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 (1958), Landauer (1960), 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 1986).
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 1983), but others report positive associa-
tions (Himmelberger, Brown, Cohen 1978; Fedrick 1978; Kelsey et al.
1978). 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.
1981). 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-l-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 1968), 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 1956), but was found to be a cocarcinogen in the
benzo(a)pyrene-tetradecanoy] 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-furyl)-2
thiazyl) formamide (FANFT)-induced urinary bladder tumors in rats
(LaVoie et al. 1985). 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 2), 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 tovaneer in
humans exposed to nicotine per se (such as with nicotine replace-
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

NITROSATION \
OM *2N 9 on

N-NO tiem N-NO
errs ore? of ot
NAB NAT

WN
NNAL NNK NNN

FIGURE 2.—Formation of tobacco-specific nitrosamines

NOTE: NNAL. 4methylnitrosamino}143-pyridylbutan-1-ol; NNK, 44methylnitrosamino)143-pyridy])-1-buta-
none: NNN, N‘-nitrosorornicotine; NAB, N’-nitrosoanabasine NAT, N’-nitrosoanatabine.

SOURCE: US DHHS (1986).

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

 

Tobacco product NNN NNK NAT + NAB

 

Smokeless tobacco

Chewing tobacco' (ppb) 3500-8200 100-3000 500-7000
Snuff! (ppb) 800-89,000 200-8300 200-4000

Mainstream smoke

Cigarette, NF (ng/cig) - 120-950 80-770 140-990
Cigarette, French Black, NF 500 220 350
Cigarette. F (ng/cig) 50-310 30-150 60-370
Little cigar, F (ng/cigar) 5500 4200 1700
Cigar ing/cigar) 3200 1900 , 1900

Sidestream smoke

Cigarette. NF ing’cig) 1700 410 270
Cigarette, F (ng/cig) 150 190 150

 

NOTE: NNN, N‘-nitrosonornicotine; NNK, 44methylnitrosamino)-143-pyridyl}1-butanone; NAT, N'-nitrosoana-
tabine. NAB, N-nitrosoanabasine, NF, without filter tip; F, with filter tip.

‘Chewing tobacco and snuff also contain < 200 ppb NNAL. 4(methylnitrosamino}143-pyridyl)butan-1-ol.

SOURCE: Hoffmann, LaVoie, Hecht (1985).

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 1976), resulting in gastroesophageal reflux and duodeno-
gastric reflux, respectively. The former may result in reflux symp-
toms (heartburn) (Stanciu and Bennett 1972), 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
References

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

ALLISON, R.D., ROTH, G.M. Central and peripheral vascular effects during cigarette
smoking. Archives of Environmental Health 19:189-198, August 1969.

ASMUSSEN, I., KJELDSEN, K. Intimal ultrastructure of human umbilical arteries.
Observations on arteries from newborn children of smoking and nonsmoking
mothers. Circulation Research 36(5):579-589, May 1975.

AYROMLOOI, J., DESIDERIO, D., TOBIAS, M. Effect of nicotine sulfate on the
hemodynamics and acid base balance of chronically instrumented pregnant sheep.
Developmental Pharmacology and Therapeutics 3:205-213, 1981.

BALLING, R.. BEIER. H.M. Direct effects of nicotine on rabbit preimplantation
embryos. Toxicology 34(4):309-313, March 1985.

BARLOW, R.B., McLEOD, L.J. Some studies on cytisine and its methylated
derivatives. British Journal of Pharmacology 35(1):161-174, 1969.

BAYER, F., BOHN, ILL, STRAUER, B.E. Das kontraktionsverhalten des linken
ventrikels unter nikotinexposition. [The comportment of the contraction behavicr
of the left ventrical under nicotine exposition.] Therapiewoche 35:1968-1974, 1985.

BECK, E.R., TAYLOR, R.F., LEE. L.Y., FRAZIER, D.T. Bronchoconstriction and
apnea induced by cigarette smoke: Nicotine dose dependence. Lung 164:293-301,
1986.

BEEMAN, J.A., HUNTER, WC. Fatal nicotine poisoning. A report of twenty-four
cases. Archives of Pathology 24:481-485, 1937.

BEKHEIT, S., FLETCHER. E. The effects of smoking on myocardial conduction in the
human heart. American Heart Journal 91(6):712-720, June 1976.

BELCH, J.J.F.. McARDLE, B.M., BURNS, P., LOWE, G.D.O., FORBES, C.D. The
effects of acute smoking on platelet behaviour, fibrinolysis and haemorheology in
habitual smokers. Thrombosis Haemostasis 51(1):6-8, February 28, 1984.

BENOWITZ, N.L., JACOB, P. HI Metabolism, pharmacokinetics and pharmacody-
namics of nicotine in man. In: Martin, W.R., Van Loon, G.R., Iwamoto, E.T., Davis,
L. (eds.) Tobacco Smoking and Nicotine: A Neurobiological Approach. New York:
Plenum Press, 1987, pp. 357-373.

BENOWITZ, N.L., LAKE, T., KELLER, K.H., LEE, B.L. Prolonged absorption with
development of tolerance to toxic effects after cutaneous exposure to nicotine.
Clinical Pharmacology and Therapeutics 42(1):119-220, 1987.

BERNFELD, P., HOMBURGER, F. High nicotine tolerance of Syrian golden
hamsters. (Abstract.) Toxicology and Appiied Pharmacology 22(2):324-325, June
1972.

BILLIMORIA, J.D., POZNER, H., METSELAAR, B., BEST, F.W., JAMES, D.C.O.
Effect of cigarette smoking on lipids, lipoproteins, blood coagulation, fibrinolysis
and cellular components of human blood. Atherosclerosis 21(1):61-76, January-
February 1975.

