Monday, May 23, 2005

Ciggerette vacine

ORLANDO, Fla., and SCHLIEREN, Switzerland, May 14 /PRNewswire/ -- Cytos
Biotechnology AG (SWX :CYTN) announced today that its vaccine candidate
CYT002-NicQb to treat nicotine addiction has achieved proof of efficacy. The
phase II clinical trial results were presented by Prof. Dr. Jacques Cornuz
(CHUV Lausanne), principal investigator, at the Annual Meeting of the American
Society of Clinical Oncology (ASCO) in Orlando, USA, on behalf of the three
Swiss study centres. The study included 341 smokers and assessed safety,
tolerability and efficacy of the vaccine candidate. Efficacy of the vaccine
was determined by continuous abstinence from smoking between week 8 and 24
after treatment start and was measured by self-reporting of the participating
smokers and by independent biochemical validation.
Two thirds of the smokers received the vaccine, whereas one third received
placebo. All smokers who received the vaccine mounted an anti-nicotine
antibody response, which corresponds to an immunological response rate of
100%. Based on the measured levels of antibodies, the vaccine-treated
smokers were grouped into a high, a medium, and a low responder group. All
smokers who received placebo had no measurable anti-nicotine antibodies in
their blood. The following table provides the continuous abstinence values of
the analysis of all smokers from whom complete antibody measurements were
available and who refrained from using nicotine replacement products
(NRT) (NRT use was considered a major protocol violation):

Continuous Abstinence

CYT002-NicQb high antibody response 57% (30 / 53)(1)
medium antibody response 32% (17 / 53)(1) 40% (64/159)
low antibody response 32% (17 / 53)(1)

Placebo no antibody response 31% (25 / 80)(1)

(1) (Number of continuously abstinent subjects/ total number of subjects
in group)

The above data show with a high statistical significance (p=0.014) a
strong relationship between the induced antibody levels against nicotine
(mechanism of action of the vaccine) and the desired clinical effect
(continuous abstinence from smoking); and this was irrespective of the
unexpected high placebo response observed. The difference of continuous
abstinence between the high responder group and the placebo group was highly
significant (p=0.004). Overall cigarette consumption in the high responder
group was less than half of that seen in the placebo group (p=0.004).
Moreover, the average cigarette consumption by those people who did not
achieve continuous abstinence was also lower in the high responder group than
in the placebo group (p=0.16). The vaccine was safe and generally well
tolerated with common side effects being local injection site reactions and
flu-like symptoms, which usually resolved within 24 hours.
Prof. Dr. Jacques Cornuz commented: "I am very excited about the outcome
of this study, as the data clearly suggest that antibodies against nicotine
are effective in helping people quit smoking. There is certainly no doubt that
new approaches such as vaccination are urgently needed. Despite the fact
that smoking causes 30% of all cancer deaths, including 87% of deaths from
lung cancer, there are 1.3 billion smokers worldwide. And each smoker looses
on average more than 10 years of lifetime as a result from this serious
addiction. I believe that the vaccine approach has the potential to
dramatically alter the way how we will treat smoking addiction in the future."
Dr. Wolfgang Renner, Chief Executive Officer of Cytos Biotechnology,
added: "We are extremely pleased about the results as the data in the high
responder group are better than anything we have seen so far. The clear
correlation between antibody levels and clinical effect greatly supports us in
the further development of this vaccine. It is now our goal to get everybody
into this high antibody response range; and to achieve this we have several
measures at hand: A) We will increase the dose of the vaccine, as we have
already done with other clinical candidates in different indications, B) we
can add more injections as even after the fourth injection there appeared to
be no antibody plateau, and C) we will certainly use these findings in our
ongoing formulation development. But most importantly, the data show elegantly
that we can use the body's own defence, the immune system,
to modulate even such complex conditions like addiction. This finding is
extremely important with respect to our pipeline of 27 vaccine candidates in
other major disease areas like high blood pressure, obesity or Alzheimer's
disease where we use the same basic Immunodrug(TM) principle."
More information about the phase II study, the vaccine candidate
CYT002-NicQb and general information about smoking and nicotine addiction can
be found on http://www.smokersvaccine.com.

About nicotine addiction
According to the World Health Organization, 1.3 billion people smoke. With
5 million tobacco-related deaths per year, tobacco use is the leading cause of
preventable death in the world today. Smoking harms nearly every organ of the
body and 30% of all cancer deaths, including 87% of deaths from
lung cancer, are attributable to smoking (American Cancer Society, 2005).
Nicotine, an alkaloid derived from tobacco leaves, has been shown to be the
principal addictive component of tobacco. Upon inhalation of cigarette smoke,
nicotine passes into the bloodstream and within seconds penetrates through the
blood-brain barrier, where it stimulates specific neurons in the brain.
Stimulation of these neurons leads to the release of messenger molecules,
which give rise to an almost immediate reward and a feeling of pleasure. This
sensory stimulus is critical to the addictive properties of nicotine and
causes a high relapse rate after quitting attempts. Although nearly 75% of
smokers in the U.S. report that they want to quit smoking, less than 5% of
those who try quitting are able to stay tobacco-free for 3 to 12 months
(Surgeon's General Report, USA, 2004).

About CYT002-NicQb
CYT002-NicQb is a therapeutic vaccine in development for the treatment of
nicotine addiction. Vaccination with CYT002-NicQb has been shown to induce
high levels of nicotine-specific antibodies that bind nicotine in the blood.
As the complex of nicotine attached to an antibody is too large to
pass the blood-brain-barrier, nicotine uptake into the brain and the
subsequent stimulation of nicotine-perceptive neurons in the brain is believed
to be significantly reduced or even prevented. In this way the addiction-
driving and satisfaction-inducing stimulus of nicotine is minimized.

About the phase II study
The study, the largest ever performed with a vaccine to treat nicotine
addiction, was a randomized, double blind, placebo-controlled, multicenter
phase II clinical trial to assess safety, tolerability and efficacy of the
vaccine candidate. It was carried out at the Kantonsspital St. Gallen, the
Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, and the Lung Center
Hirslanden Zurich, all in Switzerland. The study was conducted in 341 healthy
male and female smokers, aged 18-70 who have been smoking between 10 and 40
cigarettes per day for at least 3 years and who were motivated to
quit smoking. 5 injections of the vaccine or placebo were given at monthly
intervals at month 0, 1, 2, 3, and 4. All participants received smoking
cessation counselling by the study collaborators at each visit during three
months. One month after the first injection, the participants were asked to
make a serious attempt to quit smoking. Smoking behaviour was recorded by the
participants in personal diaries, and independent biochemical validation was
performed by measuring carbon monoxide in exhaled air (a by-product of
cigarette burn that remains in the blood for up to 24 hours).

About the analysis
Out of 341 smokers enrolled in the study, all participants were included
in the efficacy analysis from whom complete antibody measurements were
available and who refrained from using nicotine replacement therapy (NRT)
(n=239). NRT is believed to have a different effect on the two treatment
groups (CYT002-NicQb and placebo). Based on the proposed mechanism of action,
NRT products and the vaccine are expected to neutralize each other, whereas in
smokers on placebo NRT has a documented positive effect. An intent-to-treat
analysis of the entire study population has not achieved statistical
significance; therefore, the sub-group analysis based on antibody levels was
performed. In this analysis, NRT users were excluded, then, the vaccinated
smokers with complete antibody measurements were divided into three groups of
increasing antibody levels (low, medium, and high responder group), and
efficacy analysis was performed on each group. The placebo group was treated
identically: NRT users were excluded and all participants with complete
antibody measurements were included. Study participants were counted as
continuously abstinent only when at all visits between week 8 and 24 the
carbon monoxide concentration in their exhaled air was below 10 ppm and when
throughout the entire period between week 8 and 24 they declared
themselves as being non-smokers.

Media and Analyst Conferences for CYT002-NicQb phase II study results
Cytos Biotechnology will hold the following media and analyst conferences
related to the CYT002-NicQb phase II study results:

- 2 Media Conferences on Tuesday, May 17, 2005, 10.30am (CET) at Cytos
Biotechnology, Wagistrasse 25, CH-8952 Schlieren, and at the CHUV, Rue du
Bugnon 46, CH-1011 Lausanne, room "Andros" at level 8, room No 1205.
At Cytos Biotechnology in Schlieren: Dr. Wolfgang Renner, CEO, and Dr.
Philipp Muller, Executive Vice President Clinical Development of Cytos
Biotechnology, and the study investigators Dr. Felix Jungi and Dr. Karl
Klingler will be available for interviews. The presentation will be in German
(or on demand in English).
At the CHUV in Lausanne: Jakob Schlapbach, CFO of Cytos Biotechnology, and
Prof. Dr. Jacques Cornuz, principal investigator of the study will be
available for interviews. The presentation will be in French.
- Conference for analysts and investors on Tuesday, May 17, 2005, 2pm
(CET) at Cytos Biotechnology, Wagistrasse 25, CH-8952 Schlieren.
Dr. Wolfgang Renner, CEO, and Dr. Philipp Muller, Executive Vice President
Clinical Development of Cytos Biotechnology, and the study investigators Dr.
Felix Jungi and Dr. Karl Klingler will be available for interviews. The
presentation will be in English and will also be accessible by live
webcast via the internet site http://www.cytos.com.

About Cytos Biotechnology AG
Cytos Biotechnology AG is a public Swiss biotechnology company that
specializes in the discovery, development and commercialization of a new class
of biopharmaceutical products - the Immunodrugs(TM). Immunodrugs(TM) are
intended for use in the treatment and prevention of common chronic diseases,
which afflict millions of people worldwide. Immunodrugs(TM) are designed to
instruct the patient's immune system to produce desired therapeutic
antibody or cytotoxic T-cell responses that modulate chronic disease
processes. Taking advantage of the high flexibility of its Immunodrug(TM)
platform, Cytos Biotechnology has built a pipeline of 27 different
Immunodrug(TM) candidates in various disease areas, of which six are currently
in clinical development. The Immunodrug(TM) candidates are developed both
in-house (24) and together with Novartis (1) and Pfizer Animal Health (2).
Founded in 1995 as a spin-off from the Swiss Federal Institute of Technology
(ETH) in Zurich, the company is located in Schlieren (Zurich). Currently, the
company has 110 employees. Cytos Biotechnology AG has been listed
on the SWX Swiss Exchange (SWX:CYTN) since October 2002.

