Page 1: yit61e00
- _ . . ,
r"" ~,~ - --- ----s----- -- --=- ,
3 JUNE 27 lg;
f inspired part i,h
re beeause,it ]rr c;
position of punti l,
cl.cn for cl+'atal u,
in tho ml;tcssi,,.,
ure was apptuct, li:
rn cilinry retnrn..
- from the cou,tt;, .
from the pnrtirI, -
T from the luu,
: of radioactii-it,
+d' only neglihil,i
s was intestigiu,,I
e not more th.u,
+ adherent isotnp,.
NATURE VOL. 226 JUNE 27 1970
,..A,Iikrti it. E.. and Arnett,L. C., dreh. ?.'rlriramt. Ileallh;12, 90 (1D55):
13uudo, J., bluir, D. C;1'', and Thon:eon,
~ lk otel. DA n,ti1C. ,215- rw (1967),
n / 1wrt;1, 131 (1'JGH)'.
,11trr1t. G. Z., and ?3.~nJamin, nl, Brit: ttl<d: J., 3,82 (1D!lt)):
t<,t, J. E., L+1Mp Function, eeccnd ed. (ISiackwell 3cientill6 Publicatlons,
IAphmaan,:lL,xnd Albert. II: E., 3mer:Ind. I1v0.9aaoc. J., 30i,257 (1480).
T.,Iy;o, A.,, Imarisio; J. J., Dturm211, ii., and Lepper, 31. N., Amer. Rev.
J1tFpirat. lr1s., 87, 487 (1UU2)i
~Vadcl, J. A., and Cbmroe, J. IG.,,)un., J. dpp1. Ph}laio1:,18, 715 (1961):
This article has been revised in the light of constructive
criticisms from a referee, but seems not to meet the following
,gcnt criticisms: "From the average age of the subjects in the
EFFIcn:YTB. FO$ SE\'f t..
5 h olearance
6_ -0_3 A. K. ARMITAGE
80 0-08 M. TURNER
50 00D. .
07 000 Department of Pharmacology,
011 0O1 Tobacco Research Council Laboratories,
05 005 Harrogate
d particles an,l
ing, it' is possi ble
after a smoke,
t human 1t1nC,
dust and fumes
:il for a grant,
Rer. Rr.tpirat. Di+..,
C., Arch. Euriion.
:69, 1161 (1o6S):
Uia., 93. 03'(1966):
tol: .Utd:, 88, 41J
tuann, D., Canrer,
pmnnn, 1(., .a rch.
1. 515' (jp65);
M. Xealth,1s, ; 3s
dmer. h'tc. Itea-
study, tho workers wero approaching a survivor population. If
long term smoking dbes aff-ct the mucociliary mechanism of
a human lung it is likely that this occurs in tho cohort of
smokers who dovvlop smoking related lung disease. By latu
midtllo age thesu subjccts will either have died or will at least
show evidence of lung disease. The sourco of the subjects (thu
staff of the school, and volunteers from old peoplo's homes)
could noG be representative of a survivor population. Those
with most severe lung discase will have already been excluded..
The paper states that, of the sixty-ono subjects examined,
twenty-two wore then reject'ed becauso of lung, diseaso. I feelt
this is an error of study dbsign such that the findings cannot bz
interpreted with reference to long term effects of cigarette
Absorption of Nicotine in Cigarette and Cigar Smoke
through the Oral Mucosa
Nicotine in cigar smoke (pH 8'5) is much more readily absorbed
through the mucous membranes of the mouth than is nicotine in
cigarette smoke (pH 53) because there is a higher concentration of
unionized nicotine in the relatively alkaline cigar smoke.
A CIGARETTE smoker who inhales will obtain a dose of ,
nicot'ine) during the five or ten minutes he is smoking his
cigarette,, equivalent' to a series of intravenous inject'ions
between 1 and 2 ug,/kg'. Such a dose of nicotine may
well result in increased alertncss'. It is usually believed
that the, majority of cigafette smokers inhale to varying
degrees the smoke which they take into their mouths,
whereas the majority of cigar smokers do not. The ques-
tion then arises,, does a cigar smoker -,%°ho does not inhalee
get a similar dose of tucotino to a cigarette smoker who
inhales ? Kershbaum et al.s concluded that he does noti,,
because they found that cigarette smokers excreted rnoree
nicotine in the urine during a 4 It period of smoking than
did cigar smokers. The object of the experiments dl;-
scribed'here was to ascertainmore directly the degree, and
particularly the rate, of absorption of nicotine in cigarette
and' cigar smoke through the oral mucosa.
