PRIVA7E & CONFIDENTIAL.
C_ 7 RESEARCB CONFERENCE
HELD AT KRONBERG
6 th JUNE, 1969.
2 nd
Present: S. J. Green (Chairman) 1".-:-.1; 7.
Sir Charles Ellis
D. G. Felton 2 7 "N
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.-: .. ........ .. .............
R. B. Griffith
I. W Hughes ... . . . ... .............
R. A Sanford
F. Seehofer . ............
11. Sottorf
.
.............
R. S. Wade
MINUTES In resp onse to several requests it was
decided to
expand the minutes somewhat for this Conference,
but each member
agreed to be responsible for presenting a full
story to his Company
management if this is required.
2. The Conclusions of the previous Conference were
reviewed.
3. It was suggested that the the U.K.
representatives should emphasise
at the T.S. C. "Skin-Painting Conference" their
interest in the
T4/T29 comparison. This appears to be a
significant alteration in
mouse-skin bioassay reaction brought about by an
alteration in
tobacco composition. T. R. C. are hampered in
following this up by
the practical difficulties of specifying the
actual compositions of
T4 and T29. The Conference agreed to invite T.
S.C. to communicate
their findings to Dr. Griffith of the University
of Kentucky, explaining
why they could not follow them up and hoping that
the University of
Kentucky would use the wide range of tobaccos at
their disposal, of
known genetic origin, to investigate how great a
variation in "mouse-
skin reaction" could occur within a conventional
classification, e.g.
Virginian flue-cured, Burley, Oriental, etc.
Following a discussion
of the differences in the bioassay results on T.R.
C. samples T4
and T29, Dr. Hughes agreed to produce a paper on
the laboratory
tests which could be made to investigate this.
4. Fractionation experiments at Harroqate. The
Conference devoted
some time to considering the value of this line of
research. They
took note of the T. S.C. paper E 1628, which
attempted to set out
the objectives. The general opinion was that this
work should be
continued in the hope that it would be possible to
identify specific
initiators and promoters. CD
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5. Herr Sottorf re-~Aewed the Lokstedt I
Programme, and mentioned
that the Lokstedt II Programme would include
different reconstituted
tobaccos; it is not yet clear when these results
would be published.
Mr. Wade outLined the new projects which the
Canadian Industry
would be suppcrting at McGill University and the
University of
Montreal. Dr. Felton agreed to ensure that
Montreal were kept
informed of similar studies by Dr. Fletcher and
others supported
by T. R. C.
6. The position in the United States, with respect
to the gas phase,
was discussed, and the general opinion is that
this will become
an important issue, and that some publication of
the analytical
results for certain gas phase constituents will be
made within
the near future - possibly within one year. It was
guessed that the
constituents which will be measured would be
selected from the
following: acrolein, carbon monoxide,
formaldehyde, sulphur
dioxide, nitrosamines, formic acid, oxides of
nitrogen, hydrogen
sulphide, hydrogen cyanide, and phenols. It is
likely that this
will lead to great activity in the areas of
charcoal and water filters.
Dr. Sanford undertook to produce a list of
analytical methods and
their costs, and methods of removal; Dr. Felton
will consider
toxicity aspec--s and the problem of estimating
the overall toxicity
of the gas phase.
7. Dr. Griffith e--,mressed the view that H,E.W.
accept that a mouse-
skin safer ciaarette is a worthwhile objective and
the Conference
reaffirmed their opinion that this was a
worthwhile objective for
Group Research.
8. "Bridqinq the Gap". The Conference agreed that
this was an
experimental problem which could be specified and
attacked
experimentally. They accepted that to make a start
on this, it
was necessary to set up some hypothetical model of
how smoke
aerosol could cause cancer in the basal cells of
the humah'luqg
epithelium. n. ey accepted that the views advanced
by Sir Charles
Ellis could form one such hypothesis. and could
form a basis for an
investigation. In broad terms, they supported an
investigation into
the absorption of smoke constituents by the mucus
of the lung, the
identification of what was absorbed, and what
changes occurred in
time. They recognised the significance of studying
the effects on
the basal cells of such a modified mucus blanket,
but realised
that it constit7ited a major and difficult
research project that lay
beyond the resources currently available to
members.