This foregoing press release may contain forward-looking statements that
include words or phrases such as "believe," "has the potential," "it is the
goal," "will," "can," "is believed," designed to," "intend," or other similar
expressions. These forward-looking statements are subject to a variety of
significant uncertainties, including scientific, business, economic
and financial factors, and therefore actual results may differ significantly
from those presented. There can be no assurance that any other therapeutic
entities will enter clinical trials, that clinical trial results will be
predictive for future results, that therapeutic entities will be the subject
of filings for regulatory approval, that any drug candidates will receive
marketing approval from the U.S. Food and Drug Administration or equivalent
regulatory authorities, or that drugs will be marketed successfully. Against
the background of these uncertainties readers should not rely on forward-
looking statements. The company assumes no responsibility to update forward-
looking statements or adapt them to future events or developments. This
document does not constitute an offer or invitation to subscribe or purchase
any securities of Cytos Biotechnology AG.

Cigarette engineering and nicotine addiction













Additives in tobacco products



































About ASH WIDTH="73" HEIGHT="16" BORDER="0"> HEIGHT="16">Fact Sheets BORDER="0"> height="16"> height="16">





































ASH/ Product regulation/ Tobacco additives




Tobacco additives


Cigarette engineering and nicotine
addiction


Clive Bates

Action on Smoking and Health

London


Dr. Martin Jarvis

Imperial Cancer Research Fund

London


Dr. Gregory Connolly

Massachusetts Tobacco Control Program

Boston


14 July 1999




Summary



Introduction. In the European Union over 600 additives may be used in the
manufacture of tobacco products under an extremely loose and de-centralised regulatory
framework. Although tobacco additives are generally screened for their direct toxicity,
there is virtually no assessment of the impact additives have on smoking behaviour or
other undesirable external consequences. If a small quantity of a relatively benign
substance added to a tobacco product can make the product more addictive, make it easier
to start smoking or facilitate continued smoking then it may be causing great harm by
'leveraging' additional smoking. The additional smoking brings increased exposure to over
4,000 chemicals, including many that are highly toxic and carcinogenic. Given that over
500,000 people die prematurely in the European Union each year as a result of
smoking-related disease, even a one per cent change in smoking attributable to the use of
additives would have large absolute health consequences - tens of thousands of lives
annually. For this reason, tobacco additives should be seen as major public health issue
in their own right.



Evidence. This report draws on evidence from tobacco industry internal documents
released during recent litigation in the United States and held on the Internet or in
British American Tobacco's document depository in Guildford, UK. The views of the UK
Government's scientific advisory committees since 1971 are also discussed - showing that
the issue has been recognised and debated for more than twenty years.



Which brands use which additives? Though 600 additives are authorised for use in
tobacco products, only the tobacco manufacturers can say which additives are used and in
which brands. Not even the Government or the European Commission, which are responsible
for the regulation of tobacco products have this information or the power to demand it.



Findings. Most additives are not necessary and few were used before 1970. The
purpose of this report is to raise concerns about the impact of additives on smoking
behaviour. The findings suggest that there is a case to answer and that there is need for
increased regulatory scrutiny. There is cause for concern in the following areas.




  • Additives are used to make cigarettes that provide high levels of 'free' nicotine which
    increases the addictive 'kick' of the nicotine. Ammonium compounds can fulfil this role by
    raising the alkalinity of smoke

  • Additives are used to enhance the taste of tobacco smoke, to make the product more
    desirable to consumers. Although seemingly innocuous the addition of flavourings making
    the cigarette 'attractive' and 'palatable' is in itself cause for concern.

  • Sweeteners and chocolate may help to make cigarettes more palatable to children and
    first time users; eugenol and menthol numb the throat so the smoker cannot feel the
    smoke's aggravating effects.

  • Additives such as cocoa may be used to dilate the airways allowing the smoke an easier
    and deeper passage into the lungs exposing the body to more nicotine and higher levels of
    tar.

  • Some additives are toxic or addictive in their own right or in combination. When
    additives are burned, new products of combustion are formed and these may be toxic or
    pharmacologically active.

  • Additives are used to mask the smell and visibility of side-stream smoke, making it
    harder for people to protect themselves and undermining claims that smoking is anti-social
    without at the same time reducing the health risks of passive smoking.



Regulation. The existing regulatory framework is based on the assumption that
additives are useful to facilitate consumer acceptance of lower tar yield cigarettes. By
facilitating the switch to lower tar products, it was hoped that tobacco additives would
lead to 'health gains'. No data is available to show that additives are in fact used
only or predominantly in lower yielding brands. However, there is now good evidence that
questions the value of low tar cigarettes. Low tar cigarettes have generally used
perforated filters to dilute the smoke with air. Smokers learn to block the holes, often
subconsciously, thus adjusting the dilution of nicotine in the smoke. The smoker may also
compensate by smoking more intensely. With the primary rationale for a relaxed regime
discredited, it is necessary to adopt a new approach.



New regulatory framework needed. A new regulatory framework is required in which
the manufacturer is obliged to demonstrate that no additional harm arises from tobacco
product design decisions such as the use of an additive. This should include the impact of
additives on smoking behaviour, passive smoking and fire risks. While it is impossible to
make safe cigarettes, it is perfectly reasonable to prevent the manufacturers doing things
that lead to an increase in the harm caused by tobacco. Such a framework may have
the following elements:


  • Disclosure. As a first step, manufacturers should be required to disclose all
    additives used in tobacco products, by brand, to a regulator - in the UK this is the
    Department of Health. This approach has already been adopted in Massachusetts and British
    Columbia.




  • Public information. Such information should not be confidential, but made available
    to the public through publications, the Internet or on request from the regulator.




  • Packaging. There may be some additives that should be listed as ingredients on
    tobacco product packaging. This is a separate decision to a requirement for disclosure and
    making the information public in other ways -- the right approach will depend on
    assessment of the direct value of such information to consumers.




  • Disclosure of purpose. Tobacco companies should be required to disclose the purpose
    of an additive and any secondary consequences -- whether intentional or unintended.




  • Conduct and disclosure of research. Tobacco companies should be required to
    undertake extensive toxicology and pharmacological testing of all additives




  • Regulatory challenges. Regulators should have the power to challenge any of the
    existing 600 additives currently allowed and to have them removed until the manufacturer
    is able show that no extra harm to the public arises as a direct or indirect result of the
    additive. If it is impossible to supply evidence, for example because of restrictions on
    animal testing, then under a precautionary approach the additive should be banned.




  • Focus on pharmacologically active additives. There should be an automatic challenge to any
    additive thought to have a direct or indirect pharmacological influence. New additives
    should be permitted only if the manufacturer can show that no extra harm or other net
    negative consequences arise from use of the additive.




  • Permit essential additives. Any regulatory framework should permit additives
    necessary for the manufacture and storage of tobacco products providing these are safe,
    but should challenge all additives that may influence smoking behaviour.


 





Contents




1    Introduction: tobacco products and
additives    


2    Scientific advisory committee reports on
tobacco additives




2.1    First Report of the ISCSH (1975)

2.2    Second Report of the ISCSH (1979)

2.3    Third (1983) and Fourth (1988) Report of
ISCSH


2.4    SCOTH (1998)

2.5    The 1997 UK Voluntary Agreement





3    Enhancing impact -- additives with a pharmacological effect



3.1    Free basing nicotine

3.2    Ammonia Technology and The Marlboro Story

3.3    Concealing the nicotine by increasing the
vapour phase


3.4    Other additives that may enhance the effect
of nicotine



3.4.1    Acetaldehyde

3.4.2    Levulinic acid

3.4.3    Cocoa and theobromine

3.4.4    Glycyrrhizin

3.4.5    Pyridine






4    Masking the taste and immediate effects of tobacco



4.1    Additives and 'low tar' cigarettes.

4.2    Front end 'lift'





5    Additive Toxicity

6    Changing the Perception of side-stream
smoke


7    Notes




1. Introduction:
tobacco products and additives








































Cigarettes
as nicotine delivery systems

To understand the
role of additives, it is important first to have a grasp of how cigarettes work. The
long-term success of the tobacco industry is the direct result of the addictive nature of
nicotine and tobacco use. As those in the industry were first to recognise, the cigarette
- marketed as a lifestyle accessory - is in fact a delivery device for an addictive drug.
There are many tobacco industry documents that show tobacco products acting in this role,
essentially as sophisticated, highly engineered nicotine delivery systems. For a more
detailed survey see ASH's report Tobacco
Explained (Chapter Two
).1 Two examples are given below:

Philip
Morris explains...

"The
cigarette should be conceived not as a product but as a package. The product is nicotine.
Think of the cigarette pack as a storage container for a day's supply of nicotine....
Think of the cigarette as the dispenser for a dose unit of nicotine..... Smoke is beyond
question the most optimised vehicle of nicotine and the cigarette the most optimised
dispenser of smoke."2 (Philip Morris 1972)

RJR
recognises it is in the drug business

"In a
sense, the tobacco industry may be thought of as being a specialised, highly ritualised,
and stylised segment of the pharmaceutical industry."3 (RJR 1972)

Impact
of additives on smoking behaviour

Additive technology
is a major tool used by the tobacco industry in the production of this nicotine 'package'.
While some cigarettes have been marketed as additive free, according to the verbal
testimony of JL Pauly of the Santa Fe Natural Tobacco Co., the modern U.S cigarette
contains about 10 percent additives by weight, mostly in the form of sugars, flavourings,
and humectants4. But there are others - present in smaller quantities -- which may have a
more profound influence on the product. Evidence suggests that additives are actually used
by manufacturers to influence the pharmacological effects of nicotine, make individual
brands taste more appealing to young and 'aspirational' smokers and mask the taste and
immediate discomfort of smoke.

