[Federal Register: August 11, 1995 (Volume 60, Number 155)]
[Notices]
[Page 41750-41771]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]

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[[Page 41750]]

F. INDUSTRY ALTERNATIVE TOBACCO PRODUCTS

1. Industry Development of Nicotine Substitutes That Mimic Nicotine's
Drug Effects

    Tobacco manufacturers' intention to offer tobacco products that
will be used to affect the structure or function of the body is further
demonstrated by the research programs tobacco companies have undertaken
to develop ``nicotine analogues.'' Nicotine analogues are chemical
substances that are closely related to nicotine. Both Philip Morris and
Brown and Williamson have had substantial research programs to identify
nicotine analogues that would produce nicotine-like effects on the
central nervous system <SUP>524 and that either could be substituted
for nicotine if nicotine-containing tobacco became regulated or
unattractive to consumers, or that could be added to currently marketed
products to enhance the effects of nicotine.

    \524\ See the following documents:
    Kilburn KD, Underwood JG. BATCO Group Research and Development
Center. Preparation and Properties of Nicotine Analogues. Report No.
RD 953-R. November 9, 1972.
    Kilburn KD, Underwood JG. BATCO Group Research and Development
Center. Preparation and Properties of Nicotine Analogues, Part II.
Report No. RD 1048-R. October 11, 1973
    Kilburn KD. BATCO Group Research and Development Center.
Preparation and Properties of Nicotine Analogues, Part III. June 20,
1979.
    BATCO R&D. Notes on the R&D Conference. October 29, 1979--
November 1, 1979. Page 01794-01808.
    Declaration of former Philip Morris scientist Victor John
DeNoble, Ph.D., executed on February 2, 1995. (hereafter cited as
DeNoble Declaration) (A copy of the declaration is on file at FDA.)
    The Council for Tobacco Research--U.S.A. and the American
Tobacco Co. also funded research on nicotine analogues. See, e.g.:
    Report of the Council for Tobacco Research--U.S.A., Inc. 1978.
    Meacham RH, Bowman ER, McKennis H. Additional routes in the
metabolism of nicotine to 3 pyridylacetate. The metabolism of
dihydrometanicotine. J-Biol-Chem. 1972;247(3):902-08.

[[Page 41751]]

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    These programs were also designed to identify substances that
shared nicotine's ``desired'' effects on the central nervous system,
without producing nicotine's undesirable effects on the cardiovascular
system.<SUP>525 In the words of former Philip Morris scientist Dr.
Victor J. DeNoble:

    \525\ BATCO R&D. BATCO Research Conference. Hilton Head, SC.
September 24-30, 1968. Page 3.
    See also:
    U.S. Patent No. 5,138,062. Osdene TS, Secor HV, Seeman JI.
Nicotine Analogues. Philip Morris Inc. August 11, 1992. C1:57-60.
    U.S. Patent No. 5,015,741. Osdene TS, Secor HV, Seeman JI.
Nicotine Analogues. Philip Morris Inc. May 14, 1991. C1:56-60.
    See DeNoble Declaration, note 524, supra, at pp. 3-4.
---------------------------------------------------------------------------

    Our goal was to identify the effects of nicotine in the central
nervous system, and to establish structural activity relationships
among organically synthesized analogues of nicotine. The purpose of
this nicotine analogue program was to develop an analogue that would
retain the physiological effects of nicotine in the brain as well as
the behavioral effects, but not have adverse effects on the
cardiovascular system.<SUP>526

    \526\ Regulation of Tobacco Products (Part 2): Hearings Before
the Subcommittee on Health and the Environment of the Committee on
Energy and Commerce. U.S. House of Representatives. 103rd Cong. 2d
Sess. 5 (April 28, 1994) (testimony of former Philip Morris
scientist Victor J. DeNoble).
---------------------------------------------------------------------------

    The tobacco industry's programs to develop nicotine analogues were,
according to company documents, prompted by the industry's recognition
that the market for tobacco depends on the pharmacological effects of
nicotine on the central nervous system. For example, in 1968, BATCO
researchers reported the following conclusion at a research conference:

    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. [Emphasis

[[Page 41752]]
added.] <SUP>527

    \527\ See BATCO Research Conference, note 525, supra, at p. 3.
---------------------------------------------------------------------------

This document shows that BATCO was interested in using chemicals with
nicotine-like effects to replace nicotine or enhance the drug effects
of nicotine in cigarettes.<SUP>528 Another BATCO document underscores
the fact that the search for nicotine analogues was designed to
implement the industry's belief that nicotine's drug effects are
essential to sustain the market for tobacco. S.J. Green, director of
research at BATCO, in a paper on future research policy, stated:

    \528\ See also U.S. Patent No. 4,340,072. Bolt AJ, Chard B.
Smokable Device. Imperial Group Ltd. (1982). This patent describes
an alternative cigarette-like device providing an aerosol that may
contain nicotine or another psychoactive substance:
    The aerosol material may, as an alternative to a flavourant
solution, comprise a solution of a flavourant and/or nicotine in
triacetin or benzyl benzoate. Any psycho-active or physiologically
active compound such as ephedrine or a nicotine/ephedrine mixture
may be used.
---------------------------------------------------------------------------

