STRICTLY CONFIDENTIAL
Research by the Tobacco Research Council
(A) Identification of the Health Problem
"We therefore conclude that smoking to a factor,
and an Important factor,
in the production of carcinoma of the lung". These
are historic words. They
are the words which started off the smoking and
health problem in Great Britain
and they came to have a major influence on the
tobacco industry in may other
countries as well. They are the words written in a
paper by Sir Austin Bradford
Hill (as he now is) and Dr. R. Doll, that was
published it the British Medical
Journal as long ago as September, 195 0. We, in
this country, have now had the
smoking and health problem with us for over 17
years.
What Doll and Hill claim to have found was a
statistical association between
cigarette smoking and lung cancer, and they then
expressed their personal opinion
that this association meant that cigarette smoking
was an important cause of lung
cancer. From 1950 onwards, in a slowly increasing
stream, report after report
from one country after another was published
showing cigarette smoking was
statistically associated with lung cancer. Later
epidemiological studies added'
to the list of diseases which were statistically
associated with smoking. Bronchitis
was among the first to be added, then followed
coronary heart disease and various
other diseases.
The evidence against smoking has always consisted
In the main of
statistical or epidemiological evidence. As the
studies Increased, the statistical
evidence also developed. For example, it was found
that men who had given up
cigarette smoking had a lower lung cancer rate,
and also a lower heart disease
rate, thin men who continued to smoke cigarettes.
. Searches for evidence that
might throw light on the relationship of smoking
and lung cancer were made in other
fields of science. Some pathologists examined the
nature of the cells in the lungs
of men and women who had died from various causes.
They found that there was
a statistical association between the number of
cigarettes a person 6d smoked and the
frequency with which abnormal cells occurred in
the lungs. Some chemists found
that the cigarette smoke contained minute
quantities of compounds which, when
applied sometimes In large quantities to
laboratory animals, cauied cancer of or
'under the skin or in some organs Of 801ne-typeB
Of animals. Cigarette smoke
condensate Itself, when applied to the skin of
mice over a long period, was found
to cause skin cancer. In regard to the view that
cigarette smoking is a cause of
lung cancer, Dr. Doll himself wrote In 1963 that
"None, howeiver, could claim
that it had been proved in the strict logical
sense. All that can be said Is that its C>
simplest explanation of the direct evidence, that
it is not contradicted by the
Indirect evidence and that It makes biological
sense In the light of much ancHIM
evidence.
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Naturally there has been widespread and prolonged
controversy about the
validity and interpretation of the statistical
associations of smoking with disease,
and the controversy still continues. As important
as the evidence itself, however,
has the attitude of the British Government to this
evidence. The first major
statement on smoking and health by the Minister of
Health in this country was made
in February, 1954, when the Minister stated that
he accepted the view that the
statistical evidence pointed to smoking as a
factor in lung cancer. In 1957, the
Minister of Health took a further step. He said
that the Medical Research Council
accepted that there was, statistically, an
incontrovertible association between
cigarette smoking and lung cancer, and he added
that the Government would take
all steps necessary to keep the public informed of
this. The next major devel6p-ment
was the publication in 1962 of a report on Smoking
and Health by the Royal College
of Physicians. This report linked smoking to a
greater or less extent with
14 different adverse health conditions.
Immediately after publication of this reports
the Minister of Health announced that 'The
Government certainly accept that the
report demonstrates authoritatively and crushingly
the connection between smoking-
and lung cancer and the more general hazards to
health of smoking."