9. Short-term toldcity and other tests.
Historically, bioassay
c:::)
experiments were undertaken by the Industry with
the object of 11~0
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clarifying the role of smoke constituents in
pulmonary carcino-
genesis. The most widely used of these methods,
mouse-skin
painting, proved onerous and time-consuming, and
therefore
expensive to carry out and attempts were made to
find "short-
term tests". Many such have been proposcad and
developed,
and it is important to note that they were
regarded and assessed
as more speedy tests for cardinogenesis, or at the
least as
screening tests for which samples should go
forward to long-
term painting tests. When, however, it began to be
appreciated
that the physiological effects of smoke aerosol in
the broad field
of "bronchitis" were important in their own right,
as distinct
from carcinogenic effects, it became apparent that
some of the
short-term tests might be more directly relevant
to this
phenomenon.
Thus the current position is dominated by the
uncertainty of the
role. of the short-term tests, and the profound
effect that the
resolution of this uncertainty would have on the
use of mouse-skin
painting.
A priori, it seems unlikely that a short-term test
can give relevant
indications on what is essentially a long-term
process, unless
and until we can identify the early callular
changes leading to
carcinogenesis. At present, this is not in sight.
On the other hand, long-term and short-term are
descriptive phrases
which must be interpreted in relation to the life
cycle of the organism
being studied, and there is a possibility that the
experiments taking
place at R. & D.E. , Southampton, with the
membrane of the chicken
embryo might be showing genuine carcinogenic
effects in days.
The conclusion of the Conference was that at the
pre.5ent time the
Industry had to recognise the possibility of
distinct adverse
health reactions to smoke aerosol:
(a) Lung Cancer
(b) Emphysema and bronchitis
and present and future bioassay tests could
usefully be classified
according to their applicability to one or other
or to both.
10. The hyperplasia test has been developed into a
dependable empirical
technique that can be used to grade smoke
condensates. It shows
a high but not complete correlation with
mouse-skin bioassay. It
is probably closely related to "bronchitic
effects" but the nature of
this relation is not understood. The sebaceous
gland technique
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has been studied intensively and there is a body
of expert opinion
which considers that it is possible that it may
correlate closely
with longer-term carcinogenic effects. The
majority of the other
many biological reactions that have been studied
seem more
related to immediate toxic effects than anything
else. The
Conference took note with interest of B.A.T.
(Hamburg) experiments
and also of T. R. C.'s collaboration with
Professor Latner on studying
the relative amount of Lactic Acid Dehydrogenase
isoenzymes.
In an attempt to take a broad view of this
complicated situation,
the Conferance reached the following conclusions:
(a) In the foreseeable future, say five years,
mouse-skin
painting would remain as the ultimate court of
appeal on
carcinogenic effects. -
(b) There was a possibility that short-term
cellular phenomena
such as hyperplasia, sebaceous gland suppression,
alteration
in cell metabolism, reaction of chicken embryo
membrane,
might develop sufficient credibility to lighten
the burden of
mouse-skin work by screening.
M However the preceeding decision developed, it
was
already clear that techniques such as hyperplasia,
observation of goblet cell activity, and anything
that
could be directly related to changes in cell
behaviourism
marited intensive study in their own right. The
immediate
action agreed was:
W To acc-:!pt and use hyperplasia as an empirical
grading system of tobacco smoke under the proviso
that this interpretation of the results was the
responsibility of the user.
(ii) To support research into the meaning and
interpretation at the cellular level of the
various
short-term tests -
11. Dr. Green stated that hyperplasia tests could
be made available to
members for about $ 1 , 000 per test - Dr.
Griffith and Herr Sottorf
felt that greater sensitivity might be required
before adopting this
test routinely but Dr. Fordyce was of the opinion
that vttempts at
further refinement would be a waste of time. It
was agreed, however,
that, with a test of this nature, it would be wise
to take samples
with maximum differences in order to establish the
trend likely
to be found with commercial samples rather than
submit proposed C=)
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12. Dr. Seehofer suggested that It was desirable
to discover in all
short-term tests the dose level which gave a
constant and optimal
response rather than to assume that all dose
response relationships
were linear. It was agreed to consider this in
relation to all our
short-term tests.
