FFA [free fatty acid] concentration in the blood provokes increased appetite, and therefore increased food intake, or at least a permanent hunger feeling. This feeling can be satisfied either by increased food intake or by renewed smoking.
Laboratory experiments with rats confirm this mechanism: injection of nicotine induces a marked reduction in food intake in the beginning of the treatment. Chronic application of nicotine in the so-called "tolerant rats" shows after a certain time no difference in the growth curves between treated and untreated animals. Interruption of nicotine application provokes a marked increase in food intake of "tolerant rats", which increase, however, turns very rapidly to normal (in our experiments within one week). {1200.01, p. 2}
The essay concludes,
[A] tentative hypothesis for the explanation of nicotine addiction would be that of an unconscious desire to restore the normal physiological equilibrium of the corticotropin-releasing system in a body in which the normal functioning of the system has been weakened by chronic intake of nicotine. {1200.01, p. 3}
In summary, pharmacological research at Battelle sponsored by BAT in the early 1960s was based on a paradigm of addiction. It sought to elucidate "beneficial" effects of nicotine such as "tranquilising" and weight loss effects, and it also explored the extent to which other drugs might compete with cigarettes in the consumer marketplace.
The results of the Hippo projects were distributed to BAT officials around the world, including executives at Brown and Williamson. The speculative paper on nicotine addiction, however, received only limited circulation. In fact, when Sir Charles Ellis sent a copy of the essay to
Brown and Williamson's general counsel, Addison Yeaman, he attached a cover letter advising Yeaman that the essay was "a private working paper" and that it was not being circulated to the other recipients of the Hippo reports {1200.02}.
Debate About Sharing Research Findings With The Us Surgeon General
The Hippo reports prompted a flurry of correspondence between BAT headquarters and the B&W executive suite in the summer of 1963, particularly over the question of what information, if any, to disclose to the US Surgeon General's Advisory Committee on Smoking and Health, which was to issue its report the following year. Despite the fact that the Battelle research added new insight into the area of nicotine pharmacology, BAT and B&W ultimately decided to withhold the results of the Hippo projects from the Surgeon General's Advisory Committee.
A note dated June 19, 1963, from A. D. McCormick, a senior R&D executive at BAT, to Bill Cutchins, B&W's president, mentions that BAT has decided to send the results of the Battelle work to the Tobacco Research Council (TRC) in the United Kingdom and the Tobacco Industry Research Committee (TIRC) in the United States. (As described in chapter 2, TRC and TIRC were created by the tobacco industry as "independent" organizations that funded scientific research related to the health effects of tobacco.) McCormick then asks about the advisability of submitting the results to the Surgeon General's committee.
On 4th June [1963] Sir Charles Ellis sent to you copies of reports of research which B.A.T. had sponsored at the Battelle Research Institute in Geneva showing the beneficial effects of nicotine on the smoker. B.A.T. decided to make this research available to the T.R.C. here and it is being evaluated by T.R.C.'s outside medical experts. Preliminary reports indicate that these experts think the Battelle work to be a sound piece of research. It was always contemplated that if the reports stood up scientifically it might be desirable to get them submitted to the U.S. Surgeon General's Committee.
Todd of T.R.C., is to-day sending copies to T.I.R.C. with a request that they consider whether it would help the U.S. industry for these reports to be passed on to the Surgeon General's Committee.
I thought you should have this information in case you or any of your colleagues in Louisville [at B&W headquarters] might for any reason think this course of action inadvisable.
Could you please let me know as soon as you get back what your views are [emphasis added]. {1200.10}
A handwritten note on this document indicates that Cutchins asked Addison Yeaman, the general counsel at B&W, to prepare a reply.
In his reply, dated June 28, 1963, Yeaman expresses some regret that the Battelle reports were shared within the industry's jointly funded research groups. Specifically, he mentions the connections between the Battelle work and a project being conducted at B&W by R. B. Griffith, director of R&D, to develop a special filter called the Avalon filter.
I rather regret that Todd [of TRC] took this action without preliminary consultation here for the reason the Battelle nicotine report ties in so closely to Griffith's work that we would have preferred including both Griffith's work [on the Avalon filter] and the Battelle report in our consideration of submission to the Surgeon General. Moreover, Ed Jacob [a lawyer with Jacob and Medinger] in a talk with me yesterday reported that there was reason to believe that the Surgeon General's report would give particular emphasis to the part played by the aerosols in relation to possible deleterious effects of tobacco smoke. This, again, ties in so closely to Griffith's work, and by extension to Battelle's work, as to lead us to the preliminary opinion that the Battelle work and the Griffith development should—if at all—go into the Surgeon General as part of one package.
Happily Ed Jacob will be with us on Tuesday to give us the benefit of his particular and special knowledge of the Committee, its reports, etc., etc., in deciding what disclosures B&W should make of Griffith's work to the Surgeon General's Committee and, if such disclosure is to be made, whether it should be through TIRC or direct by B&W. The fact that the Battelle report is now in TIRC's hands undoubtedly will have some effect on that decision. {1802.01}
It is not clear from the documents precisely what "special knowledge" Jacob had of the Surgeon General's committee.
McCormick of BAT replied by cable a few days later to say that the independent scientists who had reviewed the Battelle reports had concluded that the results should not be submitted to the Surgeon General's committee.
T.R.C. consultant scientists advise it is too early to submit Battelle reports to Surgeon General's Committee but we think they will agree that continuation by Battelle of this work would be useful. Charles Ellis convinced of beneficial effects of nicotine but agrees further investigation desirable before publication. Please inform T.I.R.C. {1802.02}
B&W's Yeaman cabled back the same day to say that William T. Hoyt, the executive director of TIRC, had not distributed the reports to TIRC's Scientific Advisory Board (figure 3.2):
Prior to receipt your telex July 3 Hoyt of TIRC agreed to withhold disclosure of Battelle report to TIRC members or SAB until further notice from me. Finch [of B&W] agrees submission Battelle or Griffith developments to Surgeon General undesirable and we agree continuance of Battelle work useful but disturbed at its implication re cardiovascular disorders .
We believe combination Battelle work and Griffith's developments have implications which increase desirability reevaluation TIRC and reassessment fundamental policy re health. Hope to get off comprehensive note next week [emphasis added]. {1802.03}
McCormick amplified on his cable to Yeaman in a letter written the next day, but before he had received Yeaman's cable.
Charles' [Sir Charles Ellis's] view is that as the situation has now developed it would be wiser for B. & W. not to take the initiative in submitting anything to the Surgeon General's Committee but rather wait and hope that the Committee will ask the individual manufacturers for further details of their research work and then, should this happen, it would give B. & W. the opportunity of submitting the Battelle work and the work on the "Avalon" filter. As further work on both has to be done, the work would be immune from detailed criticism, but its disclosure would demonstrate that B. & W. and its associates had adopted a forward looking positive policy of research. {1803.01}
Yeaman compiled his thoughts on the nicotine research at BAT, Griffith's work on a new filter at B&W, and the Surgeon General's committee in a five-page memorandum dated July 17, 1963 {1802.05}. The memorandum presents an overview of B&W's strategic position on the health question and argues for the aggressive pursuit of selective filtration (the Griffith filter, code named Avalon) and the promotion of the beneficial effects of nicotine as revealed by the Battelle work. In Yeaman's view, the Battelle findings on nicotine could be used to justify smoking because of its positive benefits. If B&W could remove harmful constituents from smoke, it could then—with a clear conscience—promote cigarettes as nicotine delivery devices for people under stress from modern living. The memo opens,
The determination by Battelle of the "tranquilizing" function of nicotine, as received by the human system in the delivered smoke of cigarettes, together with nicotine's possible effect on obesity, delivers to the industry what well may be its first effective instrument of propaganda counter to that of the American Cancer Society, et al, damning cigarettes as having a causal relationship to cancer of the lung. The Battelle work is not in any degree responsive to that indictment nor to the Report expected to be returned by the Surgeon General's Committee on Smoking and Health. I would submit, however, that the Griffith filter offers the bridge over which the industry might
Figure 3.2.
July 3, 1963, cable from Addison Yeaman to Tony McCormick confirming agreement to
withhold scientific results on nicotine pharmacology from the Surgeon General's Advisory
Committee, which was then preparing the original 1964 Surgeon General's report {1200.12}.
pass from its present terrain of defense to a field for effective counter attack using the Battelle study as the basic weapon. I will assume for purposes of this note that the "Griffith filter" is one which permits filtration to specification; it filters taste and nicotine (and nicotine in even more effective form) free of constituent #1 to infinity, selectively. I grossly overstate and oversimplify Dr. Griffith's claims deliberately. {1802.05, p. 1}
Yeaman's statement clearly indicates that he regards nicotine as important primarily for its "tranquilizing" effects, not for its taste. In fact, he even mentions taste and nicotine separately, suggesting that they are independent in his mind. This understanding contrasts sharply with the tobacco industry's recent public claims that nicotine only adds taste and flavor.