BISHUN, N.P., LLOYD, N., RAVEN, R.W., WILLIAMS, D.C. The in vitro and in vivo
cytogenetic effects of nicotine. Acta Biologica Academiae Scientiarum Hungaricae
23(2):175-180, 1972.

BOCK, F.G. Carginogenic properties of nicotine. In: Gori, G., Bock, F.G. (eds.} Banbury,
Report 3. A Safe Cigarette? New York: Cold Spring Harbor Laboratory, 1980, pp.
129-139.

BOOYSE, F.M., OSIKOWICZ, G., QUARFOOT, A.J. Effects of chronic oral consump-
tion of nicotine on the rabbit aortic endothelium. American Journal of Pathology
102(2):229--238, February 1981.

BORZELLECA, J.F.. BORMAN, E.R., McKENNIS, H. Studies on the respiratory and
cardiovascular effects of (-)-cotinine. Journal of Pharmacology and Experimental
Therapeutics 137(3):313-318, September 1962.

609
BOUCHER, R.C., JOHNSON, J., INOUE, S., HULBERT, W., HOGG, J.C. The effect of
cigarette smoke on the permeability of guinea-pig airways. Laboratory Investiga-
tion 43(1):94-100, July 1980.

BOYLAND E. The possible carcinogenic action of alkaloids of tobacco and betel nut.
Planta Medica 11(Supplement):13-22, 1968.

BRANTMARK, B., FREDHOLM, B. Absorption of Nicotine from Swallowed Intact
Buffered Nicorette Chewing Gum, A.B. Leo Research Report No. 897. Helsingborg,
Sweden, 1974.

BRISCHETTO, C.S., CONNOR, W.E., CONNOR, S.L., MATARAZZO, J.D. Plasma
lipid and lipoprotein profiles of cigarette smokers from randomly selected families:
Enhancement of hyperlipidemia and depression of high-density lipoprotein.
American Journal of Cardiology 52(7):675-680, October 1, 1983.

CARLSSON, 1, WENNMALM, A. Effect of cigarette smoking on reactive hyperaemia
in the human finger. Clinical Physiology 3:453-469, 1983.

CARD, J.P., MITCHELL, J.A. The effects of nicotine on implantation in the rat.
Biology of Reproduction 20:532-539, April 1979.

CHAMSON, A., FREY, J., HIVERT, M. Effects of tobacco smoke extracts on collagen
biosynthesis by fibroblast cell cultures. Journal of Toxicology and Environmental
Health %5/6):921-932, May-June 1982.

CHAMSON, A., GARRONE, R., AUGER, C., FREY, J. Effects of tobacco smoke
extract on the ultrastructure of fibroblasts in culture. Journal of Submicroscopic
Cytology 12(3):401-406, July 1980.

CHATTOPADHYAY, D.K., GREANEY, M.G., IRVIN, T.T. Effect of cigarette smoking
on the lower oesophageal sphincter. Assessment of normal and symptomatic
patients using the rapid pull-through technique of oesophageal manometry. Gut
18(10):833-835, October 1977.

CHUJOH, C., NAKAZAWA, S. Inenmaku shogai ni kansura jikkenteki kenkyu toku
ni sakusan kaiyo nochiyu ni oyobosu kitsuen no eikyo ni tsuite. [Experimental
study for the gastric mucosal damage.| Japanese Journal of Gastroenterology
78(12):2285-2294, 1981.

CLUETTE-BROWN, J., MULLIGAN, J., DOYLE, K., HAGAN, S., OSMOLSKI, T.,
HOJNACKI, J. Oral nicotine induces an atherogenic lipoprotein profile. Proceed-
ings of the Society for Experimental Biology and Medicine 182(3):409-413, July
1986.

COMSTOCK, G.W., LUNDIN, F.E. Jr. Parental smoking and perinatal mortality.
American Journal of Obstetrics and Gynecology 98(5):708-718, July 1, 1967.
CRAIG, S., REES, T.D. The effects of smoking on experimental skin flaps in hamsters.

Plastic and Reconstructive Surgery 75(6):842-846, June 1985.

CRIQUI, M.H., COWAN, L.D., HEISS, G., HASKELL, W.L., LASKARZEWSKI, P.M.,
CHAMBLESS, L.E. Frequency and clustering of nonlipid coronary risk factors in
dyslipoproteinemia. The Lipid Research Clinics Program Prevalence Study.
Circulation 73(1, Part 2):1-40-1-50, January 1986.

CRYER, P.E., HAYMOND, M.W., SANTIAGO, J.V., SHAH, S.D. Norepinephrine and
epinephrine release and adrenergic mediation of smoking-associated hemodynamic
and metabolic events. New England Journal of Medicine 295(11):573-577, Septem-
ber 1976.

CSONKA, E., SOMOGYI, A., AUGUSTIN, J., HABERBOSCH, W., SCHETTLER, G.,
JELLINEK, H. The effect of nicotine on cultured cells of vascular origin. Virchows
Archiv A. Pathological Anatomy and Histology 407(4):441-447, 1985.

DAVIS, J.W., SHELTON, L., EIGENBERG, D.A., HIGNITE, C.E., WATANABE, LS.
Effects of tobacco and non-tobacco cigarette smoking on endothelium and platelets.
Clinical Pharmacology and Therapeutics 37(5):529-533, May 1985.

DIVERS, W.A. Jr., WILKES, M.M., BABAKNIA, A., YEN, S.S.C. Maternal smoking
and elevation of catecholamines and metabolites in the amniotic fluid. American
Journal of Obstetrics and Gynecology 141(6):625-628, November 1981.

