Private and Confidential. Research & Development
Establishment,
British-American Tobacco Co.Ltd.,
Southampton.'
16 th July, 1958.
7 th INTEMIATLIMAL CANCER CONGRFSJ
IMID011. 6_12th JUL1. 1958.
The Congress was attended on two days, only-, 7th
July and
llth.July, when papers were presentedx concerned
particularly
wjjA_thQ problems of 3moking and Health.
honday. 7th J%Av.
Dr. tleukomm (Lausanne) read a paper in which he
described
his rapid test using the newt. lie is now in
contact with Bock
(Buffalo) &nd has studied the amne hydrocirbons
used by the latter
in his assesament of the value of the sebaceous
glend suppre3nion test
as a rapid in-licator of potential carcinogenic
properties. With
three exceptions, the newt test and the
sebaceous.gland teat yield
identical results. The exceptions were
7,12-4imethylbenzEalanthracene
and 12-methylbenz[qjanthracene which Bock found
to' be strongly
positive but which Neukomm fouril to b a
n-7gative. one hydrocarbon
gave a positive nTwt test but failed to suppress
sobaceous gland
formation in Bock's tent.
In the aftornoon there was a group of papers
directly related
to the biological effect of cigarette smoke and
smoke fractions.
Lyons (Glasgow) described studies of the unstable
componento (free
radicals) of cig-trette smoke. Using electron
magnetic reconanco,
lie showed t-kat whole emoke tar c-)ntained 1015
free electrons per
CM,
gram and that on fractionation these were
distributed as foUbws:-
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Whole tar 10%
Residue after water extraction
Residuo after extraction with dilute acid.
Residue after extraction with alkali 50%
Residue after extraction with dilute acid
and then with dilute alkali 28%
Savaration by Chromatorran'kv
Hhole tar
11 exane fraction
Benzene fraction
Acetone fraction
MAI
0%
35!-
5 U111
Its aloo described the invi,stigation of ciGarette
smoke using
diphenylpicrylhydrazyl as a stable free radical
reagent. This showed
that the wator eoluble reactive material
constituted 60% of the whole
rcactive material. The discrepancy between tho two
methods was not
eVlaineds however.
Kovak (N.Y.U.) gave a rath.--r pedeetrian account
of some of
his fractionation of cigarette smoke condensate
from American blended
cigarettes. lie lia-9 now isolated squalene and
10-p-menthadiene.
The latter compound, aloo known as dipentwis or
limonons, is a major
constituent of oil of lemon, and has a
characteristic lemon smou.
It may be an important flavour component of smoke.
(Its inolation
from smoko by Cleno hid earlier been communicated
privately by
C:)
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I.T. Co. Research Department). Other compounds
isolated by Romak
included dietbyl ketonev diaoetylj benzene,
tolueney ethyl acetate,
phenol and ethanol.
Royer et _4 (Paris) described their work an the
inhibition of
16 kinpyrene form-ition by the use of ammonium
vulpliamate and of
-vaddising re7tgents.
-'. Neukomm. and Bannat (Lausanne) described their
prodedure for the
--chemical fractionation of smoke from MuTland
cigr%rettea without
producing any really fresh evidence of
csrcinogei-tio fractions. They
had found that brown polymeric oubstances in the
acidic and n1kaline
fractions produced tumours when mice were treated
with them. The
incidence of tumours was said to be greater than
that of control
animals (10' in 15 months as aCainst 10'11 in 22
months in the controls),
but sorious doubt uqs cast on the statistical
sigrdficance of this
in the discussion.
Kotin (Los Angeles) gnvp an account of the work
which he and
Falk had carried out an the effect of artificial
smog, produced by
ozonalysis of gftsoline vapour, an the mammalian
lung. He also
described the elution bypothesis and experiments
on the dincolution
of hydracrtrbonn, adsorbed on carbon particles, in
plasma solution.
The effect of smog in pnralysing cilin in the
bronchus and oesophagus
wis also montioncd and the consequent epithelial
denudation was
illustrated by photomicrographs.
C=)
Leuclitenberger (Cleveland) described her work on
the causation
of bronchitic conditiona in the liL%as of cios
exposed to cigarette _Ij
(.-r7
(_Ij
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smoke. Those r-hanges in tho lungs beemne
progressively worse with
increase in exposurn and resembled "carcinoma in
oittel an described
by Auerbach. 1.1hen orpocurs was terainated,
howaverg the tissues In
time reverted to normal. Consequently, the at-ite
of enrcinoma In situ,
a3 described hintologically here, is not a true
premalignant state,
although Louchtenborger did not stress Uiis.
