NICOTINE
This record contains general information for nicotine, including statements in the
literature referenced to nicotine without identification of the individual salts under
study. For compound-specific information, refer to the appropriate individual records as
listed in the field for Related HSDB Records (RELT).Human Health Effects:
Human Toxicity Excerpts:
SYMPTOMATOLOGY: 1. BURNING SENSATION IN MOUTH & THROAT, SALIVATION, NAUSEA,
ABDOMINAL PAIN, VOMITING, DIARRHEA. GI REACTIONS ARE LESS SEVERE BUT DO OCCUR AFTER
CUTANEOUS & RESPIRATORY EXPOSURES. 2. SYSTEMIC EFFECT INCL AGITATION, HEADACHE,
SWEATING, DIZZINESS, AUDITORY & VISUAL DISTURBANCES, CONFUSION, WEAKNESS, &
INCOORDINATION. 3. AT FIRST RESPIRATIONS ARE DEEP & RAPID, BLOOD PRESSURE IS HIGH
& PULSE IS SLOW. INTENSE VAGAL STIMULATION MAY CAUSE TRANSIENT CARDIAC STANDSTILL OR
PAROXYSMAL ATRIAL FIBRILLATION. PUPILS ARE GENERALLY CONSTRICTED. 4. CENTRAL NERVOUS
EXCITATION IS ALSO EVIDENCED BY TREMORS AND SOMETIMES BY CLONIC-TONIC CONVULSIONS. 5. AS
DEPRESSION DEVELOPS, THE PUPILS DILATE, THE BLOOD PRESSURE FALLS, & THE PULSE BECOMES
RAPID & OFTEN IRREGULAR. FAINTNESS, PROSTRATION, CYANOSIS & DYSPNEA PROGRESS TO
COLLAPSE. 6. DEATH FROM PARALYSIS OF RESPIRATORY MUSCLES, USUALLY ONLY A FEW MINUTES AFTER
COLLAPSE.
Nicotine is one of the most lethal poisons
known. ... More than 90 percent of toxic exposures from cigarettes in the United States
are reported in children /SRP: from eating cigarettes or cigarette butts/ less than 5
years of age. ... Most of the recently reported serious toxic states from nicotine have been from exposure to nicotine-containing
products.
... SPLASH OF PURE NICOTINE BASE IN PT EYE
CAUSED SEVERE PAIN, MUCH CONJUNCTIVAL REACTION & CORNEAL INFILTRATION. EVENTUALLY, EYE
HEALED WITH PARTIAL OPACIFICATION OF CORNEA.
CLINICAL FINDINGS: PRINCIPAL MANIFESTATIONS OF NICOTINE
POISONING ARE RESPIRATORY STIMULATION & GI HYPERACTIVITY.
NICOTINE CAUSES INITIAL STIMULATION OF
SALIVARY & BRONCHIAL SECRETIONS THAT IS FOLLOWED BY INHIBITION.
... EFFECTS ... ON GI TRACT ARE DUE LARGELY TO PARASYMPATHETIC STIMULATION. COMBINED
ACTIVATION OF PARASYMPATHETIC GANGLIA & CHOLINERGIC NERVE ENDING RESULTS IN INCR TONE
& MOTOR ACTIVITY OF BOWEL. NAUSEA & VOMITING, & OCCASIONALLY DIARRHEA ARE
OBSERVED FOLLOWING SYSTEMIC ABSORPTION OF NICOTINE.
NICOTINE MARKEDLY STIMULATES CNS. ...
PRODUCES TREMORS ... FOLLOWED BY CONVULSIONS. ... STIMULATION OF CNS IS FOLLOWED BY
DEPRESSION, & DEATH RESULTS FROM FAILURE OF RESPIRATION DUE TO BOTH CENTRAL PARALYSIS
& PERIPHERAL BLOCKADE OF MUSCLES OF RESPIRATION.
CARDIOVASCULAR RESPONSES ... ARE DUE TO STIMULATION OF SYMPATHETIC GANGLIA &
ADRENAL MEDULLA ... WHICH ... RESULTS IN VASOCONSTRICTION, TACHYCARDIA, & ELEVATED
BLOOD PRESSURE.
ONSET OF SYMPTOMS OF ACUTE, SEVERE NICOTINE
POISONING IS RAPID; THEY INCL NAUSEA, SALIVATION, ABDOMINAL PAIN, VOMITING, DIARRHEA, COLD
SWEAT, HEADACHE, DIZZINESS, DISTURBED HEARING & VISION, MENTAL CONFUSION, & MARKED
WEAKNESS. FAINTNESS & PROSTRATION ... BLOOD PRESSURE FALLS; BREATHING IS DIFFICULT;
PULSE IS WEAK, RAPID, & IRREGULAR; & COLLAPSE ... FOLLOWED BY TERMINAL
CONVULSIONS. DEATH ... FROM RESP FAILURE.
The intake of tar (estimated as mutagenic activity of the urine), nicotine,
and carbon monoxide during short term cigarette restriction was studied in 13 smokers,
aged 22-61 yr, who initially smoked an average of 37 cigarettes/day. Exposure to nicotine and carbon monoxide was expressed as the area
under the blood concentration time curve for nicotine
or carboxyhemoglobin over 24 hr. When smoking was restricted to 5 cigarettes/ day, there
were 3.4, 2.70, 3.2 fold increases in urine mutagenic activity and intake of nicotine and carbon monoxide per cigarette,
respectively, as compared with values during unrestricted smoking.
With tobacco abstinence, it was expected that nicotine
metabolism would be slower than when smoking. To test this hypothesis, the disposition
kinetics of intravenous nicotine were studied in
20 healthy smokers while smoking, after abstaining from smoking for 1 week, and (in six
subjects) when smoking again. Cardiovascular responses to nicotine
were also measured. Unexpectedly, total and nonrenal clearance of nicotine
increased by 36% and 39%, respectively, during abstinence. The increase in clearance after
brief abstinence suggests that nicotine or its
metabolites or another component of cigarette smoke inhibits nicotine
metabolism in smokers. Cardiovascular responses to nicotine
were greater after 1 week compared with overnight abstinence, consistent with loss of
tolerance.
To test the nicotine effects on the human
fetus, maternal and fetal cardiovascular dynamics were studied in 20 pregnant women when
chewing a chewing gum containing 4 mg of nicotine
and a chewing gum without nicotine given in a
randomized double blind order. The fetal blood flow was measured with a method combining
realtime ultrasonagraphy and pulsed Doppler technique. Registrations were made in ten
fetuses from the thoracic part of the descending aorta and in ten fetuses from the
intra-abdominal part of the umbilical vein. In 15 of the fetuses /measurements/ were also
made from the umbilical artery. Concentrations of nicotine
in plasma were analyzed in six women. Thus maternal plasma nicotine
concentrations increased after the nicotine gum.
Also, 4 mg nicotine gum increased significantly
maternal heart rate, systolic and diastolic blood pressure. There was no influence on
fetal heart rate or fetal blood flow. The maternal nicotine
plasma concentrations after smoking a high dose cigarette are doubled compared with the
levels after a low dose cigarette (0.8-1.1 mg nicotine)
or a 4 mg nicotine gum.
NICOTINE IS OF CONSIDERABLE MEDICAL
IMPORTANCE BECAUSE OF ITS TOXICITY, PRESENCE IN TOBACCO, AND PROPENSITY FOR CONFERRING A
DEPENDENCE ON ITS USERS.
ACUTELY FATAL DOSE OF NICOTINE FOR AN ADULT
IS PROBABLY ABOUT 60 MG OF BASE.
... Toxic by inhalation and by skin absorption.
NICOTINE MAY BE RESPONSIBLE FOR THE HIGHER
INCIDENCE OF PEPTIC ULCER AMONG SMOKERS.
Applications of nicotine were made locally on
the nasal mucosa in human controls and patients suffering from hyperreactive nasal
disorders. Ten normal subjects (controls) (mean age-32 yr, male/female = 50/50%) having no
history of nasal disease or nasal allergy, smoking or ongoing drug treatment, and patients
with vasomotor rhinitis (VMR), having sneezing and rhinorrhea and/or nasal congestion
(mean age = 39 yr, male/female = 37/63%) were tested. Patients were divided into two
groups: patients with the diagnosis of vasomotor rhinitis (n= 10); and patients with
increased nasal secretion as the dominating symptom of the hyperreactive disorder (n= 4).
Nasal application of nicotine (6.5x10-5 M,
6.5x10-4 M and 6.5x10-3 M nicotine bitartrate in
saline) induced only a mild itching sensation in the three groups. However, nicotine challenge caused a significantly larger
secretory response in the vasomotor rhinitis disorder group. Nicotine
(6.5x10-3 M) caused a secretory response on the contralateral side that was similar to
that on the stimulated side. Unilateral pretreatment with ipratropium caused a significant
reduction of the secretion on the nicotine
stimulated side, but not on the contralateral side. After pretreatment with a combination
of lignocaine and naphazoline the secretory effect of nicotine
was abolished.
Two groups of smokers (n = 10 per group) were given nicotine
(15 ug/kg body weight) or placebo, and 1 group of nonsmokers (n = 10 control) were given
placebo. Nicotine was admin with a measured-dose
nasal-spray pump. The energy expenditure of subjects was examined on two occasions, each
including a period of rest and a period of exercise on a modified bicycle ergometer at
workloads designed to simulate and standardize light daily activity. All had abstained
from cigarette smoking the night before the study. The excess energy expenditure
attributable to nicotine was more than twice as
great during exercise between groups (difference between groups, 0.51 kJ/kg/hr, or 12.1%
of the metabolic rate at rest); than during rest (0.23 kJ/kg/hr, or 5.3% of the metabolic
rate at res)t. In contrast, the expenditure was not affected by placebo during exercise or
rest in the smokers or in the control group of nonsmokers. Incr in the heart rate and
systolic blood pressure attributable to nicotine
were equal during activity and rest, but the diastolic blood pressure was unaffected by nicotine during both sessions.
Human semen from 4 nonsmokers was tested within 1 hr after collection. Nicotine was diluted with BWW medium and then added to
ovulatory bovine cervical mucus to achieve concn of 0 (control), 100, 1000, and 5000
ng/ml. 45 min after contact with semen, quantitative assessment of in vitro sperm
penetrability through the mucus samples was made. Greater numbers of motile sperm were
present at each distance (5, 10, and 15 mm) when nicotine
was added as compared with the control. A 0.2 ml aliquot of each of the 8 semen specimens
was added to 5 ml of nicotine (0, 100, 1000, and
5000 ng/ml) in BWW medium and incubated for 2, 3, and 4 hr. The expected decr in motility
over time following incubation was not significantly affected by the concn of nicotine present. Nor did the nicotine
concn affect either mean progressive velocity or mean linearity of sperm in the incubated
samples.
Eight light smokers (<20 cigarettes/day) and ten heavy smokers (> or = 20
cigarettes/day) participated in two sessions on separate days in which they received 4
administrations (1 every 20 min) of a high nicotine
dose (15 ug/kg body wt, equiv to a typical cigarette) or a low nicotine
dose (7.5 ug/kg) while heart rate was monitored during the 5 min following each
administration. Compared with light smokers, heavy smokers had significantly smaller heart
rate responses to the high dose, indicating greater chronic tolerance, but there was no
difference between groups in response to the low dose. Acute tolerance to heart rate
response across the four 5-min periods was not observed with either dose. Subsequent
examination of heart rate response in the first 2 min following each dose administration
did suggest acute tolerance, particularly for the low dose, as this more acute heart rate
response declined from the first to the last administration.
The effects of nicotine administration (2 mg
eight-times daily as nicotine chewing gum for 2
wk) on plasma lipid and lipoprotein concn were studied in young healthy male volunteers.