    While other factors cannot be ignored and their influence is not
completely understood, it seems a good assumption that nicotine plays a
predominant role for many smokers. So that a good part of the tobacco
industry is concerned with the administration of nicotine to consumers.
If this assumption is correct two long-range research projects become
immediately apparent. These are to find pharmacological alternatives to
nicotine and to explore alternatives to tobacco as a source of
nicotine.<SUP>529

    \529\ Green SJ. BAT Group Research. September 4, 1968. Page 2.
---------------------------------------------------------------------------

    Other documents show that nicotine analogues were also believed by
BATCO to be necessary to protect against three potential threats to the
company's nicotine-based market: (1) government action to prohibit the
use of nicotine because of nicotine's cardiovascular toxicity; (2) the
development by other pharmaceutical companies of alternative, more
socially and medically acceptable means of administering nicotine; or
(3) the discovery and use by pharmaceutical companies or anti-tobacco
activists of nicotine ``antagonists,'' that is, substances that block
the

[[Page 41753]]
effects of nicotine on the central nervous system.
    A BATCO research report dated November 9, 1972, and entitled
``Preparation and Properties of Nicotine Analogues,'' provided the
following rationale for BATCO's long-term research program to develop
nicotine analogues:

Summary

    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.
    * * *

 Introduction

    It has been suggested that a considerable proportion of smokers
depend on the pharmacological action of nicotine for their
motivation to continue smoking (1, 2, 3 <SUP>530).

    \530\ The page of the report that contains the citations for
these footnotes is missing from the document provided by Brown and
Williamson to Congress.
---------------------------------------------------------------------------

    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.
    The obvious starting point of a search, either for alternatives
or antagonists to nicotine, is the nicotine molecule and close
analogues of it. The present report

[[Page 41754]]
discussed nicotine and some of its analogues * * *.<SUP>531

    \531\ See Kilburn (1972), note 524, supra, at pp. 1-2.
---------------------------------------------------------------------------

    These internal documents reflect the tobacco industry's awareness
that nicotine's drug effects are critical to the continued success of
tobacco in the marketplace. Indeed, they show that the industry views
nicotine's drug effects as so important that if nicotine's drug effects
were interfered with in any way, tobacco companies would seek to
substitute another drug for nicotine to ensure the continued market for
tobacco.
    Internal documents from Philip Morris' nicotine analogue program
show that this company also sought nicotine analogues with
pharmacological effects on the central nervous system, including
effects associated with addiction.
    For example, an internal 1980 company memorandum describes the
rationale for Philip Morris' research into nicotine analogues. After
asserting that nicotine ``is a powerful pharmacological agent'' which
is ``cited often as `the reason for smoking,' '' the memorandum
describes the importance of discovering compounds related to nicotine:

    [O]ur ability to ascertain the structural features of the
nicotine molecule which are responsible for its various
pharmacological properties can lead to the design of compounds with
enhanced desirable properties (central nervous system effects) and
minimized suspect properties (peripheral nervous system effects).
There are many opportunities for acquiring proprietary compounds
which can serve as a firm foundation for new and innovative products
in the future.<SUP>532

    \532\ Philip Morris Interoffice Correspondence from J.L. Charles
to Dr. R. B. Seligman. Nicotine Receptor Program-University of
Rochester. March 18, 1980.
---------------------------------------------------------------------------

    Between 1980 and 1984, Dr. DeNoble conducted research for Philip
Morris on nicotine analogues,<SUP>533 first identifying the
pharmacological effects of nicotine on the brains and behavior

[[Page 41755]]
of animals <SUP>534 and then comparing these effects to the
physiological and pharmacological effects of nicotine analogues
synthesized by chemists at Philip Morris.<SUP>535 Dr. DeNoble's
studies, which were conducted as part of the ``Behavioral
Pharmacology'' Program at Philip Morris, were intended to characterize
the pharmacologic effects of nicotine and then to identify those
analogues that affected the central nervous system in the same way that
nicotine affects the central nervous system. An internal Philip Morris
---------------------------------------------------------------------------
document states:

    \533\ The nicotine analogue program at Philip Morris began
before Dr. DeNoble's arrival. See, e.g. Secor HV, Edwards WB. Philip
Morris Research Center. Nicotine analogues: synthesis of
pyridylazetidines. J. Org. Chem. 1979;44(18):3136.
    See DeNoble Declaration, note 524, supra, at p. 4.
    \534\ Dunn WL. Philip Morris Inter-Office Correspondence to T.S.
Osdene. Possible Restructuring of the Behavioral Research Lab. June
18, 1980. Page 100019244.
    \535\ See:
    DeNoble Declaration, note 524, supra, at pp. 2-9.
    U.S. Patent No. 4,452,984. Edwards III WB. Optically Active
Nicotine Analogues and Process For Their Preparation. Philip Morris
Inc. June 5, 1984.
    U.S. Patent No. 4,442,292. Edwards III WB. Optically Active
Nicotine Analogues and Process For Their Preparation. Philip Morris
Inc. April 10, 1984.
    U.S. Patent No. 4,332,945. Edwards III WB. Optically Active
Nicotine Analogues and Process For Their Preparation. Philip Morris
Inc. June 1, 1982.
    U.S. Patent No. 4,321,387. Chavdarian CG, Sanders EB. Process
for the Preparation of Optically Active Nicotine Analogues. Philip
Morris Inc. March 23, 1982.
    U.S. Patent No. 4,220,781. Sanders EB, Secor HV, Seeman JI.
Process for Preparing 2-ALKYL Nicotinoids. Philip Morris Inc.
September 2, 1980.
    U.S. Patent No. 4,155,909. Sanders EB, Secor HV, Seeman JI. 2-
ALKYL Nicotinoids and Processes For Their Production. Philip Morris
Inc. May 22, 1979.
    Work on nicotine analogues continued after Dr. DeNoble's
departure from the company. See U.S. Patent No. 5,138,062, note 525,
supra.; U.S. Patent No. 5,015,741, note 525, supra.; U.S. Patent No.
4,590,278. Edwards III WB. Nicotine Analogues. Philip Morris Inc.
May 20, 1986.
---------------------------------------------------------------------------

    Major objectives of the Behavioral Pharmacology Program are (1)
To develop a better understanding of the reinforcing actions of
nicotine and nicotine

[[Page 41756]]
analogues, (2) To gain insight into the neurobehavioral actions of
nicotine, and (3) To develop and use animal behavior techniques to
screen nicotine analogues for their nicotine eliciting
---------------------------------------------------------------------------
properties.<SUP>536

    \536\ DeNoble VJ, Carron L. Philip Morris Inter-Office
Correspondence to Dr. T. Osdene. Progress Report: The Behavioral
Pharmacology Program. October 14, 1980.
    See Dunn, note 534, supra, which proposes the creation of the
``Behavioral Pharmacology Project.''
---------------------------------------------------------------------------

    Dr. DeNoble's research and that of

[[Page 41757]]
    other scientists working at Philip Morris on the pharmacologic effects
of nicotine showed that nicotine is self-administered by rats (i.e., is
a ``positive reinforcer''), produces tolerance, causes a unique
``prostration syndrome'' when injected into the rat brain that
correlates to nicotine's ability to produce behavioral changes, and
that nicotine loses its effects when the rat is pretreated with
mecamylamine, a substance that blocks nicotine's effects in the
brain.<SUP>537 These studies also demonstrated that nicotine has
pharmacological activity in the brain, and that it has characteristics
of other addictive substances that make it likely to be abused.<SUP>538
To evaluate potential nicotine analogues, Philip Morris tested numerous
substances to determine whether they duplicated nicotine's effects on
the brain and whether they had the same characteristics associated with
abuse liability.<SUP>539 Dr. DeNoble and other scientists working at
and for Philip Morris used nicotine analogues in discrimination tests
in rats, in prostration studies, and in self-administration
studies.<SUP>540 As noted in FINDINGS Sec. I.B.3., supra,
discrimination and self-administration studies provide key evidence of
the likelihood that a substance will be addictive in humans.

    \537\ See:
    DeNoble Declaration, note 524, supra, at pp. 5-9.
    DeNoble VJ. Philip Morris Inter-Office Correspondence to W.L.
Dunn. Nicotine Program-Behavioral Research Laboratory. April 24,
1980. Page 2.
    DeNoble VJ, Mele PC, Ryan FJ. Philip Morris Research Center.
Nicotine as a Positive Reinforcer for Rats: Effects of Infusion Dose
and Fixed Ratio Size. Unpublished Manuscript.
    Dunn, note 534, supra, at p. 100019244.
    \538\ See DeNoble Declaration, note 524, supra, at pp. 7-9. See
also FINDINGS Sec. II.A.2., supra.
    \539\ See:
    DeNoble, note 536, supra.
    DeNoble Declaration, note 524, supra, at pp. 4-5.
    \540\ DeNoble VJ, Carron L. Philip Morris Inter-Office
Correspondence to W.L Dunn. Research Progress Concerning
Discrimination and Prostration Studies. August 18, 1980. Pages
1003030001-1003030007.
    Carron LM, Levy CJ, Allen A. Philip Morris Inter-Office
Correspondence to V.J. DeNoble. Discrimination Studies. May 7, 1980.
Pages 1003030008, 1003030009.
---------------------------------------------------------------------------

    Philip Morris documents state explicitly that the purpose of the
research on nicotine analogues was to find nicotine substitutes that
were behaviorally active and had the same reinforcing properties as
nicotine; i.e., produced effects on the central nervous system
associated with addiction. A progress report from the behavioral
pharmacology group identified as its major objectives:

Nicotine Analogues

Research Objectives

    1. Determine if behaviorally active nicotine analogues can be
directly substituted for nicotine in rats for which nicotine is
functioning as an intravenously delivered positive reinforcer.
    2. Establish nicotine analogues as an intravenously delivered
positive reinforcer.
    3. Compare the potencies of nicotine analogues to nicotine in
producing positive reinforcing effects.<SUP>541