How
nicotine addiction works -- additives play a subtle role

At the simplest
level, a cigarette delivers a dose of the main active ingredient, nicotine, into the
smokers' lungs in a mixture of smoke particles and gases. The nicotine is rapidly absorbed
into the blood through the large surface of the lungs (and mouth and throat) and reaches
the brain within ten seconds. Receptors in the brain respond to nicotine stimulation by
producing chemicals (dopamines and other neurotransmitters) that give the user what is
variously described as a 'hit', 'kick' or 'impact' - the drug effect of nicotine. Over
time the receptors become conditioned to expect nicotine (tolerance), and when deprived,
the smoker experiences nicotine withdrawal - a very unpleasant sensation for many. This
pharmacological impact and withdrawal, enhanced by psychological and social factors
related to smoking, create dependency on tobacco products. Nicotine is the main reason why
tobacco products are addictive. As this report shows there are a number of subtle ways in
which the delivery of nicotine to the brain's receptors can be influenced by additives.

Harm
caused by smoking

The smoke particles
and gases in which the nicotine is transported contain thousand of chemicals, many of which are
toxic or carcinogenic. Though nicotine itself is the reason people smoke, the other
chemicals do the bulk of the damage to health. The other chemicals are often collectively
referred to as 'tar' and provide flavour and other taste sensations. This tar and the
gases produced by combustion such as carbon monoxide, cause cancer, heart disease and
respiratory illnesses as well as many other conditions. Regulators aimed to reduce tar exposure
by insisting that tar yields should be decreased.

Low
tar cigarettes in theory

The rise of additives
in tobacco products is intimately linked with the strategy to reduce tar yields. The
amount of tar and nicotine in smoke is measured by a standard smoking machine in which the
cigarette is smoked with a fixed puff volume and frequency with tar and nicotine residues
collected on a filter and weighed. Governments have insisted on reducing tar levels as
measured by this approach, hoping that this would reduce tar exposure to smokers -- and
therefore lead to reduced harm.

Low
tar cigarettes in practice

In practice, low tar
cigarettes have been produced by the addition of filters and most importantly, by the use
of filter ventilation (Kozlowski et al, 1998).5 Holes
in the filter allow air to be drawn
in to dilute the smoke and this reduces the amount of tar and nicotine residues collected
by the machine. In the lowest tar cigarettes 80% of the 'smoke' is air drawn in through
ventilation holes. Ventilation also means that the smoke might taste 'weaker' because the
agents that give rise to flavour are diluted with air. However, smokers do not smoke like
machines. Faced with diluted smoke, smokers will tend to 'compensate' by smoking the
lower-tar cigarette more intensively, in order to obtain a satisfactory dose of nicotine.
Compensation may take the form of deeper or more frequent puffs, or blocking of
ventilation holes -- often sub-consciously. The result is that smokers of low-tar
cigarettes do not consume less nicotine (Benowitz et al, 1983,6 Bates
and Jarvis, 19997). A
survey of tobacco company documents by ASH and Imperial Cancer Research Fund ( HREF="./big-one.html">Low Tar: why low tar cigarettes don't
work and how the tobacco industry fools the smoking public
8) gives greater detail
on why low tar cigarettes do not work and what the tobacco companies knew privately and
said publicly.

Low
tar cigarettes and additives

One of the prime
justifications for the addition of artificial flavourings is to replace the lost flavour
of the diluted smoke. This has in theory been done to facilitate the switch to low-tar.
However, any hoped-for health benefits from low-tar cigarettes have largely failed to
materialise. At the same time an extremely lax regulatory regime for additives has
emerged. Although smokers of lower tar cigarettes may be consuming as much tar and
nicotine in total, they will be consuming greater volumes of diluted smoke to do it. This
is perhaps analogous to drinking watered down wine - it is possible to become
intoxicated, but drinkers will have to consume more and the flavour will be weaker.


2. Scientific advisory committee reports on tobacco additives












Scientific
advice to government

The Government takes
advice on smoking and health from a long-running scientific standing committee. Guidelines
for the monitoring of tobacco additives were initially published in the First Report of
the Independent Scientific Committee on Smoking and Health (ISCSH) in 1975.9 The
ISCSH was established in 1973, primarily to prepare guidelines for the testing of tobacco
substitutes which were being developed at the time. This section gives an overview of the
conclusions regarding tobacco additives.

Arrangements
before 1970

Prior to 1970, the
use of additives in tobacco products was prohibited without special permission from the
Commissioners of Customs and Excise, under Section 176 of the Customs and Excise Act,
1952. This permission was given only within very strict limits and mainly in respect of
flavourings in tobacco products other than cigarettes. The prohibition extended to the
importation of tobacco products containing additives as well as a ban on the production of
cigarettes with additives for export.



    2.1 First Report of
the ISCSH (1975)








The Finance Act of 1970 changed
the rules and allowed for tobacco duty to be charged on additives and tobacco substitutes,
thus paving the way for the restrictions on additives to be removed. Statutory control
over the materials used in the manufacture of cigarettes finally ceased with a revision of
the tax system in 1978. The First Report of the ISCSH stated that the Committee was
concerned that these changes in the law should not increase the health hazards of smoking
and concluded that:

"Other
means have to be found to guard against the possible risk to health."


The "other means" resulted in a
voluntary agreement between the tobacco manufacturers and the Government whereby the
companies would supply details of proposed additives. Only those approved by the ISCSH
would be permitted. Guidelines for the testing and use of tobacco products containing
additives were included an appendix to the First Report of the ISCSH, published in 1975.
In the Second Report, the guidelines were amended to include the general requirement for
an acute inhalation toxicity study and data on transference to smoke for any new additive.



    2.2 Second Report
of the ISCSH (1979)








The Second Report of the ISCSH
expresses concern that no additional "dependence-inducing" compounds should be
incorporated into tobacco. Paragraph 13 states:
size="2">

"The concept of adding flavouring ingredients to cigarettes might not
lessen the incentives to smoke and could indeed have the opposite effect."
10


The tobacco industry argues that one of
the key purposes of additives is to make lower tar cigarettes more palatable. The ISCSH
accepts this and notes:


"Some smokers find existing
low and low to middle tar brands unsatisfying, but if those who smoked middle or middle to
high tar cigarettes could switch to low tar brands whose acceptability was improved by
additives, the dangers of smoking could be reduced. The Committee recognises the potential
value of using flavouring additives in this way."11


The Second Report of the ISCSH expresses
satisfaction with the use of other additives not covered by the guidelines. These include
additives in filters, cigarette papers, filter wrappers, tips and overwrappers. Thus, such
additives could be used without reference to the Committee. Between 1979 and 1983, the
Committee revised the guidelines to include an assessment of "all substances added to
those parts of tobacco products intended to be burnt". Thus any substances added to
cigarette papers were included in the revised guidelines as appended to the Third Report.



    2.3 Third (1983)
and Fourth (1988) Report of ISCSH








The Third Report of the ISCSH concluded that
the system of providing information on additives had been working well and recommended
that the system should continue.12 The Fourth Report, published in 1988, made a
similar recommendation for the continuation of the voluntary system
.13


    2.4 SCOTH (1998)












Official acceptance
of the tobacco industry's arguments regarding the need for additives appears to have
continued until the publication of the report of the Scientific Committee on Tobacco and
Health (SCOTH) in 1998. SCOTH states:

"One
of the effects [of additives] has been the maintenance of "taste" as tar yields
have fallen with an ensuing reduction in natural flavour. The negative side of this has
been the maintenance of the appeal of a product, which might otherwise have been rendered
unacceptable through the adulteration of intrinsic flavour.
"14


SCOTH, which replaced the ISCSH,
reviewed the tobacco additive guidelines and made recommendations for their revision in
the light of scientific and technical advances. While the Committee expressed the clear
reservation about the possibility that additives may prolong use of cigarettes by making
them more palatable, SCOTH only recommends that the use of additives in tobacco products
be closely monitored. Specifically, it recommends that the Technical Advisory Group, which
reports to SCOTH, should regularly review the changing patterns and types of additives
used.

At no stage in the 25
year period has the Department of Health or its advisory committees been provided with
information regarding which additives have been used in which tobacco product brands. There
has therefore, never been evidence of whether the approved additives have actually been
used in low-yield brands, or more widely. There has also been no validation of the
anticipated health benefits that the liberal regulatory regime for additives was supposed
to offer.



    2.5 The 1997 UK Voluntary Agreement




















Existing
additives escape detailed scrutiny

The 1997 Voluntary
Agreement requires tobacco manufacturers to provide toxicological and other data for any new
additives manufacturers wish to add to the approved list, but such information is not
required for the 600 existing approved additives.

Limited
scope of evaluation

Furthermore, even for
new additives there is no requirement for companies to state the purpose of the additives,
merely that it is "desirable that the purpose of use should be detailed".
While it is possible that some additives may be harmless or even beneficial, under the
present voluntary agreement system there is no way of ascertaining the relative advantages
and disadvantages of these substances. No broad criteria for acceptance or rejection are
stated in the agreement. The criteria applied are only "the results of toxicity
testing are unsatisfactory; or acceptability cannot be judged on the basis of the
information provided." The impact on smoking behaviour is not assessed.

European
loophole

The final and fatal
weakness of the Voluntary Agreement is that it can be side-stepped in its entirety.
Directive 83/189/EEC requires the Department of Health to 'raise no objection' to the use
of an additive permitted in any other EU member state provided that certain specified
information is provided.

Conclusion

The regime
established in the 1997 UK Voluntary Agreement is not retrospective, too narrowly
focussed, can be avoided entirely. It therefore offers minimal safeguards and may be
lending spurious legitimacy to practices that cause harm to health.