Plasma levels of the nicotine metabolite,
cotinine, reached levels comparable to those seen in smokers. Plasma concn of
triglyceride, cholesterol, high density lipoprotein cholesterol, low density lipoprotein
cholesterol, and apolipoproteins AI and B, were determined repeatedly before, during and
after cessation of nicotine intake. All these
variables, as well as the activities of lipoprotein lipase and hepatic lipase in post
heparin plasma, remained unchanged throughout the study.
Prior to each exptl session, three male smokers were admin varying amounts of nicotine via either chewing nicotine
gum or smoking low or high nicotine yield
cigarettes. During the 60 min prior to some of the sessions, subjects were given 4 pieces
of nicotine gum to chew. Each piece was either
placebo or contained 2 mg of nicotine (doses
were 0, 2, 4 or 8 mg nicotine total). They were
then exposed to a free operant avoidance schedule in which a lever press postponed a point
subtraction on a counter for 20 sec (points exchangeable for money). Subtractions were
scheduled to occur every 5 sec in the absence of lever presses. Subjects participated
daily in 30 min exptl sessions, Mon through Fri (from 106 to 151 total sessions). Blood
samples were obtained just prior to nicotine
treatment, immediately following the treatment, and 30 min later on particular days.
Smoking cigarettes resulted in increased avoidance responding relative to baseline
nonsmoking rates. Smoking the low nicotine
delivery cigarettes produced increased avoidance responding in 2 of the 3 subjects; high nicotine delivery cigarettes increased avoidance in
all subjects (p < 0.05). The low nicotine
delivery cigarette condition resulted in a 11.8 ng/ml incr in one subject, but only
minimal incr in the other 2. Smoking the high nicotine
delivery cigarettes produced much larger incr in nicotine
blood levels (25.5, 19.5, 23.2 ng/ml). Chewing nicotine
gum did not produce changes in avoidance responding, however, nicotine
blood levels produced by chewing nicotine gum
were similar to levels produced by smoking cigarettes.
40 smokers and 40 nonsmokers were matched for age and gender. Smokers either smoked a
high nicotine (0.77 mg nicotine)
or low nicotine (0.13 mg) cigarette, while
nonsmokers sham smoked. Twelve min after smoking, participants viewed a stress inducing
movie. Smoking higher nicotine delivery
cigarettes during the movie, as compared to smoking for low nicotine
control cigarettes, was associated with reductions in anxiety (p < 0.05) and right
hemisphere activation, increased heart rate (p < 0.05), and enhancement of the ratio of
left hemisphere parietal EEG activation to right hemisphere activation.
Systemic effects of nicotine exposure were
studied in eight healthy male cigarette smokers (ages 27 to 61 yr; mean, 49 yr) during
free use of oral snuff, chewing tobacco, and cigarettes. Participants used either one of
the above 3 substances or abstained from all tobacco during four 3 or 4 day blocks.
Concentrations of nicotine and cotinine,
cardiovascular effects, and urine sodium, catecholamines and mutagenicity were measured
over 24 hr at the end of each treatment block. Mutagenic activity of the urine was
measured by the Salmonella-histidine auxotrophic-reversion assay. Circadian exposure to nicotine and cardiovascular effects, including urinary
catecholamine excretion, were similar for all forms of tobacco use. Urine sodium excretion
was greater while using smokeless tobacco than while smoking. Urine mutagenicity was
markedly increased while smoking cigarettes and tended to be increased while chewing
tobacco but not while using oral snuff.
Autopsy of those who died from acute nicotine
poisoning showed marked dilatation of the right side of the heart, mild pulmonary edema,
hemorrhagic gastritis, acute passive congestion of most internal organs, brain edema, and
marked renal hyperemia.
The common symptoms of moderate intoxication include nausea, vomiting, abdominal pain,
diarrhea, headache, sweating, fatigue, and palpitations. More severe symptoms include
faintness, dizziness, weakness, and confusion progressing to prostration with increasing
muscular weakness, collapse, and respiratory arrest. Most deaths occur within a few
minutes of ingestion and recovery usually occurs if the patient survives 1 to 4 hr. It has
been estimated that approximately 60 mg of nicotine
orally would be a fatal human dose.
Farm workers who hand-harvest tobacco are at risk of developing "green tobacco
sickness" /SRP: from nicotine exposure/.
Drug Warnings:
Drugs of Abuse: Contraindicated during Breast-Feeding: Nicotine
(smoking): Shock, vomiting, diarrhea, rapid heart rate, restlessness; decreased milk
production. (The Committee on Drugs strongly believes that nursing mothers should not
ingest any compounds listed /drugs of abuse/ ... Not only are they hazardous to the
nursing infant, but they are also detrimental to the physical and mental health of the
mother ... No drug of abuse should be ingested by nursing mothers even though adverse
reports are not in the literature.) /from Table 2/ [Report of the American Academy of
Pediatrics Committee on Drugs in Pediatrics 93 (1): 138 (1994)]
Allergic contact sensitization to nicotine,
confirmed by rechallenge in some patients, has been reported in 2-3% of patients receiving
the drug via a transdermal system...
Intranasal administration of nicotine
solution commonly produces local nasopharyngeal and ocular irritation. During the initial
2 days of intranasal nicotine therapy, nearly
all patients experience nasal irritation, which usually is moderate to severe. Both the
incidence and severity of nasal irritation decrease with continued intranasal therapy, but
it still is experienced by about 80% of patients after 3 weeks of therapy...
Patients with cardiac disease, recent myocardial infarction, or irregular heart rate
should consult their clinician before initiating self-medication with nicotine
preparations. A clinician also should be consulted prior to self-medication if the patient
has peptic ulcer disease, is receiving insulin for the management of diabetes mellitus, or
has uncontrolled hypertension or if they are receiving drug therapy for depression or
asthma...and, for the transdermal systems, if they are allergic to adhesive tape or have a
dermatologic condition.
Adverse GI effects occur frequently during the first week of therapy with nicotine polacrilex. The most frequent adverse
systemic effects...are indigestion and nausea, which reportedly occur in about 20-40% of
patients receiving the drug.
Adverse nervous system effect of nicotine
polacrilex include dizziness and lightheadedness, headache, insomnia, and irritability,
which reportedly occur in 1-25% of patients. Euphoria reportedly occurs in less than 1% of
patients.
Patients receiving nicotine polacrilex should
be warned that chewing the gum too rapidly may result in effects similar to those
associated with smoking a cigarette too rapidly or those experienced by nonsmokers when
they inhale a cigarette for the first time.
Medical Surveillance:
Recommended medical surveillance: The following medical procedures should be made
available to each employee who is exposed to nicotine
at potentially hazardous levels: Initial Medical Examination: A complete history and
physical examination: The purpose is to detect existing conditions that might place the
exposed employee at an increased risk, and to establish a baseline for future health
monitoring. Examination of the nervous system and cardiovascular system should be
stressed. Periodic Medical Examination: The aforementioned medical examination should be
repeated on an annual basis.
Populations at Special Risk:
Farm workers who hand-harvest tobacco are at risk of developing "green tobacco
sickness" /SRP: from nicotine exposure/.
Probable Routes of Human Exposure:
NIOSH (NOES Survey 1981-1983) has statistically estimated that 4737 workers (861 of
these are female) are potentially exposed to nicotine
in the US(1). The most probable route of human exposure to nicotine
is by inhalation of tobacco smoke and in indoor air where smoking is allowed(2). Some
segments of the general population may also be exposed to nicotine
in drinking water. Infants breast fed by woman who smoke will tend to be exposed to nicotine in the mother's milk. Worker exposure to nicotine may occur during processing and extraction of
tobacco(SRC).
Exposure of individuals to ambient nicotine
in households, offices, pubs, restaurants, coffee shops, cars, trains, and airplanes was
estimated. An estimate of the amount of nicotine
inhaled was calculated by multiplying nicotine
concentration from the personal monitor by respiratory volume (0.48 cu m/hr). Nicotine exposure was converted to an equivalent of
cigarettes smoked (representing passive smoking) by dividing the inhaled nicotine
values by the known nicotine exposure (1 mg)
from active smoking of one cigarette. Three individual offices yielded nicotine
exposure values ranging from 5.9 to 19.8 ug/cu m. The nicotine
inhaled was estimated to be 2.8 to 9.5 ug/hr, which is equivalent to active smoking of
0.003 to 0.010 cigarettes/hr. In one office where 28 to 48 cigarettes were smoked per day,
an estimated weekly nicotine exposure of 3.0 to
10.2 ug/cu m was calculated. Average nicotine
exposure levels in several public places ranged from 31.5 to 43.2 ug/cu m, with a passive
smoking exposure equivalent to no more than 50 ug nicotine/hr
(0.05 cigarettes/hr). Nicotine exposure levels
in smoking seats of trains and airplanes was 48.6 and 28.8 ug/cu m, respectively. These
values were equivalent to smoking 0.023 and 0.014 cigarettes/hr. Nicotine
intake was particularly high for individuals exposed at the workplace and at home. Daily nicotine inhaled by non-smokers (passive smoking) is
significantly less than that inhaled by active smokers.
Body Burden:
Breast milk from heavy smokers may contain 0.5 mg/l(1). Nicotine
was detected in breast milk from smokers and nonsmokers at a mean concentration of 91 and
0 ppb, respectively(2). Detected (0.2-1.6 ng/ml) in serum of newborn infants nursed by
smoking mothers(3).
Nicotine concns in hair samples taken from a
non-smoker ranged from 1.3 to 2.8 ug/g and in hair samples from a smoker ranged from 36 to
60 ug/g(1).
Urine samples of 2 groups of children (Group A: 10 mo old, 55 children; Group B: 4 yr
old, 54 children) were analyzed for nicotine and
cotinine to study the effects of exposure to environmental tobacco smoke. Twenty of Group
A and 19 of Group B children had not been exposed to environmental tobacco smoke while the
remaining children had been exposed during the last three days. The differences in urinary
nicotine and cotinine levels between the
"exposed" and "unexposed" children were statistically significant in
both age groups. Median urinary nicotine levels
in "exposed" and "unexposed" children were 2.7 ug/l and 1.3 ug/l
respectively in Group A and 2.2 ug/l and 1.1 ug/l respectively in Group B.
Average Daily Intake:
Using sidestream/mainstream ratios of nicotine
and assuming a 10 L/min respiratory rate, the recent Surgeon General's Report estimates
that from 0.6 to 30 ug of nicotine is inhaled in
one hour by passive smoking(1). As a result of all-day monitoring, it was found that the
highest amount of nicotine inhaled in a day was
estimated to be up to 310 ug, equivalent to actively smoking 0.31 ordinary cigarettes(2).
Minimum Fatal Dose Level:
The fatal adult dose is 60 mg.
Emergency Medical Treatment:
Emergency Medical Treatment:
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replication or redistribution of all or part of the POISINDEX(R) database is a violation
of Micromedex' copyrights and is strictly prohibited. The following Overview, *** NICOTINE ***, is relevant for this HSDB record chemical. |
| Life Support: |
o This overview assumes that basic life support measures
have been instituted.
|
| Clinical Effects: |
SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
o ABSORPTION - Nicotine is well absorbed via ingestion,
inhalation, dermal and rectal exposure. Oral
absorption from ingested cigarettes or cigars is
incomplete.
o Symptoms generally include nausea, vomiting, abdominal
pain and increased salivation. Confusion, agitation,
restlessness followed by lethargy, convulsions and coma
may be noted following severe exposure. Hypertension,
tachycardia and tachypnea may occur, followed by
hypotension, bradycardia and bradypnea. The duration
of symptoms is about 1 to 2 hours following mild
exposure, up to 18 to 24 hours following severe
intoxication. Co-intoxicants may complicate the
clinical course.
o Nicotine causes the blockade of nicotinic cholinergic
receptors in the brain, autonomic ganglia, and
neuromuscular junction. Thus, central nervous system,
sympathetic or parasympathetic autonomic, and
neuromuscular effects may be seen in varying
combinations.
o ONSET and duration of symptoms occur as follows:
1. TOBACCO - symptoms begin 30 to 90 minutes post
ingestion.