Cats, anaesthetized'with chloralosehad the trachea and
oesophagus tied high in the neck. Breathing occurred
through, a tube irr.5erted' in the trachea. 25 ml. of tobaccoo
smoke was introduced! into the mouth every 30 s from a
smoking, simttlator1 through a thin rubber dam held
firmly in position over the mouth by artery clips. After
10 s the smoke was blown outl. The changes in blood
pressure and movements of the cat's ears caused by
tobacco smoke or bv buffered solutions of nicotine intro-
dtzeed into the mouth were recorded. Twit'ching, of the '
ears is an action which is highly specific for nicotine and
compounds withi nicotine-like actions, and is an indication
that nicotine has reached the brains.
Blood Pressure and Ear Twitching
It was necessary to administer bctwoen twenty and'
thirty puffs of tobacco smoke in order to elicit a measur-
able pharmacological response, and this was the quantity
of smoke~used in all eight oxpcritncnt's. In four oxperi-
tnents, cig,tirotte, smoko liad no effect on blood pressuro;
in the other four, there was a risc in blood pressuro varyiiig
from 8 to 35 m¢n H'g. In only one of the eight experiments
did cigarotte smoke camso twitching of tho cnrs. Cigar
smolce, on tho other hetind,,caused a rise in blood pressuro
in all experiments, the smallest recorded' rise being, 20
and the largest 125 mm Hg. Ea° ttivitching occurred in
five of the experiments with cigar smoke ; it began towards
the end of the smoke administration period and persisted
for approximately ten minutes. These observations indi-
cate that there was a gradual accumulation of nicotine in
the brain followed by gradual decline. Fig. lb shows the
slow rise in blood pressure caused by thirty 25 ml. puffs
of cigar smoke introduced into the mouth during 145 min.
A similar quantity of cigarette smoke, however, had no
effect on blood pressure (Fig. la).
Standard! cigarettes manufactured from a flue-cured
blend of tobaeco (T 29)s and standard cigars (C 1), were
smoked in the simulator at a rate of one puff every 30 s.
The whole of each 25 ntl. puff was collected' on a Cam-
bridge glass-fibre filter disk andi the filters were analy sed
for nicotine by a method based on that of Willits et a1.646
The average nicotine content of twenty puffs of cigarette
smoke was 3133'mg, and of thirty puffs 444 mg, and was
in fact greater than that of the same number of puffs of
cigar smoke (232' and 400 mg respectively). Yet the
cigar smoke invariablyy caused a bigger pharmacological
response. What is the explanation of this apparent
One of t.ho most striking differences between cigarette
and cigar smoke is the pH of the smoke. The pF'I of T 29
cigarettes determined by the method of Grob7 «<as 5-35,
whereas the pH of the C' 1 cigars was 8-5. The buffer
capacity of the two smokcs was about the same. The
percentage nicotine present as free base in aqueous soln-
tion, calcultited from the Henderson equation, is 0T40 at
pH 5,35, 17 at pH' 6, 15 at pYT 7. 04 at pH 8 and 85 at pH
8+5. Although tobacco snto):o is an aerosol and not an
aqueous solution, the percentage nicotine as free ba;o at'
the different pHs will probably differ otily~~ proportionately.
The rulclui.rgecdtue.atine~ basoa-ill clearly diffuse into~ the
bloodstream more readily than the nicotine ion°'.
pH and Nicotine Absorption.
Fig. 1(a' and b') shows part of an experiment in
which solutions of nicotine in 01 111 phosphate buffer
in a concentration range of 02'-2-0 mg/ml. were put in the
mouth for 10 min. The riso in blood pressure caused by
Page 2: yit61e00
NATURE VOL. 226 JUNE 27 1970
, NATURE VOI
from the !
VASSEUR C'1 al.
emits a flux
energy > 50 _lX
for t'lie field of
the data in th
The two hi,
ref. 1) shoir pl
less than 2 f
lioo-ev.er, no r
period. The F
nn the order
tt ere carried
ihereforewe ,rf the influen
j~'aks in the
t ion cones c
not all cor_ta:
' e included:
1 i 5°) used ir
±ir,m of thc c
lanstA te1t illr
'4t y.one p.
n tuty lto,
':+' that th,
' dlr,tvx. TI
t li°:rD arrs t
' ' 1"hr ttd, r
Nle 12 yH 7 N)c 02 pH 8
Ftg. 1. Records of femoral blood pressure. Thirty puffs of cigar smoke irttroduced intb the mouth of
an anaesthetiied cat during 14!5 min
caused a slow rise in blood'pressure (b) whereas a similar quantity of cigarette smokc had
very-littl6 ettect(a) In another ezperiment, a'
and b'show the effects of buffered solutions of nicotine containirg-12'mg/tul: nicotine base
atpH 7 and 0 2 mgimla base aYpH 8, when-put
into the mouth aud left there for 10 min.
by 0 2
1.2 mn- mf: nicot i 7 was closely matched
myii ! a, vkL 8, The concentration of nieotlile as free base
was 0 18 ang/nll. a t pH 7 and 0 13 mg/tnl . at pH 8, sholi-illg-
that the pharmacological response is clearly dependent
on the amount of nicotine in the mouth, as free base.
