Minutes !LR(; Meetluz
Chelwood Jan 2U-22 1987
Those Present: Ur R E Thornton - BATCo Chairman
Dr S Boyse - BATCo
Dr C P J de Siqueira - Souza Cruz
Dr F Seehofer - BATCF
Herr E Koehn - BATCF
Dr F Knabjohann - BATIG
Dr 5 Massey - Imperial, Canada
Dr G Smith - BATUKE
Mr M. L Reynolds - B&W, USA - Jan 21 only
Also Present: Mr A L Heard - BATCo - Jan 20 only
(part-time) Dr R R. Baker - BATUKE - Jan 20-21 only
Dr E Massey - BATUKE - Jan 20-21 only
External
Participation: Dr G Gori - Franklin Institute, Washington.
USA Jan 21-22 only
Mr A Campbell-Johnson - UK Jan 20 only
Dr F J C Roe - UK Jan 20 only
Dr P B Farmer - Medical Research Council Laboratory
Carshalton, UK - 20 Jan only
Mr M Burke - UK - Jan 20 only
Tuesday 20 January 1987: PRESENTATIONS FROM EXTERNAL PARTICIPANTS
1. DNA and Protein Adduc Ls: Dr P k_E_atRe_r
Dr Farmer described current work at the MRC laboratories, Carshalton.
Sur re) , England.
DNA and protein adducts excreted in urine were estimated
quantitatively by GUMS analysis, although Dr Farmer pointed out that
mg quantities of such adducts as methyiated guanines were excreted by
subjects in normal health. Because of this background 3 -ine
adenine had been used instead (background levels bein3 10-3
smaller).
Ilowevet most work had been carried out with protein adducts, compounds
such as S-meth%lcvsteine or S-ethylcysteine being measured. The
sensitivity of this method was 1 in 109 amino acid residues.
equivalent to 1 in 1010 DNA residues, haemoglobin in 5ml blood
samp I es being adequate and having a long half Me (- 4 months).
More recently hydroxyetliFlviline adducts had been used (and ethylene
oxide identified as the a agent). By use of the Edman
degradation technique thiohydantoin derivatives could be obtained.
amenable to GURS techniques.
Using this method increased levels of adduct were identif ied in
smokers compared to non-smokers and in subjects occupationally exposed C=)
to ethylene oxide. 141.0
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2. other Now Mr M Burke
occupational exposure limits had been established for many compounds
on the basis of exposure for a lifetime of working 8 hours/5 days a
week. This could be applied to compounds listed in the UK ISC Third
Report. possible interactive effects being ignored.
Using the long-term limits set by the UK Health and Safety Executive,
and assuming each puff is diluted to 500cc in the lung, and all smoke
is cleared. the following compounds exceed the exposure limits:
Acrolein
Carbon Monoxide
Formaldehyde
Hydrogen Cyanide
Cadmium compounds
On threshold: Acetaidehyde.
In consideration of these compounds individually, Mr Burke made the
following comments.
Cadmium Compounds
A protein (MW 20-30,000) was excreted when chronic Cd poisoning
occurred. This could be monitored in smokers to determine if
significant cadmium exposure occurred.
In discussion Dr Roe referred to the animal studies an cadmium
compounds being carried out at the Fraunhoffer Institute, and which
had resulted in lung tumours.
Formaldehyde, Acrolein. Acetaldehyde
Mr Burke said that the ciliotoxic data was of dubious value as it was
measured in solution. Vapour-phase levels were needed.
The reasons why acetaidehyde was included in the third report of the
ISC was obscure but at high levels it apparently produces increases in
blood pressure.
Carbon Monoxide
Mr Burke was of the opinion that carbon monoxide might be a particular
problem in smokers with a heart condition as it would stress cardiac
output.
3. Dr Roe
Dr Roe's slides are enclosed as Appendix 1.
Dr Roe emphasized the problems caused by the lack of satisfactory C=)
animal models for lung cancer, heart disease and emphysema although a I'D
number of other approaches were available (slide 4). Currently tests co
for ciliotoxicity and carcinogenicity/mutagenicity were available to ___.j
supplement chemical data. co
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Wednesday 22 January 1987: S.R.G. DISCUSSIONS
4. other Noxae
Various outside publications were considered as a possible basis for
establishing priorities for "other noxae . These included the 1986
IARC Monograph (Appendix II). the 1986 MAK list and the third report
of the ISC. A variety of views existed: while the IARC monograph
considered individual smoke components as, of course, do most
regulatory authorities the ISC took the view that there was
insufficient evidence to incriminate individual smoke components
although even they had requested upper limits for tar. nicotine and
carbon monoxide. While most of the discussion centred on individual
chemical constituents of cigarette smoke it was noted that free
radicals and 'radioactivity' could also fall within the guidelines.
