70 to 110. Rechallenge with snuff after surgical removal of the
pheochromocytoma revealed only a mild blood pressure increase.
Another patient with previously controlled essential hypertension
presented with a blood pressure of 210/115 mmHg prior to surgery
(Wells et al. 1986). A mass of snuff was found in the patient's cheek.
The snuff was removed and blood pressure returned to 150!85
mmHg within 15 min.

Wound Healing

Adequate blood flow to the skin is important for wound healing.
Cigarette smoking and nicotine polacrilex gum reduce skin blood
flow (Fredholm and Sawe 1981; Allison and Roth 1969; Carlsson and
Wennmalm 1983). In rats, exposure to cigarette smoke decreases
survival of surgical flaps (Kaufman et al. 1984; Lawrence et al. 1984;
Craig and Rees 1985). Cigarette smoking has been associated with a
twelvefold increased risk of experiencing skin slough after facelift
surgery (Rees, Liverett, Guy 1984). It is conceivable that nicotine
substitution therapy might also delay wound healing, but no human
data are as yet available.

Reproductive Hazards
Teratogenicity

Nicotine rapidly crosses the placenta and enters the fetus (Suzuki
et al. 1974). Nishimura and Nakai (19581, Landauer (19601, and Khan
and coworkers (1981) have described teratogenic effects of high doses
of nicotine, which interfered with skeletogenesis in mice and chick
embryos. Chronic nicotine treatments of pregnant rats throughout
gestation produced subtle neurological changes which manifested
themselves as behavioral or electrophysiological alterations in the
offspring (Peters and Ngan 1982; Hudson, Meisami, Timiras 1973;
Martin and Becker 1971). Wang, Chen, and Schraufnagel (1984)
found that pre- and postnatal exposure to nicotine induced structur-
al changes in the lungs of fetal mice. Maternal exposure to nicotine
also inhibited glucose metabolism in fetal lung tissue (Maritz 19861.
Thus, several studies suggest that nicotine, at least in high doses,
may have toxic effects on the fetus.

Whether cigarette smoking is associated with increased rates of
congenital malformations in humans is controversial. Several stud-
ies show no association or a lower incidence of malformations in
offspring of smoking mothers (Comstock and Lundin 1967; Goujard,
Rumeau, Schwartz 1975; Meyer and Tonascia 1977; Evans, New-
combe, Campbell 1979; Shiono, Klebanoff, Berendes 1986; Hem-
minki, Mutanen, Salonieni 19831, but others report positive associa-
tions (Himmelberger, Brown, Cohen 1978; Fedrick 1978; Kelsey et al.
19781. One study has reported an association between paternal

601


smoking and the incidence of congenital malformations (Mau and
Netter 1974).

Pregnancy

Cigarette smoking during pregnancy increases the risk of low
birth weight, prematurity, spontaneous abortion, and perinatal
mortality in humans, which has been referred to as the fetal tobacco
syndrome (Nieburg et al. 1985) (also reviewed in detail in the 1980
Surgeon General's Report). Nicotine influences implantation and
embryo development in some laboratory animal studies (Hudson and
Timiras 1972; Card and Mitchell 1979; Hammer and Mitchell 1979).
At least one adverse outcome, reduced birth weight, is correlated
with the level of cotinine, the major metabolite of nicotine, in the
mother's serum (Haddow et al. 1987).

Nicotine in high concentrations markedly decreases the in vitro
development of rabbit preimplantation embryos and inhibits DNA
synthesis (Balling and Beier 1985). Injection of nicotine, 7.5 mg twice
each day from proestrus through pregnancy in rats, resulted in a
delay in the entry of the ovum into the uterus, implantation, and
subsequent development of the ovum (Yoshinaga et al. 1979). It was
suggested that nicotine acted by delaying progesterone secretion,
which is necessary to prepare the uterus for implantation, and by
other disturbances of hormone release. Another study in rats
reported that low doses of nicotine injected subcutaneously (0.1
mg/kg/day) from day 14 to the end of pregnancy had no effect on
litter size or fetal development, but higher doses (1 mg/kg/day),
comparable to those consumed by heavy smokers, reduced litter size
and increased the number of still births (Hamosh, Simon, Hamosh
1979). Further research is needed to determine if there are direct
adverse effects of nicotine on the embryo or fetus at levels of nicotine
comparable to those observed in cigarette smokers.

A likely mechanism for the reproductive problems in pregnant
cigarette smokers is placental insufficiency, which is supported by
evidence of placental hypoperfusion in cigarette smoking mothers
(Naeye 1978; Philipp, Pateisky, Endler 1984). The factors most likely
to affect the placenta are carbon monoxide and nicotine, both agents
having the potential of impairing oxygen supply to the fetus.

