en. Rm
W RESP~ml
Research
DOT/SEV/1.4.2
Dre X.V. Hughes - Louisville,
R.S. Wade - Montreal
'Horrn H. SoKorf - Hamburg
Mansger, Mo. - EydzL*y 18th January, 1973
Dear
ITO/11RC Conjoint Meeting
22 nd-23rd Nevembere 1972
We have now received the official Hinutee of the
above
mooting which supplement my own noteeo circulated
to you under
cover or my letter or 29th November# 1972. A
photocopy Is
4 ~ttachod.
Vith kind regards#
Yours sincerely,
D.G. TKLTOK
Attachmont
cc s Dr reen
*a
Dr: CS Evelyn
Dr. S.
CD
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Minutes of uie ITG 1HRC Conjoint Meeting held at
Huntingdon on 22 123 November 1972.
Present:
ITG Mr. J.G. Burgan UGB) HRC Dr. L.E. Mawdesley
-Thomas (LEM-T)
Dr. J.H. Chesterfield (]HC) Mr. D.H. Barry (DHB)
Dr. R. Binns (RB)
Dr. L.F. Chasseaud (LrC)
BAT Dr. D.G. Felton (DGF) Dr. R.M. DagneLl (RM D)
Mr. P. Healey ( P.Healey
Dr. P. Hey (PH)
Mr. B. Hunter (BH)
Mr. B.F.J. Page BFJP)
Dr. R. Stables RS)
Dr.G.L.Willey (GLW)
1. Pattern of future meetinas JGB said that he had
formed the impression that the Working Group
meetings had set a useful pattern and seemed to
serve a very useful purpose. LEM - T con-
firmed that he was much happier to discuss
research matters very openly in small and informal
groups. Large Conjoint meeUngs had the serious
weakness, apparent to everybody, that it
was unreasonable to waste the time of a large body
of people In discussion of small detail as
was done at the Working Group. Although,on rare
occasions, these latter meetings had become
a little abrasive he was generally very pleased
with the way they had gone. DHB confirmed
the real utility of getting to grips with small,
but vital, points of scientific detail.
LEM -T felt, with this development, that there was
a diminished place for detailed scientific
discussion of current projects at the Conjoint
meetings, Probably the most useful function of
there would be to discuss future research policy.
)GB considered that the decision to reduce
Conjoint meetings to two annually was very
sensible. What future structure and function would
they take ? LEM - T said that it was important to
keep Dr. Bentley fully informed on research
progress and findings. JGB said that he would have
copies of the Interim Reports, for the
Working Group, and Minutes of the meeUngs.
Probably the best funcLion for the Spring meeting
would be to discuss in some detail projects for
the ensuing fiscal year to set the pattern. Three
main points should be on the agenda. 1. To discuss
ongoing work and any possible changes
in direction. 2. To look at problems which might
be coming over the horizon In the next twelve
months. 3. To provide more opportunity for
communication betweeh ITG and HRC on the
scientific rationale behind their research
proposals. The latter point was briefly discussed
with
the conclusion that, at Least sometimes, it must
have appeared that study proposals from HRC
had been rejected by ITG without adequate, open
discussion.
LEM - T asked for opinion on the Progress Report
before the members of the meeting. It was
brief but was it too much or too little In the
whole or in any section? It was Intended as a
basis for discussion and could be modified In any
way considered desirable. JGB, thought
that the size was about right. The general
conclusions and tenor of the work was adequately
presented and if more detail was required this was
readily available by reference to the Working
Group reports that had preceded it. LEM - T
considered this new reporting structure as advan-
tageous In that details were presented more
frequently and in smaller and more easily assin-d-
lated doses. JGB referred to Item 12 in the
Minutes of the Working Group held on 21122
August 1972 which recorded suggestions for future
reporting. This seemed to him to be very
sensible and he would support Its adoption. JHC
said that the basic problem was to get in-
formation to the right place at the right time and
the proposed system should achieve this.
PH said that the October meeting of the Working
Group had not resolved paragraphs 3 and 4
of the above Item. Could he have further guidance
? In brief discussion It was agreed that
these criteria should be applied (I) to
experiments either completed or temporarily
suspended
BATCO document for Province Of BritiSh Columbia 9
November 1999


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and (~i) to cr-ier experimental work concluded
after a rigid methodology had been defined.
Read in this ccntext sach reports would for the
time being exclude current work on short term
studies such as Sebaceous gland, Goblet cell and
Macrophage assays, because, although
now well advaaced, were still being developed.