 




 





3. Enhancing impact -- additives with
a pharmacological effect






"The main technical challenge was to decrease the yield of tar in a cigarette
while maintaining a level of nicotine acceptable to the smoker."
15





(Farone, W.A. 1996 former Philip Morris scientist.)






3.1 Free basing
nicotine














































Free-basing
nicotine

At least as far as
its rivals are concerned, the success of Philip Morris's Marlboro brand stems from greater
'free' nicotine resulting from higher alkalinity (pH) induced by the addition of ammonia
technology (see section 3.2). Ammonia can speed the delivery of 'free' or unbound nicotine
to smokers by raising the pH (alkalinity) of tobacco smoke using additives. This causes
the smoker to 'freebase' the drug -- much as a crack-user takes cocaine. Dr. Jack E
Henningfield of the John Hopkins University School of Medicine explains the action of
ammonia thus:

"A third thing
that ammonia-like compounds can do is increase the pH, increase the amount of free base
nicotine, or what Dr Rickert earlier referred to as unprotonated nicotine.... The
free-based form of cocaine or the free based form of nicotine is more rapidly absorbed,
has a more explosive effect on the nervous system. Ammonia is one of the ways that you can
provide free-based cocaine or free-based nicotine." (1997)16

Nicotine
in different forms

Many documents
explain the tobacco companies' recognition that nicotine is available in different forms.
face="Times New Roman, Times" size="2">

"Nicotine may be presented to the smoker
in at least three forms: (I) salt form in the particulate phase, (ii) free base form in
the particulate phase, (iii) free base form in the vapour phase. It has long been believed
that nicotine presented as in (ii)/(iii) is considerably more 'active'."(BAT 1984)17

"Nicotine
is in the smoke in two forms as free nicotine base (think of ammonia) and as a nicotine
salt (think of ammonium chloride) and it is almost certain that the free nicotine base is
absorbed faster into the blood-stream."(BAT 1964)18

More
free nicotine means higher 'impact'

Once the relationship
between pH, free nicotine and nicotine 'impact' was established, it became a research
objective.

"The purpose of
this project is to develop a method for increasing the smoke pH of a cigarette. A low
smoke solids, low nicotine cigarette with an increased smoke pH would then have relatively
more free nicotine in its smoke, and consequently, a higher nicotine impact." (Liggett
1974)19

Changing
the chemical form of nicotine increases the 'kick'

In a paper entitled,
'Cigarette concept to assure RJR a larger segment of the youth market' RJR talk about the
'kick' of nicotine:

"Still
with an old style filter, any desired additional nicotine 'kick' could be easily obtained
through pH regulation."20 (RJR 1973)


The pH also relates to the immediacy of the nicotine impact. As the pH increases, the
nicotine changes its chemical form so that it is more rapidly absorbed by the body and
more quickly gives a 'kick' to the smoker."21 (RJR 1976)


"When a cigarette is smoked, nicotine is released momentarily in the free-form. In
this form, nicotine is more readily absorbed through the body tissue. Hence it is the free
nicotine which is associated with IMPACT, i.e. The higher the free nicotine, the higher
the IMPACT." (BAT 1988)22

Making
nicotine more potent

"Increasing
the pH of a medium in which nicotine is delivered increases the physiological effect of
the nicotine by increasing the ratio of free base to acid salt form, the free base form
being more readily transported across physiological membranes. We are pursuing this
project with the eventual goal of lowering the total nicotine present in smoke while
increasing the physiological effect of the nicotine which is present, so that no
physiological effect is lost on nicotine reduction."23(Liggett 1971)

Free
nicotine fraction increases 'physiological strength'

"Since
the unbound nicotine is very much more active physiologically and much faster acting than
the bound nicotine, the smoke at a high pH seems to be strong nicotine. Therefore, the
amount of free nicotine in the smoke may be used for at least a partial measure of the
physiological strength of the cigarette."24(RJR 1973)

Nicotine
transfer increased as a result of ammonia treatment

According to BAT, the
addition of ammonia was a technical option to enhance nicotine transfer:
face="Times New Roman, Times" size="2">

"The results show that ammonia treatment
caused a general increase in the delivery of bases including a 29% increase in nicotine.
This result, despite the decrease in nicotine content and a 10% drop in the weight of
tobacco burnt in puffing, is only partly due to a small decrease in nicotine filtration.
In other words, the nicotine transfer has increased as a result of ammonia
treatment..."25 (BAT 1965)

'Judicious'
use of additives to increase the free base nicotine

The US tobacco
company Lorillard accepts that additives can change the qualitative delivery of nicotine:
face="Times New Roman, Times" size="2">

"It should be obvious that if the
preceding goals of high physiological impact are to be realised, flavour profiles and
their effect on physiological impact must be understood, even though measures of such
perceived quantities are highly subjective... Hence judicious use of additives may
increase the pH of the delivered smoke, thereby the apparent free base nicotine."
(Lorillard, 1976)26

Additives
to increase nicotine 'kick'

Ammonia can be used
to increase the alkalinity of smoke and increase the amount of nicotine in the 'free' form
rather than in the 'bound' form of nicotine salts. R J R explains:
face="Times New Roman, Times" size="2">

"In essence, a cigarette is a system for
delivery of nicotine to the smoker in attractive, useful form. At "normal' smoke pH,
at or below about 6.0, essentially all of the smoke nicotine is chemically combined with
acidic substance hence is non-volatile and relatively slowly absorbed by the smoker. As
the smoke pH increases above about 6.0, an increasing proportion of the total smoke
nicotine occurs in 'free' form, which is volatile, rapidly absorbed by the smoker, and
believed to be instantly perceived as nicotine 'kick'."27 (RJR 1973)




 






3.2 Ammonia
Technology and The Marlboro Story






















The
Rise of Marlboro - the world's best selling cigarette

The myth is that
Marlboro man made the Marlboro cigarette: The square jawed icon of American individualism
lassoed a gullible public and herded them into the Marlboro corral. On the face of it
Marlboro's success appears to be a tribute to the power of advertising and iconography.
However, the chemical history of the brand sheds interesting light on the subject.

In
the early sixties Philip Morris was the smallest of America's six leading cigarette
companies and RJR's brand Winston had annual sales nearly three times the size of
Marlboro's. By 1978 there had been a seismic shift, Marlboro was the world's best selling
cigarette accounting for one in five of all cigarettes sold and over fifty percent of
smokers aged 17 and below.28

The
search begins for the 'soul of Marlboro'

Not surprisingly this
dramatic growth in Marlboro cigarettes instigated frenzied research by other tobacco
manufacturers. Through analysis and reverse engineering of Marlboro cigarettes, industry
competitors came to the conclusion that 'ammonia technology' was essentially the 'soul' of
Marlboro.

"Philip Morris
began using an ammoniated sheet material in 1965 and increased use of the sheet
periodically from 1965 to 1974. This time period corresponds to the dramatic sales
increase Philip Morris made from 1965 to 1974."29(RJR)

Ammonia
technology is the key to Marlboro

"What
product technology, then, makes Marlboro a Marlboro?

Looking at all of the
technology employed in Marlboro on a world-wide basis, ammonia technology remains the key
factor
."30 (B&W 1992)

Brands
that are selling well have high levels of free nicotine

The higher pH of
Marlboro cigarettes helped to maintain the same level of free nicotine as high-tar
cigarettes despite a two third reduction in overall tar and nicotine - and helped develop
a 'US standard taste', enhancing the iconography associated with the quintessentially
American 'Marlboro Man'.

"If
our data, correlations and conclusions are valid, then what has emerged is a rather new
type of cigarette, represented by Marlboro and Kool, with high nicotine 'kick', burley
flavour, mildness to the mouth, and increased sensation to the throat, all largely the
result of higher smoke pH. There is evidence that other brands, which are selling well
also, have some of these attributes, particularly increased 'free' nicotine impact.31 (RJR,
1973)




 


 


 





















Marlboro's
growth follows introduction of ammonia technology

The graph shows how
Marlboro's steady rise in sales follows increases in cigarette pH -- which also has led to
an increase in free nicotine content.

Graph


RJR, 197332

Brown
and Williamson seeks to catch up

"It
appears that we have sufficient expertise available to 'build' a lowered mg tar cigarette
which will deliver as much 'free nicotine' as a Marlboro, Winston or Kent without
increasing the total nicotine delivery above that of a 'light' product. There are products
already being marketed which deliver high percentage 'free nicotine' levels in smoke, i.e.
Merit, Now."33 (B&W 1980)
"It
would appear that the increased smoker response is associated with nicotine reaching the
brain more quickly... On this basis, it appears reasonable to assume that the increased
response of a smoker to the smoke with a higher amount of extractable nicotine (not
synonymous with but similar to free base nicotine) may be either because this nicotine
reaches the brain in a different chemical form or because it reaches the brain more
quickly."34 (BAT 1966)
align="right">High smoke pH linked to high sales Competitors
understood the link between Marlboro's sales and its alkalinity.
face="Times New Roman, Times" size="2">

"The smoke pH for Kool and Marlboro are
7.12 and 6.98 respectively confirming the relationship between high smoke pH and cigarette
sales increase."35 (Lorillard 1973)


"As a result of its higher smoke pH, the current Marlboro, despite a two thirds
reduction in smoke 'tar' and nicotine over the years, calculates to have essentially the
same amount of 'free' nicotine in its smoke as did the early Winston."36 (RJR 1973)


"Our data show that smoke from our brands, and all other significant
competitive brands, in recent years has been consistently and significantly lower in pH
(less alkaline) than in smoke from Marlboro and to a lesser degree Kool... All evidence
indicates that the relatively high smoke pH (high alkalinity) shown by Marlboro (and other
Philip Morris brands) and Kool is deliberate and controlled. This has raised questions as
to: (1) the effect of higher pH on nicotine impact and smoke quality, hence market
performance, and (2) how the higher smoke pH might be accomplished."37 (RJR 1973)




 






3.3 Concealing
the nicotine by increasing the vapour phase


















Ammonia
helps cheat the federal test for levels of nicotine and tar

The exploitation of
'free' nicotine and its enhanced effects helped cigarette companies cheat the US Federal Trade Commission (FTC) machine
measurements of tar and nicotine levels. Using additive technology they were able to build
cigarettes which registered low tar readings on the machine but delivered high levels of
nicotine to the smoker.

