guanosene 3’,5-monophosphate (cyclic GMP) and may play a role in
tissue proliferation and tumoregenesis, as well as exert effects on
ciliary function and mucosal secretion in lung tissue.

Nitrogen Dioxide

Acute lung damage resulting from exposure to nitrogen dioxide at
levels of 80 ppm for 3 hours has been reported by Langloss, et al. (28).
Blank, et al. (9) exposed rats to levels of 15 to 40 ppm for up to 5 hours.
Both of these groups reported alveolar damage with subsequent edema
followed by hyperplasia or increased biosynthesis. The relevance of
these types of exposure to smoking-related disease processes is unclear,
however, since Norman and Keith (34) reported that nitrogen dioxide
is present in cigarette smoke only in trace quantities.

Phenol

Little is known about the effects of phenol in smoke. Dalhamn (14),
however, administered puffs of smoke from cigarettes with high and
low phenol concentrations (18.8 and 2.7 mg/100 cigarettes versus a
“normal” cigarette concentration of 7 mg/100 cigarettes) and found a
clear correlation between ciliostasis and the phenol level in smoke. This
area is one that should also be explored in more detail.

14—81
Physiological Responses to Cigarette Smoke: References

(1) AHMED, S.S., MOSCHOS, C.B., LYONS, M.M., OLDEWURTEL, H.A.,
COUMBIS, R.J., REAGAN, T.J., JENKINS, B. Cardiovascular effects of long-
term cigarette smoking and nicotine administration. American Journal of
Cardiology 37: 33-40, January 1976.

(2) ARMITAGE, A.K. Effects of nicotine and tobacco smoke on blood pressure and
release of catecholamines from the adrenal glands. British Journal of
Pharmacology 25: 515-526, 1965.

(3) ARNOLD, W.P., ALDRED, R., MURAD, F. Cigarette smoke activates
guanylate cyclase and increases guanosine 3’, 5’-monophosphate in tissues.
Science 198: 934-936, December 2, 1977.

(4) BATTISTA, S.P., GUERIN, M.R., GORI, G.B. KENSLER, C.J. A new system
for quantitatively exposing laboratory animals by direct inhalation. Archives
of Environmental Health 27: 376-382, December 1973.

(5) BELLET, S., DEGUZMAN, N.T., KOSTIS, J.B., ROMAN, L., FLEISCHMANN,
D. The effect of inhalation of cigarette smoke on ventricular fibrillation
threshold in normal dogs and dogs with acute myocardial infarction. American
Heart Journal 83(1): 67-76, January 1972.

(6) BINNS, R., BEVEN, J.L., WILTON, L.V., LUGTON, W.G.D. Inhalation toxicity
studies on cigarette smoke. II. Tobacco smoke inhalation dosimetry studies on
small laboratory animals. Toxicology 6: 197-206, 1976.

(” BINNS, R., BEVEN, J.L., WILTON, L.V., LUGTON, W.G.D. Inhalation toxicity
studies on cigarette smoke. III. Tobacco smoke inhalation dosimetry study on
rats. Toxicology 6: 207-217, 1976.

(8) BINNS, R., CLARK, G.C. An experimental model for the assessment of the
effects of cigarette smoke inhalation on pulmonary physiology. Annals of
Occupational Hygiene 15: 237-247, 1972.

(9) BLANK, M.L., DALBEY, W., NETTESHEIM, P., PRICE, J., CREASIA, D.,
SNYDER, F. Sequential changes in phospholipid composition and synthesis in
lungs exposed to nitrogen dioxide. American Review of Respiratory Disease
117: 273-280, 1978.

(10) BURN, J.H., RAND, MJ. Action of nicotine on the heart. British Medical
Journal 1: 137-139, January 18, 1958.

(11) BURROWS, LE., CORP, P.J., JACKSON, G.C., PAGE, B.F.J. The determination
of nicotine in human blood by gas-liquid chromatography. Analyst 96: 81-84,
January 1971.

(12) CAHAN, W.G., KIRMAN, D. An effective system and procedure for cigarette
smoking by dogs. Journal of Surgical Research 8(12): 567-575, December 1968.

(18) CRAMLET, S.H., ERICKSON, H.H., GORMAN, H.A. Ventricular function
following acute carbon monoxide exposure. Journal of Applied Physiology
33): 482-486, September 1975.

(14) DALHAMN, T. Effect of different doses of tobacco smoke on ciliary activity in
cat. Variations in amount of tobacco smoke, interval between cigarettes,
content of “tar,” nicotine, and phenol. Toward a Less Harmful Cigarette.
National Cancer Institute Monograph No. 28. U.S. Department of Health,
Education, and Welfare, Public Health Service, National Institutes of Health,
National Cancer Institute, 1968, pp. 79-87.

(15) DAVIS, B.R., HOUSEMAN, T.H., RODERICK, H.R. Studies of cigarette smoke
transfer using radioisotopically labelled tobacco constituents. Beitraege zur
Tabakforschung 7(3): 148-158, November 1973.

(16) DEBIAS, D.A., BANERJEE, C.M., BIRKHEAD, N.C., GREENE, C.H., SCOTT,
S.D., HARRER, W.V. Effects of carbon monoxide inhalation on ventricular
fibrillation. Archives of Environmental Health 31: 42-46, January/February
1976.

14—82
(17)

(18)

(19)

(20)
(21)
(22)
(23)

(24)

(25)

(26)

(27)

(28)
(29)
(30)
($1)

(82)

DEBIAS, D.A, BANERJEE, CM., BIRKHEAD, N.C., HARRER, W.V.,
KAZAL, L.A. Carbon monoxide inhalation effects following myocardial
infarction in monkeys. Archives of Environmental Health 27: 161-167,
September 1973.