Cowdray (3t.Louis) dcacribed histological
diar(7,es in the
bronchus leading to squam=3 cell motaplasin in
human amokors. The
reason f or the localisation of these lesions In
the bronchus use
ascribed to smoke settling out in those pirts of
the bronchial tree
Ocre eddies are nost likely to occur. The smaller
pooongen of the
alWooll are lc:ss likely to be sites than are the
bronchial branches.
Friday 11orninp. 11th JOv
This wnn occupied by a diieunrion of the ActioloMr
of Cancer
of the Lung .
Dr.I.I.C. Rueper (Bathenda) mnde a strong enie for
the primary
implication of atno-3pherie pollution by metals
rnd asbestos and
discounted the cffect of cigarette smoking,
especially- in the ensuing
discussion.
Doll (M.R.O. Lonlon) was conecrrv3d to ansiYer
alternative
explp.mtions of the connection beL-jeen smoking
and lung c-ancer and
to clo.Jj:i that the statistical c,.)nnection was
one of priw.-ry cause and
affect. lie qtill mnintaimd that there was no
diflarence between
those who inh7,led n-3-1 those who did not,
q1tho-agh p1pe and eapocially
QY1
cignx nmokcra chaw little otatInticil annociation.
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Wynder (Sloan-Kettering, flow rork) who followed,
presented
evidence thatv if anything, pipe and cigar nmoke
was more eirainogenic
to Mico. Ile accepted Lindsey's figures that the
polycyclio hydrocarbon
contgbI, especially of berizpyrstio, was higher in
pipe and cigar make.
Ilo---M Oointed to the obvious discrepancy betwoen
this and the
statfitical figures for pipe and cigar onolters,
which if inhalation
is-,.Omt a factor, become incompatible. Wynder
followed his usual
theme - there is -n threshold for biolor.,icnl
activity and n reduction
of 40-50.., in the tar intake would reduce the
dosago below V!radiold.
For this purpose lie ouggasto the use of clearotte
filters and leas tar.
lie also mentiqntd the possible use of catalysts
and perhaps the use
of metals ouch as nlumbdum to reduce the
combustion temperature below
the critical SUO-85uo. In the latter connection,
lie said Viat it
seemed an if Uie 1.,itter possibility was a very
frail ons. (Ferhaps
lie has checked I!rs. Laurence's eig--irettes) .
In the dincusqion
followingv lie was challenged by Doll as to the
mcaniiig he attached to
threshold dose, Doll pointing out that thers was a
finite risk even
for light smokcra. Wynder wrifeled a little at
thin and a-xid lie
used threshold 11iii quotas". He cnlled att(wition
to a Russinn
cigarette lie had boon given, two thirds of which
was filter, and said
thin van a atop in the right direction.
Waller (1,nndon) closed the oosoion with a paper
on the possible
effect of air pollution as an notiologic-d factor
In lunpr cl-Iricer.
U-4
CO
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He interpreted tables of mortality statistics for
a series of towns
in England and Wales in terms of the popUntion
coming into equLlibrium
with a now factor ek. smoking. Contrary to Stocks
nnd to Fueper,
Vialier feels t1int air pollution due to
urbanivation is a very minor
-Mtor and put the caume fairly and squarely, onto
smoking.
- The discussion afforded a number of people the
opportunity to
--call attontion to thair own work, in pnrticular
Neukomm, an Italian
professor qnd a Cuban giving fairly lengthy
accounts wiLich tended to
reiterate the usurd charges:
Persons Contacted.
(a) Fleu)-torm end Bonnet. lb~. Anderson had
earlirr written to
Dr. Neukomn, inviting him and Dr.Donnot to It.&
D.E., SouthRmpton.
Neukomm, at first, thought that we wished to
consult him on a particular
matter, but was told it was merely reciprocal
hospitality and an
opportunity to show him some of cur work. There
were difficulties,
however, in that Neukomm and Bonnet wished to
attend all the Congress
and were then Icaving at once for Dr-ussels. In
the cirmustanoes,
and in view of difficulties in visiting I.T.Go.
Bristol, where
Dr. Bentley was now in hospital, Neukomm and
Bonnet asked to be
allowed to postpone their visit until the early
autwon (latter half
September, beginnina of October) when thay would
agnin be viniting
t1 io U.'-',. Their aix-,gestion wag accepted and
it wag left that they
(Z:Z)
would contact us nearer the tim- and arrange a
date.
\,C)
(-N
110
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(b) Dr. flana Falk. Dr. Kotin introduced Dr. Falks
who i0
the Chemist workiig with, Iriatin on tho smog
production and an the
inhibition of ciliary action by smog and cigarette
make. Matin had
alrefidy explt~inad something of this work without
going into detaLl.
