Minutes SRG Meetinx
Chelwood Jan 20-22 1987
Those Present: Dr 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 S Massey - Imperial, Canada
Dr G Smith - BATbKE
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
Tuesdav 20 Januarv 1987: PRESENTATIONS FROM
EXTERNAL PARTICIPANTS
1. DNA and Protein Adducts: Dr P B Farmer
Dr Farmer described current work at the MRC
laboratories, Carshalton,
Surrey, England.
DNA and protein adducts excreted in urine were
estimated
quantitatively by GC/HS analysis, although Dr
Farmer pointed out that
mg quantities of such adducts as methylated
guanines were excreted by
subjects in normal health. Because of this
background 3--methyl
adenine had been used instead (background levels
being 10-3
smaller).
However most work had been carried out with
protein adducts. compounds
such as S-methylcysteine or S-ethylcysteine being
measured. The
sensitivity of this method was I in 109 amino acid
residues,
equivalent to 1 in 1010 DNA residues, haemaglobin
in 5m1 blood
samples being adequate and having a long half life
(- 4 months).
More recently hydroxyethylvaline adducts had been
used (and ethylene
oxide identified as the alkylating agent). By use
of the Edman
degradation technique thiohydantoin derivatives
could be obtained,
amenable to GC/MS techniques.
Using this method increased levels of adduct were
identified in
smokers compared to non-smokers and in subjects
occupationally exposed
to ethylene oxide.
CZ)
C7 \
C::>
BATCo document for Province of BritiSh Columbia 28
October 1999


2
2. Other Noxa: 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: Acetaldehyde.
In consideration of these compounds individually,
Mr Burke made the
following comments.
Cadmium Coovounds
A protein (NW 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 on cadmium
compounds being carried out at the Fraunhoffer
Institute. and which
had resulted in lung tumours.
Formaldehvde. 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 acetaldehyde 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
animal models for lung cancer. heart disease and
emphysema although a
number of other approaches were available (slide
4). Currently tests _4
for ciliotoxicity and carcinogenicity/mutagenicity
were available to
supplement chemical data. C711
C=)
BATCO doCUrnent for Province of BritiSh Colurnbia
28 October 1999


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 MAX 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
synergi s tic/antagonis tic 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 forminA 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.
1(b) Bis-dichl orome thyl ether - 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 8
Halliwell. It was
agreed that this subject would be reconsidered at
the next
meeting after a report on Dr Halliwell's
presentation.
1(d) Heavy Metals - Further work on cadmium was
known to be in
progress, but had not yet been published.
Accordingly, it was
agreed to watch for developments in this area. 011
C=)
r\-)
C-11i
BATCo document for Province of British Columbia 28
October 1999


- 4 -
2. Ccmpounds receiving attention by regulatory
bodies in Canada and
Germany are listed in Appendix III and those
identified by the
1 A.RC and the UK ISC can also be considered here.
P,jlvcvclic hvdrocarbons. nitrosamines - No new
evidence had
occurred on polycyclic hydrocarbons in recent
years and Dr Roe's
results (no increase in skin painting activity
with 1Ox excess of
benzo(a)pyrene) were noted. Likewise Dr Roe
reported that the
recent meeting arranged by the ISC on nicotine and
its
metabolites (especially tobacco-specific
nitrosamines) was likely
to conclude that these compounds were not
sufficiently important
ta 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.
I---: 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 fo'rm
I: is to' be noted that acrolein, formaldehyde and
acetaldehyde
aze all ciliotoxic.
Finally it was noted that country-to-country
valuations in the
a:titudes of regulatory bodies towards other noxae
are
iaevitable.
Firther discussion on the other noxae was agreed
(see p.7)
liith regard to Mr Burke's comments on carbon
monoxide in relation
t3 smokers with a heart condition, it was felt
that medical
atvice was available on appropriate changes in
life style for
t!tose suffering from this, or any other illness.
5. Research on Nicotine - Dr S Boyse
For further details see hand-outs by Dr Boyse
(Appendix IV).
Major :ecommendations were that further work
should be carried out in
areas uf nicotine receptors, and the effects of
nicotine and
psychological tests on performance and memory.
6. Other ?roiects
Visits were pending to Professor Clamp in Bristol
with regard to his
ulcerative colitis project and to Dr Carter in
London regarding his C:)
projec: on atrial natriuretic peptide factor. Work
in both these
areas vas about to start.
011
It was aoted that Professor Caro, whose project on
atherosclerosis the
SRG had felt unable to support. has written a
letter requesting that
his przject be reconsidered. It was not felt that
the Position of the
SRG should be revised on this account.
BATCo document for Province of BritiSh Columbia 28
October 1999


5
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 on the outcome of the
conference.
8. Possible New Proiects
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.
c)... Jeffrey Giay - 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 sum requested was
approximately E66.000
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 Massey 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 beed
received but
would probably relate to mechanistic studies
involving a
polypeptide growth factor thought to be involved
in the
development of a plaque.
C,
BATCo document for Province of British Columbia 28
October 1999


- 6 -
e) Dr Gori noted that correlations had been made
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 Massey 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).
C__
C711
ON
BATCo document for Province of British Columbia 28
October 1999


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 meetinRs
It was decided fhat 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.
L;K: Dr Currie, Prof. Bloom, Dr Carter
12. Final Discussion. critiaue
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) C:
and that BATCo (Dr Boyse and Dr Thornton) would
produce a discussion
paper which would attempt to integrate the views
propounded at
Chelwood, together with other relevant material.
Delegates would then
attempt to reach some conclusions on the
prioritization of "other
noxae".
r\
BATCo document for Province of BritiSh Columbia 28
October 1999


8 -
Action Points
1. The scientific 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 bis-dicbloromethyl ether
should
be carried out: the means for measuring it; its
possible occurrence in the general environment,
and
its biological properties. GS
3. A report to be given on Dr Halliwell's
presentation on
Free Radicals. GS
4. It was agreed to fund Professor Raymond Levy's
application on nicotine effects and Alzheimer's
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
5. 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 noxae" for presentation at the
next
SRG meeting. Delegates would then attempt to reach
a
conclusion on the prioritization of other noxae.
RET/SB
8. Organization of next meeting (Hamburg).
RET/SB/EK
c::>
C=)
N-)
co
BATCo document for Province of BritiSh Columbia 28
October 1999


bovendices
1. Copy of Dr Roe's slides
2. Dr Massey's IARC etc. list
3. Lists from Germany and Canada's regulatory
bodies
4. Proposals for research on nicotine by Dr Boyse
5. Report on a visit to Japan by Drs. Seehofer and
Smith.
ON
BATCo document for Province of BritiSh Columbia 28
October 1999