2. GUM OR LIQUID - symptoms onset is more rapid, 15 to 30
minutes post ingestion. Onset may be particularly
rapid in children.
3. DURATION - mild exposure: 1 to 2 hours; severe
intoxication: 18 to 24 hours.
o INFANTS may be particularly susceptible to nicotine
toxicity.
o DEATH is usually due to respiratory failure and may
occur as early as 1 hour post ingestion.
VITAL SIGNS
0.2.3.1 ACUTE EXPOSURE
o Hypertension, tachycardia and tachypnea may occur,
followed by hypotension, bradycardia and bradypnea.
Respiratory stimulation is one of the principal signs
of nicotine poisoning. High doses can produce fatal
respiratory depression of both central and peripheral
origin.
HEENT
0.2.4.1 ACUTE EXPOSURE
o Increased salivation and lacrimation may occur.
o Initial miosis followed by mydriasis may occur.
o Burning sensation in mouth and throat may occur.
o Gingival recession has been observed after long-term
oral use of "smokeless" snuff.
CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
o Hypertension (low dose) or hypotension (high dose),
tachycardia or bradycardia, various atrial and
ventricular arrhythmias, and vasoconstriction have all
been reported. Cardiac arrest is a rare complication.
RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
o Initial tachypnea, followed by dyspnea is common. Late
bradypnea may occur. Increased bronchial secretions, a
cholinergic effect, are common. Respiratory tract
irritation may occur. Respiratory failure with apnea
may occur following large ingestions and may occur
quickly (5 minutes postingestion).
NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
o Headache, dizziness, restlessness followed by lethargy,
coma and seizures may occur. Initial excitation and
agitation may be followed by lethargy progressing to
coma. Headache, agitation, tremor and at higher doses,
CNS and neuromuscular depression and seizures have all
been reported.
GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
o Nicotine initially causes a burning sensation in mouth,
throat, esophagus and stomach. Increased salivation
follows. Nausea, vomiting, abdominal pain, and
diarrhea are common. Vomiting may occur very early
after tobacco ingestion, minimizing absorption and
other toxic manifestations.
GENITOURINARY
0.2.10.1 ACUTE EXPOSURE
o Signs of acute renal failure have been reported.
FLUID-ELECTROLYTE
0.2.12.1 ACUTE EXPOSURE
o Hypokalemia has been reported following elevated serum
nicotine levels.
DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
o Intense sweating may be noted. Dermatosis may develop
with chronic exposure.
0.2.14.2 CHRONIC EXPOSURE
o Nicotine sulfate is a sensitizer.
MUSCULOSKELETAL
0.2.15.1 ACUTE EXPOSURE
o Rhabdomyolysis may result from severe overdoses.
IMMUNOLOGIC
0.2.19.2 CHRONIC EXPOSURE
o Nicotine sulfate is a dermal sensitizer.
REPRODUCTIVE HAZARDS
o Nicotine is a possible human teratogen.
o Nicotine is teratogenic in mice but not in several other
species. It crosses the placenta and is excreted in
breast milk. It has reduced fertility in male and
female rats.
CARCINOGENICITY
0.2.21.2 HUMAN OVERVIEW
o Use of smokeless tobacco has been shown to cause
oral-pharyngeal cancer. A correlation between the use
of nicotine-containing sheep dip and esophageal tumors
has been noted in sheep.
GENOTOXICITY
o DNA inhibition, mutagenicity and chromosome aberrations
have been demonstrated experimentally.
|
| Laboratory: |
o Plasma nicotine levels are not usually clinically useful.
o Monitor vital signs and ECG in all symptomatic patients.
o Monitor serum electrolytes and kidney function tests in
symptomatic patients with severe exposures.
|
| Treatment Overview: |
ORAL EXPOSURE
o EMESIS is usually spontaneous. Since rapid onset of
seizures may occur, ipecac-induced emesis is NOT
ADVISED.
o GASTRIC LAVAGE: Consider after ingestion of a
potentially life-threatening amount of poison if it can
be performed soon after ingestion (generally within 1
hour). Protect airway by placement in Trendelenburg and
left lateral decubitus position or by endotracheal
intubation. Control any seizures first.
1. CONTRAINDICATIONS: Loss of airway protective reflexes
or decreased level of consciousness in unintubated
patients; following ingestion of corrosives;
hydrocarbons (high aspiration potential); patients at
risk of hemorrhage or gastrointestinal perforation; and
trivial or non-toxic ingestion.
o ACTIVATED CHARCOAL: Administer charcoal as slurry (240
mL water/30 g charcoal). Usual dose: 25 to 100 g in
adults/adolescents, 25 to 50 g in children (1 to 12
years), and 1 g/kg in infants less than 1 year old.
o SEIZURES: Administer a benzodiazepine IV; DIAZEPAM
(ADULT: 5 to 10 mg, repeat every 10 to 15 min as
needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min
as needed) or LORAZEPAM (ADULT: 4 to 8 mg; CHILD: 0.05
to 0.1 mg/kg).
1. Consider phenobarbital if seizures recur after diazepam
30 mg (adults) or 10 mg (children > 5 years).
2. Monitor for hypotension, dysrhythmias, respiratory
depression, and need for endotracheal intubation.
Evaluate for hypoglycemia, electrolyte disturbances,
hypoxia.
o HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid,
place in Trendelenburg position. If hypotension
persists, administer dopamine (5 to 20 mcg/kg/min) or
norepinephrine (0.1 to 0.2 mcg/kg/min), titrate to
desired response.
o DO NOT ADMINISTER ANTACIDS since nicotine is better
absorbed in a alkaline media.
o ATROPINE: ADULT DOSE: BRADYCARDIA: 0.5 to 1 mg IV
every 5 min. BRADYASYSTOLIC ARREST: 1 mg IV every 5
min. Maximum total dose 0.04 mg/kg. Minimum single
dose 0.5 mg. PEDIATRIC DOSE: 0.02 mg/kg IV repeat
every 5 min, minimum single dose 0.1 mg; maximum single
dose 0.5 mg child, 1 mg adolescent; maximum total dose 1
mg child, 2 mg adolescent.
o MONITOR EKG and vital signs carefully
o Maintain adequate hydration and urine output.
INHALATION EXPOSURE
o INHALATION: Move patient to fresh air. Monitor for
respiratory distress. If cough or difficulty breathing
develops, evaluate for respiratory tract irritation,
bronchitis, or pneumonitis. Administer oxygen and
assist ventilation as required. Treat bronchospasm with
beta2 agonist and corticosteroid aerosols.
o Treatment should include recommendations listed in the
ORAL EXPOSURE section when appropriate.
EYE EXPOSURE
o DECONTAMINATION: Irrigate exposed eyes with copious
amounts of tepid water for at least 15 minutes. If
irritation, pain, swelling, lacrimation, or photophobia
persist, the patient should be seen in a health care
facility.
DERMAL EXPOSURE
o DECONTAMINATION: Remove contaminated clothing and wash
exposed area thoroughly with soap and water. A
physician may need to examine the area if irritation or
pain persists.
|
| Range of Toxicity: |
o Nicotine is highly toxic; about 2 to 5 mg can cause
nausea. The estimated lethal oral dose in adults is
approximately 40 to 60 mg.
o Ingestion of as little as 1 cigarette (or more than 3
butts), one cigar butt, or any amount of nicotine chewing
gum should be considered potentially toxic.
o As little as 1 milligram of nicotine can produce symptoms
in a small child.
o Severe toxicity (eg, hypertension, tachycardia,
vasoconstriction) has occurred via buccal absorption of
the transdermal nicotine patch, Prostep(R), after biting
it (Harchelroad et al, 1992).
|
Antidote and Emergency Treatment:
For immediate first aid: Ensure that adequate decontamination has been carried out. If
victim is not breathing, start artificial respiration, preferably with a demand-valve
resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary.
Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If
vomiting occurs, lean patient forward or place on left side (head-down position, if
possible) to maintain an open airway and prevent aspiration. Keep victim quiet and
maintain normal body temperature. Obtain medical attention. /Nicotine
and related compounds/
For basic treatment: Establish a patent airway. Suction if necessary. Aggressive airway
management may be needed. Watch for signs of respiratory insufficiency and assist
ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min.
Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes
immediately with water. Irrigate each eye continuously with normal saline during transport
... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL
of water for dilution if the patient can swallow, has a strong gag reflex, and does not
drool. Administer activated charcoal ... . /Nicotine
and related compounds/
Animal Toxicity Studies:
Non-Human Toxicity Excerpts:
ALKALOIDAL NICOTINE IS EXTREMELY TOXIC
SUBSTANCE THAT TRANSIENTLY STIMULATES & THEN SEVERELY DEPRESSES CNS. DEATH ... DUE TO
RESPIRATORY PARALYSIS ... & DEPOLARIZING BLOCK OF NERVE MUSCLE JUNCTION OF SKELETAL
MUSCLE. ... NICOTINE ACTIVATES SMOOTH MUSCLES
& SECRETORY GLANDS OF DIGESTIVE TRACT /PRODUCING/ ... EXCESSIVE SALIVATION, INCR
GASTRIC SECRETION, VOMITING, INCR PERISTALSIS, & DEFECATION.
NICOTINE WAS TERATOGENIC IN MICE WHEN
INJECTED @ 25 MG/KG ON DAYS 9-11 OF GESTATION. SKELETAL DEFECTS & OCCASIONAL CLEFT
PALATES WERE PRODUCED.
... Reported an epidemic of limb deformities in the offspring of swine which fed on
tobacco stalks containing 1058 ppm of nicotine
and 115 ppm of maleic hydrazide.
In the rat ... used 0.05 mg per ml of drinking water and found a reduced size in the
newborn.
IN STUDIES WITH SACCHAROMYCES CEREVISIAE, NICOTINE
WAS ... MUTAGENIC AT 100 PPM. IN ... SALMONELLA TYPHIMURIUM, TA-98 WITH METAB ACTIVATION, NICOTINE WAS NOT IMPORTANT IN CONTRIBUTING TO
MUTAGENIC POTENCY OF SMOKE CONDENSATE. USING MAMMALIAN CELL CULTURE SYSTEM (HAMSTER LUNG),
CONCN OF NICOTINE IN CIGARETTE SMOKE HAD NO
INFLUENCE ON OCCURRENCE OF ATYPICAL GROWTH OR MALIGNANT TRANSFORMATION.
EXPTL NICOTINE INJECTED INTO ANTERIOR CHAMBER
/OF THE EYE/ OF RABBITS HAS CAUSED INFLAMMATION OF ANTERIOR SEGMENT OF EYE & MIOSIS.
... WHEN NEAR-LETHAL DOSES WERE ADMIN TO RABBITS DAILY FOR 80 DAYS, NICOTINE
PRODUCED MYDRIASIS & POOR RESPONSE OF PUPILS TO LIGHT, ATTRIBUTABLE TO DEGENERATION
INDUCED IN RETINAL GANGLION CELLS. ... IN DOGS, DAILY SC INJECTIONS ... FOR 18 MO CAUSED
ATROPHY OF RETINA, DISORGANIZATION OF LAYERS, & REDN OF NUMBER OF CELLS. CHANGES IN
BLOOD VESSELS WERE THOUGHT TO BE PRIMARILY RESPONSIBLE.
IN 3-DAY-OLD MICE NICOTINE DID NOT INDUCE
CONVULSIVE PATTERN SEEN IN ADULTS. RATE OF METAB IN VITRO CORRELATED WITH LETHAL TOXICITY
IN YOUNG MICE.
DEFORMITIES WERE FOUND IN SOME RABBIT FETUSES WHOSE DAMS WERE ADMIN 20 MG/KG, 5 TIMES
DURING PREGNANCY.
INJECTION OF 0.07-0.09 MG NICOTINE INTO MICE
RESULTED IN GROSS CHROMOSOMAL ABERRATIONS IN BONE MARROW CELLS.