"If
the desired goal is defined to be increased nicotine yield in the delivered smoke there
appear to be only two alternatives: either increase the absolute yield of delivered
nicotine, or increase the pH, which increases the 'apparent' nicotine content without
changing the absolute amount."38 (Lorillard, 1976)

Concealing
nicotine in the gas phase

The FTC machine
measures overall levels of liquid and solid nicotine, but not its concentration in the
vapour phase where 'free' nicotine is found. Additives allowed reduced tar and nicotine
without compromising the pharmacological effects -- legally required disclosure of tar and
nicotine levels on billboards and cigarette packets showed a significant reduction while
smokers were still being exposed to high levels of an addictive drug. Changes in
the state of nicotine from liquid or solid to gas would have the effect of evading the
standard measuring process which records the residues left on the filter in the standard
smoking machine.

"The
perfect example of that is that if you don't take into account the gas phase, if I do
something like increase the pH and the smoke drops so that I can put more of the nicotine
from the liquid into the gas and I am not measuring the gas, then in fact, you don't
measure that nicotine which gets in the gas phase. This has been known since the late
1960's and early 1970's."39 (Farone, W.A. 6/12/97)

Business
as usual while appearing to reduce nicotine

The increase in the
free nicotine fraction - a qualitative change in the chemical form of nicotine --
means that the same 'hit' can be obtained from less nicotine. Put another way, there can
be the appearance of a reduction in pharmacological impact without there being a real
reduction.

"The amount of
nicotine in the vapour phase can be modified by changing the acidity (pH) of the smoke.
Hence it is readily feasible to have two cigarettes which deliver the same amount of
nicotine (as measured on a Cambridge pad - the FTC method) but which are easily
differentiated on the sensory basis of impact since the acidity of the smoke (and hence
amount of nicotine in the vapour phase) is different."40 (B&W 1984)




 




3.4 Other additives that may enhance the
effect of nicotine












Evidence
of other substances with pharmacological effects

Although in the
documents surveyed, ammonia emerges as the primary chemical tool used to enhance nicotine
effects, other additives with similar functions are currently in use and more are being
researched. Of particular note are Acetaldehyde, Levulinic Acid, Theobromine and
Glycyrrhizin -- Although described by the tobacco industry as 'smoothers' and 'flavour
enhancers', all appear to have some pharmacological effect in controlling nicotine
absorption levels and/or delivery.

Synergistic
interactions...

In his testimony
during recent litigation, W.A. Farone noted that,
face="Times New Roman, Times" size="2">

"the interactions (between additives and
nicotine) may be the basis for the difference between the difficulty in giving up
pipe or cigars compared to giving up cigarettes."41 (Farone WA 1997)




3.4.1 Acetaldehyde







Acetaldehyde is produced
by the burning of sugars (the most common tobacco additives42). Industry scientists
suspected that acetaldehyde could enhance the addictive effects of nicotine. Senior Philip
Morris scientist Victor J. DeNoble began research in the early eighties, into the
behavioural effects of nicotine and acetaldehyde in rats. He discovered that the two drugs
worked synergistically to enhance the addictive nature of nicotine. DeNoble's research
papers for Philip Morris reveal the potential for acetaldehyde to act in this way:
face="Times New Roman, Times" size="2">

"The results can be summarized as
follows: 1 acetaldehyde does function as a positive reinforcer for rats. 2 acetaldehyde at
equal doses (mg) to(-) nicotine is more effective at maintaining self-administration
behaviour, 3 the endogenous opioid system is not involved in the maintenance of
acetaldehyde self administration, and 4) combinations of nicotine and acetaldehyde produce
supra-additive effects when self administered."43 (PM)


"Acetaldehyde alone maintained
lever pressing at a greater rate than nicotine at equal mg/kg doses. This is consistent
with other findings at this laboratory." (Philip Morris, 1983)44


"Overall, the effects of acetaldehyde on EEGs were similar to those of
nicotine."45 (PM 1983)


"DeNoble detected a synergistic or "additive" effect with
acetaldehyde-nicotine combinations. This experiment was extended, with a slightly
different but acceptable protocol, with one rat again using doses less than one cigarette
(8 ug/kg / dose) and again DeNoble detected a synergistic effect between acetaldehyde -
nicotine."46 (PM 1982)


Following this discovery DeNoble and his team were ordered to find the optimal ratio of
the two compounds. According to DeNoble's testimony, once the company had discovered the
optimal ratio for addiction they increased the levels of sugar in Marlboro cigarettes to
achieve the required increase in levels of acetaldehyde.


"How did they do it?
Simple, they added sugar, because if you burn sugar you form acetaldehyde. Now I ask you
this. If tobacco companies are reducing acetaldehyde as Philip Morris says why has
Marlboro increased acetaldehyde by 40% in ten years and has maintained that increase
today?"47 (DeNoble, Verbal Testimony 1997)




3.4.2 Levulinic acid















Adding straight
nicotine to tobacco has two unwanted effects. Firstly it makes the smoke harsh and
difficult to smoke, and secondly it increases the FTC reading of nicotine. RJR patented a
way round this by using a nicotine salt of an organic acid, (e.g., nicotine levulinate)
which increases the impact of nicotine whilst keeping a low tar to nicotine ratio on the
FTC reading:

The use of organic acid salts to mask the
harshness of nicotine.


It would be desirable to provide a
cigarette such as an 'ultra low tar' cigarette, which is capable of delivering a good
tobacco taste, strength and smoking satisfaction characteristic of a 'full flavour low
tar' cigarette while not being perceived as being overly harsh or irritating. In addition,
it would be desirable to provide a cigarette such as a ' full flavour low tar' cigarette,
which is capable of delivering a good tobacco taste, strength and smoking satisfaction
characteristic of a 'full flavour' cigarette while not being perceived as being overly
harsh or irritating. Cigarettes having incorporated therein a salt such as nicotine
levulinate exhibit low FTC 'tar' to nicotine ratios while (i) having a smooth palatable,
flavourful taste, and (ii) providing smoking satisfaction to the user. The cigarettes do
not exhibit a harsh or irritating character; and do not exhibit a non-tobacco or off
taste.


Patent No 4,830,028. Salts provided from nicotine and
organic acids as cigarette additives, RJR, May 16 1989.

RJR
researches techniques for enhanced binding

Titled 'Enhancement
of nicotine binding to nicotinic receptors by nicotine levulinate and levulinic acid', the
following document shows how levulinic acid enhances the effects of nicotine.
face="Times New Roman, Times" size="2">

"Nicotine levulinate and levulinic acid
significantly increased the amount of L (3H) nicotine bound to nicotinic receptors in rat
brain tissue. The observed increase ranged from 20 - 50 %, with a mean value of around 30
%. The total amount of radiolabeled nicotine bound to receptors was more than could be
accounted for by binding to high affinity receptors alone. The maximal effect which was
observed at concentrations of nicotine levulinate and levulinic acid in the low nanomolar
range, was reversed at higher concentrations. A computer model consistent with the results
was developed and tested. According to the model, levulinic acid binds to an allosteric
site on a class of low-affinity receptors and increases the affinity of these receptors
for nicotine. At higher concentrations, this effect is reversed by the levulinic acid
itself, assuming that it also has a reasonable affinity for the nicotine binding
sites."48 (RJR 1989)


"Levulinic acid (4-oxopentanoic acid) is primarily a breakdown product of
starch, cane sugar and other cellulosic materials."49 (RJR 1989)

Are
there other compounds which help nicotine bind to receptors?

The same document
possibly describing other research.

"Similarly,
it has been shown that there are some compounds which enhance the binding of nicotine to
its receptors in brain tissue"50 (RJR 1989)



The above quotes illustrate the extent to which cigarette manufacturers can manipulate
the chemistry of smoke and nicotine addiction. Levulinate and levulinic acid change the
chemistry of the brain itself so it becomes more receptive to nicotine.




3.4.3 Cocoa and theobromine








Widely used as an
additive, cocoa contains alkaloids, which may modify the effects of nicotine and have a
pharmacological effect in themselves. Cocoa also contains about 1% theobromine, a
'bronchodilator' - encouraging expansion of the airways and facilitating increased smoke
and nicotine intake.

The following quotes are from scientific and medical papers held
by Philip Morris:


"Theobromine: The principal
alkaloid of the cocoa bean which contains 1.5-3% of the base... bronchodilation effect in
asthma."51


"The bronchodilator effect of a 10mg dose of theobromine was compared with that
of 5mg of theophylline in young patients with asthma.... In this single dose study the
bronchodilatory effect produced by theobromine was clinically and statistically
significant.... improvement in all pulmonary function tests was noted after the ingestion
of theobromine or theophylline."52


It should be noted that 'improvement' refers to
a significant expansion of the airways within the smoker's lungs.