JHC said that WSP had overall responsibility for
statistics with C. Harding looking primarily
Ot the mouse 5,Lin experiments. D. Watts was
getting more familiar with the other probelms.
The overall aim was to evolve a system of
treatment of results which satisfied the
statisticians
and, at the same time, remained comprehensible to
management. JHC said that he would resist
any suggestion that a separate Working - Group sub
- committee on statistics be formed although
It might be necessary for ITG and HRC
statisticians to hold as hoc meetings from time to
time.
JGB said that ae must be kept Informed at all
stages on statistical deliberations to avoid such
considerations putting unreasonable pressure on
other work areas.
LEM - T asked if DGF would care to comment on what
he had heard discussed. DGF said that
the RAT system was different in that a Research
Committee directed operations. In general,
Research Conmittee discussions had a lower
scientific content than those of the ITG- HRC
Conjoint MeeUngs. This was always at the
discretion of the Committee which had considerable
flexibility and a wide range of options.
JGB said that. due to re- structuring at ITG, it
was pertinent to ask If factory Research Direc-
tors should at:.--nd any future Conjoint meetings.
This would be mainly directed to keeping them
Wormed and Ueir scientific input might be small.
On the other hand they now would play a
larger part in terms of actual work Input. LEM - T
thought this a good idea and it was suggested
that they should be invited to the May Conjoint
meeting.
2. Cadmium Propisal JGB said that the ITG proposal
had been further discussed and It had
been agreed that it was desirable as a first stop
to analyse tobacco samples for this contami-
nation. If the results confirmed Its presence then
steps would be taken to find the stage In the
processing of :obacco where It was Introduced.
This work was to be undertaken with Bristol
University using Atomic Absorption
Spectrophotometry as the method. It was agreed to
discuss
the analytical procedure with RMD who had highly
speciaLlsed knowledge and experience of
this.
DFG said tha: BAT had looked into this problem In
1968 and had found Cadmium In tobaccos.
It was agreed that this information could be sent
to ITG if in fact it had not already been done.
LEM - T asked if this investigation had shown any
difference of Cadmium content between flue -
cured and air cured tobaccos because this could be
a vital factor In the present controversy.
DGF could nm recall the data but the amount of
Cadmium was very small and probably not a
hazard. PH pointed oilt that although the total
dose to the body was probably small the local-
Ized dose to lung tissue could be very high. Much
was known about the distributlon of Cadmium
but Little about the mobility. In consequence
Cadmium deposited in lung tissue might be re -
moved only slowly and it was known to be a serious
biological hazard. LEM - T said that there
was a large literature on Cadmium. PH said that he
had done a good deal of retrospective
searching on ttlis and the element had been
recognised as a toxicological hazard since at
least
the early 19 Vs. LEM - T said that the proposal in
the budget book had been rather hastily
thought up but 11RC would work out better
proposals and test methods for re - submission In
the
next fiscal year.
JGB said that the television programme last week
had highlighted the 'flue - cured' versus
'air dried' tobacco controversy and was bound to
cause some publiccomment. Should ITG
now consider this problem much more seriously than
in the past ? LEM - T. said that Cadmium
might be a crucial factor. Other evidence,
although each individual report was weak, when
considered in the mass there seemed to be a case
for more careful experimentation and more
critical appradsal. PH confirmed that he too had
reached the same conclusion from a study of
all the scientLfic literature which seemed
relevant to the arguments of the ' anti-flue cured
workers.
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JGB thought it reasonable for HRC to produce work
proposals, backed by adequaLe t1terature
surveys, for discussion at, say, the Spring
Conjoint meeting. JHC thought that, at least In
some Instances, there would be a good case for
establishing means whereby HRC could carry
out preliminary exploratory work on which
subsequent proposals could be based.
LEM - T said that this would be most helpful and
as an example cited the work on Vitamin C
being done within the framework of the 'R and D'
budget. This was on the basis of the argu-
ments of PH which, if substantiated, could result
in recognition of the detrimental biological
effects of the Vitamin C depletion known to occur
in smokers. On the basis of what was known
at present it seemed Likely that many of the
hazards of smoking could be diminished by an
appro-
priately high Vitamin C Intake.
3. U.S. Clearinq House LEM - T commented that HRC
had no access to this at present. It
would be helpful to know what was going on and
would improve communication. it would be
most unlikely that HRC would benefit financially.
JGB said that he would discuss the matter
with Dr. Bentley.