    \541\ DeNoble VJ, Carron L. Philip Morris Inter-Office
Correspondence to W. Dunn. Progress in Behavior Pharmacology
Laboratory. March 27, 1981. Pages 1-32.
---------------------------------------------------------------------------

The objectives of the studies conducted by the behavioral pharmacology
group were developed in conjunction with senior management at Philip
Morris, and the study results were shared with

[[Page 41758]]
upper management as well.<SUP>542

    \542\ See:
    DeNoble Declaration, note 524, supra, at pp. 4, 11-12.
    Charles JL. Philip Morris Inter-Office Correspondence to T.S.
Osdene. March 1, 1983. Page 2: ``Because of the sensitive nature of
Vic's assignment, documentation of much of his work has been
restricted to the Director and Vice President level.''
---------------------------------------------------------------------------

    Thus, it is evident from tobacco manufacturers' interest in
developing nicotine analogues with central nervous system effects
comparable to nicotine that these manufacturers (1) believe that the
pharmacological effects of nicotine on the central nervous system, and
in particular the pharmacological effects that reinforce continued
tobacco use, are necessary to ensure a long-term market for tobacco;
and (2) intend to market products that affect the central nervous
systems of their customers.

[[Page 41759]]

2. Industry Research on Acetaldehyde As a Reinforcer

    The behavioral pharmacology program at Philip Morris also conducted
pharmacological and behavioral research on another constituent of
cigarette smoke, acetaldehyde. This research was intended to find a
combined dose of acetaldehyde and nicotine in cigarettes that would
produce ``maximal reinforcing effects.'' <SUP>543 The reinforcing
capability of a drug is a measure of the dependence-producing
properties of a drug.<SUP>544 In undertaking research on how to
maximize the reinforcing effects of cigarettes, Philip Morris
demonstrated its understanding of the dependence-producing nature of
cigarettes and its intention to manufacture and sell cigarettes that
affect the structure or function of the smoker's body.

    \543\ DeNoble VJ. Philip Morris U.S.A. Inter-office
correspondence to J.L. Charles. Project Number 1610 (Behavioral
Pharmacology) Objectives and Plans--1982-1983. July 20, 1982. Page
2.
    \544\ See:
    Balster RL. Drug abuse potential evaluation in animals. Brit. J.
of Addiction. 1991;86:1549-1558.
    Henningfield JE, Cohen C, Heishman SJ. Drug self-administration
methods in abuse liability evaluation. Brit. J. of Addiction.
1991;86:1571-1577.
    Griffiths RR, Lamb RJ, Ator NA, Roache JD, Brady JV. Relative
abuse liability of triazolam: experimental assessment in animals and
humans. Neuroscience and Biobehavioral Reviews. 1985;9:133-151.
---------------------------------------------------------------------------

    Acetaldehyde, like nicotine, is present in, and delivered to the
smoker from, cigarette smoke.<SUP>545 At the time Philip Morris
conducted research on the reinforcing properties of acetaldehyde in
cigarettes, acetaldehyde had been studied as a potential contributing
factor to the

[[Page 41760]]
rewarding effects of alcohol.<SUP>546 This information led Philip
Morris to explore its reinforcing properties in cigarettes.<SUP>547

    \545\ Acetaldehyde is present in tobacco at 1.6-7.4 mg/gm of
processed tobacco. It is contained in mainstream smoke at 18-1400 mg
per cigarette. U.S. Department of Health and Human Services.
Reducing the Health Consequences of Smoking: 25 Years of Progress. A
Report of U.S. Surgeon General. U.S. Department of Health and Human
Services, Public Health Service, Centers for Disease Control and
Prevention, Center for Chronic Disease Prevention and Health
Promotion, Office on Smoking and Health. DHHS Publication No. (CDC)
89-8411, 1989.
    \546\ See:
    Schuckit MA, Rayses V. Ethanol ingestion: Differences in blood
acetaldehyde concentrations in relatives of alcoholics and controls.
Science. 1979;203:54-55.
    Brown ZW, Amit Z, Smith B. Intraventricular self-administration
of acetaldehyde and voluntary consumption of ethanol in rats.
Behavioral and Neural Biology. 1980;28:150-155.
    \547\ See DeNoble Declaration, note 524, supra, at p.10.
---------------------------------------------------------------------------

    Researchers in Philip Morris' behavioral pharmacology program first
conducted studies that showed that acetaldehyde acts on the brain and
is a positive reinforcer when present in amounts comparable to those
delivered by cigarette smoke.<SUP>548 By this time, the company had
already demonstrated that nicotine was also a positive reinforcer. The
researchers noted that it was well-known that the presence of two
reinforcers together can modify the behavioral effect of either one,
and decided to study whether rats would self-administer nicotine and
acetaldehyde in combination. Recognizing that the reinforcing effects
of nicotine and acetaldehyde are pharmacological, the researchers
stated that their efforts were intended to determine whether the
combination produced a ``modification of the pharmacologic effect of
one compound by the other.'' <SUP>549 The researchers found that rats
self-administered the combination of acetaldehyde and

[[Page 41761]]
nicotine to a greater extent than either compound alone.<SUP>550 This
finding suggested that the combination was a more potent positive
reinforcer than nicotine or acetaldehyde alone.<SUP>551