DEBIAS, D.A., BIRKHEAD, N.C., BANERJEE, C.M., KAZAL, L.A., HOL-
BURN, R.R., GREENE, C.H., HARRER, W.V., ROSENFELD, L.M., MEN-
DUKE, H., WILLIAMS, N., FRIEDMAN, M.H.F. The effects of chronic
exposure to carbon monoxide on the cardiovascular and hematologic systems
in dogs with experimental myocardial infarction. Internationales Archiv fuer
Arbeitsmedizin 29: 253-267, 1972.

FECHTER, L.D., ANNAU, Z. Toxicity of mild prenatal carbon monoxide
exposure. Science 197: 680-682, August 12, 1977.

FEYERABEND, C., LEVITT, T., RUSSELL, M.A.H. A rapid gas-liquid
chromatographic estimation of nicotine in biological fluids. Journal of
Pharmacy and Pharmacology 27: 434-436, 1975.

FISHER, E.R., ROTHSTEIN, R., WHOLEY, M.H., NELSON, R. Influence of
nicotine on experimental atherosclerosis and its determinants. Archives of
Pathology 96: 298-304, November 1973.

FRASCA, J.M., AUERBACH, O., PARKS, V.R., JAMIESON, J.D. Electron
microscopic observations on pulmonary fibrosis and emphysema in smoking
dogs. Experimental and Molecular Pathology 15(1): 108-125, August 1971.

FREEMAN, G., DYER, R-L., JUHOS, L.T., ST. JOHN, G.A., ANBAR, M.
Identification of nitric oxide (NO) in human blood. Archives of Environmental
Health 33: 19-23, January/February 1978.

GUERIN, M.R., MADDOX, W.L., STOKELY, J.R. Tobacco smoke inhalation
exposure: concepts and devices. In: Gori, G.B. (Editor). Proceedings of the
Tobacco Smoke Inhalation Workshop. U.S. Department of Health, Education,
and Welfare, Public Health Service, National Institutes of Health, DHEW
Publication No. (NIH) 75-906, 1975, pp. 31-44.

HANSSON, E., SCHMITERLOW, C.G. Metabolism of nicotine in various
tissues. In: von Euler, U.S. (Editor). Tobacco Alkaloids and Related Com-
pounds. Oxford, Pergamon Press, 1965, pp. 87-99.

HRUBES, V., BAETTIG, K. Effects of inhaled cigarette smoke on swimming
endurance in the rat. Archives of Environmental Health 21: 20-24, July 1970.

ILEBEKK, A., LEKVEN, J. Cardiac effects of nicotine in dogs. Scandinavian
Journal of Clinical and Laboratory Investigation 33: 153-159, 1974.

LANGLOSS, J.M., HOOVER, E.A., KAHN, D.E. Diffuse alveolar damage in
eats induced by nitrogen dioxide or feline calicivirus. American Journal of
Pathology 8&3): 637-644, December 1977.

MADDOX, W.L., DALBEY, W.E., GUERIN, M.R., STOKELY, J.R., CREASIA,
D.A., KENDRICK, J. A tobacco smoke inhalation exposure device for rodents.
Archives of Environmental Health 33: 64-71, March/April 1978.

MCGILL, H.C., JR., ROGERS, W.R., WILBUR, R.L., JOHNSON, D.E. Cigarette
smoking baboon model: Demonstration of feasibility (40119). Proceedings of
the Society for Experimental Biology and Medicine 157: 672-676, 1978.

MILLER, R.P., ROTENBERG, K.S., ADIR, J. Effect of dose on the pharmacoki-
netics of intravenous nicotine in the rat. Drug Metabolism and Disposition
5(5): 436-443, 1977.

MORDELET-DAMBRINE, M., STUPFEL, M., DURIEZ, M. Comparison of
tracheal pressure and circulatory modifications induced in guinea pigs and in
rats by carbon monoxide inhalation. Comparative Biochemistry and Physiology
59A: 65-68, 1978.

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($3)

(34)

($5)

($6)

(87)

($8)

(39)

14—84

NETTESHEIM, P., GUERIN, M.R., KENDRICK, J., RUBIN, I., STOKELY,.J.,
CREASIA, D., MADDOX, W., CATON, J.E. Control and maximization of
tobacco smoke dose in chronic animal studies. In: Gori, G.B. (Editor).
Proceedings of the Tobacco Smoke Inhalation Workshop. U.S. Department of
Health, Education, and Welfare, Public Health Service, National Institutes of
Health, DHEW Publication No. (NIH) 75-906, 1975, pp. 17-26.

NORMAN, V., KEITH, C. H. Nitrogen oxides in tobacco smoke. Nature
205(4974): 915-916, February 27, 1965.

PARK, S.S., KIKKAWA, Y., GOLDRING, IL-P., DALY, M.M., ZELEFSKY, M.,
SHIM, C., SPIERER, M., MORITA, T. An animal model of cigarette smoking
in beagle dogs. American Review of Respiratory Disease 115: 971-979, 1977.

REECE, W.O., BALL, R.A. Inhaled cigarette smoke and treadmill-exercised
dogs. Archives of Environmental Health 24: 262-270, April 1972.

RINK, R. D. The acute effects of nicotine, tobacco smoke and carbon monoxide
on myocardial oxygen tension in the anaesthetized cat. British Journal of
Pharmacology 62: 591-597, 1978.

RYLANDER, R. Relative role of aerosol and volatile constituents of cigarette
smoke as agents toxic to the respiratory tract. Toward a Less Harmful
Cigarette. National Cancer Institute Monograph No. 28. U.S. Department of
Health, Education, and Welfare, Public Health Service, National Institutes of
Health, National Cancer Institute, 1968, pp. 221-229.