610
DOUSSET, J.C., GUTIERRES, J.B., DOUSSET, N. Hypercholesterolaemia after
administration of nicotine chewing gum. (Letter.) Lancet 2(8520):1393-1394,
December 13, 1986.

DOWNEY, H.F., CRYSTAL, G.J., BASHOUR, F.A. Regional renal and splanchnic
blood flows during nicotine infusion: Effects of beta adrenergic blockade. Journal
of Pharmacology and Experimental Therapeutics 216(2):363-367, February 1981.

EVANS, D.R., NEWCOMBE, R.G., CAMPBELL, H. Maternal smoking habits and
congenital malformations: A population study. British Medical Journal
2(6183):171-173, July 21, 1979.

FAULKNER, J.M. Nicotine poisoning by absorption through the skin. Journal of the
American Medical Association 100(21):1664-1665, May 27, 1933.

FEDRICK, J. Factors associated with low birth weight of infants delivered at term.
British Journal of Obstetrics and Gynaecology 85(1):1-7, January 1978.

FLORIN, I., RUTBERG, L., CURVALL, M., ENZELL, C.R. Screening of tobacco smoke
constitutents for mutagenicity using the Ame’s test. Toxicology 18:219-232, 1980.

FRANKE, F.E., THOMAS, J.E. The treatment of acute nicotine poisoning. Journal of
the American Medical Association 106(1):507-512, January 4, 1936.

FREDHOLM, B., SAWE, U. Effects of Nicorette chewing and cigarette smoking on
skin capillary blood flow. (Abstract.) Clinical Physiology 1(1):604-605, 1981.

FREEDLANDER, B.L., FRENCH, F.A. Absence of co-carcinogenic action of oxidation
products of nicotine in initiation of pulmonary adenomas in mice with urethan.
(Abstract.) Proceedings of the American Association for Cancer Research 2(2):109,
April 1956.

GARG, M. Variation in effects of nicotine in four strains of rats. Psychopharmacologia
14:432-438, 1969.

GEHLBACH, S.H., WILLIAMS, W.A., FREEMAN, J.I. Protective clothing as a means
of reducing nicotine absorption in tobacco harvesters. Archives of Environmental
Health 34(2):111-114, March-April 1979.

GEHLBACH, S.H., WILLIAMS, W.A., PERRY, L.D., FREEMAN, J.I., LANGONE,
J.J., PETA, L.V., VAN VUNAKIS, H. Nicotine absorption by workers harvesting
green tobacco. Lancet 1(7905):478-480, March 1, 1975.

GEHLBACH, S.H., WILLIAMS, W.A., PERRY, L.D., WOODALL, J.S. Green-tobacco
sickness. An illness of tobacco harvesters. Journal of the American Medical
Association 22914):1880-1883, September 30, 1974.

GENNSER, G., MARSAL, K., BRANTMARK, B. Maternal smoking and fetal
breathing movements. American Journal of Obstetrics and Gynecology
123(8):861-867, December 15, 1975.

GHOSH, S.K., PARIKH, J.R., GOKANI, V.N., KASHYAP, S.K., CHATTERJEE, S.K.
Studies on occupational health problems during agricultural operation of Indian
tobacco workers. A preliminary survey report. Journal of Occupational Medicine
21(1):45-47, January 1979.

GNASSO, A., HABERBOSCH, W., SCHETTLER, G., SCHMITZ, G., AUGUSTIN, J.
Acute influence of smoking on plasma lipoproteins. Proceedings of the Society for
Experimental Biology and Medicine 182:414-418, 1986.

GOLDFRANK, L., MELINEK, M., BLUM, A. Nicotine. Hospital Physician
16(4):22-35, 1980.

GOUJARD, J., RUMEAU, C., SCHWARTZ, D. Smoking during pregnancy, stillbirth
and abruptio placentae. Biomedicine 23(1):20-22, February 10, 1975.

GVOZDJAKOVA, A., BADA, V., SANY, L., KUCHARSKA, J., KRUTY, F., BOZEK,
P., TRYSTANSKY, L., GVOZDJAK, J. Smoke cardiomyopathy: Disturbance of
oxidative processes in myocardial mitochondria. Cardiovascular Research
18:229-232, 1984.

GREEN, M.S., JUCHA, E., LUZ, Y. Blood pressure in smokers and nonsmokers:
Epidemiologic findings. American Heart Journal 3(5):932-940, May 1986.

611
HADDOW, J.E., KNIGHT, GJ, PALOMAKI, G.E., KLOZA, E.M., WALD, N.J.
Cigarette consumption and serum cotinine in relation to birthweight. British
Journal of Obstetrics and Gynaecology 94(7):678-681, July 1987.

HAMMER, R.E., MITCHELL, J.A. Nicotine reduces embryo growth, delays implanta-
tion, and retards parturition in rats. Proceedings of the Society for Experimental
Biology and Medicine 162(2):333-336, November 1979.

HAMOSH, M., SIMON, M.R., HAMOSH, P. Effect of nicotine on the development of
fetal and suckling rats. Biology of the Neonate 35(5/6):290-297, 1979.

HARTIALA, JJ., MAPP, C., MITCHELL, R.A., GOLD, W.M. Nicotine-induced
respiratory effects of cigarette smoke in dogs. Journal of Applied Physiology
59(1):64-71, July 1985.

HARZ, AJ., ANDERSON, AJ., BROOKS, H.L., MANLEY, J.C., PARENT, GT.,
BARBORIAK, J.J. The association of smoking with cardiomyopathy. The New
England Journal of Medicine 311(19):1201-1206, November 8, 1984.