    \548\ See:
    DeNoble VJ. Philip Morris U.S.A. Inter-office correspondence to
W.L. Dunn. Progress Report from the Behavioral Pharmacology
Laboratory for the period beginning September 1, 1980, to March 30,
1981. August 24, 1981. Pages 12-16.
    DeNoble Declaration, note 524, supra, at pp. 10-11.
    \549\ DeNoble VJ, Mele PC. Philip Morris U.S.A. Inter-office
correspondence to W.L. Dunn. Progress Report from the Behavioral
Pharmacology Laboratory for the period beginning March 1, 1981, to
March 1, 1982. April 21, 1982. Pages 18-19.
    \550\ Id. at pp. 19-21.
    \551\ See DeNoble Declaration, note 524, supra, at p. 11.
---------------------------------------------------------------------------

    The culmination of this research was Philip Morris' attempt to
establish the ``optimum'' ratio of acetaldehyde to nicotine in
cigarette smoke:

    Since both acetaldehyde and nicotine are reinforcing agents and
each are contained in smoke it becomes important to determine [sic]
ratio of acetaldehyde to nicotine which produce maximal reinforcing
effects * * *. This will allow us to determine the optimum ratio of
acetaldehyde to nicotine that maintains the most behavior.<SUP>552
[Emphasis added.]

    \552\ DeNoble, note 543, supra, at p. 2.
---------------------------------------------------------------------------

As this passage makes clear, Philip Morris viewed the ``optimal'' ratio
of acetaldehyde to nicotine as the ratio that would maximize the
positive reinforcing effects of cigarettes; i.e., maximize their
potential to produce dependence in smokers.
    The behavioral pharmacology group conducted further studies
suggesting that the ratio of acetaldehyde to nicotine that produced the
greatest positive reinforcement in rats was in the range of
4:1.<SUP>553 While FDA does not know whether or how this research was
implemented by Philip Morris, Dr. DeNoble was present at a meeting at
which Philip Morris officials discussed the possibility of producing a
cigarette with this ratio of acetaldehyde to nicotine and test-

[[Page 41762]]
marketing it in South America.<SUP>554

    \553\ Philip Morris U.S.A. Behavioral Pharmacology Annual
Report--June 1, 1983. Philip Morris Research Center. Richmond, VA.
Pages 20-23. This work was still going on at the time the Behavioral
Pharmacology program was terminated at the Philip Morris Research
Center in Richmond, VA.
    See also, DeNoble VJ. Philip Morris U.S.A. Inter-office
correspondence to J.L. Charles. Project 1610 (Behavioral
Pharmacology) Objectives and Plans, 1984. September 6, 1983.
(Continued research on the ratio of acetaldehyde and nicotine with
optimum reinforcing effects scheduled for 1984.)
    \554\ See DeNoble Declaration, note 524, supra, at p. 12.
---------------------------------------------------------------------------

    It is thus clear that Philip Morris was interested in implementing
the research to maximize the reinforcing effects of cigarettes by
manipulating acetaldehyde and nicotine. The data on the reinforcing
properties of particular ratios of acetaldehyde and nicotine were also
used by researchers at Philip Morris to predict cigarette sales based
on the delivery of nicotine and acetaldehyde. The researchers found
that they could predict sales of particular brands with an accuracy
above 80 % by comparing nicotine and acetaldehyde ratios.<SUP>555 This
evidence compellingly demonstrates Philip Morris' reliance on, and
intention to increase, the reinforcing effect of cigarettes on the
structure or function of the smoker's body.

    \555\ Id. at p. 11.

[[Page 41763]]

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3. Industry Development of Alternative Cigarettes That Deliver Nicotine

    Tobacco companies have developed a number of cigarette
alternatives. These alternatives to conventional cigarettes have
generally been created in response to perceived societal pressure to
market safer cigarettes. In developing cigarette alternatives, tobacco
companies have sought to eliminate many of the traditional components
and characteristics of cigarettes and cigarette smoke, such as tar and
carbon monoxide. Tobacco companies have consistently recognized,
however, that cigarette alternatives must deliver adequate amounts of
nicotine to satisfy consumers. As a result, most of the alternative
cigarette products developed by tobacco companies are simply nicotine
delivery systems.
    Tobacco company development of alternatives to cigarettes
demonstrates the industry's knowledge that nicotine is the critical or
``active'' ingredient in cigarettes, and that smokers smoke primarily
to obtain nicotine. The nature of the alternatives they believe could
be substituted for currently marketed tobacco products strongly
supports the inference that companies intend currently marketed tobacco
products to serve as nicotine delivery systems.
    In the late 1980's, RJR developed Premier, a ``smokeless''
cigarette that contained very little tobacco.<SUP>556 Although designed
to be ``smoked'' and inhaled, Premier actually worked by

[[Page 41764]]
heating rather than burning tobacco.<SUP>557 RJR claimed that by
altering the composition of conventional cigarettes and by eliminating
the pyrolysis products produced by burning, Premier reduced by about
90% the chemical compounds delivered to smokers by conventional
cigarettes.<SUP>558 Virtually the only compound (other than the paper
and the filter) that was present in Premier in quantities similar to
conventional cigarettes was nicotine.<SUP>559