U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A
Report of the Surgeon General: 1972. U.S. Department of Health, Education,
and Welfare, Public Health Service, Health Services and Mental Health
Administration, DHEW Publication No. (HSM) 72-7516, 1972, 158 pp.
Pharmacology of Cigarette Smoke

For the habitual smoker, the smoking of a cigarette is a rewarding
experience, evidenced by the consumption of over 600 billion cigarettes
annually in the United States. It is a reward which is highly
anticipated by smokers, one that seems to satisfy a smoker's
physiological and psychological needs.

Because of the myriad compounds present in cigarette smoke, it
should be kept in mind that the pharmacological effects of smoking are
not related solely to nicotine; rather, it is the combined effect of the
whole smoke. Nevertheless, nicotine is generally accepted as the
principal constituent responsible for cigarette smokers’ pharmacologic
response (6, 20), and will be reviewed on this criterion.

Nicotine is a powerful, quick-acting, ganglionic stimulant, eliciting
its effects initially by depolarizing the ganglionic cells, stimulating
both the sympathetic and parasympathetic ganglia (15).

Nicotine Absorption

Clearly, before any pharmacologic response can be elicited by nicotine
from cigarette smoke, absorption must occur. The phenomenon of
cigarette smoke absorption has been addressed by several investigators
(2, 4, 6, 9, 16).

Some absorption takes place in the oral cavity. Based on monitoring
carotid blood levels and radiolabeled nicotine cigarettes, estimates
from three studies (2, 4, 6) show that less than 30 percent of the inhaled
dose is absorbed. Further, Artho and Grob (6) observed that there were
striking differences in nicotine absorption that are largely determined
by the pH of the total smoke. The pK» values of nicotine are 6.16 and
10.96 (9). From these data, the portions of the diprotonated nicotine
and monoprotonated nicotine as well as the free nicotine can be
calculated for a given pH. Because cigarette smoke typically has a pH
of 5-7, the diprotonated form need not be considered in this discussion.
The percentage of nicotine present as the free base is 0.40 at pH 5.35,
1.7 at pH 6, 15 at pH 7, 64 at pH 8, and 85 at pH 8.5.

The basic, lipid-soluble, uncharged nicotine is the form absorbed by
the oral muscosa (8). A contributing factor to its absorption is that
nicotine, as the free base, is volatile, which allows for rapid absorption
from the gas phase. The relationship of the effects of pH are described
in Figure 9 (9). Figure 10 (4) describes the oral absorption of nicotine
from an identical dose of a buffered nicotine solution at pH 6, 7, and 8.

Nicotine which passes the oral cavity, as in cases of deep inhalation,
is absorbed to a much greater extent than in the oral cavity. It is
estimated that more than 90 percent of the inhaled nicotine is absorbed
in the lungs (2, 6, 16). It should be noted also that retention of other
cigarette smoke components by absorption is approximately 82 to 99

14—85
 

 

% of protonated and unprotonated nicotine species

 

FIGURE 9.—Degree of protonation of nicotine in relation to pH
(pH = pKa 10g 1 - a/a (Henderson/Hasselbach)).

SOURCE: Aviado, D.M., (7).

Nicotine ng/mi. carotid blood

 

 

Time (h)

FIGURE 10.—Carotid blood levels of nicotine in ng/ml, after the
presence in the mouth for 10 minutes of buffered solutions of nicotine
at pH 6, pH 7, and pH 8. The bars show standard error of the mean.

SOURCE: Artho, A.A. (6).

14—86
percent, depending on the study. In any case, it is clear that the lung
uptake of the nicotine in cigarette smoke is very efficient.

Whether cigarette smoke or a nicotine aerosol is used seems to. make
little difference on nicotine absorption in the lung. Herxheimer (28)
found that inhalation from smoke and inhalation from a nicotine
aerosol in approximately equivalent amounts (about 100 pg every 30
seconds) produced similar increases in pulse rate and blood pressure in
healthy volunteers. The equivalence is only approximate, however, ©
_ because the nicotine delivered per puff increases as the cigarette is
smoked. This increase could explain why, although similar, the peak
effects occurred later with cigarette smoking than with inhalation of
the aerosol. Oe

Although pH of the smoke is a major factor in nicotine absorption,
other factors such as tobacco smoke contact time with mucus
membranes, pH of the mucus membrane, pH of body fluids, depth and
degree of inhalation, degree of habituation of the smoker, nicotine and
moisture content, and puff frequency must be considered (12, 20).

Armitage, et al. (3) recently studied the effects of nicotine
absorption in humans, comparing nicotine levels obtained in arterial
blood. They found that arterial blood plasma concentrations of nicotine
were comparable; however, the level rose more slowly in the smokers
of small cigars. This may be due to a greater amount of the small cigar’
smoke being absorbed via the oral cavity as compared to cigarette -
-smoke, which is primarily absorbed via the lung.

Alteration of Enzyme Systems

‘The nature of tolerance to nicotine and tobacco smoking has received
attention and a complex picture has emerged (25). Studies with
humans using high and low doses of nicotine presented apparently
conflicting results regarding nicotine-cotinine metabolism. The authors
suggested that acute high doses of nicotine produced inhibition of |
nicotine metabolism while lower daily doses on chronic exposure
produced induction of the enzyme systems. These results are not
uniformly accepted, however (51).