Inhalation of carbon monoxide results in elevation of both
maternal and fetal carboxyhemoglobin (Asmussen and Kjeldsen
1975; Longo 1977). Nicotine infusion in pregnant sheep increases
uterine vascular resistance and reduces uterine blood flow, effects
which appear to be mediated by catecholamine release (Ayromlooi,
Desiderio, Tobias 1981; Resnick, Brink, Wilkes 1979). Both cigarette
smoking and nicotine gum increase fetal heart rate during the
second trimester in humans, consistent with sympathetic activation
(Lehtovirta et al. 1983). During the third trimester in humans,

602


cigarette smoking or nicotine gum chewing decreases fetal heart rate
and reduces fetal breathing movements, both of which may be signs
of fetal hypoxia (Lehtovirta et al. 1983; Gennser, Marsal, Brantmark
1975; Manning and Feyerabend 1976). Elevated levels of catechol-
amines in amniotic fluid in human smokers during the third
trimester indicate sympathetic activation in the fetus, consistent
with fetal hypoxia and/or direct effects of nicotine (Divers et al.
1981X The above findings suggest that nicotine contributes to the
adverse effects of cigarette smoking on reproduction probably by
acting on the utero-placental circulation. Besides producing func-
tional changes, carbon monoxide and nicotine might also be responsi-
ble for the injury to the intimal ultrastructure of the umbilical
artery seen in smoking mothers (Asmussen and Kjeldson 1975). Fetal
hypoxemia has also been considered as a contributory cause of
behavioral abnormalities, such as hyperactivity, short attention
span, lower scores on spelling and reading tests, which occurred at a
higher frequency in children whose mothers had smoked throughout
pregnancy than in those born to nonsmoking mothers (Naeye and
Peters 1984).

Pulmonary Toxicity

Cigarette smoking is the major cause of chronic obstructive lung
disease (US DHHS 1984). Nicotine may directly or indirectly
influence the development of emphysema in smokers. It rapidly
accumulates in the pulmonary epithelial cells and some of its
metabolites are retained in the lung for prolonged periods (Waddell
and Marlowe 1976; Szuts et al. 1978).

Chronic bronchial wall inflammation with accumulation of alveo-
lar macrophages and polymorphonuclear neutrophils into the lung
occur in response to habitual cigarette smoke exposure (Janoff 1983,
1985). Macrophages and neutrophils release elastase, an enzyme that
destroys alveolar structure. Stone and colleagues (1983) found that
alpha-1-antitrypsin, an inhibitor of elastase, may also be partially
inactivated by cigarette smoke, probably related to effects of oxidant
gases. Nicotine, which possesses chemotactic properties for neutro-
phils (Totti et al. 1984; Jay, Kojima, Gillespie 1986) and can
stimulate the production of elastase as shown for the pancreas in
vivo (Morosco et al. 1981), may play a role in increasing elastase
levels in the lungs. In addition, nicotine may adversely affect the
repair of connective tissue since it has been reported to cause
structural alterations and inhibition of collagen synthesis in fibro-
blast cultures (Chamson et al. 1980; Chamson, Frey, Hivert 1982;
Hurst and Gilbert 1979).

Several other studies suggest that nicotine may contribute to the
development of emphysema in smokers. Lai and Diamond (1987)
showed that repeated inhalation of smoke from high, but not from

603


low, nicotine cigarettes significantly augmented experimentally
induced emphysema in rats. Lelcuk and coworkers (1986) reported
that nicotine instilled directly into the airways induced edema. In
the rat, a variety of ingredients of both the particulate and vapor
phase of cigarette smoke are capable of increasing vascular perme-
ability and producing edema in the tracheobronchial mucosa (Lund-
berg et al. 1983). This effect, which was traced to the stimulation of
substance P-containing pulmonary vagal afferent neurons, was
duplicated by nicotine (Lundberg, Saria, Martling 1982). In the
guinea pig, inhaled cigarette smoke damaged the mucosal barrier
and increased permeability to horseradish peroxidase by disrupting
the intercellular tight junctions of the bronchial epithelium (Bouch-
er et al. 1980). In smokers, Mason and coworkers (1983) documented
an increase in pulmonary epithelial permeability in all lung regions
using a radioaerosol procedure. In contrast, neither aerosolized nor
injected nicotine, given over a period of 2 to 3 weeks, causes secretory
cell hyperplasia (Rogers, Williams, Jeffery 1986) and there is little
evidence that nicotine contributes to the development of chronic
bronchitis. Further research is needed to define the magnitude of the
contribution of nicotine to the pathogenesis of smoking-induced
chronic lung disease.