    \556\ Premier resembled a conventional cigarette in outward
appearance only. It contained a carbon tip which served as the heat
source. RJR informed FDA that at least 70% of the nicotine delivered
by ``Premier'' was provided from spray-dried tobacco. This nicotine
source had been combined with glycerol and adsorbed within alpha-
alumina spheres contained within an aluminum cylinder positioned
directly behind the carbon heat source. The remaining nicotine was
provided from the cut tobacco leaf surrounding this cylinder and the
tobacco extract-treated paper filter positioned in front of the
cellulose acetate filter. Letter with enclosures from Peter B. Hutt,
outside counsel for RJR, to Kevin M. Budich, FDA, January 26, 1988.
    \557\ See R.J. Reynolds, note 300, supra. Premier was withdrawn
from the market shortly after its introduction.
    \558\ Id. at p. 8.
    Department of Health and Human Services. RJR's ``Smokeless''
Cigarette. October 23, 1987, memorandum of meeting between Peter B.
Hutt, representing RJR Nabisco Inc., and FDA representatives (Daniel
L. Michels, Sammie R. Young, Rudolf Apodaca, and Kevin M. Budich).
    \559\ See R.J. Reynolds, note 300, supra, at pp. 1-10. In the
mainstream smoke produced by Premier, the only components that were
similar in quantity to conventional cigarettes were nicotine and
carbon dioxide.
---------------------------------------------------------------------------

    RJR's willingness to eliminate from Premier almost every
conventional cigarette component but nicotine was not a coincidence.
According to a memorandum of meeting dated October 23, 1987, the
attorney representing RJR told FDA officials that for a cigarette
substitute like Premier to be successful in the marketplace, it must
contain nicotine.<SUP>560 Observing that herbal cigarettes had failed
as substitutes due to the absence of nicotine, the attorney said that
RJR would never eliminate nicotine from Premier because ``without
nicotine, you don't have a cigarette.'' <SUP>561

    \560\ See Memorandum of Meeting, note 558, supra.
    \561\ Id.
---------------------------------------------------------------------------

    RJR documents also show that the purpose of including nicotine in
Premier was to deliver nicotine to the smoker's blood and brain.
Studies conducted by RJR to determine

[[Page 41765]]
whether Premier would be an acceptable cigarette substitute show
unequivocally that RJR was interested in Premier's ability to deliver
specific blood levels of nicotine to the smoker. Delivery of nicotine
to the smoker's blood is relevant only if the company was interested in
producing physiological effects in the smoker's body. The company
itself reported, in a book published at the time of Premier's
introduction, that it wanted to assess whether differences in
composition and function between Premier and conventional cigarettes
might alter nicotine delivery to the smoker's blood and body.<SUP>562
To assure itself that the absorption of nicotine into the smoker's body
from Premier and conventional cigarettes was similar, RJR conducted
plasma studies on rats and humans comparing the levels of nicotine in
smokers' blood produced by smoking conventional cigarettes with the
levels of nicotine produced by smoking Premier.<SUP>563

    \562\ See R.J. Reynolds, note 300, supra, at p. 460.
    \563\ During its investigation FDA asked R.J. Reynolds about the
company's use of human body fluid testing to measure nicotine levels
in smokers. Counsel to R.J. Reynolds informed FDA that it ``should
come as no surprise to the Agency that RJRT [R.J. Reynolds Tobacco
Company] did some body fluids testing and used the services of
Bellomy Research, Inc. to solicit participants.'' Letter to E.
Blumberg, FDA, from R. Cooper, Williams & Connolly, on behalf of R.
J. Reynolds. November 18, 1994. Page 2. It appears that R.J.
Reynolds has conducted such testing not only in conjunction with the
development of Premier, but in other circumstances ``in which a
developmental product incorporated new technology, and the testing
was conducted in order to understand * * * for example, whether
nicotine is absorbed or metabolized differently by smokers smoking
the new technology product when compared to other cigarettes * * *''
Id.
---------------------------------------------------------------------------

    RJR found the absorption and elimination of nicotine from Premier
to be comparable to conventional cigarettes.<SUP>564 Because, however,
Premier contained somewhat less nicotine than the reference cigarette
tested, the blood levels of nicotine found in smokers of Premier were
somewhat lower than those from the reference cigarette. The blood-level
studies conducted by

[[Page 41766]]
RJR demonstrated that smokers compensated for the lower levels of
nicotine in Premier. The researchers stated that subjects smoked
Premier more intensely, speculating that they inhaled a greater volume
of the smoke from Premier.<SUP>565 Thus, while Premier contained about
52% of the nicotine of the reference cigarette, after 39 days of
smoking Premier the volunteers were absorbing 69% of the nicotine they
had absorbed from the reference cigarette.<SUP>566 RJR has patented
other cigarette alternatives whose basic function is also to deliver
nicotine.<SUP>567