HEMMINKI, K., MUTANEN, P., SALONIEMIL, I. Smoking and the occurrence of
congenital malformations and spontaneous abortions: Multivariate analysis.
American Journal of Obstetrics and Gynecology 145(1):61-66, January 1, 1983.

HIMMELBERGER, D.U., BROWN, B.W. Jr., COHEN, E.N. Cigarette smoking during
pregnancy and the occurrence of spontaneous abortion and congenital abnormali-
ty. American Journal of Epidemiology 108(6):470-479, December 1978.

HLADOVEC, J. Endothelial injury by nicotine and its prevention. Experientia
34(12):1585-1586, December 15, 1978.

HOFFMANN, D., ADAMS, J.D. Carcinogenic tobacco-specific N-nitrosamines in snuff
and in the saliva of snuff dippers. Cancer Research 41:4305-4308, November 1981.

HOFFMANN, D., BRUNNEMANN, K.D. Endogenous formation of N-nitrosoproline
in cigarette smokers. Cancer Research 43(11):5570-5574, November 1983.

HOFFMANN, D., HECHT, S$.S. Nicotine-derived N-nitrosamines and tobacco-related
cancer: Current status and future directions. Cancer Research 45(3):935-944,
March 1985.

HOFFMANN, D., LaVOIE, E.J., HECHT, S.S. Nicotine: A precursor for carcinogens.
Cancer Letters 26(1):67-75, February 1985.

HOJNACKI, J., MULLIGAN, J., CLUETTE-BROWN, J., IGOE, F., OSMOLSKI, T.
Oral nicotine impairs clearance of plasma low density lipoproteins. Proceedings of
the Society for Experimental Biology and Medicine 182:414-418, 1986.

HUDSON, D.B., MEISAMI, E., TIMIRAS, PS, Brain development in offspring of rats
treated with nicotine during pregnancy. Experientia 29(3):286-288, March 15,
1973.

HUDSON, D.B., TIMIRAS, P.S. Nicotine ingestion during gestation: Impairment of
reproduction, fetal viability and development. Biology of Reproduction
1(2):247-253, 1972.

HURST, D.J., GILBERT, G.L. Acute change in lung collagen synthesis produced by
cigarette smoke components. (Abstract.) American Review of Respiratory Disease
1194, Supplement):222, April 1979.

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. Tobacco Smoking,
IARC Monographs on the evaluation of the carcinogenic risk of chemicals to
humans, Volume 38. World Health Organization, International Agency for
Research on Cancer, 1986.

ISLES, C., BROWN, JJ., CUMMING, A.M.M., LEVER, A.F., McAREAVEY, D.,
ROBERTSON, J.1S.. HAWTHORNE, V.M., STEWART, G.M., ROBERTSON,
J.W.K., WAPSHAW, J. Excess smoking in malignant-phase hypertension. British
Medical Journal 1(6163):579-581, March 3, 1979.

JAIN, A.C., BOWYER, A-F., MARSHALL, R.J., ASATO, H. Left ventricular function
after cigarette smoking by chronic smokers: Comparison of normal subjects and
patients with coronary artery disease. American Journal of Cardiology 39(1):27-31,
January 1977.

612
JANOFF, A. Biochemical links between cigarette smoking and pulmonary emphyse-
ma. Journal of Applied Physiology: Respiratory, Environmental and Exercise
Physiology 55(2):285-293, August 1983.

JANOFF, A. Elastases and emphysema: Current assessment of the protease-antipro-
tease hypothesis. American Review of Respiratory Disease 132(2):417-433, August
1985.

JAY, M., KOJIMA, S., GILLESPIE, M.N. Nicotine potentiates superoxide anion
generation by human neutrophils. Toxicology and Applied Pharmocology
86:484-487, December 1986.

JONASON, T., BERGSTROM, R. Cessation of smoking in patients with intermittent
claudication. Acta Medica Scandinavica 221(3):253-260, 1987.

KAJJSER, L., BERGLUND, B. Effect of nicotine on coronary blood-flow in man.
Clinical Physiology 5(6):541-552, December 1985.

KAUFMAN, T., EICHENLAUB, E.H., LEVIN, M., HURWITZ, D.J., KLAIN, M.
Tobacco smoking: Impairment of experimental flap survival. Annals of Plastic
Surgery 13(6):468-472, 1984.

KAWANO, S., SATO, N., FUKUDA, M., SHICHIRI, M., KAMADA, T., ABE, H.
Inenmaku ketsuryu ni eikyo o oyobuso shoinshi no kento - (dai ippo) naishikyoka
hansha supekutory kaiseki ni yory kitsuen no eiko no kento. (Effect of cigarette
smoking on gastric hemodynamics. Analysis by reflectance spectrophotometry.]
Japanese Journal of Gastroenterology 79:187-192, 1982.

KELSEY, J.L., DWYER, T., HOLFORD, T.R., BRACKEN, M.B. Maternal smoking and
congenital malformations. An epidemiological study. Journal of Epidemiology and
Community Health 32(2):102-107, June 1978.

KHAN, M.A., PROVENZA, D.V., OLSON, N.O., OVERMAN, D.O. Nicotine toxicity in
chick vertebral chondrocytes in vitro. Chemico-Biological Interactions
35(3):363-367, 1981.

KIKENDALL, J.W., EVAUL, J., JOHNSON, L.F. Effect of cigarette smoking on
gastrointestinal physiology and non-neoplastic digestive disease. Journal of
Clinical Gastroenterology 6(1):65-79, February 1984.