4. -Possible further new vroiects DHB thought that
the proposal to investigate the effect of
tobacco smoke on macrophages under ' in vitro '
conditions was valid. He knew that CarTeras
were using this method and It would be helpful if
he could arrange to talk to them. . This was
not tissue culture In the ordinary sense because
cell replication would not occur. Maintaining
macrophages outside the body would allow them to
be exposed to much more precisely defined
smoke concentrations than are possible In the
whole animal and could lead to a new and useful
bloassay system. . DGF said that BAT had been in
touch with Sivak but he had now given up
this type of work. LEIM - T said that it had been
agreed that tissue or organ work should be
done at TRC but he was not very hopeful that the
results would be meaningful. Techniques
had changed very much In recent years. He would
support this proposal for next year but, in
view of the decisions, was It worth the Labour of
looking at methods in great detail ?JGB
thought that a proposal should be submitted.
PH reminded the meeting of a few, somewhat
aborLive, experiments carried out on Mitotic
Index in respiratory epithelium. It seemed a pity
that this had not been followed up and it
seemed fundamental to any comparison of tobaccos
produced by different curing methods.
LEM - T agreed that at least a pilot study should
be done to establish quantitative methodology.
It would be an excellent Insurance should the
present bioassay systems prove unworkable In
practice.
JHC and JGB agreed that some thought should be
given to areas noi in the current programme.
DGF referred to the situation In Canada where It
seemed that too much effort had been put Into
developing methodologies and, consequently, too
little Into their application. DHB and LEM-T
thought that, despite this caution, It would be
sound practice to have other methods to fall back
on. In retrospect it seemed that the present tests
had chosen HRC rattler than vice - versa.
DGr described some experiments recently caiTled
out on hamsters. The animals had been given
methyWtrosourea as an initiator and then exposed
to smoke. A large number of laryngeal
tumours had been produced in six months. The test
therefore measured tobacco ' promoter
effects and had been prompted by -uncertainties
about these effects in mouse skin experiments.
' Promoter ' effects were very relevant to the
overall risk of tobacco carcinogenicity but many
workers in the tobacco Industry were worried about
the political Implications. LEM - T said
that the question of 5 vs. 7 day exposure of
animals, discussed at the last Working Group
meeting, seemed very relevant to this problem. JGB
thought that this could be most profit-
ably discussed in relation to the Progress Report
which formed the next day's agenda.
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BATCo document for Province of British Columbia 9
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S. ' R&D' Budqet JGB asked LEM - T for his reasons
for devoting sonic of this money to the
development of a now smoking machine. LEM - T
replied that he had felt justified on several
grounds. Due to lmpact~on losses. the modified
Dontenwill machine altered the T.P.M. -
VapOur phase ratio by a factor probably greater
than 2 : 1 and maintenance of the equipment
was a major, and expensive, problem. A new
machine, without these problems, could In the
long term save ITG much money and provide more
realistic smoking conditions. The present
design incorporated a Venturi tube to provide the
suction and It had been shown that this would
provide at least up to 6% smoke as measured by
nicotine concentration. Further details could
be discussed with the designers tomorrow. PH
remarked that he had been asked by LEM -T
for an Independent assessment of priorities in the
' R & D ' budget and had al3o placed the new
machine at the top of the list.
LEM- T passed to JGB a list of projects approved
within the ' R & D ' budget and stated the
reasons for their inclusion. Progress on each one
was being assessed at intervals of four
weeks. For scientific reasons he would have liked
to Include a study of Cadmium but had
deferred to the known views of ITG at that time.
Thursday 23 November Consideration of the Progress
Report and items arising therefrom.
6. Sebaceous qland supnression test DHB said that
there was at present little to add to the
Progress Report. Tests were now going ahead in
accordance with JHG's priorities to corn--
pare this test with known long term results. JGB
asked if the methodology now seemed com-
pletely satisfactory. DHB replied that confidence
had Increased considerably over the past
six months but there was still a small measure of
uncertainty about the possible implications
of the apparent two day cycle in hair growth. This
was the rationale of prcscnt experiments
using J , -2L and I kills on successive days so
that this could be statistically analysed.
JGB asked if, when this was done, the test
procedure could be regidly defined. DHB
pointed out that one further decision was
necessary before this could be'done. It was to de-
fine the number of mice used in each group to
provide the required statistical precision.