    \564\ See R.J. Reynolds, note 300, supra, at pp. 496-497. See
also p. xii:
    * * * in the short-term measurements of nicotine
pharmacokinetics, the [Peer Review] Committee agreed with the
conclusion that there was no significant difference in this response
in individuals smoking either the reference or the new cigarette.
    \565\ Id. at p. 482.
    \566\ Id. at pp. 479, 482-483, 490-492.
    \567\ U.S. Patent No. 5,285,798. Banerjee et al. Tobacco smoking
article with electrochemical heat source. R.J. Reynolds Tobacco
Company. February 15, 1994. (Alternative cigarette that is designed
to generate enough heat, without burning, to volatilize and deliver
to the smoker only the nicotine and flavor materials in the
tobacco).
---------------------------------------------------------------------------

    More recently, RJR detailed plans to unveil a low-smoke cigarette,
Eclipse, in 1995. It has a charcoal heat source for the tip. Behind the
charcoal tip, there are processed tobacco parts containing more than
50% glycerine, which vaporizes at temperatures below those that burn
tobacco. Behind the processed tobacco, there is blended tobacco. The
charcoal heats the processed tobacco and glycerine, which creates
smoke-like vapor. The glycerine vapor then passes through the blended
tobacco, picking up flavor and nicotine before passing through a
standard cellulose filter, and into the smoker's mouth. According to
RJR, Eclipse vapor contains about 85% water, glycerol, and nicotine
(versus 25% in standard cigarette smoke) and about 15% tars and related
particles (versus 75% in standard smoke).<SUP>568

    \568\ Hilts P. Little smoke, little tar, but still lots of
nicotine. New York Times. November 27, 1994;A1.
---------------------------------------------------------------------------

    Other tobacco companies have also developed cigarette alternatives
similar to Premier in design and intent. In the 1960's, Charles Ellis
of BATCO developed ``Ariel.'' Like Premier,

[[Page 41767]]
Ariel eliminated most of the compounds delivered by conventional
cigarettes, but ensured delivery of a sufficient amount of nicotine to
satisfy smokers' need for nicotine. Ariel was an alternative smoking
device that contained a capsule of nicotine-enriched tobacco. The
nicotine-enriched tobacco was heated by burning tobacco surrounding the
capsule.<SUP>569 The nicotine was supposed to be released into an
aerosol and inhaled by the smoker. The patents for this device make
clear that its purpose was to provide an alternative to conventional
cigarettes that would provide the same ``satisfaction'' as a
traditional cigarette. The principal (indeed, almost the only)
ingredient it was designed to deliver to achieve this goal was
---------------------------------------------------------------------------
nicotine:

    \569\ See:
    U.S. Patent No. 3,258,015. Ellis CD, Dean C, Schachner H,
Williamson D. Smoking Device. Battelle Memorial Institute. June 28,
1966.
    U.S. Patent No. 3,356,094. Ellis CD, Dean C, Hughes IW. Smoking
Devices. Battelle Memorial Institute. December 5, 1967.
---------------------------------------------------------------------------

    This invention relates to an improved smoking device whereby an
improved smoke stream of a controlled character is delivered to the
smoker.
    * * *.
    A further object is the provision of an improved smoking device
of the above character which simulates a conventional or traditional
smoking device, such as a cigarette, in appearance and in social
habit attributes, and which affords the same benefits, pleasure and
satisfaction without the attendant disadvantages.
    * * *.
    Our invention contemplates the provision of an improved smoking
device having the appearance of a traditional smoking device and
embodying a composition which releases nicotine vapor and
potentially aerosol forming materials, including water vapor, when
subjected to an elevated temperature * * *<SUP>570

    \570\ See U.S. Patent No. 3,258,015, note 569, supra.
---------------------------------------------------------------------------

A subsequent patent for a modification of this device stated that:

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

[[Page 41768]]
smoking a conventional cigarette * * * <SUP>571 [Emphasis added.]

    \571\ See U.S. Patent No. 3,356,094, note 569, supra.
---------------------------------------------------------------------------

At a 1968 conference of BATCO researchers, the conferees succinctly
described Ariel as a ``device[] for the controlled administration of
nicotine.'' <SUP>572

    \572\ BATCO Research Conference. Hilton Head Island, SC.
September 24-30, 1968. Page 3.
---------------------------------------------------------------------------

    Other documents reveal that tobacco companies have consistently
recognized that alternative tobacco products must contain sufficient
amounts of nicotine to satisfy users.<SUP>573 For example, the minutes
of a BATCO Group R&D Conference held in 1969 disclose that the
conferees agreed that non-tobacco cigarettes could not succeed in the
marketplace without the addition of nicotine:

    \573\ See the following documents:
    BATCO Group Research Conference. St. Adele, Quebec. November 9-
13, 1970.
    S.J. Green. Appendix I. Smoking and Health: Some Recent
Findings. Memo to D.S.F. Hobson. March 2, 1967. Page 2:
    A non-tobacco smoking material has been made from cellulose and
nicotine * * *
    Proceedings of the BATCO Smoking Behaviour--Marketing
Conference. July 9-12, 1984.
    Ayres CI. Notes from the 1984 GR&DC Nicotine Conference.
Conference Outline. July 9-12, 1984.
    U. S. Patent No. 5,050,621. Creighton DE, Grieg CC. Smoking
Articles. BATCO. September 24, 1991.
    Abstract: There is provided a smoking article comprising a
heating unit aerosol generation section in flow communication at a
first end thereof with the heating unit, nicotine source in flow
communication at a first end thereof with said heating unit, a
mixing space with which said aerosol generation section and nicotine
source means are in flow communication at or via respective second
ends thereof, and a velocity accelerating orifice in flow
communication with the mixing space. [Emphasis added.]
    In a document submitted to the Food and Drug Administration in
1985 pursuant to an FDA examination of their product, Advance
Tobacco Products, Inc., offered the following description of their
smokeless cigarette:
    [It] has the appearance and feel and provides a sensation
similar to a conventional cigarette, but [ ] delivers nicotine
satisfaction to the user by inhalation of nicotine vapor in a manner
not requiring the combustion of tobacco.

[[Page 41769]]

---------------------------------------------------------------------------

    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.<SUP>574

    \574\ BATCO Research Conference. Kronberg, Germany. June 6,
1969. Page 8. Brown and Williamson representatives attended.
---------------------------------------------------------------------------

The conferees went on to express their view that, if non-tobacco
ingredients were used as part of the tobacco blend in cigarettes,
cigarette manufacturers would have to compensate for the absence of
nicotine in the non-tobacco materials by using high-nicotine tobaccos:

    However, it now seems quite likely that non-tobacco materials
will be successfully incorporated into cigarettes as blend
constituents, particularly in health orientated products. A large
usage of non-tobacco materials would be likely to increase the
demand for high-nicotine tobaccos.<SUP>575

    \575\ Id.
    See also, BATCO, note 573, supra, at p. 4. A similar expression
of the need to increase the nicotine content of the tobacco blend
where tobacco substitutes without nicotine are used as part of the
blend is contained in the minutes of a 1970 BATCO research
conference:
    The addition of nicotine to SM [a tobacco substitute] 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.
---------------------------------------------------------------------------

    A 1970 BATCO R&D Conference included a particularly telling
illustration of the tobacco industry's recognition of the central
importance of nicotine in cigarette alternatives. The minutes of that
conference contain the following finding, agreed to by the conference
attendees:
    It was agreed that, if and when total cigarette consumption
declined, great opportunities for supplying the demands 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 [both of which are smokeless
tobacco products]. 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.<SUP>576 [Emphasis added.]

    \576\ Id. BATCO Group Research Conference at p. 3.

[[Page 41770]]

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    In 1984, BATCO marketers and ``product application thinkers''
convened to discuss innovative product ideas and were still convinced
that if the tobacco industry lost a significant number of smokers, the
industry should move to administration of nicotine through moist snuff.
According to the conferees, the objective of shifting to moist snuff
would be:

    To capitalise on the potential downtrend of the smoking habit as
the only means to achieve nicotine satisfaction by participating in
a parallel product market free of social/health concerns and with
attractive profitability.<SUP>577 [Emphasis added.]

    \577\ BATCO. Structured Creativity Conference. Southampton,
England. June 25-28, 1984. List C.
---------------------------------------------------------------------------

As these passages make clear, tobacco manufacturers understand that
what both cigarettes and smokeless tobacco products have in common is
the ability to administer nicotine to consumers, and that the purpose
of the nicotine is to produce physiological effects on the consumer. If
nicotine-containing cigarettes were to become socially unacceptable, it
was the tobacco industry's intention to find another method of
supplying nicotine to consumers.
    Smokeless tobacco manufacturers, like cigarette manufacturers,
understand that tobacco substitutes must include nicotine. Unlike
BATCO, however, the major smokeless tobacco manufacturer, UST, has
considered adding nicotine to food to create a nicotine delivery system
that would function as an alternative to smokeless tobacco. At a
meeting of UST executives, researchers, and marketers held in 1968 to
discuss future directions for the company, the director of research
proposed that the company develop a ``swallowable chew: a confection
with nicotine (artificial snuff).'' <SUP>578 Later in the same
document, he made clear that the purpose of adding nicotine to
artificial snuff would be to ``satisfy'' snuff users; <SUP>579 i.e., to
satisfy their need for

[[Page 41771]]
nicotine.

    \578\ Minutes of Snuff and Chewing Tobacco Research--
Manufacturing--Marketing Meeting. New York Hilton. January 22-23,
1968. Page 5.
    \579\ Id. at p. 10.
---------------------------------------------------------------------------

    Thus, company documents related to the development of alternatives
to cigarettes and smokeless tobacco establish tobacco manufacturers'
knowledge that nicotine is the critical or ``active'' ingredient in
cigarettes and smokeless tobacco, and that consumers use these products
primarily for nicotine. Moreover, the fact that currently marketed and
alternative products are studied for their ability to deliver nicotine
to the bloodstream shows that the companies know that consumers use
currently marketed tobacco products for the effects of nicotine on the
structure and function of their bodies, rather than for taste or
flavor. The fact that the tobacco industry considers nicotine delivery
systems to be functional equivalents to tobacco demonstrates that
tobacco companies intend their currently marketed tobacco products to
deliver nicotine to consumers to affect the structure or function of
their bodies.