KLEIN, L.W., AMBROSE, J., PICHARD, A., HOLT, J., GORLIN, R., TEICHHOLZ,
L.E. Acute coronary hemodynamic response to cigarette smoking in patients with
coronary artery disease. Journal of the American College of Cardiology
3(4):879-886, April 1984.

KONTUREK, §.J., RADECKI, T., THOR, P.,. DEMBINSKI, A., JACOBSON, E.D.
Effects of nicotine on gastric secretion and ulcer formation in cats. Proceedings of
the Society for Experimental Biology and Medicine 138(2):674-677, November 1971.

LAI, Y.-L., DIAMOND, L. Effects of high or low nicotine cigarette smoke exposure on
elastase induced emphysema. (Abstract). American Review of Respiratory Disease
135(Supplement):150, 1987.

LANDAUER, W. Nicotine-induced malformations of chicken embryos and their
bearing on the phenocopy problems. Journal of Experimental Zoology
143(1):107-122, February 1960.

LARSON, P.S., HAAG, H.S., SILVETTE, H. Tobacco: Experimental and Clinical
Studies. A Comprehensive Account of the World Literature. Baltimore: Williams
and Wilkins, 1961.

LaVOIE, E.J., SHIGEMATSU, A., RIVENSON, A. MU, B., HOFFMANN, D.
Evaluation of the effects of cotinine and nicotine-N’-oxides on the development of
tumors in rats initiated with N-[4-5-nitro-2 fury})-2-thiazolyl] formamide. Journal
of the National Cancer Institute 75(6):1075-1081, December 1985.

LAWRENCE, W.T., MURPHY, R.C., ROBSON, M.C., HEGGERS, J.P. The detrimen-
tal effect of cigarette smoking on flap survival: An experimental study in the rat.
British Journal of Plastic Surgery 37(2):216-219, April 1984.

613
LEE, K.S., GRUBER, C.M. Jr. The effect of nicotine on the production of peptic ulcers
in histamine treated dogs. Archives of Internationales de Pharmacodynamie et de
Thérapie 90(4):462-465, August 1952.

LEE, L.-Y., MORTON, R.F., HORD, A.H., FRAZIER, D.T. Reflex control of breathing
following inhalation of cigarette smoke in conscious dogs. Journal of Applied
Physiology: Respiratory, Environmental and Exercise Physiology 54(2):562-570,
February 1983.

LEHTOVIRTA, P., FORSS, M., RAURAMO, L, KARINIEMI, V. Acute effects of
nicotine on fetal heart rate variability. British Journal of Obstetrics and
Gynaecology 9(8):710-715, August 1983. ‘

LELCUK, S., THRELFALL, L., VALERIE, R., SHEPRO, D., HECHTMAN, H.B.
Nicotine stimulates pulmonary parenchymal thromboxane synthesis. Surgery
100(5):836-840, November 1986.

LINDNER, E. Untersuchungen/ber das Verhalten des N-3'-phenyl-propyl-(2’)-1,1-
diphenyl-propyl{3)-amins (Segontin (*)) gegen/ber der Wirkungen des Noradrena-
lins. Archives Internationales de Pharmacodynamie et de Thérapie 146:475-484,
December 1963.

LOCKHART, LP. Nicotine poisoning. (Letter.) British Medical Journal 1:246-247,
February 11, 1933.

LONGO, L.D. The biological effects of carbon monoxide on the pregnant woman, fetus,
and newborn infant. American Journal of Obstetrics and Gynecology 129(1):69-103,
September 1, 1977.

LUNDBERG, J.M., MARTLING, C.-R., SARIA, A., FOLKERS, K., ROSELL, S.
Cigarette smoke-induced airway oedema due to activation of capsaicin-sensitive
vagal afferents and substance P release. Neuroscience 10(4):1361-1368, 1983.

LUNDBERG, J.M., SARIA, A., MARTLING, C.R. Capsaicin pretreatment abolishes
cigarette smoke-induced edema in rat tracheo-bronchial mucosa. European Jour-
nal of Pharmacology 86(2):317-318, December 24, 1982.

MALIZIA, E., ANDREUCCI, G., ALFANI, F., SMERIGLIO, M., NICHOLAI, P. Acute
intoxication with nicotine alkaloids and cannabinoids in children from ingestion of
cigarettes. Human Toxicology 2(2):315-316, 1983.

MANNING, F.A., FEYERABEND, C. Cigarette smoking and fetal breathing move-
ments. British Journal of Obstetrics and Gynaecology 83(4):262-270, April 1976.

MAOUAD, J., FERNANDEZ, F., BARRILLON, A., GERBAUX, A., GAY, J. Diffuse or
segmental narrowing (spasm) of the coronary arteries during smoking demon-
strated on angiography. American Journal of Cardiology 53(2):354—355, January
15, 1984.

MARITZ, G. Pre- and postnatal carbohydrate metabolism of rat lung tissue: The effect
of maternal nicotine exposure. Archives of Toxicology 592):89-93, July 1986.
MARKS, M.H., BURCH, J.B., COLLINS, A.C. Genetics of nicotine response in four
inbred strains of mice. Journal of Pharmacology and Experimental Therapeutics

226(1):291-302, 1983.

MARTIN, J.C., BECKER, R.F. The effects of maternal nicotine absorption or hypoxic
episodes upon appetitive behavior of rat offspring. Developmental Psychobiology
4(2):133-147, 1971.

MARTIN, J.C., MARTIN, D.D., RADOW, B., DAY, H.E. Life span and pathology in
offspring following nicotine and methamphetamine exposure. Experimental Aging
Research 5(4):509-522, August 1979.