-7 ;s;- In the course of two f airly extensive
discussions with Talk,
_-20 proeLdure for the evaluation of the nativity
of particular constituents
of-ciparette cmake uas explained. Clearly it Is
not feasible to
fractionate cig-trette onoke cberAcally and still
apply It to loolated
frog cooophneua propmrationa as an aerosol. The
technique udopted has
been to survey the knov4n constituents of smollto
and to divide the
sliectrALm into nrbitrnry classifications
depending on the amounts found.
The m-njor conronent or comnonents of each clns5
are then applied to the
prnpe-ration as -in %erosol of th,3 pure compound
and tht 1n)iibitory or
atimul,ittory effect noted. As yet, no effort has
boon made to elucidate
miy nynergism wILijzh &ny occur through two or
more compounds acting
toeether nndg clearly, in come caoeo, cheaice.1
interaotion may take
place betueen two co-mponente. 1heeo effects,
which mill take some
disentfinelin3p mill be atudled in the future.
Falk provided tho following lint of recult3 to
date. In-view
or Kotinle reluctance to any anything to the
T.11.3.C. Sub-Committee
about stirulntion of ciliary activity, come
reault3 are of c!)noiderablo
intorent. The resu.1ts are classified into
stimulatory eflocts
inhibitory effects and no effect (U) aud are
reported for
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-a-
a) 1 minute exposure
b) 60 minutes exposure
c) chronic effect, showing a trend of activity.
They are as follawas-
1 ninuto 60 Minutes Chronic Trend
VXDOSUrO Oxnaeure
+ = vtImu.DitI:) n of ciliiry action
- ir
- JUbition
of cili=7 action
0 = no offect
Acotyl pero'-.Ido -
Peracetic ncid -
II)rridine - U
Forwildchydo -
AcebaldelWde
Acetone U
igoDutyraldch.ydo 0 0.
11-Butyraldeliyde I. +
Fropionaldoliyde 0 0
liethyl bromide - +
IletIVI chlorldo 0
Butadiene - + +
C,-xbon monoxide -
Prop7leno o7lde -
Bromoform - 0.)
lletlWl,amlne U
Trimethylami-io 0 U
Bropylone U 0.) 0
Ttiocyanic ncid 0 + U
Acetic acid - 0 U
Formic ncid 0
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2-metbylbut-2-ene
2-methylpentnno
2-4-tethylpen L-2-cne
Carbon tetrachloride
Mothylene dickloride
Cyelohexene oxide
Ammonium hydroxidn
Methane thiol (mctbil
mnrcaptnn)
11-:.-thanal
EUia-nol
Acetonitrile (methyl
cynnido)
Phenol
1 minute 60 minutes Chronic Trend
exDOSUre 0XV08ure
0 +
0 0 0
0 0
-
0.)
0
+
0
0
As a numbcr of these compotuids are gasaounj
thr.7. are not
removed by a cigirette filter, even of the
Cnmbridge' absolutel filter
type. Falk atated Unt the activity of wholo
eig-trette smoke was
diminished by filtration to some extent, but was
unnble to give any
quantitative moasurn of this, nor of its rel-Rtion
to filtration
efficiency of the Ulter.
Dr. Fal1c w-in invited to 3outhamptonp but uno
un-Ale to find a
suitable dny during the Congreas. It was learned
liter t1int he
visited I.T.Co. (Driatol) on Wednesday, 9th July.
Scientif 1e Ex1ilbition
Drs.Kotin and Falk had an a.-dLibit nlong the
lint-a of the paper
read by Kotin njid of the discussion nt thc T.S.C.
meeting. Bl-rickploCk
showed photoax-a-lis UIU3trating hin technique Of
thoracotoaq ntirl
NJ
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inoculation of benzpyrens, mothylcholanthrone or
oigarette woke
condensate. One carcinoms. and on@ sarcoma from
eight rate treated
with ciLparette amoke condensate have resulted.
XreybfibW (Oslo)
had- illustrations of histologicn-1 preparations
implicating cigarette
smoking as a f-actor in lung c-ruicor.
An e.,diibit unrelated to lung cancer but which
was of some
intereot wno thit by the Oppenheiners and their
colliborators
(Columbin U. 11.1.) on carcinogerianis by Polymer
films. Implantation
of plastic films of m,!my kinds into rodents, Mve
produced
care inomRta. Thnt this is due solely to the
p1qsica-1 nature of
the film follous from the lower tutiour incidonce
when perforated
or woven mcmbrinca or spongescf tho polymers are
used, r-aid. from
the virtui2 absence of tumours when the same
materials in powder
form are embeddod. The possibUity that
carcinageneois is due to
residual free rnlicals in the pol7mor structure
seems to be Viareby
disproved.
DG.r/;'B//.6D
C:!)
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