Yeaman then offers his recommendations for possible responses to the Surgeon General's report. At the end of the paper, he returns to his discussion of nicotine. After quoting extensively from the final summary of
the Hippo II report {1211.03}, which describes the beneficial effects of nicotine, he adds,
Moreover, nicotine is addictive.
We are, then, in the business of selling nicotine, an addictive drug effective in the release of stress mechanisms [emphasis added]. {1802.05, p. 4}
As the documents reveal, B&W management knew about the work BAT had contracted for at Battelle in Geneva. Its decision to withhold important research on nicotine pharmacology from the Surgeon General's Advisory Committee is in stark contrast to the industry's public position of openness advanced in the "Frank Statement" ad and other public statements (see chapter 2).
Project Ariel
The basic pharmacology work embodied in the Hippo projects and in The Fate of Nicotine in the Body was based on the realization that cigarettes are, at root, nicotine delivery systems. They are dirty devices, though. BAT, with help from Battelle, extended the initial work on nicotine pharmacology by developing an alternative delivery system that could administer nicotine to the body free of the toxins from tobacco smoke. The design goal was a safe cigarette (discussed in chapter 4). The device was named Ariel.
Two patents were issued to Battelle on Ariel, but BAT's Sir Charles Ellis is listed in both as the lead inventor (15, 16). The patents were apparently assigned to Battelle to disguise their origin. A 1970 letter from BAT to Addison Yeaman at B&W notes that "the patents were put into Battelle's name rather than B.A.T.'s for security reasons" {1202.01}.
Ariel relied on burning tobacco to heat a centrally arranged tube containing nicotine and an aerosol generator, consisting of a material such as water, which would form an aerosol when heated and then cooled, so that the nicotine could dissolve into the droplets and then be inhaled as part of the aerosol. The consumer would inhale an aerosol enriched in nicotine but relatively deficient in the "tar" elements of cigarette smoke. The device clearly embodies Sir Charles Ellis's vision of the essence of a cigarette—that it is a nicotine delivery device. The fact that BAT funded the work in the first place indicates that this vision was also shared by others at the company at the time.
What did BAT see as Ariel's potential position in the market in the early 1960s? After all, the device was significantly different from a ciga-
rette. It would have been impossible to move all customers over to Ariel right away, so the product needed a beginning niche in the market to become established. To whom, then, would it be targeted initially? While the documents do not directly answer this question, the underlying rationale for the Hippo II project suggests a possible initial positioning: since the cigarette industry was worried about competition from tranquilizing drugs, which would help people deal with stress without the toxicity associated with cigarettes {1211.02}, a way to meet this competition head-on was to develop a substantially less toxic form of a cigarette. Thus, one potential market for Ariel was the group that otherwise might have used tranquilizing drugs to reduce stress.
The patents for Ariel explicitly emphasize the importance of nicotine for the smoking experience and indicate that its action is, at least in part, physiological. (Because nicotine is not a normal part of the body, the actions would have been more accurately described as pharmacological.) The first patent, filed February 4, 1964, begins,
This invention relates to an improved smoking device whereby an improved smoke stream of a controlled character is delivered to the smoker.
In commercially available conventional smoking devices such as cigarettes, cigars and pipes, tobacco and reconstituted tobacco, or tobacco substitutes, are ignited and the products of combustion, in the form of a smoke stream in filtered or unfiltered form, are delivered to the mouth of the smoker. The smoke stream thus formed of the products of combustion may contain components which do not enhance the quality and characteristics of the smoke.
It is a prime object of the present invention to overcome the difficulties and disadvantages heretofore encountered [presumably, all the toxins generated during the combustion process] and to provide an improved smoking device which delivers an improved smoke stream of a controlled character and which does not contain the products of combustion.
...
The smoking device incorporates a continuous smoke passageway from its outer end to its mouthpiece end and which communicates with the nicotine-releasing composition. The smoke passageway includes an aerosol-nucleating chamber between the nicotine-releasing composition and the mouthpiece. This chamber is arranged so as to cool at an appropriate rate the potentially aerosol-forming materials sufficiently to enable aerosol particles to form, and the nicotine vapor is caused to contact the aerosol particles and condense thereon, whereby the nicotine assumes the transferability of the aerosol particles on which they condense.
...
The nicotine-releasing material employed in this form of device preferably comprises cured, shredded or cut and blended cigarette tobacco or reconstituted tobacco or mixtures thereof. The nicotine content of the tobacco or
reconstituted tobacco is preferably enriched by mixing therewith a tobacco concentrate rich in nicotine so that the available nicotine in the mixture constitutes between approximately 5 and 20% by weight of the tobacco material [emphasis added]. (15, column 1, lines 10–63; column 4, lines 2–10)
Conventional cigarettes also transport nicotine in droplets, except that the droplets are largely composed of the tars produced during the burning of tobacco. In the Ariel cigarettes the droplets were derived from other "aerosol-forming materials," such as water, making them potentially much less dangerous. Smoke from the burning tobacco around the core of the Ariel cigarette would be vented to the outside.
The following additional details are from the second patent:
A total and satisfying 'smoke' can be obtained with a high nicotine to tar ratio or, as sometimes expressed, a low ratio of total particulate matter (T.P.M.) to nicotine. This latter ratio can readily be reduced to one-quarter or less of the values normally expected of smoke from cigarettes having no special provisions for reducing the ratio. If desired , the nicotine content may be made normal, but with little of the normal particulate and vapor phases.
...
Thus, when the smoking device is smoked the smoker will draw into his mouth a small amount of smoke adequate to satisfy the taste of the smoker along with the nicotine containing aerosol .
...
Although the invention thus seeks primarily to furnish a smoking device which will yield nicotine in an acceptable form, both psychologically and physiologically , but without the necessity for taking into the system so much of the products of combustion as is usual when smoking a conventional cigarette, it may also be used mainly or partially as a means for achieving greater freedom for influencing the taste of the smoke, for introducing flavors and so forth [emphasis added]. (16, column 2, lines 30–38, 52–55, and 66; column 3, line 3)
This patent demonstrates the pharmacological role nicotine plays in cigarettes. It shows that the essence of a conventional cigarette, stripped of its undesirable elements, is "a smoking device which will yield nicotine in an acceptable form, both psychologically and physiologically" (or, more accurately, "pharmacologically," since nicotine is not part of normal human physiology). The patent mentions the provision of tastes and flavors through this invention, but this benefit is clearly regarded as secondary and as a separate matter, distinct from nicotine delivery.
The Ariel patents preceded patents from R. J. Reynolds and Philip Morris for analogous alternative nicotine delivery devices by twenty years or more (17). The best known of these devices, Premier from R. J.
Reynolds, featured an insulated charcoal fuel element at the lit end of a cigarette-like device. The burning charcoal heated alumina beads coated with nicotine and glycerin, which, in turn, produced a nicotine-laden aerosol (18). Premier was sold in test markets briefly but was withdrawn because of poor consumer acceptance and opposition from the public health community (19). In 1994 RJR announced that it was conducting consumer tests on another charcoal-heated nicotine delivery device, called Eclipse, which produces an aerosol by heating glycerin adsorbed onto reconstituted tobacco. The resulting aerosol picks up nicotine and other soluble constituents from tobacco in the proximal portion of the device. As with Ariel and Premier, this device reportedly delivers nicotine while markedly lowering the delivery of other toxic constituents (20).
Brown and Williamson has continued to conduct research on Ariel-like devices. The Ariel formula of a central core that generates the inhaled aerosol and that is heated by a surrounding fuel is illustrated in two patents assigned to B&W in 1990 and one in 1994 (21–23). While the first of these recent patents envisions tobacco as the fuel, the latter two employ carbon in the style of Premier.
The flurry of patent activity in this area in the 1990s may be related to the expiration of the BAT patents on Ariel in 1983 and 1984 (originally issued in 1966 and 1967), in addition to advances in technical feasibility or market potential for these products. RJR seems to have begun the development of Premier in the early 1980s. This class of device incorporates a heating element, a reservoir for nicotine, and a means for dissolving vaporized nicotine in an aerosol for inhalation by the consumer. A cigarette contains each of these functions, but novel devices such as Ariel and Premier compartmentalize them and so make the normal operation of a cigarette easier to understand.
Ariel grew out of the realization that nicotine delivery is the essence of a cigarette and the belief that a nicotine delivery device relatively free of the major toxins of cigarette smoke could be designed. Although the product was never brought to market, its design and conception demonstrate what BAT and B&W thought was the most important part of their tobacco products: nicotine.
Bat's Internal Research On Nicotine
In addition to contracting with Battelle, BAT also conducted its own studies on nicotine at its laboratory in Southampton and at other laboratories around the world. Some of these research activities are described
in BAT's reports of its annual research conferences involving key scientists from BAT member companies with active R&D laboratories. Other research activities on nicotine are described in two site visit reports and in research reports. These documents indicate that over an extended period of time the company recognized the central importance of nicotine because of its pharmacological properties.