Gorrod and Jenner (25) concluded that the effect of nicotine is
complex, but that the data suggest the importance of dosage, length of
administration, and stress-induced effects. They also stated that a
component of cigarette smoke other than nicotine may be responsible
for the changes in nicotine metabolism observed in humans. In any
case, tobacco smoke is a known inhibitor of enzyme systems, including
dehydrogenases and oxygenases, so that inhibition of nicotine metabo-
lism or other metabolic products is a distinct possibility (27).

Catecholamine Responses

Since nicotine is a ganglionic stimulant on both the sympathetic and
parasympathetic nervous systems, it is not surprising that investiga-

14—87
350 ¢

8

nh

n

So
T

_, NOREPINEPHRINE
(pg/ml)
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-

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nn
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8

EPINEPHRINE
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ee
-10 0 10 20 30

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FIGURE 11.—Mean (+ S.E.) plasma norepinephrine and epineph-
rine concentrations in association with smoking (closed symbols) and
sham smoking (open symbols). The arrows indicate the period of

smoking (or sham smoking).
SOURCE: Cutting, W.C. (15).

tors have looked at catecholamines as possible indicators of the
nicotine-induced effects. Moreover, the catecholamines are usually
considered to be released in stress-related responses. The source of the
catecholamines is reported to be in the myocardial chromaffin tissue
and the adrenal gland (11, 29, 34), and therefore consistent with this
hypothesis.

Armitage (1) claims that the amount of nicotine inhaled during
smoking is sufficient to cause release of catecholamines, but there is
not uniform agreement on this subject (60, 63). Timing may be a
critical factor in determining any catecholamine response because the
response is likely to be transient. Cryer and coworkers (14) have
graphically shown the rapid response of nonepinephrine and epineph-
rine as a consequence of cigarette smoking (see Figure 11).

Naquira and coworkers (48) studied the chronic administration (14
days) of nicotine in rats. They observed increased tyrosine hydroxylase

14—88
and dopamine-f-hydroxylase in the hypothalamus and adrenal medul-
la, but did not observe changes in tyrosine hydroxyiase in the striatum.
The data suggest that chronic nicotine administration can produce
similar long-term alterations in both catecholamine-forming enzymes
in the hypothalamus and adrenal medulla.

Catecholamines, released as a consequence of the nicotine-induced
response, have been associated with or implicated in several biological
responses. Cardiovascular-related diseases, bronchoconstriction and
related pulmonary manifestations, fat metabolism, hyperglycemic
effects, and the patellar reflex response have implicated catechol-
amines as being either directly or indirectly involved in these biological
endpoints.

In the United States, more people die from coronary heart disease
than from any other disease, and heart disease is the single most
important cause of death among cigarette smokers(62). Epidemiologi-
cal studies such as those reported by Mulcahy, et al. (45) who found a
positive association between coronary heart disease mortality rate and
the calculated per capita cigarette consumption in 21 countries, the
Framingham study (29, 23, 33, 50), and reviews by Aronow (5) and
Kannel (32) leave little doubt as to the consequences of cigarette
smoking with respect to heart disease.

Cardiovascular and Related Effects

It is generally agreed that the acute cardiovascular effects of tobacco
smoking can be attributed to the nicotine content of the cigarette and
the amount absorbed (14, 20); similar effects have been observed by
Irving and Yamamoto on administration of a comparable amount of
nicotine by injection (31). The responses observed are those expected
from stimulation of the sympathetic nervous system (15), including
stimulation of the sympathetic ganglia, adrenal medulla, and the
release of endogenous catecholamines (14). Responses are known to
include increased heart rate and blood pressure (2, 28), cardiac output
stroke volume, velocity of contraction, myocardial contractile force and
oxygen consumption, and coronary blood flow and arrythmias (15, 20).
Activation of the chemoreceptors of the carotid and aortic bodies
results in vasoconstriction, tachycardia, and elevated blood pressure.
Nadeau and James (47) have shown that the cardiac/stimulating effect
of nicotine can be attributed to vagal stimulation. The possible role of
elevated serum corticoids, following smoking of high nicotine ciga-
rettes, in sensitizing the myocardium to the effects of the catechol-
amine has been suggested (5, 29) as also possibly contributing to
ventricular arrythmias and myocardial infarctions. Further research
has been suggested to resolve this issue (5).

Armitage and coworkers (3) have graphically described the dose-
response effects of nicotine intravenous injection and cigarette

14—89
smoking as they affect blood pressure and heart rate. These results are
described in Figure 12.

Pulmonary Effects

The respiratory effects of nicotine from smoke exposure are more
difficult to quantify than cardiovascular effects because respiratory
function may also be influenced by the solid particles or gases in
cigarette smoke (ie., CO and C02). For example, Reintjes and
coworkers (50) were able to show that airway resistance values
obtained immediately after smoking were elevated, but they did not
identify the response as being caused by the nicotine in cigarette
smoke. Aviado and coworkers (7) demonstrated that cigarette smoke
causes acute bronchoconstriction by release of histamine and by
stimulation of the parasympathetic nervous system in the lungs.
Similar responses were shown to occur with arterial injections of
nicotine. The effect is followed, however, by bronchodilation attributed
to sympathetic stimulation.

Fat Metabolism

Changes in free fatty acids and mobilization of free fatty acids (FFA)
have also been reviewed (40) as secondary effects of catecholamine
stimulation. Kershbaum and coworkers (35) were led to the conclusion
that nicotine had no direct lipolytic effect on cat or dog adipose fat
tissue. Their findings lent support to the concept that mobilization of
FFA by nicotine and cigarette smoke was a result of their stimulation
of sympathetic nervous system activity and catecholamine secretion. In
a related study (36) comparing 4 mg of nicotine in intravenously- and
intratracheally-administered cigarette smoke, the authors suggested
that tobacco smoking and nicotine caused an increased utilization of
FFA in addition to their known effect of FFA mobilization. It was
suggested that the greater FFA utilization was caused by increased
cardiac output due to nicotine. The authors further suggested that
nicotine changes the ratio of FFA incorporated into neutral lipid and
phospholipids.