MARTIN, J.L., WILSON, J.R., FERRARO, N., LASKEY, W.K., KLEAVELAND, J.P.,
HIRSHFELD, J.W. Jr. Acute coronary vasoconstrictive effects of cigarette smoking
in coronary heart disease. American Journal of Cardiology 54(1):56-60, July 1,
1984.

MASON, G.R., USZLER, J.M., EFFROS, R.M., REID, E. Rapidly reversible alterations
of pulmonary epithelial permeability induced by smoking. Chest 83(1):6-11,
January 1983.

614
MAU, G., NETTER, P. Die auswirkungen des viaterlichen zigaretten kongums aug die
perintale sterblichkeit und lie missbildungshaufigkeit. [The effects of paternal
cigarette smoking on perinatal mortality and on incidence of malformations.]
Deutsche Mediziniche Wockenshrift 99:113-1118, 1974.

McNALLY, W.D. A report of seven cases of nicotine poisoning. Journal of Laboratory
and Clinical Medicine 8:83-85, 1923.

McPHAUL, M., PUNZI, H.A., SANDY. A.. BORGANELLI, M., RUDE, R., KAPLAN,
N.M. Snuff-induced hypertension in pheochromocytoma. Journal of the American
Medical Association 252(23/30):2860-2862, 1984.

MEHTA, J., MEHTA, P. Role of blood platelets and prostaglandins in coronary artery
disease. American Journal of Cardiology 48:366-373, August 1981.

MENSCH, A.R., HOLDEN, M. Nicotine overdose after a single piece of nicotine gum.
(Letter.) Chest 86(5):801-802, November 1984.

MEYER, M.B., TONASCIA, J.A. Maternal smoking, pregnancy complications, and
perinatal mortality. American Journal of Obstetrics and Gynecology
128(5):494-502, July 1, 1977.

MEYERS, M.G., BENOWITZ, N.L., DUBBIN, J.D., HAYNES, R.B., SOLE, MJ.
Cardiovascular effects of smoking in patients with ischemic heart disease. Chest
93(1):14-19, 1988.

MINER, L.L., MARKS, M.H., COLLINS, A.C. Classical genetic analysis of nicotine-
induced seizures and nicotine receptors. Journal of Pharmacology and Experimen-
tal Therapeutics 231(3):545-554, December 1984.

MOROSCO, G.J., NIGHTINGALE, T.E., FRASINEL, C., GOERINGER, G.C. Pancreat-
ic elastase activation as a possible indicator of the relative hazard of different
cigarettes. Journal of Toxicology and Environmental Health 8:89-94, 1981.

MURTHY, S.N.S., DINOSO, V.P. Jr., CLEARFIELD, H.R., CHEY, W.Y. Simultaneous
measurement of basal pancreatic, gastric acid secretion, plasma gastrin, and
secretin during smoking. Gastroenterology 73(4):758-761, 1977.

MUSTARD, J.F., MURPHY, E.A. Effect of smoking on blood coagulation and platelet
survival in man. British Medical Journal 1(5330).846-849, March 2, 1963.

NAEYE, RL. Effects of maternal cigarette smoking on the fetus and placenta. British
Journal of Obstetrics and Gynaecology 85(10):732-737, October 1978.

NAEYE, R.L., PETERS, E.C. Mental development of children whose mothers smoked
during pregnancy. Obstetrics and Gynecology 64(5):601-607, November 1984.
NAKAMURA, M., HAGA, T., MIYANO, M., SASAKI, H., TAKISHIMA, T. Dose-
response curves of central and peripheral airways to nicotine injections in dogs.

Journal of Applied Physiology 61(5):1677-1685, 1986.

NAKAMURA, M., HAGA, T., SASAKI, H., TAKISHIMA, T. Acute effects of cigarette
smoke inhalation on peripheral airways in dogs. Journal of Applied Physiology
§8(1):27-33, 1985.

NICOD, P., REHR, R., WINNIFORD, M.D., CAMPBELL, W.B., FIRTH, B.G., HILLIS,
L.D. Acute systemic and coronary hemodynamic and serologic responses to
cigarette smoking in long-term smokers with atherosclerotic coronary artery
disease. Journal of the American College of Cardiology 4(5):964-971, November
1984.

NIEBURG, P., MARKS, J.S., McLAREN, N.M., REMINGTON, P.L. The fetal tobacco
syndrome. Journal of the American Medical Association 253(20):2998-2999, May
24-31, 1985.

NISHIMURA, H., NAKAI, K. Developmental anomalies in offspring of pregnant mice
treated with nicotine. Science 127:877-878, 1958.

PACKHAM, M.S., MUSTARD, J.F. The role of platelets in the development and
complications of atherosclerosis. Seminars in Hematology 23(1):8-26, January
1986.

615
PALLADINO, G., BRUNNEMANN, K.D., ADAMS, J.D.. HALEY, N.J., HOFFMANN,
D. Snuff-dipping in college students: A clinical profile. Military Medicine
151:342-346, June 1986.

PETERS, M.A., NGAN, L.L.E. The effects of totigestational exposure to nicotine on
pre- and postnatal development in the rat. Archives Intternationales et de
Pharmacodynamie 257(11:155-167, May 1982.

PETERS, R.W., BENOWITZ, N.L.. VALENTI, S., MODIN, G., FISHER, M.L.
Electrophysiologic effects of cigarette smoking in patients with and without
chronic beta-blocker therapy. American Journal of Cardiology 60:1078-1082, 1987.