PREGNANT SWINE FED AQUEOUS LEAF EXTRACTS OF TOBACCO AT RATE OF 16 & 32 MG/KG NICOTINE PRODUCED ARTHROGRYPOTIC NEWBORN PIGS.
NICOTINE WAS AMONG COMPOUNDS FOUND
TERATOGENIC WHEN INJECTED INTO YOLK SACK OF CHICKEN EGGS @ RATE OF 1 OR 2.5 MG/EGG ON DAY
4 OF INCUBATION AS MEASURED ON CHICK SPINALIS MUSCLE. BETWEEN SPINE LENGTH & NICOTINIC
POTENCY OF CMPD A NEG CORRELATION WAS SEEN.
GESTATION WAS PROLONGED BUT BIRTH WT WAS NOT ALTERED IN SPONTANEOUSLY DELIVERED
OFFSPRING OF PREGNANT RATS ADMIN SC 2-10 MG/KG/DAY NICOTINE.
NICOTINE DECR BIRTH WT OF OFFSPRING DELIVERED BY
CESAREAN SECTION ON 21ST DAY OF GESTATION. ADMIN OF 3 MG/KG DURING FIRST 8 DAYS OF
GESTATION OR DURING THE ENTIRE GESTATION PERIOD INDUCED THE SAME EFFECTS. IT APPEARS THAT NICOTINE AFFECTS PROCESSES ALREADY OPERATIVE DURING
THE 1ST WK OF GESTATION & THAT THESE EFFECTS MAY BE MANIFESTED IN DEVELOPMENTAL
DISTURBANCES AT LATER GROWTH STAGES.
NICOTINE CONTINUOUSLY INFUSED INTO ISOLATED
RAT HEART DEPRESSES HEART RATE & CORONARY FLOW IN A DOSE-RELATED MANNER. THESE CHANGES
ARE REVERSIBLE OVER RANGE OF CONCENTRATIONS USED.
Toxic to bees but has a repellent effect.
Numerous cases of livestock poisonings from consumption of cultivated tobacco (Nicotina tabacum) are known. Horses have died from
consumption of tobacco leaves, while pigs have been fatally poisoned when they broke into
a tobacco field. ... An unusual case is the death of a dog which consumed a package of
cigarettes.
Nicotine, at 10 mg/kg/day in rats, promptly
and drastically curtailed water consumption during the first 24 hr. Thereafter, water
intake alternately rose and fell during the rest of the 6 day infusion period, suggesting
that overriding mechanism(s) were activated. When nicotine
was abruptly withdrawn, water intake rose dramatically and remained elevated throughout
the withdrawal period. Mecamylamine at a dose of 5 mg/kg/day did not block nicotine's hypodipsic effect during the first three
days.
The deleterious effects of nicotine treatment
on skin hemodynamics and survival of acute random pattern skin flaps constructed on the
dorsum of the rat were studied. Rats were injected subcutaneously with 0.2 ml of saline
containing varying doses (0, 1, 2, 4, or 8 mg/kg; bid) of nicotine
for 5 weeks, starting 4 weeks before flap surgery. It was observed that nicotine
treatment at the dose of 2 mg/kg (bid), or higher, significantly (p < 0.05) decreased
the length and area of skin flap survival compared with the control. This dose of nicotine treatment also significantly (p < 0.05)
decreased the capillary blood flow and distal perfusion in the skin flaps compared with
the control. However, detrimental effect of nicotine
treatment on the survival of acute random pattern skin flaps was not seen if the treatment
was started 2 instead of 5 weeks postoperatively.
To detect the time after administration of nicotine
and dosage for neurochemical studies, locomotor activity of CD-1 mice was determined at 5
minute intervals between 0-60 minutes. A low nicotine
dosage (0.05 mg/kg) did not alter activity 5-15 minutes after drug injection, but
increased activity 28% at 15-25 minute post-injection. A high dosage (0.8 mg/kg) reduced
total distance 62% and rearing 87% at 5-15 minutes; at 15-25 minutes total distance
declined 56% and rearing 69%; all measures returned to control values after 30 minutes;
rearing then increased at 40 minutes after nicotine.
Pretreatment (15 minutes before nicotine) with
mecamylamine (1.0 mg/kg), but not hexamethonium (1.0 mg/kg), prevented the depressant
effect of nicotine. Dopamine and its metabolites
as well as acetylcholine synthesis were measured at the point of nicotine's
maximal depressant action. Striatal levels of dihydroxyphenylacetic acid were increased
and acetylcholine utilization was reduced in striatum (-25%) and cortex (-24%) 10 minutes
after nicotine (0.8 mg/kg).
Environmental substances were examined for their effect on interferon induction and
delayed type hypersensitivity (DTH) responses in mice. Amaranth, safrole, phenacetin, and nicotine suppressed the delayed type hypersensitivity
response, and suppressed the serum interferon titers induced by virus infection. However,
they did not affect the interferon titers which were induced by tilorone, a chemical
inducer. The peak of interferon titer was 12 hr after infection with Herpes simplex virus
type 2 (HSV-2). Therefore, amaranth, safrole, phenacetin, and nicotine
were given to mice ip 24 hours before, and 2 and 18 hours after infection with Herpes
simplex virus type 2. Safrole and nicotine
shortened the mean survival time of Herpes simplex virus type 2 infected mice when they
were given to mice 2 hour after virus inoculation.
The metabolic response of fetal and neonatal lung tissue to maternal nicotine
exposure (0.25 and 1.0 mg/kg/day) was investigated. White virgin female rats (Wistar) of
200-250 g were mated overnight and randomly assigned to control and exptl groups. One
group received nicotine during pregnancy and
lactation. The second group received nicotine
only during lactation. The suckling rats were killed 24 hr after the last dose of nicotine was administered to the mother. Maternal nicotine administration during pregnancy and lactation
stimulated total glucose turnover by 21.6 and 86.4% respectively but suppressed
glycogenolysis (32.7%), glycolysis by 24.6%. Nicotine
administration during lactation only enhanced total glucose turnover by 19.1% and
glycogenolysis by 30% but inhibited glycolysis by 25.8%. After 4 wk of nicotine
withdrawal when the rats were 7 wk old, glycogenolysis and glycolysis of those animals
exposed to nicotine via the placenta and
mother's milk were still inhibited to the same extent as during exposure. Glycogenolysis
and the glycolytic flux of lung tissue of rats exposed to nicotine
via mother's milk only returned to normal.
... Previously /it has been noted/ that a single dose of nicotine
elevates plasma adrenocorticotropin levels in rats and has a biphasic effect on plasma
prolactin. The stimulatory effect of nicotine on
these stress-responsive hormones desensitizes after a single injection of nicotine. Continuous exposure to nicotine
also induces tolerance to its locomotor depressive and hypothermic effects, which have
been associated with an increase of central (3)H-nicotine
binding. Thus, the acute and chronic administration of nicotine
might induce changes in central nicotinic cholinergic circuits that affect the
adrenocorticotropin and prolactin responses to stress. In the present study, a single dose
of nicotine (0.75-3.0 mg/kg body weight)
significantly inhibited the elevation of plasma prolactin due to restraint stress
initiated 60 min afterward. Five injections of nicotine
during 1 day produced a similar attenuation of the prolactin response to restraint stress
but neither of these paradigms affected adrenocorticotropin. In contrast, intermittent
delivery of nicotine for 7 days failed to affect
the prolactin response to restraint stress; however, after withholding nicotine
for 14 hr, high dose nicotine attenuated the
prolactin response to stress, whereas low dose nicotine
remained ineffective. On the other hand, administration of the same schedule of low dose nicotine did significantly diminish the expected
release of prolactin in response to a final injection of nicotine
(0.5-2.0 mg/kg body weight) in unstressed animals.
Inbred Fischer and Buffalo rats were exposed to nicotine
and ethanol. Fertility was greatly reduced in both strains with nicotine
treatments being much more deleterious than alcohol use. Fischer rats tolerated both
toxins better than Buffalo rats. Both strains became extinct after 1 generation of fetal
and postnatal exposure to nicotine, but alcohol
ingesting Fischer rats had > or = 3 generations of offspring. The total reproductive
period was significantly shortened in both strains under the effect of both toxins, as was
the total life span. The causes of the teratologic effects of both toxins are inflammatory
processes as evidenced by the presence of numerous lymphocytes and/or polymorphonuclear
leukocytes. Their presence occurs earlier in nicotine
than in alcohol use and earlier in Buffalo than in Fischer rats, but the damage done
during nicotine treatment is reversible when the
procedure is terminated. Inflammation is not transmitted to the newborn offspring of nicotine- or alcohol-treated mothers, but occurs in
neonates during the nursing period or later.
Adult female rats were chronically treated with nicotine
administered via the drinking water during pregnancy and/or lactation. The approximate
doses of nicotine consumed per day were 2.4
mg/kg of body weight. The pups were weaned at 20 days of age. The pups were killed by
decapitation on postnatal days 20, 30, 40, and plasma heparinized trunk blood was assayed
for luteinizing hormone. At 30 days of age untreated male and female offspring had the
highest levels of plasma luteinizing hormone compared to 20 and 40 days of age. The level
was not affected by any subsequent dose or treatment. Prepubertal females exposed to nicotine during pregnancy failed to exhibit the
pattern of luteinizing hormone levels seen in control animals, whereas those exposed
during lactation or throughout the perinatal period showed a distinctive pattern of plasma
luteinizing hormone. Chronic exposure of female offspring to the low dose of nicotine during lactation tended to increase plasma
luteinizing hormone levels at 20 and 40 days. Female offspring exposed to nicotine during pregnancy or to the low dose during
lactation showed significant deficits in body weight at 40 days of age which appeared to
correlate with a delay in vaginal opening.
Nicotine was administered iv to DBA mice
through cannulae implanted in the jugular veins. Five groups of animals were treated: a
control group which received saline and four nicotine
treatment groups. All of the nicotine treatment
groups received a dose of 4.0 mg/kg/hr. The first group received continuous infusion, the
second group received 1 mg/kg pulses four times an hour, the third group received 2 mg/kg
pulses twice an hour, the fourth group received 4 mg/kg pulses once an hour. After a 10
day treatment period, the animals were tested for tolerance to an acute ip administration
of nicotine. Mice from each of the four nicotine treatment groups were tolerant to the acute
effect of nicotine, but the extent of tolerance
varied among the groups as follows: continuous infusion < 1 mg/kg pulses four times/hr
< 2 mg/kg pulses twice/hr < 4 mg/kg pules once/hr. Chronic nicotine
infusion resulted in significant increases in the binding of L-(3)H-nicotine
in all six brain regions assayed and in significant increases in the binding of
alpha-(125)I-bungaratoxin binding in cerebral cortex and hippocampus. All increases in
binding resulted from increases in Bmax for these ligands. In contrast to the effects
observed for tolerance development, the increases in (3)H-nicotine
binding were not significantly affected by the kinetics of nicotine
infusion. However, the binding of alpha-(125)I-bungaratoxin tended to increase along with
the peak plasma concern of nicotine and
paralleled the differences in tolerance. While the average blood level of nicotine did not differ significantly among the 4
groups, peak levels were higher after infusion of both the 2 mg/kg and 4 mg/kg pulses.
Female rats were used to examine the effects of chronic nicotine
administration and withdrawal on food and water consumption and body weight. Rats with
chronic nicotine pellet implants consumed
significantly less food and water than controls for the first 5 days and then gradually
returned to control levels of consumption. The lowest level of body weight was reached on
day 9 after which there was a slow return to control weights by day 21. When the nicotine pellets were removed from the short-term
exposure group on day 14, they were removed from the short-term exposure group on day 14,
they showed significantly hyperphagia and hyperdispsia and a very rapid weight gain for
the next several days, which clearly outpaced the recovery of weight in the long-term nicotine exposure group.