Hyperglycemic Effects

Another secondary response to the catecholamines present in the blood
stream is believed to be a hyperglycemic condition as described in a
recent review (40). Such a response would be consistent with a stress-
related situation requiring an energy source for quick response. Milton
(44) has suggested that in cats the hyperglycemic mobilizing action of
smoking doses of nicotine is due entirely to stimulation of the adrenal
gland, while the hyperglycemic effect at high doses is presumably due
to stimulation of ganglia throughout the body resulting in the release
of more epinephrine.

14—90
50 60

40
Time (min)

0 20 «630

1
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FIGURE 12.—Arterial blood levels of “C-nicotine (©) and “C-
cotinine (©), heart rate ("), and blood pressure (®) during and after
smoking a cigarette labeled with “C-nicotine (a), and during and after
intravenous administration of 1 mg “C-nicotine in 10 divided doses
(b)

SOURCE: Beckett, A.H. (8).

14—91
Other Central Nervous System Effects

It has recently been reported that nicotine also causes a diminution in
the monosynaptic patellar reflex (18). This reduction in the patellar
reflex was not seen after smoking nontobacco cigarettes. The effect
thus appears to be closely related to nicotine. This was later confirmed
by Domino and Baumgarten (18) after studying the response to an
inhaled nicotine aerosol.

Metabolism of Nicotine

The metabolism of nicotine has been examined and reviewed by
several investigators (25, 27, 61). The major part of the absorbed
nicotine is metabolized rapidly in the body, and studies have
established the liver as the major organ of detoxication. McKennis, et
al. (20a-20d) have demonstrated that cotinine is the major metabolite
of nicotine in human and animal urine. Other detected metabolites are
summarized in Figure 13. Hansson and Schmiterlow (27), using
radiolabeled nicotine, were able to detect radiolabeled products only in
cotinine and COs. In studying tissue slices, they determined that
nicotine is metabolized in the kidney and lung as well as in the liver,
but not in the brain, diaphragm, spleen, stomach, small intestine, or
adrenal glands.

Armitage (2), in comparing the effects of injected nicotine and
innaled cigarette smoke, found that the half-life of nicotine in the
arterial blood of smokers ranged from 24 to 84 minutes, with a mean
value of 40 minutes when only the inhalation experiments were taken
into account.

In examining the relationship between intravenous injections of
nicotine and subsequent metabolism, Miller, et al. (43) found nicotine
had a t!/> of 55 to 64 minutes, with peak levels in the range of 297
ng/ml of plasma. While there was no effect of the administered dose
on disappearance rate, there was a suggestion that the dose affected
the distribution of nicotine. This would appear reasonable, in view of
the known vasoconstrictive properties mentioned earlier, and could
explain some of the conflicts in characterizing nicotine’s pharmacologic
properties.

Tsujimoto and coworkers (59) studied the tissue distribution of
nicotine in dogs and rhesus monkeys. Five minutes after injection the
adrenal medulla and cerebral cortex contained the highest concentra-
tion of nicotine. Other tissues containing significant quantities of
nicotine included the spleen, adrenal cortex, kidney, and pancreas.

The effect of urinary pH on the excretion of nicotine and its
metabolites has been studied by Beckett, et al. (8), Gorrod and Jenner
(25), and Feyerabend and Russell (21). They determined that the
amount of unchanged nicotine excreted in the urine after oral
administration was dependent on pH, while cotinine was dependent on

14-99
 

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s,
|

 

 

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FIGURE 13.—Nicotine metabolism.

SOURCE: Hansson, E. (27).
urinary pH and flow rate. Specifically, the more acidic the urine, the
larger the amount of unchanged nicotine. Similar results were
obtained by Schachter and coworkers in reviewing the effect of urine
pH as a result of stress-related factors (55, 56).

Metabolic Products in Test Animals from Nicotine in Cigarette
Smoke

Investigations of nicotine metabolites from cigarette smoke, using
various animal systems including man (25, 27), has led to the
identification of several metabolites. An extensive investigation of

14—93
nicotine metabolites has been performed by Gorrod and Jenner (25). In
the mouse, the metabolic products identified were cotinine, hydroxyco-
tinine, y-(3-pyridyl)-y-oxo-N-methylbutyramide, COz and two unidenti-
fied products separated by chromatography (27). The primary metabo-
lites identified by Gorrod and Jenner include nicotine-1’-N-oxide, 5’-
hydroxycotinine, cotinine, nornicotine, and isomethylnicotinium ion
(25). Other metabolic products (Figure 18) are considered to be derived
from those mentioned above. Only cotinine and nornicotine have been
examined for their pharmacologic activity in any detail; these will be
discussed below.

The complex mechanism by which cotinine, the major metabolite, is
formed involves at least two enzyme systems. Both 5’ hydroxynicotine
and nicotine AN'(5’) iminium ion have been implicated as intermedi-
ates (30, 46). Cotinine is further metabolized by pyrrolidone ring
hydroxylation; all other metabolites of nicotine are thought to arise by
cleavage of the phrrolidone ring of cotinine.

Related Alkaloids and Their Metabolites in Cigarette Smoke

It is difficult to generalize regarding the amount of various alkaloids
other than nicotine in cigarettes because of differences in the alkaloid
content and composition of the various tobacco strains employed in
cigarette manufacture. However, nicotine is usually considered to
account for about 95 percent of the alkaloids in tobacco. The remainder
consists of varying proportions of nornicotine, anabasine, myosmine,
anatabine, nicotyrine, and other alkaloids described in Figure 14 (38).

