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SMOKING AND HEALTH: FUTURE STRATEGIES FOR RESEARCH
1. EPIDERIOLOGICAL-Er"MILS
M Luna Cancer
Research claigin& that smokiN is associated with lung cancer
Further research on this topic is unlikely to be a high
priority. for the scientific community except to study the
associations between low tar products and disease. In order
to be of use. such studies would have to study a generation
who bad smoked qMJX low tar products. It would also be
necessary in drawing comparisons with previous generations
of smokers, to control for additional factors that mav have
changed in this generation e.g. dietary habits.
It is arguable that the tobacco industry should be carrving
out such research. However, this is a very long-term
project (answers could not realistically be expected for 25
years) and it is likely that. by then. the product may have
changed significantly. The results may not therefore be
directly relevant to the product of the future. In any
case. a number of such studies are known to be aLreadv in
progress e.g. funded by the ISCSH in the UK.
Other factors associated with IS" cancer
Such studies have limited value. The list of facturs
associated with lung cancer is now extremely, Ions. However.
it does not-direetiv adetress the association between smnkinst
and lung cancer unless it could he shown that. one or more af
these fac are r,,2nf ciundipjg ractors e.g. all smoker-4 who
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develop lung Cancer are pet bird keepers or are exposed to
diesel exhaust. Such research does. of course. serve to
combat suggestions that smoking is responsible for 90% or
more- of alL lung cancer deaths and resulting publ icitF may
draw attention to the fact that smokinx is not the onl v. nor
even the major factor claimed to be associated with certain
diseases.
Trends'in disease-and in cigarette looking
It has been noted by a number Of scientists (e.s. Peter Lee
using 'cohort analysis) that there is frequently a poor
correlation between the trends in a disease such as lung
cancer in the population, and patterns of cigarette
smoking. As above the value of such studies is that they
can point to the relative importance of other factors in the
disease e'.g. environmental factors. Unfortunately, the
studies are unlikely to achieve more than to point out that
anomalies exist and suggest they are due to other factors;
the identification of yhigh other factors is unlikely to be
fe sible. It is also impossible, because of inadequate
de:th certificate information, to know whether changes in
disease rates are different in smokers and non-smokers.
Trends in lung cancer sgbtXRes
A number of studies have now been published suggesting that
lung cancer rates are increasing in non-smokers relative to
smokers. This Is frequently linked to a selective increase
in lung cancer subtypes that have been found to occur less
frequently in smokers e.g. adenocarcinona. It would be
useful to investigate this trend further.
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(II) Cardiovascular disease
Research claininK that smoking Is
associated Mith cardiovascular disease
- Studies are still appearing on this subject, investiSAting
the various subtypes of cardiovascular disease. In general.
risk ratios e.g. (averaging 2 - 3 for coronary heart
disease) are low enough for many such results to fall into
the category of 'low risk epidemiology' and therefore to be
su6ject to the associated problems.
- Atheros6lerosis underlies many of the cardiovascular
diseases that are claimed to be associated with smoking. and
is also relevant to peripheral vascular disease. Particular
attention should therefore be paid to literature relating to
atherosclerosis when evaluating the claimed association
between smoking and heart disease. It Is noteworthy that
the SRG is currently supporting work in the area of
mechanisms of atherosclerosis. with Professor Kakkar at
King's CaLlese London.
- Intervention studies (e.g. MRFIT) have shown that if
individuals stop or reduce smoking there Is no benefit in
terms of a reduction in heart disease risk.
Other factors ass2giat2d with heart disease
Approximately 245 different factors have been claimed -.o be
associated with heart disease. It would therefore be
ppropriate to have such studies high on a lis' of
priorities.
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Diet has long been suspected to be a major risk factor
associated with coronary heart disease; however. recently
Professor Michael Oliver of Edinburgh University suggested
that it could be a confounding factor in studies claiming an
association between smoking and heart disease. He suggested
that the claimed increased risk in smokers was not a direct
effect of smoking, but an indirect result of smokers having
a -poor diet. Such work is certainly worth further
investigation
(HO
Research il Siming that swking is assoclAf&d
with increased risk of bronchitis and embysem
It is frequently stated that only smokers develop severe
emphysema; this claim is worthy of further investigation.