13. Members agreed that the results of all the
work done on samples
from individual companies could be circulated to
all members of
the Biological Testing Committee, preferably
identified by code
numbers. Dr. Green said that the intention was
that the results
of tests specifically paid for by a sponsor would
not be circulated
without the permission of the sponsor. *
14. Mr. Wade agreed to ask Dr. Nisbet (Montreal)
to circulate a note
on his suggestions regarding antagonistic
relationships between
smoke constituents and metabolic intermediates.
15. Following a discussion on the progress to date
on the measurement
of small solid particles in smoke deposits, Dr.
Sanford agreed to
circulate articles supplied by WITCO and
Pittsburgh companies
suggesting that the inhalation of small carbon
particles was not
hazardous. Dr. Green agreed to approach AMCEL and
Tennessee
Eastman for their views of the possibility of risk
from the inhalation
of small fragments of cellulose acetate.
16. The Conference reviewed the progress made in
reducing the amount
of carbon monoxide In smoke and agreed that it was
very unlikely
that a substantial reduction would be achieved by
filtration, and
therefore attention is being given to alteration
in the factors
controlling combustion conditions or overall
reduction of the gas
phase by ventilation.
17. Dr. Green drew attention to the proposed
non-tobacco "cigarette"
which, it is said, will be marketed by Courtauld's
Ltd. , at the
end of 1969. This is believed to contain oxidised
viscose staple
fibre and iron oxide, to be free from nicotine and
to be undergoing
a superficial bioassay test programme. It was the
view of the
Conference that such smoking materials should be
the subject of
serious biological study before being offered to
the public but the
difficulties of achieving this in all cases were
recognised. It was
agreed that T. R. C. should be urged to apply all
available methods
of bioassay to effect a comparison of non-tobacco
smoking materials,
e. g - lettuce etc. , with conventional tobaccos.
18. The work on the microbiological flora of
tobacco had been started
at R. & D.E. , Southampton. So far, there would
appear to be no
danger from bacteria, but work was continuing on
moulds where CD
there might be a hazard associated with
mycotoxins. Dr. Sanford
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said that Louisville were in agreement with this
view.
19. Dr. Green described the NAC cigarette case
which carried a
radioactive substance claimed to reducL, TPM and
nicotine in the
smoke of cigarettes stored in the case, and said
that, in addition
to being ineffective, it contravened the U.K.
Ionising Radiation
Regulations.
20. It was agreed that it would be helpful if
bodies such as T. R. C.
could be urged to investigate the smoke from
cigarettes made
from tobacco claimed to be free from pesticides
and lower than
normal in fungal spores, e.g. VENTURE.
21. The Conference reviewed Dr. A. K. Armitage's
paper on nicotine,
which confirms the intuitive approach which has
guided Group
research on nicotine in the past.
22. Following a discussion on the possible
relevance of free radicals,
Dr. Fordyce undertook to formulate a research
programme which
might resolve the matter, and which could be
undertaken by one
of the bigger laboratories.
23. A discussion followed on the criteria which
might be adopted in
considering new smoking materials, modified
cigarettes with
health orientation, and changes in commercial
cigarettes. It was
agreed that the criteria included:
W Mouse-skin painting
(ii) Hyperplasia tests
(iii) Chemical analyses for carbon monoxide and
other gas
phase components, as well as other chemical
substances,
e.g. benzpyrene
(iv) Goblet cell test
(V) cytotoxicity tests
(vi) Ciliastasis and paramecium tosts
24. Following this, a question was raised
concerning the desirability
and difficulty of weighting these tests in- som-,
way. Dr. Green
proposed an approach based on the analysis of the
important factors
common to all tests, and rating these numerically
in importance.
Each specific test may then be assessed in terms
of these factors
to yield an overall summation representing the
relative weighting.
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The Conference felt this approach was worth
pursuing further
and Dr. Green agreed to attempt this with the help
of research
staff at Southampton.