JGB asked about Immediate future plans. JHC and
LEM- T said that the work would follow
the priorities decided and Included some
replication tests. The test for 1DL would be post-
poned until the experimental design was more
defined. DHB, replying to JGB, said that the
present experiments were now running quickly and
smoothly and that It would probably be
possible to provide a ' Blue Book ' defining the
precise experimental. conditions during January
1973.
LEM - T asked if the present ' R & D ' studies
would have any impact on this. DHB thought
-that, provided that the Blue Book ' confined the
test to tobacco condensate only, there could
be no problems. The R & D ' study applied mainly
to the relevance of the method to more
general problems of carcinogenicity and the way in
which the test should be interpreted.
DGF asked if it was thought that the test would
apply if the ' initiator ' - ' promoter , ratio
of the condensate differed greatly from the normal
range. Tests carried out In Hamburg
suggested that the sebaccous gland test measured '
Initiator ' activity and that skin hyperplasia
was a better measure of ' promoter ' activity. LEM
- T said that he did not know the answer to
this. DHB said that an experiment with a pure
initiator, DMBA, proved the test for compounds
with this activity. The effect of surface activity
of mixtures was probably considerable and
experiments casried out with ' cutting oils ' had
shown large effects arising from the emulsi-
fying agents.
LEM - T asked for a progress statement In the ' R
& D ' study. DHB replied that he was study-
ing the ' activation ' effect In low doses or low
activity condensates. When it occurred the
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statistical treatment became complicated and
difficult to Interpret. When this had been done
It -as proposed to study the effects of order of
administration of ' initiator ' and ' promicter
and then to look at effects of various chemical
types of surface active agents. JGS said
that'ITG would awalt- these results with Interest
and especially any implications of them for
the basic test methodology.
7. Goblet cell tests JGB asked for a verbal
amplification of the Progress Report staternent.
DHB
said that during the past year there had been many
problems. With the availability of the new
Smoking area it had been possible to Improve
measures designed to reduce infections. Each
experiment had Its own room allocated. Between
experiments the room was sterilized with a
' formaldehyde bomb '. In progress now was the
large experiment covering the permutations
of smoke concentration, exposures per day and
number of weeks of exposure. Because of the
large number of animals Involved it had been
necessary to divide this experiment into two
parts.
The first part would finish by the end of December
and the second would follow Immediately. If
all went well with this it would provide a basis
for another ' Blue Book ' defining the conditions
to be used In the test. LEM - T pointed out that
this left out of consideration the ' 5 day , vs.
' 7 day ' exposure regime. DHB said that he could
offer no views on this except that It was
obviously desireable to check it. Provided however
the 'exposure regime was defined It seemed
probable that the test would be satisfactory. This
was further discussed and concensus
opinion was that a test to determine the above
point should be done.
DGF asked about using Goblet cell numbers as the
criterion of irritancy. LEM -T said that
most of the fundamental work on the origin of
Goblet cells had been done on those in the gut.
In the lung, there 'were problems about how they
became differentiated from basal epithelium
but it would require extensive research to
elucidate this.
JGB asked about statistical progress. DJiB said
that the current large test would provide a
much better basis for an examination of this
aspect. JHC asked in the meantime that as much
as possible of the raw statistical data of past
experiments be sent to WSP and it was agreed
that this should be done.
8. Pmokinci machines JGB said that most studies of
smoke Inhalation were hampered by lack of
knowledge of what happened in the smoking machine.
DGF said that Dontenwill's philosophy
was that, so long as a standard procedure was
adopted, this was of little Import. JHC and
LEM-T pointed out that this was unlikely to hold
when using ' NSM ' or other greatly modified
.tobaccos.
RB said that the modifications of the Dontenwill
machines had at least provided much more
consistent performance and less loss of TPM than
the original. Maintenance was however a
serious problem; machines had to be mechanically
checked and adjusted daily and It was neces-
sary to have a mechanic on immediate call in the
event of Interim troubles.
LEM - T said that this confirmed his view of the
necessity of a now machine of less complex
design. We should certainly give serious
consideration to shortening the time scale for the
development.
P. Healey showed the small Venturi device so far
tested for this purpose. It could produce a
vacuum of up to 4 ft. of water and, at lesser
airflows, ' SmoLe ' a cigarette very rapidly
producing up to 6% smoke concentration which could
be reduced by introducing extra air.
After ' smoking ' sixty cigarettes through it
there was no evidence of impaction occurring.
DGr suggested the possibility of using a ' fluid
logic ' system to maintain a uniform TPM
concentration from one end of the cigarette to the
other. This complication was however
considered unrealistic.