It is certainly not the case for bronchitis.
Other factors associated witb respiratory disease
- A large amount of research has suggested other factors that
have been associated with both bronchitis and emphysema.
Again. there is probably little direct value in giving high
priority to this kind of research.
(iv) Other diseases
A number of other cancers and diseases have been claimed to
be associated with smakint. For most of these, authorLtieS
such as the US Surgeon General accept that the ev is
insufficient . to determine that a causal relationship
exists. For other cancers. however. a causal rel at ictsh
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has also been suggested e.g. laryngeal. oesophageal and
oral cancers. The majority of industry-funded work has
tended to concentrate on lung cancer and therefore
relatively little attention has been paid to anomalies in
the lit erature relating to other cancers. It would be
useful to pay a little more attention to these diseases in
future.
EPTDENIQLOGY: 'IMPLICATIONS FOR RESEARCH
Kilh Priorit
Trends in lung cancer subtypes. It would be useful to commission a
review considering whether the dissociation between adenocarcinoma and
squamous and small cell carcinomas (in terms of their association with
smoking) is a distinct one. From this, for example, it may be
suggested that surveys should be carried out in key countries to
provide more information about the relative incidence of lung cancer
in sackers and non-smokers, and associated subtypes.
Diet and heart disease, in particular relation to diet as a
confounding factor in the association between smoking and heart
disease. Michael Oliver could be approached as an initial step.
Is it the case that only smokers develop severe emphysema? A
consultant's opinion could be obtained as an initial step.
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Low Priority research
t. Trends in disease in relation to cigarette sookinx habits.
- Research into other factors in smoking-associated diseases e.S. pet
birds.
- Wng-term epidemiological studies into the effects of changes in the
product.
2. MOLE=AR BIOLOGYMECHANIM OF DISEASE
Lune Cancer
- The most informative study in this area would be to identify a
genetic factor 'that Increases the risk of lung cancer. and to
investigate whether incidence of the particular factor is different
in smokers and non-smokers. Idle's work on metabolism of
procarcinotens has so far covered the first part of this question,
but has not yet adequately covered the second. However, before
additional funding were to be committed, some additional questions
need to be answered e.g. do the enzymes that Idle is interested In
metabolism chemicals that may be relevant to the development of
lung cancer?
An alternative approach comes from Dr Helmut Bartsch from the IAJtC
In Lyon. Dr Bartsch is investigating the relevance of P-450
systems in animals, which may shed some Light on Professor Idle's
research. They have also carried out work In smokers investigating
the activity of such enzyme systems. which appear to be induced
during smoking. Further research of this kind would complement
Professor Idle's work, and possibilities are currently being
discussed with Dr Bartsch.
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A large amount of attention (both scientific and media) has been
paid to the formation of DNA adducts for chemicals that occur in
cigarette spoke. It is frequently assumed that this might have
some bearing oh carcinosenesis. However, this is by no means
certain. and a recent review by Ashby (1988) suggests that care
must be taken in application of tests based on such measures. It
may not be appropriate to actually carry out research in this area
if the relevance i.-V in total doubt, however, Dr. Peter Farmer.
Dr. Bartsch and Professor Bruce Ames are potential contacts in this
area.
Inswunolony is another area that is increasing in importance. For
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smoking. it has so far been relevant in two different areas: M
respiratory disease and (ii) cervical cancer.
(I) A number of studies have claimed that smoking affects immune
components of the respiratory system e.g. alveolar
macrophage activity. The relevance of such studies is not
totally clear but it has been suggested that a reduction in
immune capacity would render an individual susceptible to
disease and possibly even to the development of cancer. It
would be extremely useful to have a review of this area to
assess the potential need for further research in the field
of Immunology.