3.4.4 Glycyrrhizin







An ingredient of
liquorice - another commonly used additive, glycyrrhizin also acts as a bronchodilator.
face="Times New Roman, Times" size="2">

"What does a bronchodilator do? The
bronchodilator makes it easier for you to inhale, so obviously if you are having
difficulty putting smoke in your lungs, it's good to have a bronchodilator in there. Now I
was asked recently whether I knew whether the glycerizon being delivered is delivered in
adequate concentration to cause that to happen. I do not know the answer to that question.
It would be interesting to know whether that has been studied by the industry. If they
have studied it, it would seem that that is the kind of information that should be shared
with regard to ingredients. The point is, however, that we know it can happen, it is a
bronchodilator. The probability that it happens is very high, but that would be related to
studies that should be done."53 (Farone WA 1997)



 




3.4.5 Pyridine







A testimony from WA
Farone, a former Philip Morris employee, speculates on the impact of adding alkaloids
other than nicotine to cigarettes:

"We
normally think only of nicotine, but we have to remember there are other alkaloids in
tobacco. As an example of that I have here a very old book on pharmacy and therapeutics.
It was written in 1894, published in 1895, and I'd like to just read you one little thing.
This is on the section under tobacco and it says, 'It contains a very powerful and
poisonous food alkaloid named nicotine'. It goes on to say, "It's combustion gives
rise to several products of which pyridine and its compounds of the sheath having the same
action as nicotine but of less severity." So here we are back in 1894 knowing full
well that pyridine acts like nicotine at least in some regard, and if you go to a modern
book.... you are going to find out that it is a central nervous system depressant, much
the same as nicotine. So if I now add pyridine, either in the form of pyridine itself or
in the form of some chemical, which when I combust it or pyrolyse it , it converts to
pyridine, then I have increased the pyridine that the smoker gets if I put pyridine in
with nicotine I increase the total central nervous system effect, and it becomes very,
very important for us to understand the interactions between the additives the
ingredients, and what is happening with the pharmacological effects of nicotine."54
(Farone WA 1997)


The following BAT report explores the
absorption of pyridine and its synergy with nicotine. While the report says that the
levels of pyridine found in tobacco smoke are 'unlikely' to be high enough to cause any
effect, due to lack of disclosure it is difficult to ascertain weather current level of
pyridine are high enough to be pharmacologically active.


"Peripherally, i.e. the
tissue of the body excluding the brain, whether acting similarly, by nicotine receptor
stimulation, or by different mechanisms pyridine and nicotine act synergistically."55
(BAT)


"Centrally, pyridine and nicotine produce opposite antagonistic effects,
nicotine being stimulant, pyridine depressant."56 (BAT)


"...This is indicative that pyridine is producing this effect by stimulating a
nicotinic receptor at this site."57 (BAT)


"Discussion of the Interaction of Pyridine with Nicotine.


It would appear that in the majority of cases there is a degree of addition between
the effects of nicotine and pyridine. It does not really matter if the two agents are
producing their effects by different mechanisms, as with their effects on heart rate.


This conclusion seems to be true for the peripheral effects, but as can be seen from
the results of the section concerned with the CNS effects of pyridine, and from the
results of the mouse and rat toxicities in: the absorption section of the report, pyridine
and nicotine have directly opposite effects on the brain, and thus will antagonise each
others effects."58 (BAT)




  4 Masking the taste and immediate effects of tobacco
































































Is
an 'improved' cigarette desirable?

Tobacco products
enjoy widespread exemptions from consumer safety and product liability legislation through
historical accident. Tobacco products are also the only consumer products that cause
disease and death when used as intended by the manufacturer. Because of this unique
anomalous status, additives to tobacco products present an unusual philosophical problem.
For most products, the use of additives for 'improvement' does not lead to any harmful
consequences arising from modest extra consumption. However, if the cigarette smoke
is made to taste 'better' more people may start to smoke, continue to smoke or decide not
to quit. This concern was reflected in the 1998 SCOTH report:
face="Times New Roman, Times" size="2">

"One of the effects [of additives] has
been the maintenance of "taste" as tar yields have fallen with an ensuing
reduction in natural flavour. The negative side of this has been the maintenance of the
appeal of a product, which might otherwise have been rendered unacceptable through the
adulteration of intrinsic flavour."59

Additives
are needed to modify the taste of nicotine

An ex Philip Morris
employee explains in testimony one of the main functions of tobacco flavouring additives.
face="Times New Roman, Times" size="2">

"It is widely known that harshness and
bitterness of nicotine is not acceptable alone in a cigarette. There is strong scientific
evidence to support both the need for nicotine in the products and the need to modify its
flavour to make its delivery acceptable to the smoker."60 (Farone, W.A. Ex-Philip
Morris employee. 1996)

The largest single
additive used is sugar - around three percent of the total weight - masking the
unpalatable taste of nicotine. Choosing a sweetened or flavoured cigarette brand allows
smokers to inhale increased volumes of smoke, more easily absorbing the desired dose of
nicotine. Over 80% of new smokers start below eighteen years of age - this is recognised
by the industry and targeted in production and marketing strategies.61 The use of sugars,
honey, liquorice, cocoa, chocolate and other flavourings make cigarettes more palatable
and 'aspirational' - particularly to children and the young.

"Flavouring
do effect smoking behaviour"

"Is it
not the flavour that distinguishes the brands and cause some cigarettes to be more
successful in the marketplace than others? The marketplace is probably one of the greatest
proofs that flavourings do affect smoking behaviour."62
(Farone, W.A. 1996, Ex employee of Philip Morris.)

Use
additives to replace lost flavours

Reducing tar levels,
in an attempt to neutralise serious health concerns, caused manufacturers major problems -
tar provides a strong flavour and mouth sensation, masking the harsher, bitter taste of
nicotine - unpalatable to new smokers and uncomfortable to established smokers. The
response was the use of additives to play the role of the missing tar.
face="Times New Roman, Times" size="2">

"The Merit concept of utilising flavour
technology to circumvent the tar problem by using flavour from additives instead of
flavour from tar may represent the best compromise between the demand for a product with
high flavour and/or physiological impact and/or degree of nicotine satisfaction, and at
the same time low tar and nicotine." (Lorillard, 1976)63

Additives
have multiple purposes

A BAT document gives
some indication of the role of tobacco additives. Four of the seven reasons for additives
involve masking the taste of tobacco.
face="Times New Roman, Times" size="2">

"The Role of Tobacco Flavour Additives.
Tobacco flavour additives of all types are gaining importance in manufacturing practice
for a number of reasons. Additives may be required:


1. To introduce a u.s.p [unique selling point] to a product.


2. To modify the smoke sensory characteristics of poorer quality grades particularly
where government or economic compulsion dictates that the better quality material is not
available for manufacturing.


3. To achieve a satisfactory smoking quality in situations where league tables
influence the design of the product.


4. To counter the effect on smoke quality of including synthetic smoking materials in
the blend.


5. To maintain brand character.


6. To improve the smoking quality of an existing brand.


7. To improve side-stream smoke character."64 (BAT)

Added
ammonia reacts with sugar to create 'milder' smoke

Competing companies
were obsessed with the success of Marlboro, and ran countless experiments to unravel its
secrets. These are discussed in greater detail in the previous section. What they found
was a cigarette packed full of additives.
size="2">

"There is more to PM's [Philip Morris'] ammonia processing than simple
addition of ammonia, which leads to different results. They somehow force much of it to
react with tobacco constituents in a manner such that pectin is released, while also
forming sugar-ammonia reaction products that contribute to a mild and natural tasting
smoke."65 (BAT 1985)

Additives
enable PM to use cheaper tobaccos in there cigarettes

"PM
people often state in public that additives are important to them with regard to
controlling smoke chemistry and taste. Indeed, their leaf people have been known to say
that the additives are one reason that they can buy some cheaper tobaccos. Casings are an
obvious choice of a vehicle for use of such additives."66 (BAT 1985)
"The
wide scale use of sugars in casing formulas (adopted originally on the basis of smoker
acceptance) and the general observation that most blends which have received wide scale
consumer acceptance have significant sugar levels would certainly suggest that sugar level
is important to quality."67 (BAT 1963)

Liquorice
boosts the sweetness of tobacco

According to BAT, face="Times New Roman, Times" size="2">

"Although each tobacco manufacturer
carefully guards the secrets of his casing (and flavour) formulas, it is well known that
casings for smoking products often contain sugar, liquorice, cocoa, or chocolate liquor
and sometimes natural extracts. Of these, liquorice deserves special mention. Just as
sugar is used in 'casing' the tobacco to mellow and smooth the smoke, liquorice is used as
an adjunct to boost the sweetness of tobacco products. The taste of liquorice to the
smoker is that of a mellow sweet woody note which, at proper use levels, greatly enhances
the quality of the final product."68 (BAT)

Additives
may be flavour enhancers or flavour suppressers

"The
greater use of reconstituted tobaccos presents two major problems to the flavour industry.
Stems have higher nicotine content. You run into a second problem with them that you don't
run into with the blend tobaccos. Reconstituted tobaccos will start off with a bad
character. You've got a twofold problem. You've got to suppress a bad flavour and
neutralise harshness, and you've go to put a good flavour back in. So, in some cases, we
make suppressants ----- flavourings that, in effect, neutralise and diminish a bad
flavour. On top of that, we have to add a flavour to bring it to a point where it's
acceptable. One is an eraser and one is a writer."69 (Tobacco Reporter 1979)

 

Chocolate
gives better mouth feel

"The
tobacco leaf of and by itself does not have sufficient impact. So, what you do is try to
round off some of the harsher edges; try to add nuances of chocolate, for instance, which
give you a better mouth feel when the smoke comes in and that's why these additives go
in."70 (Tobacco Reporter 1979)
"As far
as liquorice is concerned, the smoothing effect of this is probably due to the
Glycyrrhizin present which is renowned for its demulcent therapeutic property."71 (BAT
1963)

Glycyrrhizin is an effective
demulcent; it is also a bronchodilater and carcinogenic when burnt.72

Cocoa
butter reduces harshness of smoke

"Although
by no means conclusive, the results now presented lend some support to the claim that
treatment of tobacco with cocoa butter reduces the harshness of the smoke."73 (BAT
1967)
BAT adds around 1250
tonnes of cocoa to its cigarettes per year.
size="2">

"I have circulated all Companies in the Division, and from their
replies, estimate that the Company uses about one and a quarter million kilos of Cocoa in
its tobacco products each year."74 BAT 1978



  4.1 Additives and 'low tar'
cigarettes.




















Low
tar cigarettes have low desirability without additives

"Low
delivery cigarettes are commonly judged to lack acceptable levels of flavour. Attention is
increasingly being focussed upon novel methods of incorporating flavours in cigarettes so
that the desirable flavour level can be re-established."75 (BAT 1982)
"As
attempts are made to go lower in both tars and nicotine, flavour additives are needed to
bring taste levels up to par."76 (Tobacco Reporter 1979)
"Tobacco
companies are concerned with putting something into a low yield cigarette to compensate
for the loss of flavour and bring the taste partially back to the level of a higher
delivery product."77 (Tobacco Reporter 1979)

Ethics
questioned...