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',RB p 'ointed out that the budget allowed for the
purchase of three Dontenwill machines. If
the money for these, and their modifications,
could be re - allocated it would go a Icng
way to meeting development costs of the new
machine. If a change was to be made these
machines would be a waste of money. RMD again made
the point that the present Dontenwill
machine required a great deal of money for
maintenance and for nicotine assays.
DGF raised the question of international agreement
on smoking machine designs. LEM-T
thought that the Lorillard machine was likely to
be accepted. DGr was not sure aboLft this
a decision was more likely on political than on
strictly merit or scientific grounds.
9. Macroohaoe test Replying to JGB, DHB said that
the decision to use mice in place of rats
had been implemented. With a view to defining the
test a parallel experiment to the present
Goblet Cell test was being done.
10. Ultrastructural bioassays DHO said that an
experiment on.hamsters was in progress to de-
terrnine the exposure pattern necessary to produce
changes in the enzyme sys tems studied.
The description ' stained ' applied to Figures 4,
5, 6, 7 was accidental and not strictly
accurate ; the desciption should be ' Localized
JGB asked enlightenment on the meaning of the
changes reported and DHB explained these.
LEM - T summarized by saying that all were
connected with high energy systems and this was
related to Life or death of each cell. No decision
had been reached about which enzyme to
study in the endoplasrnic reticulum.
DHB outlined experiments on quanLItation. There
were problems in coupling a ' Quantimet
directly to the electron microscope. 7he most
likely direction seemed to be to take 35 mm,
photographs of the fields and to exaraine these by
a Quantimet.
11. fmphysema study DHB said that the 3 month kill
in this study had taken place but the
sections had not yet been read.
12. Ouantimet automation DHB said that p;,ogress
on this was very satisfactory and could
accelerate some work. He was glad that the
decision to make it an independent Instrument
had been taken.
13. Inhalation work RB said that ongoing studies
would help to evaluate the modified Donten-
will machine. Should the present experiment on
Emphysema be modified ? On discussion
it was agreed to maximise the exposure from now
on. LEM - T said that few changes were
expected in the early months. D14B pointed out
that in an early pilot experiment minimal
changes had been seen after three months of
exposure.
14. Smoke monitorina BFJP said that at present all
the modified Dontenwill machines were
monitored at weekly intervals for nicotine in the
air of the exposure chamber. On occasion
machines had been monitored throughout a working
day. Performance was quite reasonably
consistent In both test situations but occasional
larger variations occurred. In the present
form the machine was somewhat difficult to set up.
RMD surveyed the problem in general
terms. The need for consistent checking was time
consuming and expensive. An experi-
ment now In progress would enable a test schedule
to be designed to provide adequate cover-
age. DHB pointed out that the mean dose level
should be close to that stipulated and fairly
constant if meaningful biological results were to
be obtained.
PH suggested that a quick supplementary test of
smoke concentration could be obtained by
nephelometric methods using a Light - photocell
probe. At least It could provide an almost
immediate indication if smoke density was greatly
different from the normal range.
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R8 Said that he was of the Impression that weekly
monitoring had provided consistent figures.
DHB confirmed that the biological responses were
satisfactory. BFJP said that more confl-
denc e In the machine was needed. The variations
in smoke concentration were not large but
further confirmation was necessary.
15. Inhalation dosimetry BFJP said that now the
problems of spiking cigarettes with 14 C - hexa-
decane had been overcome and deliveries had been
deteradned it was justifiable to purchase a
Dontenwill smoking machine for the study. Initial
experiments had been done on a few mice
using a single 'Harrogate ' type smoker. Cutting
sections from frozen , Inflated Lungs had
Presented problems because of the great tendency
for the tissue to collapse. This was dis-
cussed and it seemed certain that a little further
experience plus internally available exper-
tise would solve this difficulty. BFJP added that,
despite these difficulties, autoradiographs
Of mouse lung tissue were in process of being
made. It was clear that much deposition was
occurring in the nasopharynx. Some was found also
In the oesophagus and a surprising amount
on the fur of the head.
16. Blood nicotine studies BFJP said that many
details of the current work had been given in the
Interim reports prepared for the Working Group
meetings. In hand at present was an extension
of the time scale to study the further decay In
nicotine and cotinine levels and, also to study
the cumulative effects of several doses of
nicotine at Intervals of about an hour. Similar
work
was also going on using Squirrel monkeys and doses
of nicotine used In the past EEG work
this would be correlated with brain distribution
also.