As stated above, nicotine is considered to be primarily responsible for
eliciting the pharmacologic effects in cigarette smoke. Nevertheless,
Using a battery of tests, Clark and coworkers (13) compared the
pharmacological activity of a number of the minor alkaloids known or
suspected to occur in tobacco smoke. Their results are summarized in
Table 21. It should be noted, however, that only nicotine was optically
pure. Others either were prepared synthetically, yielding racemic
products, or were isolated under conditions resulting in optically
inactive forms; therefore, the pharmacological responses reported may
be less than would have been obtained had the optically active
compounds (where appropriate) been tested. The LDso values of several
alkaloids in various species have been tabulated (57). Extrapolation of
these data to other species and to the effects of multiple dosing,
however, may not be useful because of variation in metabolic pathways
among species.

Pharmacodynamics

Until recently, relatively little attention was devoted to the pharmaco-
dynamics of cigarette smoke. However, with increasing interest in
smoking cessation techniques (42), tobacco industry emphasis on

14-—-94
R=H. Nomicotine
R = CHg: Nicotine

iy:
i)
Nn? R
R=H, Nomicotyrine

R = CH. Nicotyrine

 

2,3-Dipyridy!

 

R=H, Anabasine
R = CHg: N-Methy?
anabasine

 

Myosmine

 

 

Nicotine 1'— N-oxide

 

H, Anatabine

R = CH3: N-Methy-

anatabine

 

N-Methyimyosmine

 

Catinine

FIGURE 14.—Structural formulas of some tobacco alkaloids.

SOURCE: Larson, P.S. (40).

14—95
96—FI

TABLE 21.—Relative molar potency of nicotine and other cigarette smoke alkaloids

 

 

Pressor ‘Release of Bineeie Inhibition Inhibition _—*mhibition
Contraction : catechol- Contraction of Inhibition : of chick
: : action i : of cat of chick
Alkaloid of guinea a amines of frog contraction of cat crossed
vo in pithed ° flexor flexor
pig ileum rat from cat rectus of knee jerk reflex reflex extensor
adrenal diaphragm reflex
Nicotine 100 100 100 100 100 100 100 100 100
Nornicotine 45 22 55 61 3 54 54 36 27
Metanicotine 4 3 20 - <08 04 <0.6 ~ 125
Anabasine 175 20 5 23 50 iW 33 33 20
Myosmine 0.2 5.5 - 3 2 3 <3 13 3
Nicotyrine 03 25 - 0. <0.08 17 <10 51 10
2:3-Dipyridyl 02 - - 4 <01 <01 - -
Dihydrometanicotine <0.025 0.5 - - <08 <0.4 <0.6 - -
N-Methylanabasine <0.028 46 ~ 3 35 2 <5 - 12
Cotinine <0.001 <0.1 0.03 - <08 <0.05 <0.5 - -
Nornicotyrine <0,028 2 - - <09 - - ~ -

 

SOURCE: Clark, M.S.G. (13).
lowering tar and nicotine in cigarette smoke (49), and major efforts
undertaken in the research sector to develop and evaluate a less
hazardous cigarette (24), the interactions between the physi-
ecal/chemical characteristics of the cigarette and the behavior-
al/physiological characteristics of the smoker are being given increas-
ing attention.

As discussed elsewhere in this report, there are many theories about
why people smoke. While in most cases the explanation is not simple,
nicotine is a generally agreed-upon factor. Nicotine has long been
considered as habitual at least and, by some persons, as an addictive
drug (22, 37, 54). The Third Report of the Royal College of Physicians
of London (1977) is quite explicit in stating that “Tobacco smoking is a
form of drug dependence different from but no less strong than that in
other drugs of addiction” (50a). The pharmacodynamic implications of
smoking have generated detoxification techniques in smoking-cessa-
tion programs, the search for nicotine substitutes or antinicotine drugs
(e.g., lobeline (26)), the presentation of nicotine in an alternate vehicle
(eg., chewing gum (52)), and the evaluation of nicotine aerosol
techniques in terms of their impact on modifying smoking behavior
(28).
Because of the role of nicotine in creating a dependency for the
smoker, it is appropriate to consider smoking patterns and the effects
these patterns have on response to cigarette smoke components. There
are many ways to characterize smoking patterns:

Type of cigarette smoked. Cigarette brands vary radically today in
terms of nicotine and tar delivery and somewhat less in terms of CO,
acrolein, HCN and NOx’s.

Number of cigarettes smoked. This ranges from none to a maximum
of about 100 cigarettes a day.

Amount of cigarette smoked. Smoking patterns range from smoking
only the first few millimeters to smoking down to a few millimeters
from the butt end. Inasmuch as the tobacco at the butt end of the
cigarette acts as a filter and builds up nicotine and tar as the cigarette
is smoked, the last few puffs on a cigarette smoked all the way down
will have a much higher nicotine and tar delivery than the first puffs.

Number of puffs. This can range from one or two puffs up to about
20.

Depth of inhalation. Again, this can vary from the pattern of the
noninhaler to deep inhalation.

Length of inhalation. The longer the cigarette smoke is held in the
lungs, the greater the absorption and thus, the deposition of smoke.

Since it would be possible for an individual smoking 10 cigarettes per
day to absorb more of the components of cigarette smoke than one who
smoked many times that number, realistic evaluation of smoking
impact calls for the development of dosimetric techniques applicable to
research, screening, and smoking-pattern modification programs.

14—97
As might be expected, the smoking pattern affects absorption of the
content of cigarette smoke, and consequently the toxic effects,
differentially. Some of the contents and characteristics of the smoke
also modify smoking patterns.