PETITTI, D.B., KLATSKY. A.L. Malignant hypertension in women aged 15 to 44
years and its relation to cigarette smoking and oral contraceptives. American
Journal of Cardiology 52(3).297-298, August 1983.

PHILIPP, K., PATEISKY, N., ENDLER, M. Effects of smoking on uteroplacental
blood flow. Gynecologic and Obstetric Investigation 17(4):179-182, April 1984.
QUICK, C.R.G., COTTON, L.T. The measured effect of stopping smoking on
intermittent claudication. British Journal of Surgery 69(Supplement): 524-526,

1982.

QUIMBY, G.F., BONNICE, C.A., BURSTEIN, S.H., EASTWOOD, G.L. Active smoking
depresses prostaglandin synthesis in human gastric mucosa. Annals of Internal
Medicine 104(5):616-619, May 1986.

RATTAN, S., GOYAL, R.K. Effect of nicotine on the lower esophageal sphincter.
Studies on the mechanism of action. Gastroenterology 69(1):154-159, July 1975.

REES, P.J., CHOWIENCZYK, P-.J., CLARK, T.J.H. Immediate response to cigarette
smoke. Thorax 37(6):417-422, June 1982.

REES, T.D., LIVERETT, D.M., GUY, C.L. The effect of cigarette smoking on skin-flap
survival in the face lift patient. Plastic Reconstructive Surgery 73(8):911-914, June
1984.

RENAUD, S., BLACHE, D., DUMONT, E., THEVENON, C., WISSENDANGER, T.
Platelet function after cigarette smoking in relation to nicotine and carbon
monoxide. Clinical Pharmacology and Therapeutics 36(3):389--395, September
1984.

RESNICK, R., BRINK, G.W.. WILKES, M. Catecholamine-mediated reduction in
uterine blood flow after nicotine infusion in the pregnant ewe. Journal of Clinical
Investigation 63(6):1133-1136, June 1979.

RIEBE, M., WESTPHAL, K. Studies of the induction of sister-chromatid exchanges in
Chinese hamster ovary cells by various tobacco alkaloids. Mutation Research
124(3/4):281-286, December 1983.

RIEBE, M., WESTPHAL, K., FORTNAGEL, P. Mutagenicity testing in bacterial test
systems, of some constituents of tobacco. Mutation Research 101(1):39-43, March
1982.

RIGOTTI, N.A., EAGLE, K.A. Atrial fibrillation while chewing nicotine gum. (Letter.)
Journal of the American Medical Association 256(8):1018, February 28, 1986.

ROGERS, D.F., WILLIAMS, D.A., JEFFERY, P.K. Nicotine does not cause “bronchi-
tis” in the rat. Clinical Science 70(5):427-433, May 1986.

SAXENA, K., SCHEMAN, A. Suicide plan by nicotine poisoning: A review of nicotine
toxicity. Veterinary and Human Toxicology 27\61495-497, December 1985.

SCHMAHL, D., OSSWALD, H. Fehlen einer carcinogenen Wirkung von cotinin bei
Ratten. [The absence of a carcinogenic action of cotinine on rats.! Zeitschrift f/r
Krebsforschung 71:198, 1968.

SHEPHERD, R.J., COLLINS, R., SILVERMAN, F. Responses of exercising subjects to
acute “passive” cigarette smoke exposure. Environmental Research 19:279-291,
1979.

SHIONO, P.H., KLEBANOFF, M.A., BERENDES, H.W. Congenital malformations
and maternal smoking during pregnancy. Teratology 34(1):65-71, August 1986.

616
SIESS, W., LORENZ, R., ROTH, P.. WEBER, P.C. Plasma catecholamines, platelet
aggregation and associated thromboxane formation after physical exercise,
smoking or norepinephrine infusion. Circulation 66(1):44—-48, July 1982.

SOLOMON, T.E., SOLOMON, N., SHANBOUR, L.L., JACOBSON, E.D. Direct and
indirect effects of nicotine on rabbit pancreatic secretion. Gastroenterology

7(2) 276-283, August 1974.

SONNENFELD, T.. WENNMALM, A. Inhibition by nicotine of the formation of
prostacyclin-like activity in rabbit and human vascular tissue. British Journal of
Pharmacology 71:609-613, 1980.

SRIDHARAN, M.R., FLOWERS, N.C., HAND, R.C., HAND, J.W., HORAN, L.G.
Effect of various regimens of chronic and acute nicotine exposure on myocardial
infarct size in the dog. American Journal of Cardiology 55(1):1407-1411, May 1,
1985.

STANCIU, C., BENNETT, J.R. Smoking and gastrooesophageal reflux. British
Medical Journal 3(5830):793-795, September 30, 1972.

STEWART, P.M., CATTERALL, J.R. Chronic nicotine ingestion and atrial fibrilla-
tion. British Heart Journal 54(2):222-223, August 1985.

STONE, P.J., CALORE, J.D., McGOWAN, S.E.. BERNARDO, J., SNIDER, G.L.,
FRANZBLAU, C. Functional a,-protease inhibitor in the lower respiratory tract of
cigarette smokers is not decreased. Science 221:1187-1189, 1983.

SUZUKI, K., HORIGUCHI, T., COMAS-URRUTIA. A.C., MUELLER-HEUBACH, E.,
MORISHIMA, H.O., ADAMSONS, K. Placenta] transfer and distribution of
nicotine in the pregnant rhesus monkey. American Journal of Obstetrics and
Gynecology 119(2}:253-262, May 15, 1974.

SZUTS, T.. OLSSON, S., LINDQUIST, N.G., ULLBERG, S., PICOTTI, A., ENZELL, C.
Long term fate of 14 C-nicotine in the mouse: Retention in the bronchi, melanin-
containing tissues and urinary bladder wall. Tuxicology 10(3):207-220, July 1978.