JGB asked If the sum of nicotine plus cotinine
could be related to the dose given. Were there
other metabolites, e.g. nicotine - N - oxide,
which contributed materially to the picture ?
BJFP replied that this computation had not yet
been done but It seemed unlikely to be a large
factor. A lot of data was being accumulated.
JHC said that a sample of cotirline had been sent
to PH' for HRC studies. Since this there
had been doubts about the purity and the suggested
method of purification. PH asked If the
suspected Impurity originated In the synthetic
method or it only general atmospheric oxidation
products weresuspected. In either case,
particularly the latter, preparative TLC might be
a better method of purification than the vacuum
distillation suggested by Mr. Phlilpotts. In
discussion It was agreed to return the sample to
ITG for further treatment.
DGF asked if any sex difference in the excretion
pattern had been noted. This seemed a real
possibility. BJFP replied that no data suggesting
this had become javailable.
17. Absorption of nicotine BJFP referred to rigure
11 of the Progress Report which was typical
of many traces obtained.with the flow- cell and
scintillation counting method. At present the
time constant of the apparatus was too short and
this resulted in an oscillating trace of the type
shown. A longer time constant was being
Incorporated and would give a smoother trace. This
would be ready very soon and experiments studying
both venous and arterial levels simultan-
eously would then proceed on the lines planned.
18. Brain distribution of nicotine BFJP said that
the plan to correlate brain levels of nicotine and
cotinine with those occurring In the blood. In
regard to cotinine there was some discussion of
the ' blood- brain' barrier during which LFC said
that the neonatal mouse was, weight for
weight, Less sensitive to nicoLine than was the
aduLt.
19. Mouse skin paintinci JHC said that there
seemed to be an Inordinate delay in the final
reports
on completed experiments. He suspected that most
of this occurred at Bristol In the statistics
department. BH said that all the results of
experiments up to and including 5- 21 noted In
the Progress Report as terminated had been sent to
Bristol.
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JGB. asked If any Important points were emerging
from the other experiments in progress. BH
replied that there was nothing to add to the
statements contained In the Progress Report. JHC
asked If any decision had been made concerning 5 -
24. BH replied that this had been dis-
cussed and that it was deemed desireable to let It
run to natural termination.
JHC reviewed the prognostications about future
work. The carbon fitter cigarettes for experi-
ment S- 32 were being made by Wilts and should be
ready by 29th January 1973. Bil asked
If this date was sufficiently firm to justify
ordering the mice. There were some delays and
uncertainties in delivery. It was agreed
justifiable to alert Carworth with a view to
supply-
Ing the mice for a start In raid - February.
Three out of the four cigars for 5 - 3 3 were now
going into bond but trouble might be experi-
enced with the fourth. It was thought probable
that this experiment could start in early
March.
Cigarettes for 5 - 31 had presented difficulties
in blending. at the Players factory and It was not
possible to forecast any starting date.
JGB explained the situation by saying that
facilities now existed at Raleigh Road for
manufac-
ture of small batches of experlemental c4garettes.
Equivalent blending facilities did not how-
ever exist and therefore reliance had to be placed
on the factories. ITG would do their best
to keep pace with experimental requirements.
Bif said that he had spoken to Mr. Kingman about
condensates for sebaceous gland tests cores-
ponding to early mouse skin painting experiments
and about which there seemed to be some
measure of confusion. JHG said that he would
discuss the matter with Mr. KJngman but clearly,
if results were to be compared, the condensates
should have been prepared under identical con-
ditions.
20. Prima e behaviour studies RS said that this
study was In the process of run down towards
temporary suspension. During the last two weeks
experiments had been possible using a back
pack injector which could be switched on and off
by radio control. This system had many advan-
tages in that injections could be made at any time
without disturbing the animal. The initial
results were very encouraging. After a 20 minute
control pcriod, nicotine adrninistration had
produced significant changes in the CAIFR
schedule.
JGB asked for prognostications about publishing.
RS replied that It was hoped to add some of
the later data obtained with the new back pack In
this paper. Analysis of the existing data into
a form suitable for publication would take some
time. In further discussion It was agreed that,
If possible, the paper would be submitted during
March 10,73. LEM - T said that It was useful
to have a definite date clearly in mind but that
It should not be too rigid ; undue haste or
pressure
would probably be to the detriment of care and
quality.
