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:

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

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.