Since nicotine is absorbed through the mucus membranes and the
skin as well as the alveoli, it will be absorbed, to a lesser degree, even
by the noninhaler. (The nicotine from snuff and chewing tobacco is
absorbed only through the mucus membrane route as is the case for
most noninhaling cigar smokers.) Although the absorption of nicotine
is to some degree independent of smoking patterns, there is significant
evidence, not uniformly accepted, that a number of dimensions of
smoking patterns are to a large degree dependent on nicotine content
of the cigarette. Increasing evidence indicates that chronic “nicotine-
dependent” smokers tend to titrate or compensate their inhalation
profile in order to develop a desirable blood level of nicotine (41). This
is done by modifying the number of cigarettes smoked, the number of
puffs, the amount of cigarette smoked, or the depth of inhalation (9,
39). The implication of this apparent compensatory modification of
smoking pattern to assure a preestablished nicotine titration level in
the smoker has broad ramifications when considered in the context of
the increasingly popular lower-nicotine cigarettes designed to give low
delivery. Since this is an area to which major attention has been
devoted only recently, a serious research effort should be mounted in
order to better understand this “titration” phenomenon. The implica-
tions for differential tax sanctions based upon nicotine delivery, as
well as for the direction of development of less hazardous cigarettes,
need exploration in depth. Since the pH of the urine affects the rate of
elimination of nicotine from the blood stream, it might be expected to
have an impact on the nicotine titration process with accompanying
modification of smoking patterns (53); hence it should also be
examined in greater detail.

Another characteristic of cigarette smoke which modifies smoking
patterns is the pH (9). As has been mentioned earlier, cigarette smoke
of the bright type or U.S. blending formula is mildly acidic, which
results in relatively little irritation to the mucosa as compared to
mildly basic smoke, and can accordingly be inhaled without unpleasant
effects by many smokers. Cigar smoke, on the other hand, is mildly
basic and is quite irritating to the mucosal tissues; for this reason,
cigar smokers are less apt to inhale, or to inhale deeply, than are
cigarette smokers. It has also been suggested that cigars are satisfying
without being inhaled.

The remaining major toxic elements of cigarette smoke (CO and
NO,’s) are absorbed primarily through the alveoli (acrolein and HCN
are water soluble gases and ‘are readily absorbed in the upper
respiratory tract), and accordingly the inhalation characteristics of the
smoker will have a direct impact on the short- and long-range effects

14—98
of these substances. Further, the ciliatoxic effects of HCN and the
ciliastatic effects of acrolein will depend to a major extent on the
inhalation pattern of the smoker. Lastly, the contribution of the NO,’s
to chronic obstructive pulmonary disease depends to a major extent on
the presentation of these substances at the alveolar site; as a result,
inhalation practices will strongly affect the pathological sequelae of
the NO, compounds.

Thus, the consequences of cigarette smoking would appear to be
dependent not only on the composition of the smoke itself, but also on
the smoking patterns of the individual smoker. More extensive effort is
needed to develop dosimetric and puff-analysis tools and techniques as
a basis for better understanding of the pharmacokinetic and smoking
behavioral dimensions of cigarette smoking.

Summary

The smoking of a cigarette seems to satisfy a smoker’s physiological
and psychological needs, and it is generally accepted that nicotine is
the principal constituent responsible for cigarette smokers’ pharmaco-
logic responses.

Nicotine is rapidly absorbed in both the oral cavity and lungs,
especially at basic pH. It is a quick-acting ganglionic stimulant on both
the sympathetic and parasympathetic ganglia.

Nicotine causes the release of catecholamines, epinephrine, and
norepinephrine. Several physiological responses have been attributed
to nicotine and/or catecholamines, such as increased heart rate and
blood pressure, cardiac output, stroke volume, velocity of contraction,
myocardial contractile force, oxygen consumption, coronary blood flow
and arrythmias, bronchoconstriction and related pulmonary manifesta-
tions, increased mobilization and utilization of free fatty acids,
hyperglycemic effects, and a decreased pateller reflex response.

Considering the nicotine metabolites in cigarette smoke and the
presence of minor amounts of related alkaloids, nicotine exerts the
strongest response in a variety of biochemical and physiological tests.

Considerable evidence exists, although it is not uniformly accepted,
that smoking patterns of chronic smokers are dependent on the
nicotine content of the cigarette and dependent on what the nicotine
delivery would be when measured by the standard methodology.
Smoking patterns are dependent, to varying degrees, on the type of
cigarette smoked, the number of cigarettes smoked, the length of the
cigarette rod burned, the number of puffs, the depth of inhalation, and
the length of inhalation. Nicotine absorption is also dependent on the
above-mentioned parameters as well as on urine pH, which affects the
rate of elimination of unmetabolized nicotine.

14—99
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14—108
Reductions of the Toxic Activity of Cigarette Smoke
Gas Phase

During the last decade there has been a reduction in the concentration
of toxic and tumorigenic agents in cigarette smoke. Measured on
experimental animals, these reductions of harmful smoke constituents
are reflected in diminished ciliatoxicity, overall toxicity, and tumori-
genicity of low-tar, low-nicotine cigarettes.