(II) A study recently suggested that Langerhans cells. a
component of the immune system. were reduced in the cervix
of smokers. It was claimed that this reduced immune
activity would make individuals more susceptible to viruses
that may be associated with cervical cancer. However,
Langerhans cells are just one component of the immune
system: others were not studied. Aga a review would be
useful leading to further research If necessary.
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Heart Disease
Lt is frequently claimed in the scientific literature that smoking
raises blood lipid levels and affects clotting. It would be useful to
have someone review this area in order to anal yse the evidence and
determine whether more research would be useful.
Biological testiar for LI
An extremely-large number of recent reviews on the subject of
carcinogenicity t6sting have cautioned that extreme care must be taken
when extrapolating. from in vitro and in vivo genotoxicity tests to
human carcinogenesis. The relevance of such tests is not an yet
established. Similarly. the appropriateness of other non-genotaxic
annual models 6f carcinogenesis to the human situation has been
questioned. Bearing this in mind. there would seem to be so
particular value in spending a great deal of effort in developing new
tests until such time as their relevance and the appropriateness of
the model is more clear. The exception to this, of course, is that
where regulatory authorities recommend the use of specific tests for
the purposes of testing novel or modified products, when we should
ensure that we have the capacity to carry then out.
Nish priority research
- Genetic differences that say influence the risk of lung cancer.
Already being carried out with Professor Idle, and approaches made to
Dr Bartsch at IARC.
- A review of immunology as it relates to smoking-associated diseases
e.g. respiratory disease and cervical cancer.
- A review of the claimed effects of smoking on factors that my be
relevant to heart disease.
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Low priority research
- ..Research related to the formation of DNA adducts. until such time as
its relevance to carcinosenesis is more clear.
- Detailed research into novel animal models of carcinogenesis,
including both in vitro and in-vivo studies, except where recommended
by regulatory..authorities.
3. ENVIROMENTAL-TODAMD SMOKE
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- With the majority of studies (17 out of 23, with all their
flawsi showing no statistically significant effect, there is
little justification for carrying out others.
- Studies of potential confounding factors in epidemiological
studies would be very useful. Although Peter Lee is still
very enthusi"tic about misclassification, it is not gaining
particularly wide acceptance as a critical factor. Further
studies in this area are unlikely to be of value (there are
already several). It would be more useful to concentrate on
other factors such as diet; this is currently being
investigated in Hong Kong, e.g. by Linda Koo.
cold, - The majority of studies have not shown a significant
association between ETS and heart disease; however, there
are some studies showing a significant association between
ETS and the development of respiratory effects in small
children. Further analysis of these studies would be
useful . along with some research into potential confounding
factors.
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GO Indoor Air Oual I ty
- Research into sick building syndrome has established that
ETS is mat a significant factor. It is unlikely to be
useful to carry out further research in this area unless
required for specific purposes. e.g. in countries where such
studies have not previously been carried out.
- We now have (thanks particularly to the Southampton ErS
programe), a large body of data indicating that ETS is
present- in extremely low levels in a large variety of indoor
situations. Future research in this area should probably
now be restricted to studies that are useful for particular
purposes e.g. to fight an airline ban on smoking; or in
countries -where EM is just emerging as a problem, to give a
local example of the kinds of levels of ETS that may be
present in the air. For example. it has been suggested that
there has been little investigation of ErS levels in the
workplace in the USA.
- Research into indoor environments in wars climates has been
relatively neglected, and it way be useful to carry out a
study in such a country. This is currently being
investigated with Covington & Burling in the Par East.
- Further investigation into the correlation between measures
of nicotine levels in the air and measures of nicotine
Levels in saliva would be useful to address Martin Jarvis'
work in children, which claims that they have very high
cotinine Levels in saliva if their parents are smokers.
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Gii) Chloistry at ErS
- Volatile organics in the air maybe of importance,
particularly since the EEC are concentrating upon them. It
would be useful to have more information about levels in the
air.
- Aldehydes are major constituents of ErS: it might therefore
be useful to know more about their concentrations and
behaviour.