Nicotine can also worsen pulmonary function in smokers who
already have lung disease. Acute exposure to nicotine induces
constriction of both central and peripheral airways (Yamatake,
Sasagawa, Yanaura 1978). The increase in airway resistance by
nicotine involves vagal reflexes and stimulation of parasympathetic
ganglia in the bronchial wall (Nakamura et al. 1986). The magnitude
of bronchoconstriction observed in experimental animals and hu-
mans following acute inhalation of cigarette smoke is correlated
with the level of nicotine in the smoke (Shepherd, Collins, Silverman
1979; Rees, Chowienczyk, Clark 1982; Lee et al. 1983; Nakamura et
al. 1985; Hartiala et al. 1985; Beck et al. 1986), suggesting that
nicotine may be an important factor in the increased airway
resistance of smokers.

Genotoxicity and Carcinogenicity

Smoking of cigarettes is causally related to cancer of the respira-
tory tract, the upper digestive tract, pancreas, renal pelvis, and
bladder; cigarette smokers also face an increased risk for cancer of
the cervix (US DHHS 1982; IARC 1986). Many carcinogenic agents
have been identified in cigarette smoke, however, not a single
component nor chemical group(s) of components is solely responsible
for the carcinogenic activity of cigarette smoke in the various organs.
Laboratory bioassays suggest that polynuclear aromatic hydrocar-
bons and N-nitrosamines play significant roles in the induction of
cancer in smokers (US DHHS 1982; IARC 1986). Nicotine, the

604


principal alkaloid in tobacco smoke, has also been examined for its
genotoxic and carcinogenic activity. In the Ames' Salmonella
typhimurium mutagenesis and mammalian cell cytogenetic assays,
nicotine did not possess any genotoxic activity, although it induced
reparable DNA damage in the Escherichia coli pol A+ /A- system
(Bishun et al. 1972; Florin et al. 1980; Riebe, Westphal, Fortnagel
1982; Riebe and Westphal 1983).

In earlier studies, nicotine and its primary metabolites were
reported to possess weak tumorigenic activity (Truhaut, De Clercq,
Loisillier 1964; Boyland 19681, which subsequent investigations did
not confirm (Schmahl and Osswald 1968; Martin et al. 1979; Toth
1982; LaVoie et al. 1985). Nicotine lacked cocarcinogenic activity in
the urethane-induced mouse pulmonary adenoma model (Freelander
and French 19561, but was found to be a cocarcinogen in the
benzo(a)pyrene-tetradecanoyl phorbol acetate mouse skin tumorigen-
esis model (Bock 1980). The mechanism of cocarcinogenic activity is
not clearly understood. Two primary metabolites of nicotine, coti-
nine and nicotine-N'-oxide, failed to promote N-(4-(5-nitro-2-fury&2
thiazyl) formamide (FANFTtinduced urinary bladder tumors in rats
(LaVoie et al. 19851. On balance, it appears that nicotine does not
possess direct carcinogenic activity.

During processing and pyrolysis of tobacco, nicotine can be N'-
nitrosated to form N'-nitrosonornicotine and other related com-
pounds (Figure 2) (Hoffmann and Brunnemann 1983; Hoffmann and
Hecht 1985). These tobacco-specific N'nitrosoamines are found in
substantial concentrations in American snuff, as well as in main-
stream tobacco smoke (Table 21, and in the saliva of snuff dippers
(Hoffmann and Adams 1981; Palladino et al. 1986). Tobacco specific
N-nitrosoamines are highly carcinogenic in animals and are suspect-
ed to contribute to cancer related to cigarette smoking and smokeless
tobacco use (Hoffmann, LaVoie, Hecht 1985; Hoffmann and Hecht
1985). There is also concern that nicotine may be N-nitrosated within
the human body. Endogenous formation of N-nitrosoproline (a
noncarcinogenic marker of endogenous N-nitrosation) has been
documented in cigarette smokers (Hoffmann and Brunnemann 1983;
Tsuda et al. 1986). Whether nicotine-derived nitrosoamines are
formed endogenously in amounts sufficient to contribute
humans exposed to nicotine per se (such as with
ment therapy) remains to be determined.

Gastrointestinal Disease

In peptic ulcer disease, cigarette smoking is a risk factor for its
development, and an even stronger risk factor for delayed healing,
failure to respond to therapy, and relapse (Kikendall, Evaul,
Johnson 1984). In animals, nicotine potentiates peptic ulcer forma-
tion induced by histamine or pentagastrin (Konturek et al. 1971; Lee

605


NICOTINE NORNICOTINE ANABASINE ANATABINE
Qe @Y & &

Nl I-ROSATION

NNAL             NNK      NNN      NAB     NAT

FIGURE 2.-Formation of tobacco-specific nitrosamines

SOTE: NNAL. 4~methyln~trosamino~l~3-pyr~dylIbu~n-l-ol; NNK. Umethylnitroeamino~l~kpyridyl~l-buts-
none: NNN. N'-nltroso:`ornicotine. NAB. N'-nitrosoanabasine NAT, N'-nitrcexmatabine.
SOURCE US DHHS f1986).