In September 1969 D. J. Wood from R&DE (Research and Development Establishment) at BAT gave a presentation to company executives about the R&D work the company was doing. The notes of his talk summarize the work being done on nicotine:
The presence of nicotine is the reason why the tobacco plant was singled out from all other plants for consumption in this rather unusual way.
Nicotine has well documented pharmacological action. It is claimed to have a dual effect, acting both as a stimulant and a tranquilliser. It is believed to be responsible for the "satisfaction" of smoking, using this term in the physiological rather than the psychological sense.
Investigations at R.&D.E. are aimed at finding out more about the factors controlling nicotine absorption in the human respiratory system.
Extractable and Non-extractable nicotine (define) [see below].
Possibility of getting satisfaction from fairly low nicotine cigarettes, provided sufficient nicotine is in the extractable form.
Certain medical studies would seek to blame nicotine for cardio-vascular disease, so high levels of total nicotine are not likely to be fashionable in health-conscious countries in the future.
Mention absorption of nicotine via the mouth, e.g. cigar smokers. {1184.02, p. 7}
The documents provide numerous details about this systematic program of pharmacological research.
Overview Of Program, 1967
Robert J. Johnson, a senior scientist with B&W research and development, summarizes a June 20, 1967, meeting at which BAT's past and present research on nicotine was discussed. Johnson described six separate areas of research on nicotine that members of the BAT R&D group at Southampton had on their agenda:
Project ARIEL —This is dormant for the moment. The first samples tried gave a tremendous kick, even though the nicotine delivery was quite small. It would appear that the project will be reinitiated within a few months.
Dr. S. R. Evelyn is presently investigating the absorption of extractable and non-extractable nicotine in the mouth, albeit with a mechanical mouth.
Dr. J. D. Backhurst is setting up an analysis for pH of whole smoke on a puff-by-puff basis. This correlates with his previous interest in extractable nicotine[.]
Mr. H. G. Horsewell continues to work with alkaline filter additives which selectively increase nicotine delivery.
Dr. R. E. Thornton will be synthesizing ring-labeled nicotine as his first project in the new radiochemical facilities. This will initially be to determine the percentage of nicotine which is destroyed during smoking.
Dr. D. J. Wood will be assigning the new physiologist to a study into the organoleptic [sensory, especially irritation] effects of nicotine. {1201.01, pp. 10–11}
The research program was concerned with understanding the delivery of nicotine in smoke and its absorption. The organoleptic work described comes closer than anything else in the documents to suggesting an interest in the taste and flavor of nicotine, but it actually seems to be more concerned with understanding the irritating properties of nicotine on mucous membranes. This is an important problem in cigarette design, since alkaline nicotine, which is readily absorbed in the mouth, is also irritating to the throat (13).
Some of the internal research reports for the work in progress mentioned by Dr. Johnson were available to us in summary form. These reports deal mainly with the absorption of nicotine.
A 1966 report describes "Further Work on 'Extractable' Nicotine" {1205.10}. Nicotine that is "extractable" (more soluble in chloroform than water) proved to be a better gauge of perceived "strength" by the smoker than whole nicotine content. Most "extractable" nicotine was recognized to be nicotine base, so the "nonextractable" nicotine was the acidic salt. The report speculates on why "extractable" nicotine has a greater perceived strength:
The reasons for the relationship between smoker response and "extractable" nicotine content of the smoke remain obscure. Several possible explanations have been considered and, at the present time, it would appear that the increased smoker response is associated with nicotine reaching the brain more quickly. {1205.01, p. 1}
It is now widely recognized that what BAT scientists were calling "extractable nicotine," nicotine base (also called free nicotine or unionized nicotine), is readily absorbed in the mouth and nose, while the ionized form that exists in acidic environments is hardly absorbed at all in the mouth (3). The internal research reports indicate that BAT had a sophisticated understanding of this distinction thirty years ago.
A series of reports from 1968 and 1969 document the interest of the research scientists at BAT in the variables that account for nicotine absorption in the mouth, as from pipe and cigar smoke {1214.01; 1205.05; 1205.06}. Nicotine retention in the mouth was found to be a function of the pH (acidity) of the smoke, while absorption was a function of the pH of saliva. "Extractable nicotine content" was directly related to pH. The design criterion for the membrane used in the artificial mouth was that it permit the passage of unionized (free-base) nicotine but not that of ionized nicotine (salt) {1214.01, p. 12}. An appropriate imitation of the way an actual mouth works, absorbing unionized but not ionized nicotine, was an explicit feature for the model system. This is yet another indication that the scientists at BAT knew the importance of nicotine absorption. The last report in this series notes that, in contrast to pipe and cigar smokers, cigarette smokers usually inhale {1205.06}.
These research reports put flesh on Dr. Johnson's brief summary and demonstrate that in the late 1960s BAT's R&DE had a tremendous interest in achieving a better understanding of how nicotine is best absorbed into the body from pipes, cigars, and cigarettes.
Montreal Research Conference, 1967
The 1967 R&D conference was held in Montreal over three days in October {1165.01; 1165.02; 1165.03}. The document we have is probably a draft, since the official minutes are quoted in the minutes of the 1970 conference and differ somewhat from these notes (see below). The draft lists the main "assumptions made by R&D scientists," noting that they were listed "without any attempt to justify them or to agree on their correctness at this time." Although the draft is explicit that no attempt had been made to agree on these "main" assumptions, the minutes of the 1970 St. Adele conference reviewed the final 1967 assumptions and listed them without this qualification. The following assumptions had to do with nicotine:
There is a minimum level of nicotine. Smoking is an addictive habit attributable to nicotine and the form of nicotine affects the rate of absorption by the smoker .
...
If there is no inhaling, there is no lung cancer or respiratory disease.
Smoking has both physiological and psychological effects.
There will be some government involvement in the tobacco industry in the future [emphasis added]. {1165.01, p. 2}
A handwritten edit in the document changes the phrase "an addictive habit" to "a habit."
The meeting notes reflect a concern with the inevitability of future government regulation.
It was agreed that smoking is likely to be associated with health continuously in the future and that it was not a passing phase. It was likely, moreover, that tobacco would be involved in legislation of a food and drug administration nature in respect both of product and of manufacturer [emphasis added]. {1165.01, p. 4}
Thus, the nine assembled BAT scientists, including B&W representatives from Louisville, acknowledged that health concerns were never going to disappear. Furthermore, they felt that FDA-style product regulation could be justified by the public health community.
In a discussion of concurrent developments in cigarette filters, the use of "an alkaloid additive" to affect "the ratio of extractable to non-extractable nicotine" was emphasized {1165.02, p. 1}. The filter additive PEI (polyethyleneimine) was mentioned as a way to "be helpful in rendering the nicotine more available to the smoker" {1165.02, p. 4} in a "low TPM, normal nicotine" cigarette. TPM is total particulate matter; it consists mostly of tar. The participants also considered the development of a "low TPM, low nicotine cigarette" but wondered whether consumers would be attracted to such a brand. Someone mentioned that in Germany per capita cigarette consumption had risen as nicotine content had fallen. Participants agreed that more information was needed on the "optimal level" of nicotine for the smoker.
Ariel was discussed, as was "a cigarette aimed to be pleasantly non-inhalable" {1165.02, p. 5}. Moreover, "it was noted in passing that the trend towards making cigarlets [little cigars] milder and therefore more easily inhalable was undesirable on health grounds" {1165.02, p. 5}. These two comments echo sentiments recorded at other research conferences. They emphasize the importance of inhalation to the normal functioning of cigarettes as well as the fundamental problem that it poses in the causation of cancer and respiratory disease.
The importance of nicotine was emphasized in the discussion that closed the second day of the conference.
A general discussion followed on basic assumptions which guided thinking in the field of smoking and health. While recognizing the importance of psychological factors in smoking and the possibility that some smokers would accept non-nicotine cigarettes, it was felt that nicotine is important for the majority of smokers and that the form of nicotine can be significant . It was
also considered that nicotine will be increasingly subject to attack. It was agreed that there will be increasing government involvement in the industry [emphasis added]. {1165.02, p. 6}
In the context of the previous and current laboratory work conducted by BAT, these comments about nicotine can only refer to the importance of nicotine as a drug in tobacco products.
Hilton Head Research Conference, 1968
Twelve members of R&D groups from various BAT companies participated in a research conference at Hilton Head, South Carolina, on September 24–30, 1968. A terse report of conclusions was prepared by the conference chairman, Dr. S. J. Green, head of BAT's Research and Development Establishment at Southampton. The participants recognized the emerging evidence that nicotine has adverse effects on the cardiovascular system {1112.01, p. 2} and agreed that researchers should look for substances that would have the actions of nicotine in the brain but would not be toxic to the circulation. The intended effects were "brain stimulation and stress-relief":
In view of its pre-eminent importance, the pharmacology of nicotine should continue to be kept under review and attention paid to the possible discovery of other substances possessing the desired features of brain stimulation and stress-relief without direct effects on the circulatory system . The possibility that nicotine and other substances together may exert effects larger than either separately (synergism) should be studied and if necessary the attention of Marketing Departments should be drawn to these possibilities.