- Information about levels and behaviour of "other nozae' in
ETS ,@ould be useful if it were possible to measure them.
High Priority research,
- further research into confounding factors in epidemiological studies
relating to US e.g. #let.
- Analysis of studies claiming to show respiratory effects of ETS in
small children, with a view to further research Into e.g. confounding
factors.
- Research into levels of ErS components in buildings that will serve a
particular purpose e.g. to combat a ban La a particular country. The
ErS group in Southampton should be available to do this.
- Research into levels of ErS in buildings in wars climates e.g. Far
East or Central America. Currently being Investigated with Covington
& Burling, and in Costs Rica.
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- Further investigation into the correlation between measures of
nicotine Levels In air and in saliva. Currently underway by Chris
Proctor.
- Research (where possible) into levels of 'Other Mozae' in ETS.
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PciguLty-muArsb
M fill ics of Misclassirical ifin.
Research into sick building svndrome.
Non-Largeted research into I eve I of ETS component , in air.
4. THE EFFECTS OF NICOTINE
M Addictiah
- It is 4ifficult to identify research areas that will have a
bearing on the subject of whether or not nicotine is
,call addictive-' There is al readv some evidence indicat:nx
differences between nicotine and drugs that are gene
accepted, to be addictive, from both human and ania4l
studies. Any additional evidence in this category would be
useful but is should be borne in mind that even amongst 'he
drugs that are accepted to be addictive there are
differences.
- Work on alternative theories or explanations far why per;.
smoke would be more constructive. To date. David Warburt
has been something of a lone voice on the suggestion thAt
sackers smoke. not because they are addicted. but because
smoking fulfils is useful runction far them. An analysis 1
the validity of Warburton's claims and further. art
detailed work in this area is already going on At :-@e
University of Leeds.
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I t is extrem-1 di rf iruj I10) i dent i fV I-t-search into
biological wechanisms or acid i c I i on. x i rwe i I i s nev I t: I ea r
what they Actually are. However. BAT is already supporting
work in this area with Dr Rnv Wise in Montreal, I oak at
effects of nicotine compared to other drugs in brain
pathways and behavioural systems relating to reward and
dependence.
(ii) Other effects
- Since there are a number of scientists who agree that
nicotine has no carcinogenic or cardiatoxic effects.
research in this area should have low priority.
- Effects of nicotine in situations of stress. anxiety, and on
wood and performance are all relevant to the addiction
question and therefore worthy of support. Work in this area
is already planned &L the University of Leeds.
5. PRODUCT 140DIFICATION AND INNOVATION
To date. scientific evidence concerning specific components of
cigarette smoke does not easily form a firm basis for the removal of
specific compounds from cigarette smoke. Many of the animal models in
which these compounds have been tested have little relevance tG the
development of cancer of the lung. However. in spite of this, bo -
such as the rARC and regulatory authorities around the world nave
issued lists of compounds that they believe to he part icu I ir I%
problematic in relation to cigarette smoke.
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From a pragmatic polint fit hev.114%4- the %6ent if it- eviderivs. 1%
4:1)"I. Utis i vt; and because I hese ro%u I a I co rv ;6111 hus. i I ills wuls I if I befts'..,
nced t t) approve an@- signif ocant. joroduCt modification tit innovat; its.
the acts t sensible approach for BAT In adapt. would be its foll4ito It-!ir
recommendations as far is possible. The following areas hAve ':ten
-.0ansidered by regulatory asithoriLies:
1. Lower Tar i.e. non-specific reduction uf all smoke components.
It is generally believed that. in markets such as the UK, tat mas
now been. reduced to the limit in terms of consumer acceptAbil:tv.
Regulatory authorities such as the ISMH have therefore suggested
that the tar:nicotine ratio of the product be altered such thit
lower @ar does not result in lower nicotine. This. of course.
assumes ' that nicotine is the most crucial component of cigarette
smoke. Work, in this area is conf I icting but the overal I consensus
has been that the nicotine level thaL smokers generally take in is
0.8 mg per cigarette. The recommendation also assumes 'hat
nicotine is an acceptable (in "health" terms) component of
cigarette smoke. Such an approach is certainly valid and RothmAns
are also known to favour it.