These have been the successive attitudes of the
Government of this country
on smoking and health to which the manufacturers
have had of course to give due
weight. During the first few years of the
controversy the industry expressed to
the Minister of Health detailed criticisms of the
statistical evidence. Towards
the end of-1953, however, the industry, on the
advice of the Minister of Health,
gave E250, 000 to the Medical Research Council for
research into smoking and
health. This seemed, and indeed was, a large sum
for this purpose at that time,
and it took the Medical Research Council nine
years to spend it. After a few
years, however, the manufacturers decided that
further research was necessary
in addition to the research being undertaken by
the Medical Research Council and
in 1956 they formed the Tobacco Research Council
(to use our present name). The
Council slowly built up a research programme based
upon support of independent
research workers in various hospitals,
universities and other institutions. After
a few years, it became clear that it was not
possible to find sufficient outside
research workers to cover all the lines of
research which it was essential to
undertake. In 1961, therefore, the Counci I
purchased some land at Harrogate-
for the purpose of building their own
laboratories. The first laboratory blocks
were no sooner completed than we found it
necessary to extend them, and in fact,
still not complete. The total staff at Harrogate
laboratories to just under
300 and includes 17 graduates.
We are extremely fortunate in having a staff of
brilliant scientists at
our Harrogate laboratories, under the leadership
of Vrofessor Frank Dickens, P.R. S.
ever since the land was purchased, building has
gone on continuously, and is
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Major advances have been made in a number of
aspects of the subjects
investigated. To date, the Tobacco Research
Council has spent E4. 000, 000
on research, and our annual expenditure, under
capital and revenue headings,
is about El, 000, 000 a year.
0
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(B) Why the industrv must adopt a Working
Hypothesis
It is doubtless obvious that all research must
have a clearly defined
objective; otherwise it is simply aimless. It is
therefore useful to use a
"working hypothesis" because it forces you to
formulate in a specific way the
precise extent of existing knowledge and to decide
the assumptions on which
you are going to carry out research. The research
often takes the form of a
test of the validity of the working hypothesis,
proving the hypothesis to be right
or wrong. Following this, the next step can be
taken, which is frequently that
of testing a furthe r hypothesis. In this way,
scientific knowledge to built UP
brick by brick.
The Tobacco Research Council has come to base its
quantitative
biological research on the working hypothesis that
cigarette smoke affects
the respiratory epithelium - i.e. the lining of
the airways in the lungs - by direct
contact. But this does not mean that the Council
believes this working hypothesis
to be ture: it is essentially an a~ssumption made
for the purposes of research.
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(C) Main Lines of T. R. C. Activitv
Work at Harrogate
If cigarette smoke contributes to lung cancer,
then before we can
remove the groups of compounds from the smoke
which cause cancer, we have
first to identify these groups of compounds. In
other words, we have first to
be able to cause cancer with cigarette smoke
before we can modify the smoke
so that it no longer causes the cancer it
previously produced. We are therefore
in the remarkable position of having to try to
cause cancer with cigarette smoke,
and we are finding this almost impossible to
achieve. Obviou-sly we cannot
experiment on human beings and laboratory animals
have to be used. go far
the only form in which undoubted cancers can
regularly be produced in a relatively
large percentage of the animals, by a product that
bears even a remote
relationship to cigarette smoke, is by repeatedly
applying large closes of
cigarette smoke condensate to the skin of mice.
We are therefore using the mouse skin as a
scientific measuring
instrument, as one might use a ruler or other
measuring instrument. I would
particularly emphasise this point. We are not
using the mouse skin because we
think the results obtained from it can necessarily
be applied to man. It is quite
impossible to say what precise relevance, if any,
our reaulta have to
we
are assuming that our results will have some
relevance to the human lung cancer
problem since we have no wish to engage on a
purely academic exercise. But it
is not for us to assess what relevance our
conclusions may have for human
smokers. In fact, the Tobacco Research Council
does not regard it as part of
its functions to comment on the relevance of
research results, even of its own
research results, to human experience.
Our chemists have developed procedures for
4;;V-"g' cigarette smoke
condensate into various fractions, and we are
painting these fractions on the skin
of thousands of mice in order to see if it to
possible to track down and pin point
the groups of compounds in cigarette smoke
condensate that are actually
responsible for producing mouse skin cancer. The
experiments take along time.