It was, however, agreed that nicotine or tobacco extracts should not be put in a part of the cigarette, e.g. the filter, where they could be readily ingested.
In a discussion of devices for the controlled administration of nicotine, the current position of the ARIEL project was reviewed, and it was requested that Southampton should supply some ARIEL devices to the overseas laboratories for examination [emphasis added]. {1112.01, p. 3}
The fact that the inhalation of tobacco smoke was an expected part of smoking a cigarette came through in the discussion of the "non-inhalable" cigarette. Finally, Ariel remained a focus of interest in relation to the "controlled administration of nicotine."
Kronberg Research Conference, 1969
The minutes of the research conference at Kronberg, Germany (June 1969), deal mostly with smoking and health concerns (discussed in
detail in chapter 4), but there are several salient comments related to nicotine.
PEI (polyethyleneimine), a filter additive that boosted the delivery of "extractable nicotine" in cigarette smoke, was used in a series of human test panel experiments {1205.03}. Increased levels of "extractable nicotine" increased the "impact of inhaling" while producing a "small increase" in throat and nose irritation. The minutes note that a suggested upper limit for PEI is 3 percent of the filter by weight, because of concern about adverse effects on bioassay results {1169.01, p. 8}. The PEI work is discussed at several different places in the documents.
Nicotine received specific attention when the participants discussed the development of nontobacco materials for smoking.
There was a general discussion on non-tobacco materials and, largely due to the difficulties foreseen with the addition of nicotine, the Conference did not envisage at present the likely success of a totally non-tobacco cigarette. However, it now seems quite likely that non-tobacco materials will be successfully incorporated into cigarettes as blend constituents, particularly in health oriented products. A large usage of non-tobacco materials would be likely to increase the demand for high-nicotine tobaccos [emphasis added]. {1169.01, p. 8}
The development of a completely tobacco-free product was seen as unlikely because nicotine would have to be added. In making this judgment, the participants may have been thinking about a regulatory barrier. If nicotine were added to a tobacco substitute material, a drug regulatory authority such as the FDA might raise questions about whether the nicotine in this instance was a drug.
St. Adele Research Conference, 1970
At the 1970 research conference, held at St. Adele, Quebec, the consensus statements agreed upon at the Montreal conference three years earlier (see above) were reviewed. The changes in the wording of the consensus statements between these two meetings appear to reflect a growing awareness of the legal implications of scientific statements. On nicotine, the 1970 conference agreed,
Nicotine is important, and there is probably a minimum level necessary for consumer acceptance in any given market. The chemical form of nicotine has been shown to affect the rate of absorption by the smoker [emphasis added]. {1170.01, p. 1}
In contrast, the corresponding statement in the minutes of the 1967 meeting (which, in turn, differs from that quoted from the draft minutes, in the above section headed "Montreal Research Conference, 1967") reads:
Nicotine is important and there is probably a minimum level of nicotine to which for many people the habituated effects of smoking are attributable. The form of nicotine probably affects the rate of absorption by the smoker [emphasis added]. {1170.01, p. 1}
The statement on inhalation was changed markedly. The 1967 draft statement that we have reads:
If there is no inhaling, there is no lung cancer or respiratory disease {emphasis added]. {1165.01, p. 2}
The 1970 version:
It was accepted that, without inhalation, no association between smoking and respiratory disease could reasonably be allege [sic ] [emphasis added]. {1170.01, p. 2}
The corresponding 1967 statement is not quoted in the 1970 minutes, which note somewhat ambiguously, "In 1967 the corresponding statement was not agreed" {1170.01, p. 2}.
Participants agreed that R&D was an essential activity for the company and that one of the general objectives of R&D was to "enhance the technological base of the company, and specifically to create a framework for product design " (emphasis added) {1170.01, p. 2}. This objective emphasizes the commercial intent behind much of the work done in R&D, presumably including the work on nicotine and the work on developing technologies to reduce toxicity. This explicit objective may be relevant to the matter of intent and the potential for FDA regulation.
The participants considered what their company's business might look like in a world in which cigarettes were no longer acceptable.
It was agreed that, if and when total cigarette consumption declined, great opportunities for supplying the demand of other socially acceptable habits could follow. Discussion followed on those opportunities which might arise. Amongst those discussed were a) chewing products, and b) wet snuff. It was felt that this whole area, much of which is already in the tobacco industry, should be examined more thoroughly. Particular attention should be given to buccal administration of nicotine and other physiologically active ingredients. At the same time, it was re-affirmed that we would not contemplate the incorporation of nicotine in edible products. {1170.01, p. 3}
This discussion fits into the wishful thinking evident at other conferences about a noninhalable cigarette. Once again, nicotine is central to this speculation. Pure nicotine was not to be used as an additive in a tobacco product, but a high-nicotine tobacco extract was within the rules.
The addition of nicotine to SM [substitute smoking materials] was considered, and it was recommended that nicotine per se , should not be used inside any tobacco factory. However, high nicotine content tobacco extract might be added. So long as SM remains a blend constituent, it would not be considered desirable for the supplier to include nicotine in the formulation. Nevertheless, for purposes of laboratory experimentation under suitable controls, nicotine-containing materials offered by suppliers may be used. {1170.01, p. 4}
The development of tobaccos with high nicotine content was expected, but the participants also called for research into the role of other nicotinic alkaloids and encouraged the Canadian subsidiary to explore the development of reconstituted tobacco with high nicotine content {1170.01, p. 5}. They recommended that cigarettes made by competitors be compared on the basis of extractable nicotine per puff, since such comparisons might provide a coherent basis for understanding market segmentation among consumers {1170.01, p. 7}.
Finally,
It was agreed that insufficient work is being done on those benefits perceived by the consumer, and that psychological and pharmacological studies should be initiated, both at industry and group level, to identify the consumers' needs. {1170.01, p. 9}
This stress on pharmacological research to determine consumer needs illustrates again the underlying intent of BAT and B&W to deliver controlled amounts of pharmacologically active nicotine to their customers.
Studies On Central Nervous System Effects Of Nicotine
The documents include summaries of several research reports that examine the effects of nicotine on the central nervous system (CNS). All but one are internal BAT reports. The exception is a 1971 report from the labs of the Imperial Tobacco Group, Limited, in the United Kingdom.
G. Lawrence Willey and D. Neville Kellett of the Huntingdon Research Centre of the Imperial Tobacco Group reported their preliminary work with nicotine administration to squirrel monkeys in early 1971 {1218.01}. Experiments in this series of studies were to include
measurements at the brain surface of acetylcholine, the naturally occurring neurotransmitter that nicotine mimics; effects of nicotine on the electroencephalogram; electrical stimulation studies of the brain; and behavioral effects. In their report the authors explicitly acknowledge that their experiments with monkeys sought to model the human experience.
Actions of nicotine at peripheral sites in the body have been extensively investigated, but much less is known about its central effects. The aim of the studies to be reported here is to determine whether, in doses comparable to those taken into the blood by smokers, nicotine affects physiological processes and behavioural functions of the central nervous system of the primate. {1218.01, p. 1}
Later in the report, the authors again explicitly acknowledge that the experiment was based on the conceptualization of nicotine as a drug.
We also intend to compare changes produced by nicotine with those elicited by other drugs which are known to affect central nervous system function e.g. caffeine, amphetamine, chlorpromazine [an antipsychotic drug], meprobamate [a sedative]. {1218.01, p. 4}
Two electroencephalograph (EEG) studies of smoking were reported in late 1974 {1205.15; 1221.01}. The first, by R. F. Brotzge and Dr. J. E. Kennedy of B&W, describes an increase in alpha brain wave activity of adults after they smoked a cigarette {1121.01}. The report speculates that the effect "may reflect both psychological and physiological responses." (In this context, as mentioned, the term "physiological" appears to mean "pharmacological.") Evidently, this study was undertaken at B&W to facilitate product development.
The development of new products and the modification of existing ones requires that we have some knowledge of the smoker toward whom these efforts are directed. The work described in this report is focused on the acute, or immediate physiological response of smokers. {1221.01, p. 1}
By saying that product design can be guided by pharmacological studies such as this, the authors reveal an intention to affect the structure or function of the body. As with other material in this chapter, it contributes to a determination that the FDA has jurisdiction over tobacco products.
The second EEG study was conducted by A. K. Comer and R. E. Thornton at BAT's Southampton laboratory {1205.15}. The study found that smoking increased the activity being measured in some subjects but decreased it in others. In their discussion the authors note that nicotine "has been assumed to be the main pharmacologically active component
in smoke." They speculate that the disparate results may be explained by the hypothesis "that smoking may assist some people to optimise the level of activity in the brain."