Fig. 2 shows the mean carotid blood levels of nicotine
in ng,lml. after the introduction~ into the mouth for 10 mim
af solutions of ninotine at pH 6, 7-and 8 each of which con-
tained 04 mg,!ml. (1'3 µCi/,m1.) (2'='aC); nicotine. \icotine
concentrations in blood (2 mlh samples) were determined
by the method described by Turner10: The graphs were
drawn from data olitaiiied in nine experiments. Whether
nicotine exerts a pharmacological response depends on
the rate at which, it appears in the blood and' on the peak
concentration attaitled''1. ThA nezik concentr t.inn of
nic at .1H 8 was a rosimatel 2.5 at at
pH 7 and~ our tunes !~rt',at pH6. The rate at which, the
'toncentratton~ of nicotino ln t e blood increased in the
first 25 milLat vH 8' waa about 3-5 tilnes the rate at
1 15 2
FSR: 2. Carotid hlou?d lt,v(is of nuutine lu nq/nil. after the preeence iu
pti 7(p -- !s) and lrlt I:,trh~Fras.h is the mean of three
experiments: the bars show staudam rMrrut of the rnean:
pH 7 and eight times that at pH 6. These striking dif. #
ferences are consistent w~fi 1-tPiS"'dtfterences in the pharttut
cological effects of the relatively large amounts of cigarctac
and cigar smoke used in the present experiments.
ti'1'e have recently shown that twenty intravenous itljir
tiotls of nicotine (4 µg/kg)i given rapidly at nunutr
intervals for 20 min caused during the first 2,5 ntiii :r
15 ngJrnl./min rise in the concenfration~ of nicotino nr
carotlid blood' and a peak concentration of 100 ng/ntl. at.
20 min. This is probably the sort of blood; concen'ra! ir,:r ~
pattern that must be achieved to elicit a stimulant ro-- i
ponse. The data illustrated' in Fig: 2 show that sur lrf
blood levels are achieved (hut only just at pH ti}
nicotine is present in the mouth continuously for 14) t-rur
at the relatively high concentration of 0-8 mgfml. l~ttrire_
the smoking of a cigarette or cigar, however, stuo[c «
taken into the mouth, intermittently and held therr i,u
only a fe«-seconds. The concentration of nicotine batlin1::
the mucous membranes of the mouth is not, known, 1 rr:l,
clearly the conditions are less' favourable for absorpl om
than in the ehperiments o£ Fig. 2. The present evide:r'-
indicates that cigarette smakcrs uho~ do not inhale trn,,~
not obtain a"stitnulant" dose of nicotine from relrttix, , lY
acidic cigarette smoke. It may, ho-wever,, be posytltli !'rl
a cigar smoker to obtain such a doGe without inhalii:_:
We thank Mr C. A. Grant for the nicotine analys"'wrll
pH determinations of cigarette and cigar smoke, Dr li.
Roderiak for providing the (- )-(2'-10C) nicotine hydr-,-r
tartrate, Mr C. M. Sellers an6 Mrs D. Kendall for tccluucnl
assistanee and 1Pir B. Emmett for preparing the figvirr;.
Received January 28; reviacd .lfareh 2tt, 1970.
' Armitage, A. S,,,Etit. J. Phannacol., 25, 515 (1'J05):
: Armita'ge, A. K., Ha]l, 0:1-1., and Morrison, C. F., Nahrre,217, 33t(1.-
' Hrr+hbaums A., Bellet, S:, liirahalashi, ll., Feinberg, F. J., and ),,Ir
R., ArcJr. Intern. Med., 120, 311i (1967).
' Annitnge, A. K., Hall, (3: H., and Neneage, F.:, Bril, J. Pharamrcd:, 36
(196'J). . ~
Armita~e, A. S;, ~lilton, A. S., and I~torribon, C. F., Drit. J. Pharora> 1.=+ ~
'\1 ilfitP, C. t1,,Fwain, ht. w., CounllqJ. A., and Brice, B. A. Arral (4e'" O
22, 480 (1950): 11,~
r Grub, K., llcitr. TnLae, ForgY., -No: 3, 07(15151),
'Albert, A., in Srlrctfre ?bzicily/, chapter 8(licthu~t, Londun.,10"'"' ~ t
'Triwgs; ]:'. J., theib,,Uhiversity of London, 130 (1067).
"'1'urner, L: AL, J1iocJrero. J:,115, BB9t (10'90); l
" AYrnitnFe, A. K., and btilton. A. 9. in Tobvuen, Alkalulrtg arr i'
Cuurporoalb (cdlt. by von ttiuier, U, S,);,20L (Hergamun. Uxford