It takes about 2 years for skin cancers to develop
in mice so that each
experiment leasts about 2j to 3 years.
If this approach is successful, the next step will
be to try to find means
of removing the responsible compounds from
cigarette smoke condensate. So
-'j;
far we do not know whether this approach by
fractionation will succeed. And
of course, If it should succeed, we do not yet
know whether it will be possible
to remove the groups of compounds that produce
mouse skin cancer, tbDugh our
chemists are reasonably optimistic about this.
Moreover. as Dr. Green will be
Pointing out. cigarette smoke, at the moment it to
born, consists of an aerosol
of aily droplets suspended in a mixture of gases.
The cigarette acnoke co.-i-n-to'
of which I have been speaking, consists only of
the particulate material or the
material in the smoke that can be condensed. It to
qutte diderent from whole
X.
7
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cigarette smoke in its form and in its age.
It is obviously very different in form and it is
different in age because,
when we started up at Harrogate, we could not
mass-produce condensate that
was less than about 24 hours old. Sir Charles
Ellis, in one of the many inspired
suggestions which he has contributed to our
research effort, urged us to try to
develop a machine that-produced "instant
condensate. 11 As a result of this
.7
suggestion, a machine was developed that produced
condensate within about
40 seconds. Although a vast improvement on 24
hours, this is still much older
than the smoke which a smoker inhales. Next, Dr.
Seehofer at the B.A.T.
laboratories in Hamburg succeeded indeveloping a
device that produced cigarette
smoke condensate in about five seconds. Using this
B.A.T. apparatus at
Harrogate we have recently succeeded in producing
two skin tumours on the backs
of mice in 18 weeks, which is very nearly the
shortest time in which we have
ever produced turnours with a product related to
cigarette smoke.
For overa year now we have also been exposing mice
to cigarette smoke
in such a way that they are forced to breathe the
smoke into their lungs. Although
we have used several hundred animals and exposed
them daily for many months
to the maximum amount of smoke that they can
tolerate without dying of nicotind
or carbon monoxide poisoning, we have not yet
succeeded in producing a single
cancer in their lungs.
As an intermediate step between painting mouse
skin with condensate and
exposing mice lungs to cigarette smoke, we have
put condensate or its fractions
directly into the lungs of rats. This intermediate
step has also so far failed
to produce a single lung cancer.
Sponsored Research
At first, all the research which the tobacco
industry supported was
carried out by outside experts attached to various
research organisations, to
hospitals or to other kinds of institutions. We
still support extra-mural
research of this nature, and there are two fields
in which our extra-mural
research is particularly important.
The first field is what is called the
investigation of the characteristics
of " susceptible minorities. 11 Only a minority of
even heavy cigarette smokers
develop lung cancer. If it was to become possible
to identify in advance all
people who were I ikely to develop lung cancer at
some future date and to
persuade them to stop smoking, the statistical
association between smoking
and lung cancer would eventually disappear.
All-other cigarette smokers could
then smoke without fear of developing lung cancer.
What an achievement this would
be. At present, because some people should not
smoke, we have a propaganda
cr%
policy in Ministries of Health throughout the
world that is based on what Winston __4
Churchill would doubtless have described as
"equality of misery". L_n
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The Tobacco Research Council has therefore
financed several
investigations which we hope will provide
information that can be used to
identify the types of people who are most liable
to develop lung cancer,
bronchitis or coronary heart disease at some
future date. Of these three
diseases, it has so far proved much the most
difficult to get information -about
the characteristics of those who are lung cancer
prone. A C-ertain amount of
information has been obtained about the
characteristics of those who are prone
to bronchitis. In this respect bronchitis has the
advantage that it provides
an early warning signal in the form of a constant
cough in which the cougher
brings up phlegm. Coronary heart disease is the
one in which most progress
has been made in identifying the characteristics
of those most liable to develop
the disease. The most susceptible to coronary
heart disease have five main
characteristics:-
I . They come from families which have more than
average experience of coronary heart disease.