2. Reductign in specific components. This has been considered in
detail by BAT in the "Other Noxae" list. and a similar appr:lch
was adopted by RJ Reynolds in relaLlon to 'Premier'. In 4ny
product modification or innovation, reduction or removal of tbtse
compounds should have priority.
3. Nicotine, It is generally accepted that nicotine is not
senotoxic, carcinogenic or teratogenic. Although Hoffman anti -.is
group have assumed that nitrosamines formed from nicotine MA% bf
carcinogenic. this idea has not received widespread scientific
acceptance. For cardiovascular disease. many scientists aVet
that nicotine is not cardintoxic. such errects an nicotine car bt-
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seen to ho% -- tho I h,- r.ird i tovawul as s v.% t ein al r .,cute .118-i n.)t
sixni f icani I v LI if ferent Is in t it.. elli-i-ts gil mild exerci%e. -.he
maji)r a r ea of sc i en t i f i t- c on t rove r 4. %- re I at i nn I onicol ino itt
whether it is addictive. However. IN! VS Svirrvon-General'.-,; Re-,--,r1
made surprisingly little impact except Amongst anti-smoking groups
and the cri.ticisax that list been made of it e.g. by Da-.id
!@'Warburton are valid and acceptable to many scientists. Except ior
the problem of the "imaite" of nicritine (it ip a drur; without it.
is would lie difficult to argue that smoking is addictive thert Is
presently no justification for its removal. Hevertheless. Wt do
not want a. product based on nicotine alone; the pharmaceuticAl
companies are covering this field ititite adequately.
Philip Morris., however, have taken a different approach and
too,", introduced a n icotine-free cigarette. It will be interesting to
set whether or ndt this is acceptable to the consumer.
4. Sidestream Lm_g&. Regardless of conflicting research res;:ts
relating to the claimed effects of ETS, regulatory authorities
have reduction of sidestream as a priority. This should Le a
priority of BAT for aesthetic reasons, even if its reduction -.for
health reasons is not justifiable. Regardless of the health
issue, many people would like to see smoking banned because they
find it is unpleasant and an irritant. Reduction of sidest:tan
spoke is therefore a critical response. It would be particula-tv
useful to decrease visiblq sidestream.
Testin of product modification or innovations
This area has been considered in some detail by the SRG in rclatilir to
RJR's launch of 'Premier' and the projects currently being undertaken by
the BAT group. During the SRG's review process it was suggested that !he
comprehensive approach of RJR had perhaps set something of a preceilent.
and that it would probably be necessary for future prexturts 1: 'w
subjected to an equally exhatustive battery of tests.
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The most critical area to consider is on what grounds. i.e. on the basis
of what tests, would a regulatory authority be prepared to concede that a
particular new product might provide some kind of advantage over existing
products?
In their various reports and discussions. regulatory authorities have
considered the aspects of tobacco products discussed above (lower tar.
reduction of specific components. the role of nicotine and the presence of
sidestreas smoke). It would be necessary to have a regulatory authority
concede that a -company had followed its recommendations in producing a
/0011*1 novel product; if-it did so then by definition It would have to concede
that such a product must constitute an improvement over existing
products. Presumably then, for example. the UK Independent Scientific
Committee an Socking and Health would have to concede by its own criteria
that a product that had lower "tar". lower specifically identified
chemicals and lower sidestresm. would represent an improvement over
current products.
Complications, - of course. arise if. in modifying the product or
introducing a totally novel product. new constituents are used and
different chemicals are produced. It would then be necessary, as far as
possible, to determine that these novel constituents did not have effects
that could be interpreted as toxic. This is the process that was
undergone by R. J. Reynolds in relation to glycerol as a major constituent
of 'Premier'. A list of biological tests that the SRO considered that
regulatory authorities would wish to see carried out is appended.
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