TABLE 2.-Tobacco-specific nitrosamines in commercial
      U.S. tobacco products

Tobacco product                 NNN           NNK       NAT + NAB

Smokeless tobacco

Chewmg tobacco ' Ippb)         3500-8200          KC-3ooo       500-7Ocm
Snuff' `ppbl               80049,ooo         2oe4300       2oo4oo

Mainstream smoke

Cigarette. NF Ing/cig)           120-950           80-770        140-990
Cigarette. French Black, NF       500             220           350
Ctgarette. F lng/cigl            x-310           30-150         m-370
Llrtle cgnr. F Ingicigar)         5500            4200          1700
Cigar \nyicigarl              32co            1900          1900

Sidestream smoke

Cigarette. NF u&c@          1700             410           270
Cqarette. F !ng/clgj            150             190           150

SOTE .VNN. N'-nltrosonornicotine. NNK. 4~methylnitrcsamino~liSpyridyl~I-butanone; NAT, N'-nitromena-
rablne. NAB. N -natresoanabasme. NF. without filter tip, F, with Filter tip.
~`herw~~ tobacco and snuff also contam ~2CO ppb NNAL. 4~methylnitrosamino~l-(3pyridyl)butsn-lal.
SOL'RCE Hoffman. IaVow. Hecht (19851

and Gruber 1952). Several mechanisms by which nicotine acts in this
regard have been proposed. (1) Chronic treatment in rats increases
basal acid secretion, an effect which appears to be mediated by
parasympathetic mechanisms (Thompson and George 1972). Chronic
cigarette smoking may induce hypersecretion of acid in response to
secretory stimuli. (2) Infusion of nicotine in animals and cigarette
smoking by people reduces pancreatic bicarbonate secretion, which
normally neutralizes acid entering the duodenum (Solomon et al.

606


1974; Murthy et al. 1977). This could result in increased acid delivery
to the duodenum, thereby increasing the risk of ulceration. (3)
Smoking may impair the mucosal barrier to acid-mediated injury.
Smoking, apparently acting through nicotine, decreases mucosal
blood flow and inhibits mucosal prostaglandin synthesis, both of
which may impair the effectiveness of the gastric mucosal barrier,
which protects the stomach lining against acid (Chujoh and Nakaza-
wa 1981; Kawano et al. 1982; Quimby et al. 1986). (4) Cigarette
smoking reduces both lower esophageal and pyloric sphincter
pressures (Chattopadhyay, Greaney, Irvin 1977; Valenzuela, Defilip-
pi, Csendes 19761, resulting in gastroesophageal reflux and duodeno-
gastric reflux, respectively. The former may result in reflux symp-
toms (heartburn) (Stanciu and Bennett 19721, while the latter may
cause reflux of bile acids and lysolecithin, which are known to break
down the gastric mucous barrier. A direct role of nicotine is
suggested by studies in opposums showing that intravenous nicotine
reduces lower esophageal sphincter pressure (Rattan and Goyal
1975).

The relative importance of local exposure to nicotine (as from
swallowing nicotine from nicotine polacrilex gum) versus exposure to
nicotine via the bloodstream in producing the above effects is
unclear. In view of the extremely high concentrations of nicotine in
saliva as compared to blood, local toxicity must be considered until
proven otherwise to be an additional risk of nicotine polacrilex
chewing gum for patients with ulcer disease or symptoms of
esophageal reflux.

Summary and Conclusions

1. At high exposure levels, nicotine is a potent and potentially
lethal poison. Human poisonings occur primarily as a result of
accidental ingestion or skin contact with nicotine-containing
insecticides or, in children, after ingestion of tobacco or tobacco
juices.

2. Mild nicotine intoxication occurs in first-time smokers, non-
smoking workers who harvest tobacco leaves, and people who
chew excessive amounts of nicotine gum. Tolerance to these
effects develops rapidly.

3. Nicotine exposure in long-term tobacco users is substantial,
affecting many organ systems (Chapters II and III). Pharmaco-
logic actions of nicotine may contribute to the pathogenesis of
smoking-related diseases, although direct causation has not yet
been determined. Of particular concern are cardiovascular
disease, complications of hypertension, reproductive disorders,
cancer, and gastrointestinal disorders, including peptic ulcer
disease and gastroesophageal reflux.

607


4. The risks of short-term nicotine replacement therapy as an aid
to smoking cessation in healthy people are acceptable and
substantially outweighed by the risks of cigarette smoking.

608


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