The behavioral response to nicotine was
examined in photocell activity cages. Groups of rats were tested using doses from 0.1 to
1.6 mg/kg both before and after all rats were exposed for 5 days to a common dose of 0.2
mg/kg/day. Prior to the 5 day exposure, there was a dose-related stimulant response to nicotine, with a max response seen at 0.4 mg/kg. After
the 5 day exposure, the dose-effective curve was shifted upward, so that greater
stimulation was produced at each dose of nicotine.
Other groups of rats were exposed for 5 days to doses of nicotine
ranging from 0.01 to 0.30 mg/kg/day. On the 6th day all rats received a common test dose
of 0.2 mg/kg and their response was measured in the activity cages. In animals exposed to
0.1 mg/kg/day, the test day response was not different from saline controls, but the
groups exposed to higher doses showed increased stimulation in response to the common test
dose. Measurements of nicotinic receptor binding using (3)H-acetylcholine found increased
binding in groups receiving 0.03 mg/kg/day or more, but not in the group that received
0.01 mg/kg/day. Rats given high doses (1.6 mg/kg, twice/day) did not show increased
behavioral stimulation to a test dose of 0.2 mg/kg.
Behavioral effects of d-nicotine (0.1-10.0
mg/kg), l-nicotine (0.01-1.0), d-nornicotine
(0.1-10.0), l-nornicotine (0.1-10.0) and l-cotinine (1.0-100.0) were studied in two
paradigms. In expt 1, 6 male rats responded under a multiple fixed-interval (FI) 5 min,
fixed-ratio (FR) 20 schedule of food presentation. Aside from differences in potency and
time course, l-nicotine and the stereoisomers of
nornicotine produced qualitatively similar effects on rates of responding. Rate-increasing
effects of cotinine were not blocked by mecamylamine. In expt 2, 2 groups of 8 male rats
were trained to discriminate between l-nicotine
(0.1 mg/kg sc) and saline (0.1 ml/kg sc) in a two-bar, operant conditioning procedure
under a tandem variable-interval 9 min, fixed-ratio 10 schedule of food presentation. Full
generalization was obtained to d-nicotine and to
l- and d-nornicotine. Generalization to cotinine occurred only with large doses that
contained significant amounts of nicotine
present as an impurity. The rank order of potency for nicotine
and its analogs was similar in experiments 1 and 2: l-nicotine
was 10-20 times more potent than d-nicotine and
the stereoisomers of nornicotine (which did not show stereoselectivity in the rat).
Cotinine was at least several hundred times less potent than nicotine.
The response of male Sprague-Dawley rats to nicotine
soln was examined with the brief-exposure, taste reactivity test and a two-bottle, 24 hr
preference test. Groups of 8 naive nondeprived rats were admin intraoral infusions (0.8 mL
infused during 1 min) of distilled water and 1 ug/ml, 5, 10, 25, 50, and 100 ug/ml nicotine. The oral motor, taste reactivity responses
of the rats were recorded during the infusion. Nicotine
soln up to a concn of 50 ug/ml elicited a number of ingestive taste reactivity responses
similar to that by water. Ingestive responses significantly decreased, and aversive taste
reactivity responses significantly increased in response to 100 ug/ml nicotine.
On the basis of these results, two-bottle preferences for water versus 1 ug/ml, 5 ug/ml,
and 0 ug/ml (water control group) nicotine were
measured in three groups of naive rats (n=7-9). Rats initially showed an equal preference
for 0 and 1 ug/ml nicotine. After 16 days of
exposure, however, rats developed a significant preference for 1 ug/ml nicotine.
The preference ratio for 5 ug/ml nicotine
significantly increased during the expt, but the preference ratio remained significantly
less than that for 1 ug/ml and control solutions. TR responses elicited by 0.8 ml
intraoral infusions of 1 ug/ml and 5 ug/ml nicotine
were then measured in 17 rats having had the two-bottle experience. Rats showing a
two-bottle preference for the 1 ug/ml nicotine
solution displayed significantly more ingestive taste reactivity response to 1 ug/ml and 5
ug/ml nicotine than did the control rats.
Groups of 50 male Sprague-Dawley rats (200-250 g) were either given water (controls),
or water containing 1.0 mg% nicotine ad lib.
Mean daily nicotine intake during the 6 wk
treatment period was 0.7 +/- 0.01 mg/kg body wt. At the end of wk 6, both groups were
given daily sc injections of 1 mg/kg haloperidol for 0-12 days. Two days after the last
injection, the rats were killed by decapitation. Rat striata were dissected from the
brain, reacted with (3)H-domperidone (benzene ring (3)H), and assayed for D2-dopamine
receptor. Daily admin of haloperidol to controls led to a progressive incr in maximal
binding capacity or receptor density (Bmax) of striatal D2-dopamine receptor. The maximal
incr in Bmax was observed on the 7th day of haloperiodol treatment (Bmax, day 0 = 848.5
and day 7 = 2161.0; , an incr of more than 150%, and it remained unchanged on further
treatment for at least 12 days. In contrast, haloperidol-mediated incr in Bmax were
completely blocked in rats receiving nicotine in
their drinking water. . The affinity constant of the receptor also seemed to incr with
haloperidol treatment in control but not nicotine-treated
rats.
After a 48 hr prewarming period at 20 to 22 C or 32 to 34 deg C, male NMRI mice were
given nicotine (0, 0.3, 1, or 3 mg/kg sc) 4
times at 30 min intervals. Haloperidol (65 or 160 ug/kg), (+/-)-sulpiride (50 or 100
mg/kg), apomorphine (2 mg/kg), gamma-hydroxybutyric acid (750 mg/kg), or saline (control)
were admin ip after the second nicotine dose. 10
mg/kg hexamethonium was given ip 30 min before the first nicotine
(or saline dose) to prevent the effects of nicotine
on autonomic ganglia. When the effect of body temp on the apomorphine-,
gamma-hydroxybutyric acid-, or nicotine-induced
decr of 3-methoxytyramine was studied, apomorphine (5 mg/kg) and gamma-hydroxybutyric acid
(750 mg/kg) were admin ip after the 4th and 3rd nicotine
doses, respectively. Striatal contents of dopamine and its metabolites homovanillic acid,
3,4-dihydroxyphenylacetic acid and 3-methoxytyramine were measured. Hexamethonium did not
change the striatal dopamine metabolism. At 32 to 34 deg C, nicotine
and haloperidol incr the striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid
contents additively, whereas apomorphine counteracted the effect of nicotine.
Nicotine (3 mg/kg x 4) decr 3-methoxytyramine
content by 42 to 49% in hexamethonium pretreated mice at 20 to 22 deg C. In hypothermic
mice nicotine was better at inhibiting
haloperidol- and (+/-)-sulpiride induced incr of homovanillic acid content than those of
3,4-dihydroxyphenylacetic acid content. In apomorphine-treated mice both the
gamma-hydroxybutyric acid- and nicotine-induced
decr of 3-methoxytyramine fell further. gamma-Hydroxybutyric acid did not alter the nicotine-induced incr of 3-methoxytyramine content.
Unlike gamma-hydroxybutyric acid and apomorphine, nicotine
decr 3-methoxytyramine content only in hypothermic mice.
During a conditioning period, Male albino Wistar rats were given 6 injections of nicotine (0.6 mg/kg sc). In some cases, mecamylamine
was admin ip 30 min before nicotine. After each
injection, rats were transferred to a wire test cage. During test sessions, rats were also
exposed to white noise and smell of acetic acid. Exposure to conditioned stimuli lasted 90
min. On the same day, about 6 hr later, rats were injected with saline and put into their
home cages. Pseudo-conditioned rats were injected with saline before being placed into the
test cage and with nicotine before being
transferred in to the home cage. A third group (naive rats) was exposed to test and home
cages with the same frequency, but injected with solvent only. On the test day (24 hr
after the last nicotine admin), all groups of
rats were injected with nicotine (0.6 mg/kg sc)
and placed into the test cage. Behavior was observed for 10 sec in 5 min intervals.
Subsequently, rats were conditioned (or pseudo-conditioned, respectively) for 4 additional
times and tested with saline injection in the test cage. Nicotine
(0.15, 0.3, and 0.6 mg/kg) produced dose-dependent incr in locomotor activity,
hyperkinesia, and stereotyped sniffing. The effects produced by 0.6 mg/kg nicotine were significantly inhibited by mecamylamine
(1 mg/kg ip), but only in part by haloperidol (0.2 mg/kg ip). When rats were given saline
in presence of the conditioned stimuli 24 hr after the last conditioning session,
locomotor activity, hyperkinesia, and stereotyped sniffing were significantly higher in
conditioned than in pseudo-conditioned drug-naive rats. Similarly, when the rats were
injected with nicotine (0.6 mg/kg sc) in
presence of the conditioned stimuli 2 hr after the last conditioning session, locomotor
activity and stereotyped sniffing were most pronounced in the conditioned animals.
Atrial tissue from denervated dog hearts was incubated with H(3) choline. When compared
with controls, nicotine at concn of 10-5 and
2x10-5 M released more acetylcholine (ACh) from denervated atria, but not at nicotine concn of 5x10-5 M. In parallel contractility
studies using tissue from these same atria, the neg inotropic response to nicotine was enhanced at 5x10-6 and 10-5 M, but not at
2x10-5 or 5x10-5 M nicotine.
The effect of nicotine on growth and
fecundity of Daphnia pulex was tested in 16-day static renewal, full-life-cycle bioassays.
For each concn, 15 Daphnia neonates were placed in individual test tubes in a chamber.
Recovery rates for nicotine at 1 hr after
preparation in water only was 57% and 89% in test media. At 48 and 72 hr after
preparation, nicotine concn in water had dropped
to 24 and 9%, and in test media to 3 and 0%, respectively. Estimated LOEC's (lowest
observable effect concn, were based on nominal concn which were much higher than the
actual concn. Mortality of the original daphnids was 10%, 6%, 4%, 10%, 20% and 66% at 0,
0.02, 0.07, 0.12, 0.18, and 0.24 mg/l, respectively. Nicotine
significantly reduced growth and fecundity of daphnids at nominal concn from 0.02 to 0.24
mg/l. The lowest observable effect concn for length was 0.07 mg/l and the lowest
observable effect concn for fecundity was 0.18 mg/l. Fecundity approached 0 at 0.24 mg/l.
The influence of nicotine on the outflow of
calcitonin gene-related peptide, which is present in sensory nerves, and neuropeptide Y,
which is co-stored with noradrenaline from the isolated guinea-pig heart, was studied in
vitro. 5-min perfusion with 1 x 10-5 M nicotine
was not associated with significant effects on the outflow of calcitonin gene-related
peptide-like activity, while 10-4 M nicotine
induced release of calcitonin gene-related peptide- as well as neuropeptide Y-like
activity in a concn- and Ca +2-dependent manner. After capsaici pretreatment, the nicotine-induced (10-4 M) outflow of calcitonin
gene-related peptide-like activity was abolished, but the change in frequency and the
contractile force inducted by nicotine were not
significantly influenced.
Level of urinary nicotine were measured in 21
non-smokers, 26 smokers of blond tobacco, 9 smokers of black tobacco and 5 smokers of both
types, all eating a similar diet. Two 24 hr samples from the subjects were collected over
a 3 day period. Statistically significant positive dose-effect relationships were obtained
between the urinary nicotine + cotinine levels
and the number of revertants (Salmonella typhimurium TA 98, with a metabolic activation
system. A linear dose-effect relationship between urinary mutagenicity (ie log revertants
of S typhimurium TA98) and nicotine + cotinine
levels or number of cigarettes per day, was established for smokers of blond tobacco.
Smoke condensates prepared from blond and black Italian cigarettes were tested in S
typhimurium TA98 and in E coli PQ37 using liquid incubation procedures. Plate
incorporation assays with Salmonella were also performed. Cigarette smoke condensate from
blond tobacco contained 37 ug nicotine/mg
cigarette smoke condensate, while that of black tobacco contained 67 ug. Smoke condensate
of black tobacco was 1.2 to 1.4 times more mutagenic than that of blond tobacco when
activity is expressed per mg cigarette smoke condensate. The order was reversed when
mutagenicity was expressed per ug nicotine, as
black tobacco cigarette smoke condensate contained 1.8 times more nicotine
than blond cigarette smoke condensate. Liquid incubation assays revealed a 12- to 14-fold
higher mutagenicity than plate incorporation. Both cigarette smoke condensates were found
to be directly active in inducing DNA repair functions.