Carbon Monoxide

Carbon monoxide is one of the compounds in cigarette smoke judged
most likely to contribute to the health hazards of smoking. Certain
modifications in the makeup and fillers of cigarettes, as well as the use
of special preparations of charcoal in filter tips, can lead to a slight
reduction of carbon monoxide in cigarette smoke (32); however,
selective filtration of CO does not seem to be feasible. For certain filter
cigarettes (those without perforated filter tips) the CO yield has
remained comparable to that of nonfilter cigarettes or has even
increased slightly (40). The major, and possibly the only, significant
reduction of CO in cigarette smoke can be achieved by air dilution with
perforated filter tips and/or perforated cigarette paper (33). With
increasing air dilution, CO is selectively reduced as compared to tar
and CO2(27, 29). This CO reduction occurs because the air dilution holes
permit rapid diffusion out of the smoke stream and because lowering
the effective puff volume through the fire cone alters the combustion
process and lowers the CO:CO2 ratio. As Table 22 shows, the CO
reduction is greater with ventilation than the decrease in tobacco
burned during puffing, as indicated by percent ventilation. For
example, where the ventilation of a cigarette is 52 percent, the CO
reduction is 67 percent. However, the smoker of cigarettes with
perforated wrappers and/or ventilated filter tips may compensate for
air dilution by taking increased puff volumes when he inhales. Overall,
though, ventilated filters do improve the CO/nicotine ratio. At present,
data on the carboxyhemoglobin levels of long-term smokers of these
types of cigarettes are not available for comparison.

As expected, the smoke of cigars and pipes is high in CO because of
the nearly complete lack of ventilation through the cigar wrapper or
pipe bowl (21, 30).

Reduction of Ciliatoric Smoke Compounds

It is assumed that mucociliary clearance is essential for the mainte-
nance of a normal pulmonary environment. Any interference with the
lung clearance mechanism can result in an accumulation of toxic and
tumorigenic agents and, consequently, in respiratory diseases. Studies
of humans have shown that in certain smokers, lung clearance returns
to normal after 3 months’ cessation of smoking (5). These consider-

14—104
TABLE 22.—Effects of various forms of air dilution on carbon
monoxide and carbon dioxide deliveries

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Sample Ventilation CO(mg) COxmg)
Filter Cigarette A 22% 10.6 35.1
perforated tip
Filter Cigarette A 13.6 43.5
unperforated tip
S reduction 2l 19
Cigarette B with 43% 87 30.7
tip open perforated
Cigarette B
unperforated tip 172 52.3
% reduction 49.4 41.2
Cigarette C with 52% 5.6 30.4
line perforated
paper
Cigarette C without 17.1 574
line perforations
% reduction 67 48.7

 

SOURCE: Sloan, C.H. ($2).

ations have led to efforts towards the identification and reduction of
ciliatoxie components in cigarette smoke. Bioassays for the evaluation
of the ciliatoxicity of cigarette smoke and of individual smoke
components are carried out with isolated ciliated tissues, with organs,
or with the intact animal (1, 48).

While the particulate matter of cigarette smoke inhibits mucociliary
clearance to some extent, certain volatile smoke constituents show
significant ciliatoxic potency. Table 23 lists gas phase components with
relatively high ciliatoxicity as measured on isolated chicken trachea (1).

One or more successful methods for the specific reduction of
ciliatoxic volatiles in cigarette smoke is charcoal filtration, a technique
thoroughly explored over many years (13, 18, 44). The efficiency for
removal of gas phase constituents of charcoal filter tips is listed in
Table 24 (12, 31). An extensive study demonstrated that air dilution
filters lowered delivery of gaseous aldehydes, CO, HCN, ete. (12).

The design of cigarettes can also significantly influence the
ciliatoxicity of the mainstream smoke. This is important since
modification of the design characteristics of cigarettes is primarily
aimed at lowering tar and nicotine content of smoke and may not
concurrently consider ciliatoxicity of the smoke. Studies on the
mainstream smoke of cigarettes made from certain reconstituted
tobacco sheets or tobacco substitutes and on mainstream smoke of
filter cigarettes with air dilution have shown a reduction in ciliatoxici-

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TABLE 23.—Vapor phase constituents with high ciliatoxic
potency—in vitro

Amount in smoke

 

 

Compound Potency (ug /puff)
Typical (Range)

Hydrogen Cyanide +++ 38(16-63)
Formaldehyde +++ 5(25-11)
Acrolein +++ 10(5.6-10.4)
Sulfur Dioxide +++ <1
Crotonaldehyde ++ 16
2,3-Butanedione ++ 12
Ammonia ++ 1
Nitrogen Dioxide ++ <10
Methacrolein + 1
Vinyl Acetate + 05
Nitric Oxide + 60(12-75)
Score ED;{8 puffs}
+++ High =<50 (ug/puff)
++ Moderate = 50-100
+ Low = 100-500

SOURCE: Battista, S.P. (1).

ty as well as lower levels of hydrogen cyanide, formaldehyde, and tar
(24-26),

Volatile Phenols and Catechols

In the experimental setting, volatile phenols were considered to
contribute to the tumor-promoting activity of cigarette smoke. Several
studies have demonstrated that various types of cellulose acetate filter
tips selectively removed volatile phenols from cigarette mainstream
smoke (10, 31, 44). However, in bioassays on mouse skin with cigarette
tar and in inhalation studies with diluted whole smoke on Syrian
golden hamsters, a selective reduction of volatile phenols was not
paralleled by a selective reduction of tumorigenicity (8, 24-26).

Catechols, which are known co-carcinogens in the experimental
setting, are not selectively reduced by filtration from cigarette smoke
(3, 22). Cigarette fillers low in wax layer components, either by use of
tobacco stems, reconstituted tobacco sheet, or tobacco extracted with a
hexane-ethanol mixture, delivered smoke significantly reduced in
eatechols (6). Although it has not been directly established that a
selective reduction in catechol leads to a significant reduction of the
tumorigenic potential of cigarette smoke, it is of interest that all those
tars or whole smokes of cigarettes which are low in catechol also have a
significantly lower tumorigenic activity (7, 8, 24-26).

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