2. They are over-weight and suffer from obesity.
3. They have high blood pressure.
4. They have a high level of cholesterol, which is
a particular type of fatty substance in their
blood.
5. They are heavy cigarette smokers.
Those susceptible to coronary heart disease have
quite a number cf
other characteristics but these are the five main
ones. Although heavy cigarette
smoking is undoubtedly found more often in those
who develop coronary heart
disease than in those who don't, this does not
necessarily mean that smoking
contributes to the disease. One of the most
eminent research workers inthe
field of nicotine and cardiovascular disease, Dr.
Richard Bing of Detroit, has
said: 11 think that it is all right for a healthy
man to smoke as far as the heart
is concerned because, just like bicycling, it
increases coronary flow - and
it is a lot easier because one can do it lying
down."
The most important research project, de3igned to
throw light on the
characteristics of the susceptible minorities,
which the Council is financing,
is a project being carried out in the Department
of Medical Statistics and
Epidemiology at the London School of Hygiene and
Tropical Medicine, and which
is expected to last 10 years and to cost E500,
000. Prof. D. D. Reid, who directs
the project, has planned a number of inter-rel
ated research projects, each of
which will throw light on different facets of lung
cancer, bronchitis and heart
disease. One of the main investigations of this
project is a study of 15, 000
Civil Servants in the main Government Departments.
Professor Reid has set up
a battery of tests and questions which these Civil
Servants complete. The future
01-
history of these men will be followed up through
the medical records of the
Civil Service, and analysis will show how far it
is likely to be possible, from -the U
results of tests and questions dthis nature, to
pick out the actual individuals who,
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if they continue in their present ~Yay of life,
will develop on e of these diseases.
Another study, which the Council is financing,
aims at detecting people
whose lungs have undergone changes from normal mid
are in now a pre-cancerous
state. It is hoped to detect thi-se -people by
examining cells coughed up in the
sputum. This is another long term prospective
study and is being carried out
by Dr. S.W. A. Kuper at the Royal Post Gradeuate
Medical School in London.
If any study is going to throw useful light on the
characteristics of the
minorities susceptible to lung cancer these two
are as likely to succeed as any.
In addition, of course, Prof. Reid's project
should throw more light on those
susceptible to bronchitis and heart disease.
In addition to investigating the characteristics
of those most liable to
develop coronary heart disease, the Council is
supporting a certain amount of
research into the fundamental nature of
cardiovascular disease. The moat
important cause of death in this country is
coronary thrombosis. In this a
thrombus or lump develops in the wall in a
coronary artery of the heart and
eventually, for one reason or another, a blockage
occurs. If a blockage occurs
in a main coronary artery, the person may well
die. If it occurs in a minor
artery, or if the blockage is incomplete, the
efficiency of the heart wi 11 be
permanently impaired and a further blockage, which
may be fatal, can easily
occur. A thrombus or blockage in other arteries of
the body can similarly occur.
We do not know how these thrombi are really
caused, and if it should be that
smoking contributes either to the thrombi
themselves or to the coagulation of
the blood, we do not know the mechanisms by which
these happen.
The Council has therefore sponsored a number of
research projects
by expert extra-mural workers designed to throw
light on the basic causes of
cardiovascular disease.
Finding out why people smoke
The smoking of tobacco.by the personal observation
of most smokers,
helps us to relax when we need to relax and helps
us to concentrate' when we
have to do something that requires concentration.
While there are millions of
smokers who believe that smoking actually does
have these effects, a number of
scientists and some medical officials have claimed
that these beliefs are i1lusione
and that the smoker finds them only because he has
conditioned himself to expect
to find them. T. R. C. has therefore carried out
some research into the
pharmacological effects of smoking, in an attempt
to try to obtain objective
evidence about the effects of smoking, and into
the psychological motives for
smoking.
Some highly sophisticated experimental techniques
have been developed
in our pharmacological laboratories at Harrogate.