The comparative acute toxicity of a branded American cigarette and kreteks (Indonesian
cigarettes containing approx 60% tobacco and 40% ground clove buds) was assessed by
exposure of groups of 10 male and 10 female rats to 3 different but equivalent (in terms
of total particulate matter) concn of smoke (1.15 to 6.00% v/v) from each type of
cigarette. The smoke was delivered "nose only" using a rodent smoking machine
within a single 1-hr period, with a total delivery of 30 min smoke and a 15 min
air-breathing period between the 2 smoke exposures. By gross observations of rats and
their respiration during exposure, the only differences observed were more severe signs of
smoke intoxication in the America smoke exposed rats which, at least in part, was
attributed to the higher concn of carbon monoxide. Plasma nicotine
concn wer determined after smoke exposure. Both absolute and relative plasma nicotine values shows plasma nicotine
concn are higher, and are approx linearly related to the incr in total particulate matter
in the American smoke-exposed groups. In the kretek groups, the plasma nicotine
values are also increased at the higher concn of smoke but the relationship between the
two is unclear and appear to be limited at the highest concn of smoke exposure. No
differences were seen upon observation and measurement of body wt, food and water
consumption of a sub-population for 14 days following exposures. No histopathological
differences or differences in lung wt were seen. However, a slight incr in the incidence
and severity of focal alveolar hemorrhage was present in the high dose American group at
24 hr compared with the high dose kretek group.
The influence of nicotine on zymosan
stimulated guinea pig pulmonary alveolar macrophage oxidative metabolism was examined. At
5X10-10 and 5X10-8 M nicotine, the
chemiluminescence response was augmented to 132% and 113%, respectively. At concentrations
of 5X10-7 M and 5X10-4 M, chemiluminescence responses were inhibited to 83% and 51% of the
control, respectively. Superoxide anion release was enhanced to 226% at a nicotine concentration of 5X10-10 M and 209% at 5X10-9
M; and was inhibited to 53% and 58% of the control at concentrations of 5X10-5 M and
5X10-4 M, respectively. The cholinergic antagonists atropine or hexamethonium did not
affect the action of nicotine, a cholinergic
agent.
Groups (n= 5) of adult male Sprague Dawley rats were given 0, 0.5, 1.0, 2.0, 3.0, and
4.0 mg% nicotine water for 60 days. Continuous
oral admin of 2 mg% or less nicotine,
corresponding to a daily oral nicotine intake of
2.35 + or - 0.25 mg/kg or less, did not alter body weight gain or feed intake. Nicotine consumption resulted in a significant incr in
the number of D1 dopamine receptors (p < 0.025 at 0.5, 1.0, and 2.0 mg%), the ratio of
D1 to D2 receptors (p < 0.05 at 1.0, 2.0, 3.0, and 4.0 mg%) and dopamine uptake sites,
but not the number of D2 dopamine receptors. The number of binding sites increased
significantly (p < 0.025) with incr concn of nicotine,
reaching a maximum at 1.0 mg% nicotine, which
then declined steadily at higher nicotine concn.
The effects of 10 nicotine injections (0.8
mg/kg, sc) in 14 days to male Sprague Dawley rats on the levels of brain amines following
challenge with either saline or nicotine (0.8
mg/kg sc) on the 15th day were examined. Dopamine, DOPAC, HVA, 3-methoxytyramine,
norepinephrine, 5-hydroxytyramine, and 5-HIAA were measured in the frontal cortex,
olfactory tubercle, nucleus accumbens, caudate-putamen, substantia nigra and ventral
tegmental area. Ten min after nicotine was given
to rats that had previously received only saline the levels of dopamine and its metabolite
DOPAC indicated an incr in dopamine turnover in the nucleus accumbens. Of the areas
examined the accumbens was the most sensitive to nicotine,
with few significant amine changes in other regions. Twenty-four hours after the last nicotine injection the levels of dopamine and its
metabolites indicated a sustained decr in dopamine turnover in the accumbens induced by
repeated administration. Following repeated nicotine
a nicotine challenge still induced an acute incr
in dopamine turnover in the accumbens, but the response was less than in rats not
previously given nicotine.
The effects of arterial chemoreceptor activation by nicotine
on coronary artery diameter was studied in anesthetized, artificially ventilated greyhound
and mongrel dogs. Left circumflex coronary artery diameter, coronary blood flow,
calculated mean coronary resistance, systemic arterial blood pressure and heart rate were
measured. In control dogs (n = 10) the injection of nicotine
(100 ug) into the carotid artery evoked an incr of arterial pressure (+ 22 + or - 9 mm Hg)
and a decr in heart rate (- 36 + or - 13 beats/min), and tended to incr coronary blood
flow (+ 7 + or - 4 ml/min). Intracarotid nicotine
had no effect on large coronary artery diameter (+ 0.02 + or - 0.03 mm) or total coronary
resistance (+ 0.04 + or - 0.09 mm Hg min/ml) under these conditions. When heart rate was
controlled by beta-adrenoceptor blockade (propranolol, 1 mg/kg iv) plus pacing of the
right ventricle (n = 4) or beta adrenoceptor blockade plus bilateral vagotomy (n = 7), the
chemoreflex-induced constriction of the large coronary artery (- 0.07 + or - 0.02 mm and -
0.12 + or - 0.03 mm, respectively. In contrast, there was no chemoreflex-induced change in
total coronary resistance after beta-adrenoceptor blockade plus pacing (+ 0.01 + or - 0.09
mm Hg min/ml, but after beta-adrenoceptor blockade plus vagotomy coronary resistance was
increased (+ 0.75 + or - 0.31 mm Hg min/ml. The constriction of both large and small
coronary arteries was abolished by phentolamine (0.5 mg/kg iv).
Chronic nicotine treated adult rats were
shown to develop locomotor hyperactivity which was mediated by changes in nicotinic and
dopaminergic receptors in the striatum. The possibility of such changes occurring in pups
that were prenatally exposed to nicotine was
examined in 14-day-old offspring from dams which were implanted with osmotic minipumps
containing nicotine (1.5 mg/kg/day) throughout
the entire gestational period. Prenatal nicotine
treatment lowered the number of male pups born and reduced the postnatal gain in body wt
and length of both male and female offspring. Prenatal exposure to nicotine
did not alter the motor coordination of the pups. A decr in the number of striatal
dopaminergic receptor binding sites (Bmax) was detected in the male pups, however an incr
in the ligand affinity to the receptors (1/KD) had been simultaneously detected. No change
in the characteristics of nicotinic receptor binding sites and the levels of dopamine and
its metabolite, 3,4-dihydroxyphenylacetic acid was found in the striatal region.
The acute administration of nicotine
(0.01-1.0 mg/kg ip) to male albino BKW mice incr the time spent and rearings and line
crossings in the aversive brightly illuminated white area of a two compartment white/black
test box, with a corresponding decr in the black. This profile of change was maintained
during twice daily administration (0.1 mg/kg ip) for 14 days. Eight to 96 hr following
withdrawal of nicotine (14-day treatment), the
behavioral profile was reversed to a preference for the black area. By 240 hr, values had
returned to control levels.
Six naive male Wistar rats were admin 96 daily iv infusions of nicotine
(0.125 mg/kg/infusion, 12 mg/kg/day) for at least 10 days. They were trained to respond on
a tongue operated solenoid driven drinking device that delivered 0.005 ml of a glucose and
saccharin soln per lick. When nicotine access
was terminated for 6 days, there was a marked suppression in behavior (67% of baseline)
reinforced by the sweetened soln, and this disruption was immediately reversed when nicotine was reinstated. In contrast, nicotine removal also resulted in a decr in food
intake on the first day, but on subsequent days food intake was significantly higher than
when nicotine was admin. When cotinine (0.25
mg/kg/infusion) was substituted for nicotine for
6 days, similar disruptions resulted in responding maintained by glucose+saccharin (55 to
70% of baseline on the first day), but food intake was not significantly decr on the first
day of nicotine abstinence.
The most sensitive indicator of nicotine
action is an increase in motor activity, which is seen at dosages as low as 0.05 mg/kg
(subcutaneous) in the rat and is followed by tremor at intravenous doses ranging from 0.35
to 0.6 mg/kg.
...toxicity depends very much on the species; sheep and goats appear to tolerate high
amounts in comparison to other mammals.
IV INJECTIONS OF NICOTINE IN RATS INDUCE VERY
RAPID & DISCRETE REDN OF HYPOTHALAMIC CATECHOLAMINE LEVELS ASSOC WITH INCR OF ACTH,
VASOPRESSIN & PROLACTIN SECRETION GIVING FURTHER EVIDENCE FOR THE EXISTENCE OF NICOTINE-LIKE CHOLINERGIC RECEPTORS INVOLVED IN
REGULATION OF THESE HORMONES.
Cigarette smoking can alter the pharmacokinetics and activity of many drugs. The
mechanism of such interactions usually is induction of liver microsomal enzyme activity by
the polycyclic hydrocarbons in cigarette smoke. This enzyme induction differs
qualitatively and quantitatively from that produced by phenobarbital. Enzyme activity
remains elevated up to six months after cessation of smoking. /Cigarette smoking/
The effect of acute infusion of nicotine on
local cerebral glucose utilization was studied in discreet regions of the central nervous
system of the rat. Nicotine was administered in
3 dosages: 0.5, 1.58, and 5 ug/kg/min. The resulting plasma concentrations of nicotine were 10, 39, 114/ng/ml plasma. During the
experiment, blood pressure, heart rate, body temperature, hematocrit, acid-base status,
and plasma glucose concentrations showed no negative or minor negative changes. Nicotine significantly increased local cerebral
glucose utilization in a dose dependent manner in the following 9 of 45 examined
structures: substantia nigra (compact part), superior colliculus (superficial gray layer),
interpeduncular nucleus, and cingulate cortex; lateral geniculate body, optic chiasm,
anteromedial nucleus of thalamus and mamillary body.
The effects on rat brain tissue monoamine and monoamine metabolite concentrations of
chronic nicotine administration at 3 or 12
mg/kg/day using constant infusion were studied. After 21 days of treatment, tissue
concentrations of dopamine, norepinephrine, 5-hydroxytryptamine, and several metabolites
in striatum, hypothalamus, and frontal cortex were determined by high performance liquid
chromatography with electrochemical detection. Compared with a control group, nicotine treatment decreased norepinephrine in frontal
cortex but not in other regions. The concentration of 5-hydroxytryptamine also was
decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5-hydroxytryptamine metabolite
5-hydroxyindolacetic acid was not altered in any region. The 5-hydroxytryptamine index was
decreased in the hypothalamus and increased in frontal cortex at the higher dose.
Concentrations of dopamine and the metabolite homovanillic acid were not altered by nicotine. Nevertheless, decreases in the dopamine
metabolite dihydroxyphenylacetic acid were observed in both striatum and hypothalamus.
Moreover, the dopamine index was decreased in all 3 brain regions.
Alpha-2 and beta-adrenoceptors, and muscarinic cholinoceptors in cerebral cortex and
hippocampus were measured in rats which received either tap water or nicotine
added to the drinking water (5-8 mg/kg/day) for 4 wk and immobilization stress (daily 2
hr) for the last 5 days. The repeated stress induced a redn in the max number of binding
sites (Bmax) for (3)H-dihydroalprenolol in the cerebral cortex of rats with tap water,
without affecting (3)H-clonidine binding. Nicotine-treatment
also caused a decrease in the Bmax of cortical (3)H-dihydroalprenolol binding comparable
to the case of stress, and increased the (3)H-clonidine binding. However, the combination
of nicotine and stress treatments failed to
induce any further changes in the two radioligands binding.