Although there were
concerns about lost taste, the priority was to ensure that smokers could continue to
receive enough nicotine.

"Compensatable
Filters.


Strategic Objective:


To make it easier for smokers to take what they require from a cigarette. This means in
effect that the filter will be compensatable and implies a high taste to tar rates."


Constraints:


Is this the ethical thing to do?"78 (BAT 1985)


In effect this means that the
cigarette is designed to allow smokers to take a much higher level of tar and nicotine
from the cigarette than is registered on official machines.



 




4.2 Front end 'lift'








The
cigarette is designed around smoker's vulnerabilities

BAT uses additives
and design to play to the smokers largely unconscious smoking desires. The very first puff
on a cigarette can be engineered to have the greatest impact -- both relieving the pent up
nicotine withdrawal symptoms and providing the best taste.
face="Times New Roman, Times" size="2">

"Front-end lift.


Strategic objectives:


To improve the taste and flavour of the first few puffs on cigarettes.


It is assumed that smokers are most likely to make judgements about the cigarette
quality in the first few puffs.


It is assumed that 'need' for smoking is highest when a cigarette is lit."
79 (BAT 1985)



  5 Additive Toxicity




















The limited
regulation of tobacco additives has tended to concentrate on the toxicity of the additive
itself. This has tended to draw upon food regulation -- however, it is quite likely that
the toxicity of an additive when ingested as food may differ from its effect when inhaled
in smoke. There should, therefore, be caution in accepting the effectiveness of even these
limited safeguards:

"
Because the delicate respiratory system lacks the powerful enzymes and detoxifying
metabolic pathways of the digestive system, these compounds may be significantly more
toxic when inhaled than when ingested. Pyrolysis of additives may also produce novel toxic
constituents, thereby creating additional health risks to the smoker."80 (Connolly,
Lymperis, 1998)

Coumarin

Health concerns
surrounding the use of a highly toxic flavouring compound called coumarin (which causes
severe liver damage) began to emerge in the late fifties. Cigarette manufacturers
voluntarily removed coumarin from the permitted list in September 1997. Although the
controversy is almost four decades old, it serves as a reminder of the bias towards sales
over health concerns within the tobacco industry as a whole.
face="Times New Roman, Times" size="2">

"In the meantime we think you would be
interested to know that in America the manufacturers of all food products intended for
human consumption abandoned the use of coumarin during 1953/54 'until such time that
adequate tests and investigations were completed wherein the use of coumarin may be
considered to be deleterious and injurious to health.'81 (BAT, 1959)


Cigarette manufacturers have been
subject to a relatively liberal legislative framework, partly on the grounds that the
industry should regulate themselves - evidence shows they are unlikely to do so:

BAT
test additives for carcinogens

"Mutagenic
Activity of Flavour Compounds: Some 270 compounds have been assayed for mutagenic activity
in Ames test ........ In these experiments a number of flavour compounds have been shown
to be positive mutagens......

Acetaldehyde: Is a positive mutagen, it is embryotoxic,
teratogenic and induces respiratory tract tumours in hamsters when inhaled.


Furfural: This is confirmed by complementary work as a clear mutagen and, in
conjunction with other respiratory tract carcinogens, e.g. benzo(a)pyrene, it may act in a
concerted way to increase the yield of tumours.


Furfural Acetate: The work of Mortelmans et al. is the only mutagenic study on this
compound. However, the experiments on fufural and furfuryl alcohol would seem to indicate
a general mutagenic reactivity of this family of compounds.


Maltol: The positive mutagenic activity is confirmed by other studies in vitro;
however, the compound does not seem to have been tested in vivo.


O-Methoxycinnamaldehyde: Does have the potential to be a positive carcinogen.


Recommendations:


Acetaldehyde, furfural and furfural acetate....... If these agents are to be added
to tobacco, it would appear prudent to review the levels of addition in the light of the
above evidence. For maltol and o-methoxycinnamaldehyde, the evidence indicates a possible
carcinogenic potential of these agents. This would again suggest reviewing the use of such
agents for human use."82 (BAT 1986)

A
dilemma: reduced toxicity or reduced sales?

There is evidence to
suggest that the tobacco companies do not have adequate internal controls over potentially
harmful additives:

"We were
quite well aware that Eugenol is a phenol ...We also agree with you that phenol is a dirty
word at present."


"Really this comes down to a point of asking ourselves this question: Would we be
willing to accept a possibly slightly undesirable means to accomplish a desirable
end?"


"It has occurred to us that whereas there would be no reason to fear any health
danger from the use of Eugenol if the question of phenols had never been raised, yet now
that it has been so raised we have got to take it into account since Eugenol is itself a
phenol."


"Is the chemical evidence adequate to justify immediate sale of the cigarettes to
the public subject to further chemical and/or biological tests being carried out with
reasonable despatch.?"83 (BAT 1982)




 


 


 





6 Changing the Perception of side-stream smoke





 

































Additives
to reduce the appearance of passive smoking

Additives are also
used to mask the effects of environmental tobacco smoke (ETS), primarily to undermine the
negative image of smoking and remove some of the social pressures that make smokers more
likely to quit.

Environmental tobacco smoke is a big problem for the industry. Since
the 1970s scientific evidence has accumulated proving that exposure to ETS is a serious
health hazard (in the UK alone several hundred deaths are attributable to ETS each year) href="#_Toc5014">84.
This discovery had a profound effect on the politics of smoking - moving from an issue of
individual choice to one of social responsibility - and encouraging even more smokers to
reassess their habit.


The tobacco industry response was twofold; firstly research was conducted specifically
to find evidence countering claims that exposure to ETS was a health hazard, and secondly
chemical additives were identified to reduce its anti-social and irritating effects -
making it harder for non-smokers to avoid or criticise. There were also some attempts to
reduce overall ETS, however the primary concern was modifying perception of the smoke
rather than its properties.

Choose
the result then find the proof

"Strategic
objectives (of sidestream smoke research) remain as follows: 1. Develop cigarettes with
reduced sidestream yields and/or reduced odour and irritation. 2. Conduct research to
anticipate and refute claims about the health effects of passive smoking."85 (BAT 1984)

Reducing
the visibility of ETS may increase its toxicity

"It was
thought prudent to ensure that the Company could show no adverse effects on sidestream
toxicity for a product designed to have a lower visibility sidestream."86 (BAT 1984)
face="Arial, sans-serif" size="2">

Worryingly this opens up the possibility that work on
lowering the visibility of side-stream smoke was increasing its overall toxicity.

Additives
used to stop quitting because of social pressure

" To
pre-empt potential volume decline from smokers under pressure in social and work
environments by providing them with an offer which combines re-assurance in social smoking
with taste and satisfaction."87 (BAT 1984)
"Studies
into alternative burn additives that reduce visible sidestream: As a result of these
studies sodium acetate has been used to replace tri-potassium citrate in low visibility
sidestream papers...Potassium salts give greater reductions in sidestream
visibility."88 (BAT 1987)
"It has
been found that a 'Ca (OH)2 filled cigarette paper gives a reduced visible sidestream
smoke...It was noticed that the cigarettes made with treated papers gave a more pleasant
and less irritating sidestream aroma than the cigarettes made with untreated papers. Also
the taste of the mainstream smoke had changed and seemed to be milder than for the
cigarettes made with the treated papers"89 (BAT 1983)

BAT
reduce visibility but are not interested in toxicity

"Smoke
control: sidestream reduction: Visibility. RD&E is interested in work dealing with
sidestream smoke reduction, but is not interested in the biological testing of products
produced. David will explain this to Allen Herd and ask whether projects could be run
without biological testing."90 (BAT 1986)
size="2">

It appears that while reducing the visibility of side-stream smoke is
considered important, the toxicity of the resultant vapour is not.




 


 


 




7. Notes




  1. Action on Smoking and Health, Tobacco Explained: the truth about the tobacco industry in
    its own words, June 1998. See www.ash.org.uk/papers/tobexpld2.html


  2. Philip Morris, 1972, Dunn W.L, Motives and incentives in cigarette smoking. Minn Trial
    Exhibit 18089.


  3. RJR, 1972, C Teague, Research planning memorandum on the nature of the tobacco business
    and the crucial role of nicotine. Minn Trial Exhibit 12408


  4. Santa Fe Natural Tobacco Co. An analysis of the ingredients added to tobacco in the
    manufacture of cigarettes: Health and Legal Implications. FDA GRAS&FDA approved food
    additives. Santa Fe Natural Tobacco Company; October 12, 1994 p3


  5. Kozlowski LT, Mehta NY, Sweeney CT, et al. Filter ventilation and nicotine content of
    tobacco in cigarettes from Canada, the United Kingdom, and the United States. Tobacco
    Control
    1998; 7:369-375.


  6. Benowitz NL, Hall SM, Herning, RI et al. Smokers of low-yield cigarettes do not consume
    less nicotine. New England Journal of Medicine, 1983; 309: 139-42.