21. Self administration experiment RS reported
that, as stated in the Progress Report, the first
restraining arms, despite their basic strength,
had not survived more than a few weeks of trial.
A new, and much stronger, jointed steel arm had
been devised and this seented quite satisfac~
tory after 5-21 weeks of use. A cannula had been
implanted in one animal on this arm and was
being tried out using saline and the lever and
associated recording equipment to obtain base line
data. Nicotine solution would be substituted for
the saline In due course. RS was cordident
that steady progress could be maintained. There
was some general discussion of the objective
of this experiment and speculation regarding the
outcome. PH said that the ultimate objective
was to measure motivation to obtain nicotine and
the degree of addiction It would produce.
22. EEC, studies JGB said that there was no
statement In the Progress Report on this. RS
replied
that all that could be reported at this juncture
was that design of equipment was being actively
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pursued and, In fact, the Hewlett- Packard
representative was coming this day to discuss
final
dctaLi Is .The estimated cost at present was
between E13,500 and C14,000 as compared with
the provisional figure of El 3, 500 in the budget.
This small increase was due to minor design
modifications considered necessary since the
budget was drawn up. LEM - T asked to be In-
formed immediately if the figure of El 3, 500 was
exceeded. JGB asked LEM - T to get In
touch with him If there was any budgetary
difficulty.
23. Lonq term rat physioloqy studv RB could add
nothing to the statement In the Progress Report.
The experiment would be stopped In mid- December.
PH asked JHC; If the supply of the two
' Fletcher ' cigarettes-was adequate for this and
was assured that there was no cause for present
concern. JGB concluded that there seemed to be
little prospect of useful results. RB replied
that when the results were analysed there would be
a clear difference between control and smoke-
exposed animals but Little chance of
distinguishing between cigarettes. The experiment
had been
proposed and conducted in good faith but failure
should be acknowledged. PH thought that the
failure might, at least in part, be attributed to
the use of the original Dontenwill machines which
provided only a low smoke concentration.
JGB asked if any other useful information could be
got from the data. LEM - T said that sub-
ject to the budgetary limitatlons he would get as
much pathology done as possible.
24. Monkev smokina experiment RD said that the
Progress Report statement presented the situation
adequately. Studies of lung mechanics showed
emergence of a clear differentiation between
control and smoke exposed animals but the Latter
could not yet be separated according to cigar-
ette type. Considering all the data together it
seemed Likely that the situation could now change
rapidly. The animals continued to ' smoke ' thirty
cigarettes a day this being the maximum
practicable. The interim report to the Working
Group showed that smoking animals showed a
reduced gaseous exchange. In this, and other,
measurements lung size must be taken into
account and calculations could not be expressed on
the basis of group- mean data. The new
lung function machine and computer would
automatically take variations of this nature into
account.
JGB asked to be reminded how far out was this
study. RD replied that the animals had been
smoking for fifteen months. JGB said that,
Initially, two years had been envisaged. LEM - T
said that this had been discussed at the Working
Group. In terms of overall useful Information
It might be good value to continue for
considerably longer. JGB noted that the
possibility of
changing from five to seven days per week exposure
had been discussed. LEM - T thought it
undesireable to change parameters in the middle of
an experiment. DGF suggested that the
smoking groups could be split so that half the
animals were exposed for Ove days and the other
half for seven days each week but RD and LEM - T
pointed out that the resulting sub- groups
would be too small and the expense of operation
would be considerably Increased thereby. JGB
asked for recommendations about this. It was
possible that in the long run it might save some
cost by a reduction of the total time. It was
agreed that HRC should estimate running costs
and make these recommendations to him. PH asked
that WSP should be consulted before any
decision on a change was implemented.
JHC said that Figure 8 ( p. 18 ) In the Progress
Report seemed to him to have the control and
.smoked ' animals Inverted. PH confirmed the
correctness of the Figure however ; the point
was explained in the first paragraph on p. 19. His
Initial reaction on seeing the Figure had
been the same as JHC's and he had immediately
consulted with the authors.
25. Mouse Irritancy tnst The results of very
recent experiments on TRC cigarettes were
discussed.
The order of ranking seemed to be 16 17 < 18 < 19
< 20 but statistical interpretations
would change this to 16 = 17 < 18 19 = 20.
RB said that the last Working Group had discussed
measuring Irritancy of known, single major
smoke components. So far, this had not been
followed up because much time had been used in
Q:)
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training new staff. Statistical analysis of
results could now be based on linearity and there-
fore presented fewer problems than the current
Progress Report implied. Replying to DGF,
RB said that although most of the irritancy was
connected with the particulate phase there were
nevertheless some differences in vapour phase
Irritancy.