The fetal and postnatal development of binding sites for (3)H-nicotine
was examined in brain regions of normal rats and rats whose mothers received nicotine injections or infusions, starting before
fetal implantation (gestational day 4) and continuing to gestational day 20. The normal
ontogenic pattern of binding indicated a small but detectable concn of sites during late
gestation, and a substantial increase after birth, primarily during the period in which
the majority of cholinergic synapses is forming. The adult pattern of regional selectivity
of binding capabilities, namely, midbrain plus brainstem > cerebral cortex much greater
than cerebellum, was not present at birth, but rather developed over the ensuing 3 wk
postpartum. Fetal exposure to nicotine produced
an elevation in binding detectable during the course of drug exposure (gestational day
18), a finding similar to that of nicotine's
effects in mature brain. However, examn of the subsequent development pattern of (3)H-nicotine binding indicated a generalized disruption of
receptor acquisition, in that alterations persisted far beyond the period in which drug
exposure was terminated. The greatest effect was seen in a region relatively poor in
receptor sites (cerebellum), and a larger stimulation was obtained with injected than with
infused nicotine.
The properties of the binding sites for radiolabeled acetylcholine (measured in the
presence of atropine), nicotine, and
beta-bungarotoxin were compared in brain tissue prepared from both rat and mouse. These
three binding sites were tested for the following properties: affinity and density of
ligand binding, effects of competitive inhibitors, regional distribution, effects of
treatment with dithiothreitol, and the reversal of these effects by treatment with
5,5-dithiobis(2-nitrobenzoic acid), thermal lability, effects of protease treatment, and
response to chronic administration of nicotine
in vivo. The binding sites for acetylcholine and nicotine
were affected identically for all measurements, whereas the binding site for
alpha-bungarotoxin was affected in a manner different from that for the other two ligands.
Although the regional distribution of nicotine
and acetylcholine binding differed between rat and mouse brain, other properties of this
binding site were very similar between the two species.
Nicotine administration, using mini-osmotic
pumps, to male guinea pigs (31 ug/hr for 10 days) resulted in a significant elevation of
plasma epinephrine and enkephalin-like peptides but not norepinephrine. The increase in
plasma epinephrine-like peptides was not accompanied by corresponding alterations in
either adrenal medullary synthesis or blood pressure and heart rate.
The acute effects of nicotine and ethanol
were studied in low and high rates of intracranial self-stimulation of the medial
prefrontal cortex in the rat. Nicotine tended to
increase low intracranial self-stimulation rates but did not change or even reduce high
intracranial self-stimulation rates.
Non-Human Toxicity Values:
LD50 Rat oral 188 mg/kg
LD50 Rat ip 30 mg/kg
LD50 Mouse oral 24 mg/kg
LD50 Rat oral 50-60 mg/kg
LD50 Rat skin 140 mg/kg
LD50 Rat iv 1 mg/kg
LD50 Rat scu 25 mg/kg
Metabolism/Pharmacokinetics:
Metabolism/Metabolites:
IN VITRO STUDIES WITH RABBIT LIVER MICROSOMES, /NADPH/, & O2, INDICATED THAT
METABOLISM OF NICOTINE PROCEEDED THROUGH
HYDROXYLATION TO 5-(3'-PYRIDYL)-N-METHYLPYRROLIDINE-2-OL; OXIDATION TO COTININE; &
DEAMIDATION OF COTININE TO 4-(3'-PYRIDYL)-4-METHYLAMINO-BUTYRIC ACID. NO CARBON DIOXIDE
WAS OBSERVED.
/AFTER ADMIN OF NICOTINE TO DOGS, ORAL &
IV, CMPD ISOLATED & IDENTIFIED FROM URINE WERE/ (-)COTININE, (-)DESMETHYLCOTININE,
HYDROXYCOTININE, GAMMA-METHYLAMINO-GAMMA-(2-PYRIDYL) BUTYRIC ACID,
BETA-OXO-GAMMA-(3-PYRIDYL)-N-METHYLBUTYRAMIDE, /&/ 3-PYRIDYLACETIC ACID ... NICOTINE ISOMETHONIUM ION WAS ALSO FOUND ...
SPECIES DIFFERENCES WERE FOUND IN IN VITRO METAB OF (R)(+)- & (S)(-)-NICOTINE, USING LIVER SUPERNATANT PREPN FROM RATS,
RABBITS, MICE, GUINEA PIGS, & HAMSTERS. (S)(-)-ENANTIOMER FORMED PREDOMINANTLY
(R,S)-CIS-NICOTINE-1'-N-OXIDE, WHEREAS (R)(+)-NICOTINE GAVE PREDOMINANTLY (S,R)-TRANS-NICOTINE-1'-N-OXIDE.
FORMATION OF NICOTINE-1'-N-OXIDE FROM NICOTINE IS CATALYZED BY GUINEA PIG LIVER 10000XG
SUPERNATANT; REACTION REQUIRES NADPH BUT IS NOT INHIBITED BY SKF-525A /ENZYME INHIBITOR/.
... BASIC AMINES, EG NICOTINE ... ARE
N-OXIDIZED BY NON-CYTOCHROME P-450-DEPENDENT SYSTEM ...
... Cotinine has been shown to be the major metabolic product. ... The route of
cotinine formation is apparently through the immediate hydroxylation product,
2-hydroxynicotine. /2-hydroxynicotine/
... Following the administration of 0.1 mg nicotine/kg
(labeled in 2-(14)C-pyrrolidone) to rats, the assay was used in a pharmacokinetic
investigation. Radioactivity due to nicotine and
cotinine was detected in substantial amounts in plasma samples. Nicotine
disappearance was biexponential, with an elimination half life of 1.0 hour. Cotinine
appeared as the major metabolite in plasma and had elimination half life of 5.2 hours. In
urine, nicotine-1'-N-oxide was the major
metabolite of nicotine.
Mammals metabolize the tobacco alkaloid (S)-nicotine
primarily to the lactam (S)-cotinine by a pathway involving an initial cytochrome p450
catalyzed two-electron oxidation at the prochiral 5'-carbon atom. The stereochemical
course of this oxidation was examined with human microsomal preparations and the E and Z
diastereomers of (S)-nicotine-5'-d1. The
metabolically generated d1'(5')-iminium ion intermediate was trapped and analyzed as the
corresponding diastereomeric 5'-cyano derivatives by a capillary column gas
chromatography-electron ion mass spectrometry selected ion monitoring assay. The results
of these studies established that this biotransformation proceeds with stereoselective
abstraction of the 5'-pro-E proton, that is, the C-5' proton transfers to the bulky
pyridyl group. The observed stereoselectivity was independent of proton vs deuteron
abstraction. Additionally, the extent of (S)-cotinine formation was minor and did not
influence the stereochemical composition of the metabolically derived alpha-cyano amines.
Studies with male Dutch rabbit liver microsomal preparations gave similar results.
Toxicologically, it is of interest that /the microsomal flavin-containing
monooxygenase/ is responsible for the oxidation of nicotine
to nicotine-1'-N-oxide, whereas the oxidation of
nicotine to cotinine is catalyzed by two enzymes
acting in sequence: p450 and a soluble aldehyde dehydrogenase. Thus, nicotine
is metabolized by two different routes, the relative contributions of which may vary with
both the extrinsic and intrinsic factors.
The cytochromes p450 oxidize (S)-nicotine to
a mixture of cis- and trans-N-'-oxides. In contrast, (S)-nicotine
is oxidized by human flavin-containing monooxygenases exclusively to the trans-N-1'-oxide.
Absorption, Distribution & Excretion:
NICOTINE IS READILY ABSORBED FROM RESP TRACT,
BUCCAL MUCOUS MEMBRANES, & SKIN. ... BOTH NICOTINE
& ITS METB ARE RAPIDLY ELIM BY KIDNEY. THE RATE OF URINARY EXCRETION OF NICOTINE IS DEPENDENT UPON PH OF URINE; EXCRETION
DIMINISHES WHEN URINE IS ALKALINE. NICOTINE IS
ALSO EXCRETED IN MILK OF LACTATING WOMEN WHO SMOKE. MILK OF HEAVY SMOKERS MAY CONTAIN 0.5
MG/L. ... APPARENTLY THE GASTRIC ABSORPTION OF NICOTINE
FROM TOBACCO TAKEN BY MOUTH IS DELAYED BECAUSE OF SLOWED GASTRIC EMPTYING, SO THAT
VOMITING MAY REMOVE MUCH OF THE TOBACCO REMAINING IN GI TRACT.
IN MICE, DOGS, & GUINEA PIGS, EXPOSURE TO NICOTINE
SMOKE PERMITS ... DETECTION IN VISCERAL STORAGE COMPARTMENTS, INCL LIVER, KIDNEYS, LUNG,
& BRAIN. ...
... 7.5% OF ALKALOID APPLIED TO INTACT SKIN OF DOG WAS ABSORBED IN 1 HR; 16% OF APPLIED
DOSE WAS ABSORBED IN SAME TIME THROUGH WOUNDS.
ELIMINATION OF NICOTINE FROM PLASMA IS
BIPHASIC IN MAN WITH TERMINAL PHASE T1/2 OF ABOUT 30 MIN. ... EXCRETION OF NICOTINE IN SALIVA IS SPECIES-SPECIFIC IN DOG &
MONKEY & DISTRIBUTION WITHIN BRAIN HAS BEEN SHOWN TO BE AGE DEPENDENT IN MOUSE ...
ALTHOUGH NICOTINE IS ABSORBED RAPIDLY OVER
LARGE SECTION OF GI TRACT, ABSORPTION OF N-OXIDE IS LIMITED TO AREA RELATIVELY HIGH IN
INTESTINE. N-OXIDE IS REDUCED TO NICOTINE IN GUT
& NICOTINE PRODUCED IS ABSORBED LOW ENOUGH
IN GI TRACT TO AVOID FIRST PASS PHENOMENON.
IN CIGARETTE SMOKERS, EXCRETION OF UNCHANGED NICOTINE,
BUT NOT OF COTININE, INCR WITH INCR URINARY VOLUME & DECR URINARY PH ... TUBULAR
RE-ABSORPTION OF THE TWO ALKALOIDS IS INVERSELY PROPORTIONAL TO THEIR METABOLIC TURN-OVER
...
NICOTINE & ITS METABOLITES APPEARED IN
FETUS WITHIN 5 MIN OF IV INJECTION OF TRITIATED (-)-NICOTINE
IN RATS ON DAY 19 OF GESTATION. FROM 30 MIN THROUGH 20 HR, CONCN OF RADIOACTIVITY IN
PLASMA OF FETUS WAS GREATER THAN IN MOTHER. BY 60 MIN, EQUILIBRIUM WAS ESTABLISHED BETWEEN
MATERNAL PLASMA & AMNIOTIC FLUID WITH RESPECT TO CONCN OF RADIOACTIVITY. FETAL PLASMA
AS WELL AS MOST OF THE FETAL TISSUES HAD A GREATER PROP OF TRITIATED NICOTINE
TO METABOLITES THAN DID MATERNAL PLASMA.
FREE ALKALOID IS ABSORBED RAPIDLY THROUGH SKIN AND GASTROINTESTINAL AND RESPIRATORY
TRACTS, BUT ABSORPTION OF ITS ACID SALTS IS LESS COMPLETE.
Male ICR mice, received 4 uCi (0.22 to 0.26 ug/kg) (3)H-nicotine
in 0.9% over 5 sec via the tail vein. Total and nonspecific binding were estimated in mice
pretreated sc with either 0.9% NaCl (2 ml/kg) or unlabeled l-nicotine
(5 mg/kg base), respectively, 2 min before (3)H-nicotine
injection. 5% of mice given 5 mg/kg nicotine
convulsed and died. 10 mg/kg killed most of the mice tested. Radioactivity entered the
brain rapidly, was heterogeneously distributed, and declined after 5 min. Estimated
specific binding was highest in the medial and posterior cortex, midbrain
thalamus/hypothalamus and medulla/pons; intermediate in the cerebellum, caudate/putamen,
frontal and frontoparietal cortex; and lowest in the hippocampus and olfactory bulb.