These three reports illustrate the fact that, twenty years ago, Imperial, B&W, and BAT each thought that it was useful to examine the effects of nicotine on the central nervous system.
Smoker Compensation Studies
Compensation, the tendency of a person to smoke a cigarette having a lower machine-measured nicotine delivery more vigorously than a higher-delivery product, was mentioned for the first time in documents from the mid-1970s. The studies reported at the research conference held at Duck Key, Florida, in 1974 show that the tobacco industry was years ahead of the general scientific community in examining and understanding this phenomenon. The first study of compensation listed in the Surgeon General's 1988 report on nicotine addiction (3) is from 1980 (24). The work was confirmed three years later (25).
Specifically, the report of the conference notes:
The Kippa study [a study of nicotine delivery at the German BAT laboratory] in Germany suggests that whatever the characteristics of cigarettes as determined by smoking machines, the smoker adjusts his pattern to deliver his own nicotine requirements (about 0.8 mg per cigarette) .
It is recommended that such studies should be considered for application in other countries where B.A.T. has a substantial interest in understanding more about smoking behaviour either for direct commercial or for health reasons [emphasis added]. {1125.01, p. 2}
Later in the report, an additional experiment to measure compensation in the context of cigarette ventilation is recommended: putting small holes in the filter or paper so that air is drawn into the smoke stream, thereby diluting it and reducing smoke delivery.
The effect of ventilation on smoking behaviour should be explored in a McKennell-type test. {1125.01, p. 3}
By the 1970s dilution of mainstream cigarette smoke with room air had become a major technique for reducing machine-measured tar and nicotine deliveries. Termed "ventilation," dilution was accomplished with a variety of techniques, including the use of porous cigarette paper and the drilling of holes around the filter tip. We do not know what a "McKennell-type test" is.
An apparent replication of the German work was completed the following year in Canada. The "Chronology of B&W's Smoking and Health Research" includes the following item for 1975:
Compensation study conducted by Imperial Tobacco Co., a BATCo affiliate, [shows that a smoker] adjusts his smoking habits when smoking cigarettes with low nicotine and TPM [total particulate matter] to duplicate his normal cigarette nicotine intake (Imperial Tobacco Project T-8077) [emphasis added]. {1006.01, p. 27}
Overall cigarette consumption data in the United Kingdom between 1965 and 1973 demonstrated a compensation effect {1190.09}. In 1975 G. F. Todd of the Tobacco Research Council analyzed per capita cigarette consumption for men and women for each year over this nine-year period, during which tar yields were steadily declining. Per capita cigarette consumption rose for both men and women through the period, indicating that smokers were smoking more in partial compensation.
Additional work on compensation was conducted by an outside contractor but reported through the R&D lab at Southampton by J. R. Courtney and A. K. Comer {1208.02}. Completed in 1978, the study analyzed the butts of cigarettes smoked by humans and compared the smoke constituents with those found in machine-smoked cigarettes. The technique permitted an estimation of actual delivery of smoke to the consumer. The study found compensation effects.
By 1980 B&W was beginning to recognize the legal and political dimensions of smoker compensation. In response to a questionnaire circulated by Dr. Alan Heard of BAT R&D about the proposed agenda for the upcoming research conference at Sea Island, Georgia {1132.01}, Dr. R. A. Sanford, vice president of R&D at B&W, indicated that B&W had "definite interest" in the proposed discussion of "compensation/smoker behaviour," but he also noted that this area of research was "dangerous" and questioned, "Is this in our best interests?" {1132.01, p. 3}. Research on smoker compensation was showing that consumers smoked cigarettes in ways that defeated the low-tar designs of the products. This finding undermined the implied benefit of low-tar smoke as less hazardous than normal cigarettes. In any event, the minutes of the conference did not include a discussion of compensation {1177.01}.
The 1983 research conference in Rio de Janeiro covered a variety of topics related to nicotine {1180.07}, including smoker compensation. The minutes of the conference note,
Compensation is now attracting the interest of Government and medical authorities in many parts of the world. This is based on the increasing number of new studies and, in part, by the evidence submitted by the industry to the FTC [Federal Trade Commission] in the Barclay investigation—much of which has already been communicated to Government authorities in Australia, Belgium, Finland, Holland, Switzerland and the UK.
There is now an urgent need to assess whether there are ways in which the industry can either counter the situation or alternatively turn it into a commercial advantage.
A direct consequence of this growing interest in compensation is the possibility that the FTC, and other authorities, may call for a change in the standard smoking machine test procedure for all products. If this were simply to be a modification to the existing standard procedure (increased puff volume, duration or interval) the effect would be to increase delivery levels but it would probably have little effect on League Table rankings [relative tar and nicotine yields]. A more extreme possibility is that an entirely new test procedure could be developed, eg a biological index. ...
Either move would weaken the concept of low tar and would both confuse and concern the smoker . Operating Companies around the Group should, therefore, do everything possible to defend and maintain the present standard test procedure. If, however, the FTC or any other authority takes action to change the procedure the strategy should then be to stretch out any discussions (both with the authorities and later at ISO) until exhaustive studies have established that an alternative procedure is in fact more relevant.
In the meanwhile it is essential that we should increase our own research into how and why people smoke: eg what the smoker needs or gets from the cigarette in terms of nicotine and other sources of satisfaction. Until we have such knowledge we shall not be in a position to judge what would be best for the industry in the longer term.
...
Whatever the outcome of the various public debates on compensation and test procedures, we must aim to use our knowledge to develop products that give improved smoker satisfaction. The concept of 'smoke elasticity' can be expected to play an important role [emphasis added]. {1180.07, pp. 8–9}
The Barclay investigation was spurred by B&W's competitor's crying foul to the FTC about the test results for B&W's Barclay brand of low-tar cigarettes. Competitors charged that the Barclay cigarette was designed to be smoked one way by the machine and another way by the consumer. The resulting investigation focused FTC attention on the compensation problem for the first time and provided the agency with some of the industry's data on the problem. This increased attention did not lead to any change in regulatory approach for many years. (It was not until late 1994 that there was some visible movement on this issue. In
December the National Cancer Institute convened a meeting to examine alternatives to the FTC test method.)
BAT scientists were concerned that a governmental agency might impose a new measure for product labeling which would have an uncertain or at least initially unknown relationship to product strength and nicotine satisfaction. The company's strategy was to jawbone regulators to delay any settlement of the matter until it could be sure that any resulting labeling scheme would not upset its ability to market cigarettes effectively to its various market segments.
BAT scientists, meanwhile, continued to work on compensation. By 1984 the consensus among them, as the proceedings of a joint R&D/marketing conference indicate, was that consumers adjust their smoking behavior to achieve specific nicotine dosing. The immediate signal for gauging nicotine dose is the "impact" of the puff on the throat. The impact, in turn, is directly related to nicotine dose.
[It] is accepted that nicotine is both the driving force and the signal (as impact) for compensation in human smoking behaviour. {1226.01, p. 56}
The 1984 Montreal conference materials also demonstrate that BAT laboratories were evaluating design features of cigarettes that influenced a parameter called "elasticity." Elasticity quantifies the ability of the consumer to affect nicotine dose through compensation (by smoking the cigarette differently). The study appeared to measure the effect of different cigarette ventilation designs on smoke composition under conditions of differing puff volumes {1226.01, p. 58}.
The fact that people smoke in ways that defeat the engineering tricks of low-tar, low-nicotine cigarettes did not become widely appreciated in public health circles or the medical profession generally until the early 1980s, when Neal Benowitz published his studies showing that consumers smoke low-yield cigarettes more vigorously than they do higher-yield ones (25). In fact, the doses of nicotine delivered from all but the lowest-yield cigarettes are remarkably similar, and those from the lowest-yield versions are far higher than would be predicted from strict comparisons of machine-measured yields. Nonetheless, until about 1983 standard primary care medical textbooks advised physicians to recommend low-tar cigarettes for patients who were unable to stop smoking (26). Indeed, the tobacco industry promoted this view (see chapter 9).
Had the results of these internal BAT studies been generally known in the mid-1970s, medical advice in this matter might have changed earlier. The fact that smokers compensate for low-yield cigarettes seriously
undermines the implicit claim that low-tar, low-nicotine cigarettes reduce the risk of harm from smoking. In 1994 Jack Henningfield and his colleagues at the National Institute on Drug Abuse advanced a proposal to change the way the Federal Trade Commission (FTC) requires nicotine delivery to be reported by manufacturers, so that the amounts reported will more closely reflect the actual bioavailability of nicotine to the consumer (27).
A research conference held at Pichlarn, Australia, in 1981 focused some discussion on the regulatory aspects of compensation.