DGF asked if particle number might be a major
factor in determining irritancy. This interesting
point was briefly discussed. JGB summed up by
saying that there would be formidable practi-
cal difficulties but the matter might profitably
be discussed with Peter Adams. RB said that
WSP had asked for much data on this test. He would
send this on but could not understand the
reason for the request. JHC thought that WSP
wanted to see If other analytical methods could
be applied to the data for discussion at a Working
Group meeting.
26. ~unq clearance study RB said that the monkeys
were in process of being monitored after three
to four months of exposure to smoke. B. Wolsgrove
was confident that meaningful results were
emerging but it was important to realise that this
could not be done On the basis of group mean
data. Quite short exposure to smoke produced
changes of the type shown In Figure 9 (p. 26
of the Progress Report which showed a delay In
onset and reduced rate of primary clearance.
The two colour presentation of FIgure 9 excited
brief comment. PH said that this was not diffi-
cult to do. Registration was accurate, within 0.5
mm, and the printing department welcomed
the exercise as a small break from routine.
27. Materials for cvtoqehiCity studies JGB
promised to look into the supply situation. LEM-T
said that it was important to avoid undue delay
because the work had to be completed in the
current fiscal year.
28. Atherosclerosis study The present study was
stated ( LEM - T ) to be well in hand and should
start early in January. The HRC staff were pooling
ideas and these could be discussed at a
future Working Group but probably not at the one
scheduled for January. In the meantime some
aspects of methodology for quantitatior, were
being actively pursued. Before the next phase of
the experiment It would be necessary to decide
what smoke components should be given to
animals and the meams of adminstration.
29. PMO study RIC said that ITG had tried the
publishcd synthetic method for this material.
The yield in a small scale experiment had been
satisfactory but it dirairdshed in larger batches.
How much would be required ? PH said that he had
looked into this and had concluded that for
a Goblet Cell test, as at present designed, the
requirement would be about 60g but this would
depend on a fcw factors such as weight of tobacco
in cigarettes and the exposure parameters
decided. He would look Into the matter in more
detail and transmit the data and considerations
to Jlic.
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Decisions taken at the meeting
Minute
1. The present system of Working Group meetings,
held at about two monthly Intervals,
and supplemented by Conjoint Meetings In the
Spring and Autumn was satisfactory.
The style and information content of Reports for
both types of meetings was likewise
satisfactory. An important item on the Agenda of
the Spring Conjoint meeting would
be to discuss, In open session, study proposals
for the next fiscal year.
ITG factory researcn directors should be Invited
to attend on-e Conjoint meeting annually.
2. There should be a discussion on means whereby
HRC might carry out limited exploratory
experimental work on whicn to base proposals ror
larger studies.
3. There should be discussion of and possible re -
appraisal of the ITG1 HRC 1U. S. Clearing
House for smoking and health situation.
4. A 'Blue Book ' giving a standardized procedure
for the Sebaceous Gland Suppression test
could be published in the near future, probably
during January 1973.
7. 'Blue Books ' giving standardized procedures
for the Goblet Cell and Macrophage tests
wuuld be published cis soon as possible. This
would probably be during March 1973.
a. Some of the monies scheduled for purchase of
additional Dontenwill smoking machines In
1972173 should be diverted and used to accelerate
progress on the development of the
'HRC' smoking machine.
Ii. The sample of impure coUnine, sent to 11RC,
would be returned to ITG for examination
and purification.
23. As soon as possible after cessation of
experimental work a paper for pubLication of
results
obtained in the Primate Behavioural Studios should
be written. The objective would be
to submit this during March but this urgency
should not ba to the detriment of careful
analysis and presentation.
22. Any increase, envisaged only as small, in the
Capital requirement for the EEG programme
would be discussed with JGB.
23. As much pathological examination as possible,
wiViln the budget structure, would be done
on the rats used in the long - term physiology
study.
24. Consideration would be given to increasing the
monkey exposures from 5 to 7 days per
week. HRC would provide information on the
additional cost of doing this. WSP would
be consulted If any change in the regimen was
considered practicable or desireable.
27. JGB would look into the supply of materials
for the cytogenicity studies as a matter of
urgency.
29. PH would provide JHC with data to establish
the amount of PMO needed to be synthe-
sised at ITG for the study of this compound.
(Z--)
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