Dr Roe had also commented on the problems associated with the
restricted range of animal tests evaluating relative risk and
additional problems existed in respect of likely
synergistic/antagonistic effects.
After further consideration it was suggested that other noxae should
be considered at two levels:
1. Compounds where recent scientific data had not yet been evaluated
by regulatory authorities.
2. Compounds where regulatory authorities had made, or were likely
to make recommendations which would result in pressure to alter
the product.
Under these two categories the following were considered:
1 (a) Compounds forming adducts with DNA or Proteins - While Dr Farmer
had developed an interesting analytical approach to measuring
exposure the interpretation of his results were, at present,
equivocal. It was agreed that this area should be monitored, but
at present, no further action was required. However a literature
review, and possible opinion on the likely sources of the
ethylene oxide moiety attached to proteins, was required.
I (b) Bis-dichloromethylether - After discussions it was agreed that a
literature survey should be carried out on possible analytical
methods for measuring this compound, its possible occurrence in
the environment generally and its biological properties, to be
ready for the next meeting.
1(c) Free Radicals - TAC (UK) were having a presentation on this
subject in February from an UK expert, Dr B Ralliwell. It was
agreed that this subject would be reconsidered it the next
meeting after a report on Dr Halliwell's presentation.
I (d) Heavy Metals - Further work on cadmium was known to be in co
progress, but had not yet been published. Accordingly, it was -4
agreed to watch for developments in this area. co
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2. Compounds receiving attention by regulatory bodies in Canada and
Germany are listed in Appendix III and those identified by the
IARC and the UK ISC can also be considered here.
Polycyclic hydrocarbons, nitrosamines - No new evidence had
occurred on polycyclic hydrocarbons in recent years and Dr Roe's
results (no increase in skin painting activity with lox excess of
benzo(a)pyrene) were noted. Likewise Dr Roe reported that the
recent meeting at-ranged by the ISC on nicotine and its
metabolites (especially tobacco-specific nitrosamines) was likely
to conclude that these compounds were not sufficiently important
to preclude the development of low tar normal nicotine products.
Nevertheless, because these compounds were known animal
carcinogens they were likely to be the subject of constant
attention by regulatory authorities.
If Mr Burke's method of prioritization was accepted the following
compounds exceed TLV levels and result in the following
priorizitation order: Carbon Monoxide
Acrolein
Formaldehyde
Hydrogen Cyanide
Acetaldehyde
possibly cadmium depending on chemical form
It is to be noted that acrolein. formaldehyde and acetaldehyde
are all ciliotoxic.
Finally it was noted that countrv-to-country valuations in the
attitudes of regulatory bodies towards other noxae are
inevitable.
Further discussion on the other noxae was agreed (see p. 7)
With regard to Mr Burke's comments an carbon monoxide in relation
to smokers with a heart condition, it was felt that medical
advice was available on appropriate changes in life style for
those suffering from this, or any other illness.
lo- 5. Research on Nicotine - Dr S Boyse
For further details see hand-outs by Dr Boyse (Appendix IV).
Major recommendations were that further work should be carried out in
areas of nicotine receptors, and the effects of nicotine and
psychological tests on performance and memory.
6. Other Proiects
Visits were pending to Professor Clamp in Bristol with regard to his
ulcerative colitis project and to Dr Carter in London regarding his
project on atrial natriuretic peptide factor. Work in both these
areas was about to start. C=)
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It was noted that Professor Caro, whose project on atherosclerosis the ___4
SRG had felt unable to support, has written a letter requesting that 00
his project be reconsidered. It was not felt that the position of the
SRG should be revised on this account.
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7. Conference on Nicotine
A Symposium on nicotine will take place in Brisbane. September 1987 as
a satellite of the IUPHAR conference of Pharmacology. Dr Thornton and
Dr Boyse will be attending this on behalf of BATCo and will be
reporting back to the SRG an the outcome of the conference.
S. Possible New Projects;
a) With regard to the question of the effects of nicotine on
performance. Dr Stavrou of the Royal Free Hospital had been
approached with regard to his computerized tests on psychological
function. He had expressed interest in carrying out a small
study on the effect of smoking in these tests as a preliminary to
a possible long-term project. It was hoped that a further
proposal would be available in May.
A group in the Psychology Department in Leeds University headed
by Dr Ian Hindmarch might also be approached on this question.
b) In the area of nicotine receptors Dr Susan Wonnacott, currently
funded by the TAC, tentatively suggested that BAT might consider
continuing her funding when it terminates in 1988.