It is felt that the time is close when Government agencies worldwide will take more notice of compensation—and of the scale of the differences, for a given commercial product, between smoking machine numbers and the dose of smoke actually obtained by smokers. This issue may well go beyond the simple technical measurement of deliveries. If for no other reason than defence, we must pay increasing attention as to how our products—especially new products—are smoked by different categories of smokers. {1178.01, pp. 13–14}
The concern was misplaced at two levels. First, governments did not get seriously interested in this problem for another dozen years. Second, dealing with the compensation problem in a conscientious manner requires more than taking a merely defensive, public relations-oriented posture.
Montebello Research Conference, 1982
The first entry in the minutes for the 1982 Montebello research conference, under the heading "Subjects of Major Group Importance," is "Human Smoking Behaviour."
More must be known about how different consumers smoke different products and derive different levels of satisfaction or response therefrom. We are concerned with two aspects:
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The minutes refer to work under way in Germany on precise nicotine dose measurements in consumers; Canadian studies of puff duplication techniques to measure how the smoker smoked the cigarette; and work planned in the United States at B&W on surreptitious videotaping of smoking to measure smoking behavior in natural settings. Similarly, the Southampton program, although it was aimed at identifying market
segments based on "smoking bahavioural characteristics," also was paying attention to "the biochemistry and pharmacology associated with the inhalation of major smoke components" {1179.01, p. 3}. The minutes of the Montebello conference specify a design objective for new products:
to enhance or maximise sensory and pharmacological sensations, ie to 'make the smoke work harder' so as to achieve maximum sensation at a given delivery level without encouraging the smoker to compensate [emphasis added]. {1179.01, p.3}
Once again, the R&D staffs of BAT and B&W show their understanding of the purpose of a cigarette as a nicotine delivery device. Pharmacological sensations are not only intended to occur; they are to be manipulated so that the consumer can get the desired dose of nicotine without taking in more tar than intended.
BAT's R&D group at Southampton held a series of informal discussions on the characteristics of cigarette smoke in late 1982 or early 1983. These discussions seem to have been sparked by recommendations made at the 1982 Montebello conference. Colin Greig, a participant in the Southampton discussions, compiled his notes, and C. I. Ayers circulated them to the heads of BAT research labs in the United States, Germany, Australia, Brazil, and Canada in February 1984 {1179.02}. Under the heading "Physiological Consequences," Greig's notes include the following comment about nicotine:
It is well known that nicotine can be removed from smoke by the lung and transmitted to the brain within seconds of smoke inhalation. Since it is the major or sole pharmacologically active agent in smoke, it must be presumed that this is its preferred method of absorption and thus why people inhale smoke. {1179.02, p. 10}
In short, the purpose of cigarette smoke inhalation is the absorption of nicotine and the transport of nicotine to the brain.
Nicotine Dose And "Smoker Satisfaction"
The R&D unit at BAT contracted for a major study of smoking in the mid-1970s. Project Wheat was designed to measure the personal characteristics of a large group of male smokers in the community and then to ask each smoker how well he liked or disliked cigarettes containing different tar and nicotine deliveries {1206.01; 1206.02; 1206.03}. The project was to rely on the sophisticated statistical technique of factor
analysis to assess what characterized different smokers' preferences. The goal was to separate smokers into various group on the basis of "inner need" to smoke (this group was thought to inhale more heavily) and "health concern." These groupings make sense only if one believes that tar is toxic and that nicotine satisfies an "inner need." The results were somewhat unclear—partly because, as it turned out, the cigarettes used in testing did not actually meet the design specifications. The matrix of "inner need" and "health concern," though, illustrates the frame of mind of the BAT scientists who approved the protocol.
Two BAT Southampton R&D reports describing methods for measuring nicotine and cotinine levels in blood and urine provide valuable insights into the important role BAT scientists thought nicotine played in smoking behavior {1208.04; 1208.05}. The first report, from May 1980, states,
In some instances, the pharmacological response of smokers to nicotine is believed to be responsible for an individual's smoking behaviour, providing the motivation for and the degree of satisfaction required by the smoker (5, 6). {1208.04, p. 2}
The second report, from 1981, describes a technique for estimating the "whole body nicotine dose to the fat following intravenous administration." The authors' direct interest in using knowledge of the absorbed dose of nicotine as an aid in cigarette design is revealed in the report's description of the value of the new technique:
This technique has an immediate and direct relevance for
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Thus, the absorbed dose of nicotine is an important consideration in cigarette design.
A similar concern with the relationship of nicotine dose and product design is evident in a paper describing the conclusions of a research conference setting priorities for the R&D group at Southampton in 1984 {1210.01}. Under the category "Smoker Behaviour," a series of studies are planned, which, among other things, would explore "the efficient use of smoke nicotine through pH modification" {1210.01, p. 2}. The goal of this series of studies is described as follows:
These studies will identify the relationship between nicotine dose and nicotine-related subjective improvement. This will further help to identify
the relationship between product acceptability and smoker satisfaction. {1210.01, p. 2}
This comment—which ties together the terms "satisfaction," "nicotine dose," and "nicotine-related subjective improvement"—is about affecting the structure or function of the body.
The importance of pH in fine-tuning nicotine delivery was emphasized ten years later in testimony by the head of the FDA, Dr. David Kessler, on June 21, 1994, before the House of Representatives Subcommittee on Health and the Environment (5). Kessler reported that at least one major cigarette manufacturer uses ammonia compounds as additives to tobacco blends, to enhance nicotine delivery in cigarette smoke by pH adjustments. The Wall Street Journal has reported that UST, a maker of tobacco snuff, uses additives to adjust the acidity (pH) of moist snuff products (28)—a practice resulting in levels of free nicotine that vary in accordance with their market niche (28–31).
Research Agenda On Nicotine, 1983
At the 1983 research conference in Rio de Janeiro, participants developed a research agenda on nicotine itself. Here are the notes from the minutes on this subject:
The growing concern about compensation is focussing attention on the role of nicotine in the smoking process. It was agreed that we must know as much as possible about:
factors that affect the transfer of nicotine from leaf to smoke aerosol
factors that influence the rate of transfer of nicotine from particulate matter to the vapour phase
the contribution of nicotine to smoke sensory characteristics (including harshness and irritation)
the site and mechanisms of absorption of nicotine within the human system
the way nicotine stimulates both the central nervous system and the peripheral organs (eg heart and lung)
the metabolism of nicotine within the body, including rates and equilibrium levels.
The developing programme of research at Southampton was supported, albeit that greater emphasis should be placed on direct human studies rather than on animals—particularly in view of recent major advances in brain pharmacology . It is envisaged that much of such work will be undertaken under contract.
It was proposed that a senior person at Southampton should be responsible for coordinating all the relevant interest and work throughout the Group. There is an urgent need to prepare a status review on all major aspects of the pharmacological influences of nicotine in the smoking process [emphasis added]. {1180.07, pp. 13–14}
BAT scientists clearly regarded nicotine as a drug. The reference to the action of nicotine on the lung as well as the heart may be in recognition of the fact that the lung has an extensive network of nerve endings that can respond to nicotine and directly stimulate the brain (3). The earlier discussion on compensation made it clear that R&D felt under some pressure to get one step ahead of the regulators in test design. Here, the compensation problem was driving these scientists to look more closely at nicotine itself. The practical result of such research might be seen in testing procedures, in product design, or both.
In any case, the reason for the emphasis on nicotine in these conference minutes is the perceived need, the intention, to have a product that delivers a reliable and predictable dose of nicotine.
Views Of Nicotine In 1984
In June 1984 a three-day technical exchange meeting on nicotine was held in Southampton. The summary of the meeting appears in a set of notes for the 1984 BAT research conference in the United Kingdom {1181.07}. The summary is reproduced below in its entirety because it shows very clearly the importance of nicotine for the normal, expected functioning of a cigarette in the opinion of BAT scientists only a decade ago.
The main conclusions reached were:—
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There is an urgent need for experimental cigarettes in which the levels of nicotine in smoke (and smoke pH) are carefully controlled [emphasis in original]. {1181.07}
This summary indicates that BAT scientists had a sophisticated and up-to-date understanding of nicotine and its role in smoking behavior. The importance of smoke pH in designing an effective product at lower nicotine deliveries is apparent. Satisfaction is described as being related to the effects of nicotine on the body, especially on the brain, and the importance of inhalation is emphasized. This is the only place where we have seen a definition of the term "satisfaction" offered by tobacco company personnel. In most instances the term's meaning in relationship to the pharmacological effects of cigarette smoke must be inferred. Here it is explicit.