25. The Conference reviewed the progress of
studies of smoking
behaviour in the U.K. , U.S.A. and Germany,
carried out since
the last meeting and concluded that these were
important not
only from the aspect of smoking and health, but
also because
of the light shed on market requirements. For
example, it has
been indicated that smoking consumption tends to
vary with the
bodyweight, which might lead to the suggestion of
lighter,
thinner cigarettes for women; there is also some
evidence that
heavy smokers tend to maintain their intake of
smoke constant,
even when the size of the cigarette or its
delivery of TPM is
changed. If this finding were to be confirmed, it
would be a
matter of great significance, particularly in
relation to the social
objectives in publishing TPM figures.
In view of the likelihood that smokers may modify
their smoking
habits when presented with impingement filters,
ventilated and
cther unconventional filters, it was suggested
that these products
should be evaluated using a "slave" smoking
machine and a
number of human subjects.
26. The Conference agreed that all the evidence
continues to demonstrate
the importance of nicotine to the smoker, and
again emphasises the
importance of keeping separate TPM and nicotine
figures. It was
suggezted that all analytical data should be
reported in relation
to the nicotine values.
27. There was a full discussion on the use of PEG
as an additive to
filtcrs to enhance the removal of phenol(s) and
the Conference
agreed that it would be generally desirable to
continue its use,
although it was recognised that cost savings could
clearly be
achieved if it were eliminated. The substitution
of extra triacetin
for PEG is not as effective in phenol removal over
a long period.
It was interesting to learn from Dr. Fordyce that
consumer tests
showed a preference for filter tip cigarettes
containing PEG;
results from Canada and Louisville tended to
confirm this.
Because of the German Food Regulations, PEG is not
used on
filters in Germany.
28. There was a discussion on the use of DEG, and,
while the Conference
appreciated the special position in G,-~rmany, it
endorsed the AGP
recommendation. Dr. Seehofer pointed out that the
DEG used
was subject to a rigidly specified limit of 0. 04%
monoglycol.
While it was recognised that the AGP Minutes
should not include
the scientific detailed reasons for the
recommendations., Dr. Felton CO
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agreed to supply the background scientific
references to the
decisions for the use of research staff
29. Herr Sottorf informed the Conference that,
although the threatened
ban of the use of coumarin on tobacco products had
not yet occurred,
the German Industry had voluntarily discontinued
the use of
coumarin on cigarettes, while continuing its use
on pipe tobaccos.
Dr. Seehofer agreed to send the relevant
scientific paper by Bar
and Griepentrog to Dr. Felton, so that the matter
might be taken
up with BIBRA. Meanwhile, the Conference agreed
that the
Additives Guidance Panel's advised limits should
stand. There
was some discussion on coumarin substitues, and
Dr. Sanford
agreed to supply samples of octahydrocoumarin
either directly
or ihro'ugh Dr. Hughes.
30. The Conference considered the bioassay results
of PEI-treated
filters, and although these are somewhat
inconclusive, suggested
an upper limit of 3% weight of the filter.
31. There was a general discussion on non-tobacco
materials and,
largely due to the difficulties foreseen with the
addition of
nicotine, the Conference did not envisage at
present the likely
success of a totally non-tobacco cigarette.
However, it now
seems quite likely that non-tobacco materials will
be successfully
incorporated into cigarettes as blend
constituents, particularly
in health orientated products. A large usage of
non-tobacco
materials would be likely to increase the demand
for high-nicotine
tobaccos.
32. It is foreseen that the use of reconstituted
tobaccos will increase
both for economic reasons and on health grounds,
despite the
possibility of increased carbon monoxide
production. It also
appears likely that some of the non-tobacco
binding materials
are becoming more attractive. Dr. Seehofer agreed
to supply
samples of cigarettes, made by a variety of
reconstitution
processes from a single blend of tobacco, for
submission'to the
hyperplasia and other short-term bio tests. Dr.
Fordyce also
offered to send some cigarettes containing
non-tobacco binders.
Dr. Hughes suggested that R. & D.E. might examine
the combustion
characteristics by thermo gravimetric analysis and
other techniques.