O Jeffrey Gray - Professor of Psychology at the Institute of
Psychiatry in London - had approached Dr Boyse about possible
funding for a joint project with Professor Raymond Levy and Dr
Barbara Sahakian on the effects of nicotine in patients with
Alzheimer's disease. The sun requested was approximately 466,000.
over 3 years. There was general agreement on this and it was
noted that Dr Thornton and Dr Boyse would visit the group and
report further in May.
It was also felt that a possible protective effect of long-term
smoking in the development of Alzheimer's disease was a separate
but equally important issue that should be investigated. It was
decided to ask Mr Peter Lee. a BATCo Consultant, to review the
literature in this field and ask his advice about a prospective
study. Dr Hassey also noted that Dr Verner Knott in Canada might
be involved in such a project and he agreed to pursue the matter
and report to the SRG in May.
d) Dr Thornton said that- a provisional application had been received
from Professor V V Kakkar for work related to the development of
atherosclerosis. The full project had not yet been received but
would probably relate to mechanistic studies involving a
polypeptide growth factor thought to be involved in the
development of a plaque.
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e) Dr Gori noted that correlations had been'nade between mental
illness such as schizophrenia and manic-depression and heavy
smoking. It was believed that there may be therapeutic benefits
of smoking to these patients. It was suggested that this area
should be closely watched in the future.
Dr S Hassey would also report on Verner Knott's possible work in
this area in May.
9. Dr Seehofer gave a general overview on his visit, with Graham Smith.
to Japan. For further details see their report (Appendix V).
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Thursday 22 January 1987
10. Report on visit to Japan
Dr Smith explained the background and highlights of the visit to Japan
made by himself and Dr Seehofer.
In particular it was noted that Dr Hireyama now works in virtual
isolation. A substantial amount of work on nicotine is being carried
out under contract and in the context of a substantial programme of
work on other materials. Much work had been done on
self-administration of these materials by monkeys, as described in the
visit report.
Delegates felt that the visit had been very successful in establishing
the scope of relevant research in Japan and in breaking the ice. In
particular the work of Dr Tomoji Yanagita, on behavioural effects of
nicotine in comparision with other materials, was thought to be of
considerable interest.
It was considered essential to capitalize on the visit by keeping in
active contact.
11. Scope and Venue of next meetings
It was decided that future meetings would retain the broad format of
the present meeting with presentations by outside speakers addressing
themes identified by the SRG. The following programme was suggested:
May 25-27 1987, Hamburg - Social Acceptability of Smoking, further
views on Other Noxae.
Nov 2-4 1987. Rio de Janeiro - Research work sponsored by Tobacco
Industry.
April/May 1988, UK - Molecular Biology.
Possible Speakers
Hamburg: Prof. Pavlik, Prof. Jurna. Dr Yanagita
Rio de Janeiro: Dr Sheldon Sommers, Representative of Japan Tobacco
Inc.
UK: Dr Currie, Prof. gloom, Dr Carter
12. Final Discussion, critique
During the final discussion the meeting's progress towards assessing
other noxae was reviewed. It was concluded that a further discussion
was needed (to be incorporated into the May 1987 meeting of the SRG)
and that BATCo (Dr Boyse and Dr Thornton) would produce a discussion co
paper which would attempt to integrate the views propounded at 4
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Chelwood. together with other relevant material. Delegates would then C:)
attempt to reach some conclusions on the prioritization of "other L.N
noxae".
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Action Points
I. The scientif ic literature relating to DNA and protein
adducts should be monitored in the future, and a
literature review on the likely origin of the ethylene
oxide moiety attached to proteins should be prepared. GS
2. A literature survey on bio-dichloromethyl ether should
be carried out: the means f or measuring it; its
possible occurrence in the general environment, and
its biological properties. GS
3. A report to be given an Dr Hallivell's presentation on
Free Radicals. GS
4. It was agreed to fund Professor Raymond Levy's
application on nicotine effects and Alzbeimer#$
Disease for the sun of L66, 000 over 3 years.
Drs. Thornton and Boyse would-visit the group and
report back in May. RET/SB
S. Peter Lee, a BATCo consultant. should be asked to
review the epidemiological literature in the field of
long-term smoking and the development of Alzheimer's
Disease. Dr Massey would Investigate possible work in
this field going on in Canada. RET/SB/SRM
6. It was decided to keep in active contact with Japanese
Scientists following a visit made by Drs. Seehofer and
Smith. GS
7. Drs. Thornton and Boyse would produce a discussion
paper on "other noxaell for presentation at the next
SRG meeting. Delegates would then attempt to reach a
conclusion on the prioritization of other noiae. RET/SB
8. Organization of next meeting (Hamburg). RET/SB/EK
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