  7. Bates C., Jarvis M., Letter Tobacco Control 1999;8:106-112


  8. Bates C., Jarvis M. Low Tar: why low tar cigarettes don't work and how the tobacco
    industry fooled the smoking public. 1999 Edition. March 1999. HREF="./big-one.html">www.ash.org.uk/papers/big-one.html


  9. First Report of the Independent Scientific Committee on Smoking and Health, HMSO, 1975


  10. Second Report of the Independent Scientific Committee on Smoking and Health, HMSO, 1979


  11. Second Report of ISCSH, 1979


  12. Third Report of the Independent Scientific Committee on Smoking and Health, HMSO, 1983


  13. Fourth Report of the Independent Scientific Committee on Smoking and Health, HMSO, 1988


  14. Report of the Scientific Committee on Tobacco and Health, The Stationery Office, 1998


  15. Farone WA, The manipulation and Control of Nicotine and Tar in the Design and
    Manufacture of Cigarettes: A Scientific perspective. Statement March 19, 1996


  16. Henningfield, Jack E. Verbal Testimony. Jan 30 1997.


  17. Riehl T, McMurtrie D, Heemann V, et al Project SHIP review of progress November 5-6 1984
    BAT, November 12th , 1984, Minn Trial Exhibit 10752.


  18. Anderson HD. Potassium carbonate Memo to RP Dobson, BAT, August 7th 1964,
    Minn Trial Exhibit 10356.


  19. Liggett, January 29th 1974, Development of a Cigarette with an Increased
    Smoke pH


  20. Colby FG. Cigarette concept to assure RJR a larger segment of the youth market. December
    4th 1973, Minn Trial Exhibit 12464.


  21. RJR 1976, McKenzie JL. Product characterisation definitions and implications. Minn Trail
    Exhibit 12270.


  22. BAT June 1988, The significance of pH in Tobacco and Tobacco Smoke." Minn Trial
    Exhibit No 12 223 p5.


  23. Williams RL, Development of a cigarette with increased smoke pH. Liggett, December 16th
    1971, Minn Trial Exhibit 11903.


  24. Woods JD Harlee GC. Historical review of smoke pH data and sales trends for competitive
    brand filter cigarettes. RJR, May 10th 1973, Minn Trial Exhibit 12337.


  25. BAT 17th May 1965, FN B2107 BN105454359-4346 The Effect of Additives on Smoke
    Chemistry.


  26. Chen Leighton, pH of smoke, a review, Lorillard Research Centre, 1976, Minn Trial
    Exhibit 10110.


  27. RJR , August 14th, 1973, Minn Trial Exhibit 13155


  28. Richard Kluger, Ashes to Ashes , 1998 page 292


  29. RJR, Minn Trial exhibit 13141.


  30. B&W, October 26, 1992, Minn Trial exhibit 10001, p51.


  31. RJR, 14th August, 1973, Teague CE, Implications and Activities Arising from
    Correlation of Smoke pH with nicotine Impact, Other Smoke Qualities, and Cigarette Sales.
    Minn Trial Exhibit 13155.


  32. RJR, 14th August, 1973. Implications And Activities Arising From Correlation
    Of Smoke pH With Nicotine Impact, Other Smoke Qualities And Cigarette Sales. Minn Trial
    Exhibit 13155.


  33. Gregory CF, Observation of free nicotine changes in tobacco smoke, B&W, January 4th,
    1980 Minn Trial Exhibit 13182


  34. Blackhurst JD. Further work on "extractable" nicotine. Report issued by I w
    Hughes, BAT September 30th, 1966, Minn Trial Exhibit 17825.


  35. Lorillard, 8th February 1973, Minn trial exhibit 10095.


  36. RJR, 14th August 1973, Implications and activities arising from correlation
    of smoke pH with nicotine impact, other smoke qualities, and cigarette sales. Minn trial
    exhibit 13155.


  37. RJR, 14th August 1973, Implications and activities arising from correlation
    of smoke pH with nicotine impact, other smoke qualities, and cigarette sales. Minn trial
    exhibit 13155.


  38. Lorillard, July 12th, 1976, Chen L. pH of smoke: a review Minn Trail Exhibit
    10110.


  39. Farone, William A, Verbal Testimony, June 12 1997.


  40. Proceedings of the smoking behaviour- marketing conference, July 9-12th, 1984
    session to Dr L C F Blackman and Mr AM Heath B&W, July 30th 1984, Minn Trial Exhibit
    13430.


  41. , Farone W A, Department of public health. Proposed hearing on proposed regulations:
    Reports of added constituents and nicotine ratings. June 12 1997.


  42. Santa Fe natural tobacco Co, 1994


  43. Philip Morris, Termination of chronic acetaldehyde administration does not result in a
    physical dependence syndrome. Tobacco Resolution, Bates Number 1000060695-60704


  44. Philip Morris, 1983 Victor J DeNoble 'Behavioral Pharmacology annual report'. Tobacco
    Resolution, Bates Number 206056611-


  45. Philip Morris 1983, "Behavioural Pharmacology Annual Report" V. J. DeNoble.
    Tobacco Resolution, BN 206056611-6612


  46. Philip Morris 1982, Evaluation of the DeNoble nicotine acetaldehyde Data, Tobacco
    Resolution, BN 2056144727-4728.


  47. DeNoble V.J. Verbal Testimony 1/3/97 p77


  48. RJR 1989, Lippiello PM, Fernandes KG. "Enhancement of nicotine binding to nicotinic
    receptors by nicotine levulinate and levulinic acid." September 25 1989.BN508295794


  49. RJR 1989, Lippiello PM, Fernandes KG. "Enhancement of nicotine binding to nicotinic
    receptors by nicotine levulinate and levulinic acid." September 25 1989. BN508295794


  50. RJR 1989, Lippiello PM, Fernandes KG. "Enhancement of nicotine binding to nicotinic
    receptors by nicotine levulinate and levulinic acid." September 25 1989. BN508295794


  51. Philip Morris, Bates number 2060535086


  52. Philip Morris, Bates number 2060535081-85


  53. Farone WA, Verbal testimony, Public hearing on proposed regulation: Reports on added
    constituents and nicotine ratings, Massachusetts tobacco control program, June 12th
    1997.


  54. Farone WA, Verbal testimony, Public hearing on proposed regulation: Reports on added
    constituents and nicotine ratings, Massachusetts tobacco control program, June 12th
    1997.


  55. BAT, The absorption and mechanism of action of pyridine and its interaction with
    nicotine, FN AW2730, BN 402419398-9486.


  56. BAT, The absorption and mechanism of action of pyridine and its interaction with
    nicotine, FN AW2730, BN 402419398-9486.


  57. BAT, The absorption and mechanism of action of pyridine and its interaction with
    nicotine, FN AW2730, BN 402419398-9486.


  58. BAT, The absorption and mechanism of action of pyridine and its interaction with
    nicotine, FN AW2730, BN 402419398-9486.


  59. Report of the Scientific Committee on Tobacco and Health, The Stationery Office, 1998


  60. Farone, W A, March 27 1996 "thoughts on Philip Morris response on manipulation and
    control. The use of casings and flavourings." p4


  61. Action on Smoking and Health, Tobacco Explained: the truth about the tobacco industry in
    its own words, June 1998. Chapter 3 - see HREF="../../conduct/html/tobexpld2.html">www.ash.org.uk/papers/tobexpld3.html


  62. Farone, W A. "thoughts on Philip Morris response on manipulation and control. The
    use of casings and flavourings. Instalment 2" draft document, March 27 1999 p4.


  63. Chen Leighton, pH of smoke, a review, Lorillard Research Centre 1976, Minn Trial Exhibit
    10110.


  64. BAT, Casings and Flavourings,BN401375070, FN EQ 2295.


  65. BAT February 1985, The Unique Differences Of Philip Morris Cigarette Brands, BN
    109359953,FN K762


  66. Ibid., BN 109359981


  67. BAT September 18th 1963 Minn Trial Exhibit 10,856.


  68. BAT, Tobacco Flavouring For Smoking Products, BN104805407, FN F1500


  69. Tobacco Reporter, September 1979.


  70. Tobacco Reporter, September 1979


  71. BAT January 15th, 1963, Additives Australia, FN G443, BN 102630086-102630092


  72. Connolly, G. and Lympers, D. 1998 summary of evidence, findings and conclusions
    concerning the nicotine yield ratings of and added constituents of cigarettes and
    smokeless tobacco products. The Massachusetts department of public health tobacco control
    programme, p 281.


  73. BAT October 1967, Cocoa Butter As A Tobacco Additive. BN 105534584, FN B4263


  74. BAT 20th April 1978, BN 110034159 FN M453


  75. BAT, June 1982, Methods Of Flavouring Cigarettes. BN105525477, FN B3650.


  76. Tobacco Reporter, September 1979.


  77. Ibid. Frank Mild, Manager of flavour research, Fritzsche Dodge & Olcott.


  78. BAT 1985 FN J81, BN 100501670


  79. BAT, 1985,New Brand development post lights, BN 100501668, FN J81


  80. Connolly, G. and Lympers, D. 1998 summary of evidence, findings and conclusions
    concerning the nicotine yield ratings of and added constituents of cigarettes and
    smokeless tobacco products. The Massachusetts department of public health tobacco control
    programme.


  81. BAT April 21st 1959 FNM463, BN 10067349


  82. BAT December 12th, 1986, Mutagenic Activity of Flavour Compounds. FN AQ2222,
    BN 400916808-400916815


  83. BAT December 12th 1962, Letter regarding Eugenol, FN M456, BN
    110090779-110090785


  84. SCOTH report March 1998


  85. BAT 1984, Summary of research activities. See the Cigarette Papers by Stanton Glantz p
    391.


  86. BAT 1984, R&D conference report. See the Cigarette Papers by Stanton Glantz, p409.


  87. Ibid.


  88. BAT 1987, June 15th. Studies into alternative burn additives that reduce
    visible sidestream. FN AW 1428, BN 402385586-402385589.


  89. BAT September 9th, 1983, The addition of sugar solutions of Ca(oh)2 in sugar
    to cigarette paper. BN 100480228-0229 FN J562


  90. BAT February 17th, 1986, See the Cigarette Papers by Stanton Glantz et al
    p245.