The proposal that ethanol-extracted tobacco might
be combined
with one of the non-tobacco binders was accepted
and Dr. Seehofer
undertook to arrange a supply of such a product at
the optimal sheet
thickness. This means in the long run that the
basic technology
of the cigarette industry will move more into the
realm of chemical
engineering, and this could have important effects
on many other
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33. The Conference considered what the
characteristics of the "safest"
cigarette might be, in terms of the criteria
established earlier. It
would contain some or all of the following
features:
(a) . Reconstituted and/or non-tobacco smoking
materials
(b) CRS treated by the St. Pauli or similar
process
(c) tobacco bearing additives to modify combustion
(d) a triple filter containing carbon and possibly
water,
sodium carbonate, manganese dioxide
(e) possible construction as an axial and/or
ventilated
cigarette
It was decided to accept as a research objective
that such a prototype
cigarette should be developed. When it is judged
to have sufficient
acceptability of taste as a prototype product, it
should be manufactured
on a scale sufficient to permit complete bioassay.
Dr. Hughes agreed
that R. & D. E. , Southampton, would undertake
this, and Dr. Seehofer
offered to supply stems treated by the St. Pauli
process.
34. The ARIEL project was reviewed and samples
were distributed by Dr.
Hughes. It was agreed that this had been well
worth pursuing, but
it was felt that this should not be taken further
at this stage. It
was also agreed that the patent coverage might
well be reduced to a
few key countries.
3 s. The Conference recognised that problems
associated with pesticides
and insecticides were matters of world-wide
concern to the whole
industry, and were outside the competitive field.
The special
position in Germany was appreciated by the
members, and it was
agreed that any specific information requested by
Dr. Seehofer
should be sent to him as quickly as possible.
36. The Conference was informed of the current
investigation into
Black Fat tobacco, and agreed that, prima facie,
further investigation
of this product would be desirable on health
grounds.
37. There was a general discussion on the role
played by the new Research
Planning section, established following the last
Conference. Great
appreciation was expressed all round for the
service being provided
on Smoking and Health Information, and
particularly for the critical
commentary provided. The planning activity,
however, has not yet
proceeded far enough for its usefulness to be
assessed. Sir Charles
Ellis suggested that the various programmes,
including Harrogate,
Lokstedt, JANUS, and Huntingdon, might be usefully
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under the following headings:
(a) Modified Tobaccos
(b) Health Research
(c) Consumer preference and psychological and
physiological factors
(d) Process Improvement, etc.
The Conference agreed to assist in this task by
informing Dr. Felton
of the project objectives listed in the
programmes. The aim is for
each laSoratory to control its own work in such a
way that it
integrates into a total effort, so that the
laboratory gets the
maximum advantage.
38. There followed a full discussion on the
application of Rasearch
and Development techniques for Product
Development. It appears
likely that Philip Morris, in particular, are more
successful in this
thanB.A.T. Dr. Griffith adversely compared the
general position
of Research in the B.A.T. Group with that in
Philip Morris. He
reported that Philip Morris are currently doubling
their research
expenditure and stated, for example, that they are
using low
resolution mass spectrometry techniques to
determine how to
utilise Venezuelan tobaccos.
The members reviewed the methods of analysis of
competitors'
blends, and recognised that all the techniques
available rely on
visual examination and separation which is
necessarily time-
consuming and somewhat crude. It was agreed that
there would
be enormous advantage if more precise techniques
could be
developed but there was no indication that this
was likely.
39. A general discussion on the problems of
product design and sensory
assessment concluded that professional psychology-
- cbuld play
an important part in this field, particularly if
integrated Into
research programmes along with other disciplines -
40. Owing to the trend towards reduced TPM and
nicotine, it was agreed
that more attention must be given to flavour. It
was, however,
pointed out that in some situations the
maintenance of nicotine
delivery at the normal level may overcome taste
and flavour
deficiencies due to low TPIA. The use of
non-tobacco materials
would accentuate this problem. The use of
finely-cut tobacco and
tobacco extracts in the filter in order to enhance
the flavour are C=)
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41. The Meeting agreed that, in general, a
substantial reduction in
TPM (e.g. from 15 mg to 10 mg) will lead to
considerable differences
in taste and that these differences will be
observed particularly when
the observers are aware that changes have been
made; however, as
far as the reaction of the smoking public is
concerned, it may be
possible to make such changes without significant
reaction, especially
if these are made slowly.