THOMPSON, J.H., GEORGE, R. Chronic effects of nicotine on gastric secretion in rats
with hypothalamic lesions. American Journal of Digestive Diseases 17(6):513-518,
June 1972.

THYBERG, J. Effects of nicotine on phenotypic modulation and initiation of DNA
synthesis in cultured arterial smooth muscle cells. Virchows Archiv 52(1):25-82,
1986.

TOTH, B. Effects of long term administration of nicotine hydrochloride and nicotinic
acid in mice. AntiCancer Research 2(1/2):71-73, January-April 1982.

TOTTI, N., McCUSKER, K.T., CAMPBELL, E.J.. GRIFFIN, G.L., SENIOR, R.M.
Nicotine is chemotactic for neutrophils and enhances neutrophil responsiveness to
chemotactic peptides. Science 223(4632):169-171, January 13, 1984.

TRUHAUT, R., DE CLERCQ, M., LOISILLIER, F. Sur les toxicités, aigué et chronique
de la cotinine, et sur son effet cancérigéne chez le rat. Pathologie-Biologie 12:39-42,
January 1964.

TSUDA, M., NIITSUMA, J., SATO, 8., HIRAYAMA, T., KAKIZOE, T.. SUGIMURA,
T. Increase in the levels of N-nitrosoproline, N-nitrosothioproline, and N-nitroso-2-
methylthioproline in human urine by cigarette smoking. Cuncer Letters
30(2):117-124, 1986.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Heaith Conse-
quences of Smoking for Women. A Report of the Surgeon General. U.S. Department
of Health and Human Services. Public Health Service, Office of the Assistant
Secretary for Health, Office on Smoking and Health, 1980.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Cancer. A Report of the Surgeon General. US. Department of
Health and Human Services, Public Health Service, Office on Smoking and
Health. DHHS Publication Ne. (PHS) 82-50179, 1982

617
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Cardiovascular Disease. A Report of the Surgeon General. US.
Department of Health and Human Services, Public Health Service, Office on
Smoking and Health. DHHS Publication No. (PHS) 84-50204, 1983.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Chronic Obstructive Lung Disease. A Report of the Surgeon
General. U.S. Department of Health and Human Services, Public Health Service,
Office on Smoking and Health. DHHS Publication No. (PHS) 84-50205, 1984.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Cancer and Chronic Lung Disease in the Workplace. A Report
of the Surgeon General. U.S. Department of Health and Human Services, Public
Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 85-
50207, 1985.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Involuntary Smoking. A Report of the Surgeon General. U.S. Depart-
ment of Health and Human Services, Public Health Service, Centers for Disease
Control, Office on Smoking and Health. DHHS Publication No. (CDC) 87-8398,
1986.

VALENZUELA, J.E. DEFILIPPI, C., CSENDES, A. Manometric studies on the
human pyloric sphincter. Effect of cigarette smoking, metoclopramide, and
atropine. Gastroenterology 70(4):481-483, April 1976.

WADDELL, W.J., MARLOWE, C. Localization of nicotine?*C, cotinine-’*C, and
nicotine-1'-N-oxide-'*C in tissues of the mouse. Drug Metabolism and Disposition
4(6):530-539, November-December 1976.

WALD, N.J., IDLE, M., BOREHAM, J., BAILEY, A.. VAN VUNAKIS, H. Serum
cotinine levels in pipe smokers: Evidence against nicotine as cause of coronary
heart disease. Lancet 2(8250):775-777, October 10, 1981.

WANG, N., CHEN, M., SCHRAUFNAGEL, D.E., YAO, Y. The cumulative scanning
electron microscopic changes in baby mouse lungs following prenatal and
postnatal exposures to nicotine. Journal of Pathology 144(2):89-100, October 1984.

WELLS, D.G., RUSTICK, J.M. Hypertension from smokeless tobacco. (Letter.)
Anesthesiology 65:339, 1986.

WEIZENECKER, R., DEAL, W.B. Tobacco cropper’s sickness. Journal of the Florida
Medical Association 57(12):13-14, December 1970.

WERNER, B. Interviews with parents of 595 children with poisoning accidents.
International Conference of Poison Control, June 4, 1969.

WINNIFORD, M.D., WHEELAN, K.R., KREMERS, MS., UGOLINI, V., VAN DEN
BERG, E. Jr., NIGGEMANN, E.H., JANSEN, D.E., HILLIS, L.D. Smoking-induced
coronary vasoconstriction in patients with atherosclerotic coronary artery disease:
Evidence for adrenergically mediated alterations in coronary artery tone. Circula-
tion 73(4):662-667, April 1986.

WIRTH, W., GOSSWALD, R. Pharmacologische Untersuchungen in der Reihe der
Diphenylcarbamidsaure-thioester: Il Mitteilung. Arch. Int. Pharmacodyn.
155-393-417, 1965. (Cited in Larson, P.S., Silvette, H. Tobacco: Experimental and
Clinical Studies, Supplement II. Baltimore, Maryland: Williams and Wilkins Co.,
1971, p. 198.)

YAMATAKE, Y., SASAGAWA, S., YANAURA, 8S. Drug responses of canine trachea,
bronchus and bronchiole. Chemical and Pharmaceutical Bulletin 26:318-320,
January 1978.

YOSHINAGA, K., RICE, C., KRENN, J., PILOT, R.L. Effects of nicotine on early
pregnancy in the rat. Biology of Reproduction 20(2):294-303, March 1979.

618