The experiments at
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Harrogate, which necessarily have had to be
carried out on animals and not on __J
LA
human beings, have led to two main conclusions.
The first to that cigarette smoking
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is an extremely efficient way for an individual to
dose himself with nicotine.
The nicotine -quickly enters the blood stream from
the smoke, reaches the
brain and has its effect on the central
nervbTs-sygtem within a very short space
of time. Secondly, there is very good evidence
that nicotine stimulates and
improves the performance of laboratory animals.
They learn to carry out
tasks more quickly and their performance improves.
The result is comparable
to the result that would be achieved by a human
being who reports that smoking
had aroused him and helped him to concentrate.
It is more difficult to find clear evidence that
nicotine has a
tranquillizing effect in laboratory animals and we
cannot claim from the results
of animal experiments that cigarette smoking has a
tranquillizing effect. On the
other hand, evidence of a tranquillizing effect
emerges very clearly from a
psychological study which we recently financed.
According to this study, the
underlying cause of confirmed smoking is the
experience of disturbing emotions.
When a person is subjected to emotional strain,
internal strategies for control
may come into play. For example, a person may keep
busy to avoid worry or he
may try to give himself some rational explanation
by way of dealing with the
situation. Alternatively, he may seek some
external way of controlling his'
over-arousal of emotion. Cigarettes.-are one of
the few available external means
of controlling emotional arousal which can be used
by individuals in the widest
possible range of situations without censure from
others and with the minimum
interruption of on-going activities. Other
external controls, such as violent
exercise, hobbies or illegal drugs require more
time and effort and the
disruption of normal life patterns.
In addition,of course many cigarettes and pipes
are lit simply because
smoking is a pleasant habit rather than for the
purpose of reducing tension or
aiding concentration. And there are many people
who smoke because it is
sociable to smoke.
If there are different reasons for smoking, there
are also many
variations in the way smokers smoke. For example,
many, and indeed most
cigarette smokers in Britain inhale, and probably
at least three quarters of
the men and women who smoke 25 or more cigarettes
a day inlLile deeply or
moderately.
Cigarette and cigar smokers also differ in the
length of butt or stub they leave,
and it has even been suggested that the longer
cigarette butt length which is left
on the average in U.S.A., compared with those left
in this country, is largely
responsible for the lower lung cancer rates in
U.S.A. compared with Britain.
In this country, some smokers keep the cigarette
in their -mouth between
C7-
puffs while others hold It between their fingers.
One doctor has claimed that those
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who tend to keep the cigarette in their mouths
have twice the lung cancer rate
that those who remove the cigarette from their
mouth between puffs.
Some smokers extinguish many of the cigarettes
they smoke before
they are completely smoked and re-light the
cigarette on a later occasion.
According to one investigation, that those who
frequently re- light their
cigarettes in this way have a higher lung cancer
rate than those who smoke
the cigarettes straight through.
Some cigarette smokers take more frequent and
deeper puffs than
others, and it has been suggested that these
differences may also give rise
to differences in lung cancer mortality.
We know that smokers differ in these and many
other respects, and
that these differences can have a substantial
effect on the volume of smoke actually
taken into their liftsr'by different smokers. It
has been estimated by a Swiss
research chemist that, of two men smoking exactly
the same number of
cigarettes a day, one may in fact take as much as
39 times the amount of
smoke into his lungs which the other takes in. In
epidemiological studies,
it is therefore not really enough simply classify
smokers according to the
number of cigarettes which they have stated that
they normally smoked each-
day. Unfortunately, it is extremely difficult to
obtain reliable information
about individual smoking and puffing
characteristics. The smoker himself
does not always know the answer to some of the
relevant questions. If an
attempt is made to obtain answers by observing the
smoker with his
permission, the fact that he 1i beiiig observed
will inevitably make the smoker
self-conscious and could easily change his smoking
and puffing characteristics.