The discussion held at this technical exchange were reviewed in detail at the joint R&D/marketing conference in Montreal in July 1984. Both the notes summarizing the technical exchange and the minutes of the discussion mention the importance of considering nicotine levels in product design {1226.01, pp. 61–63}. The minutes note,
[An] improvement in our understanding of nicotine action is of major importance for future product development. {1226.01, p. 63}
At this same meeting, G. A. Read, Group Leader, Smoker Behaviour, GR & DC, at Imperial Tobacco, gave a fairly technical presentation on the constituents of smoke that affect product design, acceptability, and smoking satisfaction. It is clear from this material, presented at a mar-
keting conference, that BAT appreciated the key role of nicotine in selling cigarettes. The talk focused primarily on the role of nicotine in smoking behavior and included slides on nicotine absorption and pharmacology. In contrast to public statements made by the tobacco companies, Read's slides note:
strong indirect evidence for smokers smoking nicotine
...
underlying smoking maintenance through nicotine, and as a consequence nicotine probably provides the basis of smoking satisfaction
in its simplest sense puffing behavior is the means of providing nicotine dose in a metered fashion {1224.01, pp. 46–47}
Read concluded by suggesting that the minimum dose requirement for nicotine to maintain smoking behavior should be determined and that product quality and satisfaction would be enhanced if this minimum dose of nicotine were provided.
The Search For Nicotine Analogues
The documents show that, although the tobacco industry considered nicotine a mostly harmless drug, it was concerned about the potentially harmful effects of nicotine on the cardiovascular system. For example, nicotine acts directly on the heart and arteries, and carbon monoxide in the smoke reduces the ability of the blood to transport oxygen. The industry tried to solve this problem by looking for analogues to nicotine, drugs that could mimic the effects of nicotine on the brain without affecting the cardiovascular system. Although Philip Morris pursued this approach in the 1980s (4, 32), the documents show that BAT was interested in the problem in the early 1970s.
A decade before the first research report on nicotine analogues from BAT's R&DE (Research and Development Establishment) lab, Sir Charles Ellis described the research program the tobacco manufacturers in the United Kingdom were undertaking to investigate the cardiovascular toxicity of nicotine. In his keynote address at BAT's 1962 research conference in Southampton, Sir Charles said,
You are of course aware that smoking, by means of its nicotine content, is supposed to have an effect on the cardiovascular system. T.M.S.C. [Tobacco Manufacturers' Standing Committee] has agreed to contribute £12,000 over three years to Dr. Shillingford of the Cardiovascular Research Group of the Medical Research Council to enable them to extend their experiments to cover
the effects of nicotine. We think that it is well worth while having this work carried out by a skilled authoritative group with which we will have close contact.
It is the case that most previous work on the effects of nicotine on the cardiovascular system has been done with old techniques, and much of it is of doubtful quality. What T.M.S.C. believes is of particular importance is that Shillingford has developed entirely new techniques for analysing heart function and circulation in health and disease. These are based on observing changes in blood-flow by the use of short-lived radioisotopes which, for example, make it possible to measure the heart output every five minutes for an hour without using the old-fashioned catheter. You will be interested to know that Dr. Shillingford accepts the existence of beneficial effects of smoking and believes that although nicotine undoubtedly affects the cardiovascular system these effects are probably quite innocuous for normal healthy people [emphasis added]. {1102.01, pp. 19–20}
Concrete evidence of BAT's interest in nicotine analogues is documented in three research reports from the BAT Group Research and Development Centre in the 1970s {1205.11; 1205.13; 1208.03}. None of the reports indicate precisely what problem with nicotine the analogue work is designed to solve. However, when researchers for Philip Morris conducted a more extensive study of analogues in the 1980s, they were looking for compounds that had the central nervous system effects of nicotine while avoiding the cardiovascular effects (4, 32). BAT's concern with nicotine analogues may well have been based on the same considerations.
The abstract of the first of the three reports (written in November 1972) emphasizes the importance of the pharmacological actions of nicotine for smokers: "[T]he present scale of the tobacco industry is largely dependent on the intensity and nature of the pharmacological action of nicotine" {1205.11, p. 2}. The abstract emphasizes the need to develop acceptable substitutes should nicotine itself come to be regarded as unacceptable, and describes an analogue developed at Bath University through a postdoctoral fellowship supported by BAT. The summary reads as follows:
Should nicotine become less attractive to smokers, the future of the tobacco industry would become less secure.
Factors that could influence the attractiveness of nicotine are discussed, and it is concluded that substances closely related to nicotine in structure (nicotine analogues) could be important. Synthetic studies at Bath University have produced a compound that was shown by Bioassay Limited to have a powerful inhibitory effect on some of the pharmacological actions of nicotine.
It is recommended that this work continue with suitable collaborators to clarify some of the possible threats to, and opportunities for, the Company [emphasis added]. {1205.11, p. 1}
Although couched in somewhat hedged terms, the introduction amplifies the sentiment expressed in the summary and further discusses the importance of the pharmacological effects of nicotine.
It has been suggested that a considerable proportion of smokers depend on the pharmacological action of nicotine for their motivation to continue smoking [references omitted].
If this view is correct, the present scale of the tobacco industry is largely dependent on the intensity and nature of the pharmacological action of nicotine.
A commercial threat would arise if either an alternative product became acceptable or the effect of nicotine was changed.
An alternative product could come from the pharmaceutical industry. With a socially acceptable route for administration, and with medical endorsement, the product could be successful.
The effect of nicotine could be inhibited by an antagonist, and cigarettes would tend to become insipid. Such an antagonist could arise by accident or design from the pharmaceutical industry. It might be used tactically to advance that industry's alternative product, or its general use could be advocated by the anti-smoking lobby, with or without government support [emphasis added]. {1220.01, p. 2}
The concern about a "commercial threat" might be related to the work reported by Murray Jarvik earlier that year at a CTR-sponsored symposium on nicotine-blocking drugs (33). Jarvik's experiments, which had been supported by the American Cancer Society, included one on nicotine-blocking agents. He reported that a centrally acting agent called mecamylamine, which blocks the effects of nicotine in the brain, was associated with a compensatory increase in smoking in a short-term experiment. However, over time, such a blocking drug would be expected to reduce the attraction of smoking by preventing the reinforcing effects of nicotine on the central nervous system. In this way, smokers would become less and less compulsive about the use of tobacco products. Mecamylamine itself was unsuitable as a therapeutic agent because it also caused a marked lowering of blood pressure. However, Jarvik's experiment held an obvious lesson for BAT: conventional pharmaceutical companies might be able to market a safe nicotine antagonist that would prevent the nicotine in tobacco products from doing its thing. The nicotine analogue work may have been seen as a way to get ahead of this disturbing possibility.
The abstract of a second report, from 1973, indicates that the work did, in fact, continue, at least to some extent. The abstract describes the pharmacological activity of an isomer of a previously synthesized analogue {1205.13}. In this instance, the synthetic work had been performed at the School of Pharmacy of London University. The full reports are not available.
The third report, dated June 10, 1979, describes the testing of an analogue, including tests on muscle tissue {1208.03}. This may have been a screening test for cardiovascular activity, since Dr. Victor DeNoble indicated that tests of smooth-muscle reactivity had served this function in the Philip Morris research program (32). The results in this instance were not encouraging, but there seem to have been plans to test additional compounds.
The Industry's Public Statements On Nicotine
The tobacco industry has repeatedly told the public that nicotine is not addictive. Most specifically and most dramatically, at a congressional hearing on April 14, 1994, seven tobacco company CEOs—each in turn—stated that nicotine is not addictive. Thomas Sandefur, the CEO of B&W, testified, "I do not believe that nicotine is addictive."
In discussing the pharmacological properties of nicotine, the industry has largely relied on the way nicotine was discussed in the 1964 Surgeon General's report (2). This report draws a distinction between habituating and addicting drugs based on the then current understanding of the importance of tolerance and withdrawal phenomena in defining addiction. However, the report clearly states that nicotine is responsible for a variety of pharmacological actions in smokers and that the habituating nature of the process can make it difficult to stop. The addictive nature of nicotine is now well documented and widely appreciated (3). Significantly, even before the 1964 Surgeon General's report, B&W and BAT privately had concluded that nicotine is addictive.
Although industry representatives have suggested that nicotine contributes to the flavor of tobacco, the Food and Drug Administration, in its investigation of nicotine-containing cigarettes and smokeless tobacco products, found no evidence that nicotine serves such a function (6). In fact, the agency found that consumers perceive nicotine as an irritant, and that the industry uses additives to disguise the sensations which nicotine contributes to the experience of ingesting tobacco products.
The documents include an example of one industry formula for discussing the addiction question. It is contained in an undated set of questions and suggested answers (which appear to date from the early 1980s), titled "Tobaccotalk," that a B&W employee might use when questioned by people outside the industry.
Q: Aren't cigarettes addictive?
A: It is difficult to discuss addiction today because people apply the term to many different circumstances. Some people say their children are addicted to TV. The 1964 Surgeon General's report concluded that cigarettes should be classified as habituative, like coffee, and not addictive, like morphine. Many people have given up smoking. Why do some people continue to smoke who say they want to quit? Why do people continue to overeat when they say they are overweight? {2133.01, p. 5}
The exchange coaches the B&W employee on how to deal with this issue from the industry perspective. The proposed answer confuses the matter by blurring the term "addiction" to include a very broad array of activities, such as compulsive TV watching. Nicotine is addicting in exactly the same sense that heroin, cocaine, and alcohol are addicting (3). It is a drug that has powerful, reinforcing actions on the brain, and repeated use tends to produce continued use. The 1964 Surgeon General's report employed a different definition of addiction than is generally understood today. At about the same time, B&W's general counsel, Addison Yeaman, accepted, without hesitation, the fact that nicotine is addictive and that "we are ... in the business of selling nicotine, an addictive drug" {1802.05, p. 4}.