42. In discussing the possible taste deficiencies
associated with low
TPM cigarettes, Dr. Fordyce suggested that
attempts might be made
to express sensory responses in terms of intensity
per unit weight
of TPM..
43. The Coiiference confirmed its belief that the
trend towards multiple
filters, including carbon filters, would continue.
This should
achieve lower gas phase deliveries. In this
connection, the idea
put forward by Dr. Smith of Montreal on mixed-bed
filters with
coincident specificity was considered well worth
pursuing. Mr.
Wade agreed to follow this up and to explore the
patent situation.
44. General opinion was that further filter
development should be
aimed largely at changing the composition of the
smoke in a desirable
sense, instead of merely reducing the total
quantity of smoke.
45. The Conference agreed that Montreal should be
encouraged to pursue
their suggestion on the treatment of tobacco with
sodium silicate in
order to alter smoke characteristics.
46. Dr. Fordyce described the treatment of
Australian tobacco with 2%
citric acid in an autoclave for short periods of
about 2 minutes,
and the benefits conferred on the smoking
qualities. The irritation
of the smoke was reduced, and there was a marked
increase in the
filling power of the tobacco. Dr. Fordyce will
send details of this
process to members so that the effect on a wide
variety.of tobaccos
can be investigated on the laboratory scale. The
Conference agreed
.that this could represent an opportunity for
co-ordinated action by
the Group, which could obtain results more quickly
and over a wider
range than those which could be achieved by any
one Company. It
was agreed that, if the process continued to look
promising, R. & D.E.
Southampton, would make a more detailed study of
the effects on smoke
quality; Dr. Sanford also offered, subject to B. &
W. Management
approval, to carry out a theoretical study of the
scale-up of the
process. It was agreed further that Australia,
Southampton and
Louisville should consider the patentability of
this process in various
countries
47. Following an account of the similarity between
the changes which
can be brought about by processing conditions, and
those attributable
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to ageing, the meeting felt that considerable
caution should be
exercised in reducing holding times in the tobacco
process, and
in terms of tobacco durations, merely to gain
short-term economic
advantages in terms of inventories etc.
Nevertheless, there may
present an opportunity for the development of
methods of accelerated
ageing.
48. Freeze-drying of tobacco was discussed,
particularly in the light
of the recent publicity from the University of
North Carolina. The
process is in a very early stage of development,
and is unlikely
to become of any importance for the next few years
at least. It
was concluded, however, that such a process might
affect the
combustion characteristics of tobacco, and it was
agreed that
R. & D.E. , Southampton, should explore the effect
of this and
of other processes in this respect.
49. Consideration was given to the Interesting
proposal advanced by
Dr. Smith of Montreal for the ozone treatment of
tobacco and the
conclusion was that R. & D.E. should consider this
as part of
their general programme of Investigating the
effects of various
tobacco treatments.
50. Mr. Wade reported on the progress made at
Bristol on the irradiation
of tobacco for mould inhibition. This work is
continuing.
51. There was a discussion on information
retrieval and the progress
of keyword coding at Louisville, Montreal, Hamburg
and Sydney.
Dr. Sanford agreed to circulate his keyword
thesaurus, and to
send to Southampton the keywords so far abstracted
from R. & D.E.
reports. The other members also agreed to
circulate their keyword
indices.
52. The Meeting was unanimous in agreement that
the Conference had
been well worthwhile, and it agreed that a period
of about nine
months between meetings seemed about right.
53. Dr. Green thanked Herr Sottorf and Dr.
Seehofer for the excellent
orgranisation and for their hospitality. It was
agreed that, in general,
there were considerable advantages in holding
these Conferences at
places not too near Company operating centres. Dr.
Green suggested
the next meeting might be In the United Kingdom at
a date to be agreed
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