All that can be said is that we have here a number
of factors which substantially
affect the volume of smoke. per cigarette which,
reaches a smoker's lungs,
that these factors could conceivably decide
whether or not a smoker becomes
a member of a disease group statistically
associated with smoking, and that we
have not yet solved-the problem of classifying
smokers according to these
factors. We are still working on this problemi--
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(D) U.K. does not stand alone
All those who are trying to contribute to
knowledge about smoking and
health have many extremely difficult problems on
their hands. Those employed
by TR . C. are, of course, frequently criticised
for their connection with
commercial interests, and in these circumstances,
it is heartening for us
to have the co-operation of colleagues who are in
a corresponding position
in other countries. What is even more important in
contributing to results
is that we exchange scientific information with
these colleagues.
Amer! ca was the first country in which the
tobacco industry set up an
organisation for research into smoking and health.
The approach of the
American industry to the problem has, however,
differed fundamentally from
the British approach in that the American industry
supports only extra-m-ural
research. There is no equivalent in U.S.A. of our
labomtories at Harrogate.
But in supporting extra-mural research, the
American tobacco industry has
done so on a massive scale and devoted many
millions of dollars to research.
There has, at all times been a close relationship
between the Council for
Tobacco Research - U.S.A. and ourselves.
The closest parallel to our own course of
development is that which
took place in Germany. Like us, the German
cigarette industry's Research
Centre started by supporting extra-mural research.
Like us, they found it
necessary to devlop-their own facilities for
biological research, for chemical
analysis and for pharmacological research. Like
us, their biological research
was first based on painting the skin of mice with
cigarette smoke condensate.
For these reasons, we have come to have perhaps a
closer relationship with
the German Research Centre than with corresponding
organisations in any
other country.
We do, however, have opposite numbers in France,
Sweden and other
countries. In fact, we have agreements for
exchange of research information
with Germany, France, Sweden, Holland Austria and
Norway. We have alAo
a particularly close relationship with research in
the Republic of Ireland.
Jb.
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Only the Tip of the Iceberg
But even this collaboration with corporate
research organizations
of the tobacco industry in other countries is not
thd end of the resources
that are being devoted to solving the problems of
smoking and health. The
four leading tobacco manufacturers in Britain, in
addition to playing their
part asmanbers of the Tobacco Research Council,
are themselves carrying
out research into the problems of smoking and
health. A considerable part
of this research is chemical research and, of
course, the cigarette
manufacturers have a far more extensive and
profound knowledge of the
chemistry of tobacco smoke than any other
investigators possibly could have.
In addition, the four British tobacco
manufacturers are also carrying
out research Into other aspects of the smoking and
health problem, and
especially into various biological effects of
cigarette smoke. Each
manufacturer naturally has his own idea of the
areas of the smoking and
health problem which call most urgently for
investigation, and has
supplemented in these directions the work which
the Council is carrying
out or supporting. The members of the Council,
have however, an agreement
under which they pool significant results from
their Individually~financed
research. The four manufacturers concerned have
already pooled results
which are of significance, and in this way, each
has helped the progress Of
the others' research and of research at Harrogate.
This, however, is one of the subjects which I will
leave to Dr. Green,
and I will also leave to Sir Charles Ellis the
problem of pecring into the.
future.
C)
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Conclusion
To sum up, between them TRC and the tobacco
manufacturers are
trying to cover all objectives that are likely to
be relevant in smoking and
health research. The three most important
objectives at which T. R. C. is
currently aiming are to produce sound scientific
information about:
(1) The principles on which. cigarettes that do
not produce
mouse skin cancer would have to be based.
(2) The characteristics of men and women most
likely to
develop lung cancer, bronchitis or heart disease
at some
time in the future.
(3) The stimulant and tranquillizing effects of
nicotine in man..
If we can achieve these objectives in substantial
measure within
reasonable time, and can then persuade the medical
authorities and the
public that we have done so, we will have gone a
long way towards solving
the main problems of smoking and health.
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November 1999