The fact that many people have stopped smoking is no more proof that nicotine is not addictive than is the fact that many people who have been clearly addicted to other drugs, such as heroin, have stopped using them as well (3, 34). Spontaneous recovery is part of the natural history of addictions, and indeed forms the basis for public health advice about drug use. Focusing on those who have recovered from addiction ignores those who still use a substance but who would like to stop. As discussed above, in any given year about a third of smokers attempt to quit, but only about 10 percent succeed, because of nicotine addiction (3). B&W's suggested answer seeks to avoid the real question at hand.
The tobacco industry has consistently avoided talking about nicotine in its marketing campaigns. One of the documents {1203.01} shows how references to nicotine and withdrawal (a drug addiction term) were edited out of an externally prepared prospectus for a marketing campaign for a low-delivery cigarette. Around 1978 Lisher and Company, a marketing
management consulting firm in New York, submitted a draft proposal for a low-delivery cigarette to B&W for review. The goal of the project was to develop cigarettes that matched the parameters suggested as desirable by Dr. Gio Gori of the National Cancer Institute, discussed in chapter 4. Before editing, the second paragraph of the proposal had read,
Current market trends clearly indicate a major trend toward low-tar brands, although current "ultra" low tar brands have had limited success because of their failure to deliver satisfaction/maintain an adequate nicotine level . An ancillary concern relative to nicotine delivery is that if a satisfying, low-nicotine cigarette were to be developed, it could represent an effective means of withdrawal with severe implications for long-term market growth [emphasis added]. {1203.01, p. 1}
The editor changed it to read,
Current market trends clearly indicate a major trend toward low-"tar" brands, although current "ultra" low "tar" brands have had limited success because of their failure to deliver satisfaction. {1203.01, p. 1}
All specific mention of nicotine, including the stated need to maintain an "adequate nicotine level," was excised. As originally written, the paragraph accurately reflects a concern with providing a pharmacologically sufficient dose of nicotine to consumers. The editing process concentrated all of this meaning into the euphemism "satisfaction." This is an example of the use of code words such as "satisfaction" to obscure the genuine pharmacological intent of the tobacco companies. The intent to provide satisfaction is, in this instance, clearly an intent to maintain an "adequate nicotine level." Examples such as this comprise one kind of evidence that the FDA could use to make the case that tobacco companies intend that tobacco products affect the structure or function of the body.
As discussed in more detail in chapter 7, the documents include another comment on nicotine from a public relations perspective. It appears in an attachment to a memo from Ernest Pepples, B&W's assistant general counsel, to J. V. Blalock, the director of public relations, dated February 14, 1973 {1814.01, p. 1}. Pepples asked Blalock to assemble current clippings on nine different topic areas regarding tobacco. One of those topic areas was addiction, and this is how Pepples framed the problem:
ADDICTION —Some emphasis is now being placed on the habit-forming capacities of cigarette smoke. To some extent the argument revolving around "free choice" is being negated on the grounds of addiction. The threat is that
this argument will increase significantly and lead to further restrictions on product specifications and greater danger in litigation [emphasis added]. {1814.01, p. 3}
"Restrictions on product specifications" because of addiction did not become a realistic possibility for another twenty years, when the Food and Drug Administration began to show an interest in this area (4) and when lawsuits focusing on the plaintiffs' addiction began to be filed. The industry's defense is now as it has been in the past: a denial that nicotine is addictive and that the industry in any way intends the pharmacological effects that nicotine provides.
Even as this position comes to appear more and more absurd, some commentators with ties to the industry have actually argued that addiction does not impair free will (35). This argument has been used to help justify the conclusion that it would not be good public policy to raise excise taxes on tobacco products (36).
Conclusion
A 1973 handout for a talk by Dr. S. J. Green, who headed R&D at BAT in the 1970s, at a conference of industry executives includes the following definition of nicotine:
A pharmacologically active material present in tobacco and tobacco smoke. It can act as a stimulant or depressant depending very much upon the person and the situation. In even small quantities it is a poison but it is metabolized rapidly by humans and not stored in tissue. When smoke is inhaled the nicotine is largely retained by the smoker. {1184.01, p. 4}
There is no mention of any taste or flavor value for nicotine, only its pharmacological effects. The definition assumes that inhalation is a normal way to ingest this "pharmacologically active material."
The private papers of Dr. Green include a revealing diagram of the importance he accorded nicotine {1186.08}. It is undated, but it uses company jargon from the early 1970s. Titled "Approaches to Problems in the Association of Smoking and Disease," the schematic places "nicotine administration" at the top, as the overall goal to be achieved. The very bottom of the diagram indicates that nicotine is to be administered to the mouth, in the case of noninhalable forms of tobacco, or to the mouth and lungs if the product is to be inhaled (i.e., cigarettes).
Strategic research was to involve nicotine itself (including "dosing" issues), "alternative pharmacological agents," and "health-oriented
cigarettes" (cigarettes that produce less disease). Tactical research and product development included "re-assurance" or "health-image" cigarettes and ways of responding to public health pressures such as the publication of tar and nicotine yields. "Health-image" cigarettes, as discussed in chapter 4, were intended to provide the appearance of reduced harm.
Again and again, the documents demonstrate the central importance of nicotine to the normal use of tobacco products. The role of nicotine in tobacco products is that of a pharmacological agent: B&W and BAT value nicotine not for its taste and flavor but for what it does to the brain. The dose of nicotine absorbed by the consumer is a factor to be considered in product design. Moreover, at least in the early 1960s, some B&W and BAT officials almost seemed to take pride in the addictive nature of nicotine.
Taste is irrelevant to nicotine as it is discussed in these documents. Sensory panels occasionally described in the documents were not asked to measure taste. Rather, they were concerned with the level of irritation nicotine in different forms causes, or with whether it has a certain "impact." Whereas taste is irrelevant, the documents demonstrate that inhalation is essential to the normal functioning of a cigarette. Inhalation is essential for nicotine absorption from a cigarette. It has no other purpose.
BAT's idealized cigarette was Ariel, a product designed to minimize toxic smoke components and deliver but one main active ingredient: nicotine. While not as fully laid out for BAT as for Philip Morris, the nicotine analogue program betrays the same focus: the purpose of the product is the delivery of a pharmacologically active substance to the brain—preferably a substance with lower toxicity to the heart and blood vessels. The logical goal of Project Ariel (provide a smoke-free nicotine aerosol), combined with the analogue work (find a less hazardous form of nicotine), is the creation of a product that delivers a nicotine analogue and no other active ingredient.
The public relations posture of B&W differs markedly from the internal working views expressed within B&W and BAT over the years. While the public posture has been that nicotine is not addicting and the company does not intend any of the pharmacological effects that occur, the internal writings consistently assume addiction and throughout demonstrate a keen interest in all aspects of the pharmacology of nicotine.
The contract work and the internal company research projects reviewed here have not been published in the scientific literature. Often,
the work was well ahead of its time. The Battelle work in Geneva was at the cutting edge of pharmacological work on nicotine at the time. The work on smoker compensation in the 1970s preceded the main published reports by a decade. Today B&W accepts one, and only one, conclusion from the 1964 Surgeon General's report: that nicotine is a habituating, not an addicting, drug. Yet high-level executives at B&W and BAT did not accept this conclusion in 1964.
In early 1992, BAT considered whether to purchase a manufacturer of nicotine patches (37). B&W's chief attorney, Mick McGraw, objected because of the unwanted attention such a move might draw to the cigarette business from the FDA. He also felt that selling a nicotine patch to help people manage withdrawal symptoms as they tried to stop smoking would undercut the company position that people choose to smoke and that they can stop at will. In contrast to McGraw's feelings, Patrick Dunn, the head of research at the Canadian subsidiary, Imperial Tobacco, regarded the patch business as a natural extension of the cigarette business. A scientific analysis of the nicotine patch prepared by B&W staff compared the nicotine delivery rate from a cigarette with that from a patch. These candid appraisals of the nicotine patch, written in 1992, demonstrate that the perspectives on nicotine reflected in the documents from the early 1960s through the mid-1980s, which have been reviewed in this chapter, were still operative at BAT and at its subsidiaries only two years before Thomas Sandefur, B&W's CEO, told Congress, "I believe that nicotine is not addictive."
Are cigarettes drugs? Do cigarette manufacturers intend that their products affect the structure or function of the body? The documents reviewed in this chapter, taken as a whole, demonstrate that, for B&W and for BAT at least, the answer is yes. This answer, in turn, means that cigarettes made by these companies come under the jurisdiction of the FDA through the federal Food, Drug and Cosmetic Act.
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