Autoradiography showed similar patterns. Mice received 0.8 uCi (3)H-nicotine
with incr doses of unlabeled l-nicotine iv.
Either NaCl or 5 mg/kg l-nicotine was injected
sc (2 ml/kg body wt) 5 min before (3)H-nicotine.
The level of specifically bound (3)H- with incr concn of unlabeled l-nicotine,
approaching nonspecific binding. IV doses of l-nicotine
above 0.5 mg/kg were not tolerated by mice. Nicotinic agonists reduced radioactivity in
the thalamus/hypothalamus. Percentage reductions in tissue radioactivity were : l-nicotine (2 mg/kg), 37 + or - 4.4; l-nicotine
(5 mg/kg), 45 + or - 2.6; d-nicotine (2 mg/kg),
24 + or - 3.9; d-nicotine (5 mg/kg), 38 + or -
2.0. Nicotinic antagonists were less active.
Level of urinary nicotine were measured in 21
non-smokers, 26 smokers of blond tobacco, 9 smokers of black tobacco, and 5 smokers of
both types, all eating a similar diet. Two 24-hr samples from the subjects were collected
over a 3-day period. The sum of urinary nicotine
and cotinine levels was used as a measure of exposure to the number of cigarettes smoked.
The nicotine + cotinine content in 24 hr urine
was 0, 0 to 0.5, 0.5 to 1.5, 1.5 to 2.5, and > 2.5 umol/mmol creatinine for subjects
who smoked a average of 0.47, 3.56, 14.3, 18.9, and 19.8 cigarettes in 24 hr,
respectively.
...more slowly absorbed from acidic than alkaline smoke.
Following small doses, about 4-12% is excreted unchanged in the urine. Following larger
doses, a higher proportion is excreted, and the rate of increase is linear; 30% of the
dose was recovered unmetabolized from the urine of a dog dosed intravenously at the rate
of 48 mg/kg. Urinary excretion of nicotine is
virtually complete in the rat in 16 hr and in the dog in 16-36 hr.
Nicotine crosses the placenta and is freely
distributed into milk, reportedly producing concentrations in breast milk averaging 2.9
times those in plasma. Nicotine concentrations
in amniotic fluid, placental tissue, and fetal serum exceed corresponding maternal serum
concentrations in women who smoke cigarettes... Small amounts of nicotine
appear in serum and urine of infants of nursing women who smoke cigarettes.
...nonhuman primate studies show that after absorption, nicotine
is concentrated in the brain (where up to 8% of the dose is localized at 5 minutes after
injection), the kidney (where more than 14% of the dose is localized), the stomach mucosa,
the adrenal medulla, the nasal mucosa, and in the salivary glands.
The kinetics of nicotine elimination are
dose-dependent: 4% to 12% is excreted unchanged in human and dog urine after small doses;
however, after exposure to a large (48 mg/kg) quantity, 30% of the dose appeared in dog
urine as unchanged nicotine. In rats and dogs,
urinary elimination is complete within 16 to 36 hr, respectively.
Some 1 to 4.5 mg of nicotine is absorbed
following smoking of a small cigar, smokers generally have some 0.4 ppm nicotine
in their blood or less, but concentrations can range up to 2 ppm. Circulating nicotine concentrations in fatalities range from 30 to
100 ppm.
Biological Half-Life:
ELIMINATION OF NICOTINE FROM PLASMA IS
BIPHASIC IN MAN WITH TERMINAL PHASE T 1/2 OF ABOUT 30 MIN.
Mechanism of Action:
Nicotine ... affects the ganglia of the
insect central nervous system, facilitating trans synaptic conduction at low
concentrations and blocking conduction at higher levels.
In mammalian tissues, nicotine is known to
act as acetylcholine does, but only at the junction and at the ganglion. ... Nicotine can attack some of the cholinergic junctions
and all neuromuscular junctions of mammals by acetycholine-like actions.
... The drug /nicotine/ can increase the
heart rate by excitation of sympathetic or paralysis of parasympathetic cardiac ganglia,
and it can slow the heart rate by paralysis of sympathetic or stimulation of
parasympathetic cardiac ganglia. ... Nicotine
causes a discharge of epinephrine from the adrenal medulla, and this hormone accelerates
cardiac rate and raises blood pressure.
The major action of nicotine consists
initially in transient stimulation and subsequently in a more persistent depression of all
autonomic ganglia. Small doses of nicotine
stimulate the ganglion cells directly and facilitate the transmission of impulses. When
larger doses of the drug are applied, the initial stimulation is followed very quickly by
a blockade of transmission. ... Nicotine also
possesses a biphasic action on the adrenal medulla; small doses evoke the discharge of
catecholamines, and larger doses prevent their release in response to splanchnic nerve
stimulation.
Nicotine tends to produce a discharge of
epinephrine from the adrenal medulla, and this hormone accelerates cardiac rate and raises
blood pressure. Small doses of nicotine
stimulate the ganglion cells directly & facilitate the transmission of impulses. When
larger doses of nicotine are applied, the
initial stimulation is followed very quickly by a blockade of transmission. Nicotine initially stimulates by depolarizing the
ganglion cell and that, with adequate doses of nicotine,
depression of transmission occurs both during the period of depolarization & after the
depolarization has dissipated. The second phase of the ganglionic blockade is probably due
to a competitive type of blockade of ACh similar to that produced by drugs such as
hexamethonium.
Nicotine is much more active on ganglia than
on skeletal muscle. It also possesses a biphasic action on the adrenal medulla; small
doses evoke the discharge of catecholamines, and larger doses prevent their release in
response to nerve stimulation. In addn, nicotine
apparently causes the release of catecholamines in a number of isolated organs. This
action results in a sympathomimetic response that is blocked by drugs known to prevent the
effects of catecholamines. The excitation of resp is a particularly prominent action of nicotine; although large doses act directly on the
medulla oblongata, smaller doses augment resp reflexly by excitation of the chemoreceptors
of the carotid and aortic bodies. Death results from failure of resp due to both central
paralysis and peripheral blockade of muscles of resp.
The effects of nicotine on the
gastrointestinal tract are due largely to parasympathetic stimulation. The combined
activation of parasympathetic ganglia and cholinergic nerve endings results in incr tone
and motor activity of the bowel and occasionally in diarrhea.
Bovine aortic endothelial cells were exposed to 1 ml serum-free Dulbecco's modified
Eagle medium in the presence or absence of nicotine
(10-9 to 10-5 M). Nicotine incr plasminogen
activator secretion, determined by (125)I-fibrin plate assay, in a time- and
dose-dependent manner. At all points, nicotine
treatment (2.5 x 10-7 M) was associated with enhanced secretion of plasminogen activator
activity. Maximum effects after 24 hr incubation were observed at 10-8 M nicotine,
which corresponded to about a 2.6-fold incr over control. Nicotine
(10-8 M) plasminogen activator stimulation required both RNA and protein syntheses, as
evidenced by its inhibition (35%) by 2 ug/ actinomycin D and 2 ug/l cycloheximide.
Although activities of all species of plasminogen activator were enhanced by nicotine, it had no significant effects on the release
of plasminogen activator.
Golden Syrian Hamster oocytes were cultured for up to 24 hr in the presence of 0,
0.0005, 0.005, 0.05, 0.5 and 5.0 mM nicotine.
Meiotic status was scored cytogenetically from chromatin spreads. Each treatment level had
at least 2 replicates (10-15 oocytes) and was repeated 3 times. In another series of expt,
oocytes were cultured in the absence or presence of 5 mM nicotine
for 8 to 24 hr. Five mM nicotine caused marked
perturbations at both the first and second meiotic divisions which resulted in
degenerating blobs of chromatin at 24 hr (p < 0.001). After 24 hr culture, 68% of
oocytes exposed to 5 mM nicotine exhibited
either one or 2 blobs of chromatin. The most pronounced of these perturbations was either
blockage at Metaphase I or disruption of homolog segregation to result in 2 groups of
bivalents formed at Anaphase I. Concn of nicotine
at or below 0.5 mM did not adversely affect the meiotic process. No oocyte at any nicotine level was classified as being at the GV stage
(immature).
Nicotine was administered acutely and
subchronically (14 days) to male Sprague-Dawley rats to determine whether various synaptic
mechanisms are selectively altered in the nigrostriatal and mesolimbic dopaminergic
system. When added to tissue preparations in vitro, nicotine
had no effects on tyrosine hydroxylase, synaptosomal uptake of (3)H-dopamine or binding of
(3)H-spiperone to D2 receptors in either system. However, acute treatment in vivo
stimulated tyrosine hydroxylase activity in the nucleus accumbens. This effect was
prevented by pretreatment with a nicotinic antagonist. Subchronic exposure to nicotine had no effect on tyrosine hydroxylase. In
vivo treatment with nicotine did not alter
dopamine uptake or receptor binding.
Interactions:
THE DELETERIOUS EFFECTS (INCR IN GESTATIONAL PERIOD & DECR IN FETAL NUMBER &
WT) CAUSED BY INJECTION OF NICOTINE INTO
PREGNANT RATS WERE PREVENTED AFTER SIMULTANEOUS ADMIN OF PHENTOLAMINE.
PRETREATMENT OF RATS WITH NICOTINE DECR
BENZOPYRENE HYDROXYLASE ACTIVITY IN VITRO. FINDINGS SHOW THAT NICOTINE
INHIBITS THE METABOLISM OF 3,4-BENZOPYRENE IN VIVO & IN VITRO.
NICOTINE ... FOUND TO ACT AS COCARCINOGEN
WHEN APPLIED TO MOUSE SKIN WITH BENZO(A)PYRENE &
12-0-TETRADECANOLYLPHORBOL-13-ACETATE.
The effects of acute administration of ethanol and nicotine
either singly or in combination, have been studied on the plasma amino acids levels and
certain biochemical and hematological parameters in the rats. Both ethanol and its
combination with nicotine produced significant
reduction in the levels of a number of amino acids and the total amino acid pool. Only the
levels of taurine and hydroxyproline were increased in the ethanol treated rats, whereas
its combination with nicotine resulted in
markedly elevated levels of hydroxyproline, ornithine, and taurine. These changes were
also accompanied by a significant rise in blood glucose, ALT, AST, blood urea and uric
acid and a significant reduction in the total protein and triglycerides level.
Rats with unilateral 6-hydroxydopamine lesions of the substantia nigra became briefly
sedated and hypothermic after the acute injection of nicotine
sc (0.4 or 0.8 mg/kg free base). When nicotine
was repeated 5 days/wk there was a rapid tolerance for the sedation and slower tolerance
for the hypothermia and the lesioned animals began to rotate ipsiversively after each
injection. Stereotypic behavior was also noted. Rats injected with nicotine
5 days/wk and nigrally lesioned on the 24th day rotated promptly on their 1st
postoperative injection of nicotine. The
nicotinic antagonist, mecamylamine (1.0 mg/kg, ip), completely blocked the induced
rotation. The appearance of rotation did not seem to depend on tolerance to sedation. The
direction of rotation indicated enhancement of activity in the intact nigrostriatal
system. However, 10 min after the acute injection of 0.8 mg/kg nicotine
no change was found in the ratios of dopamine to its metabolites DOPAC and homovanillic
acid in the substantia nigra, caudate-putamen, nucleus accumbens, olfactory tubercle,
frontal cortex, or ventral tegmental area. Rats given 0.4 or 0.8 mg/kg nicotine
5 days/wk either lesioned prior to nicotine or
lesioned during the 3rd wk rotated during the 6th week without any sign of tolerance. One
day after the 30th injection in intact or lesioned rats the ratios of dopamine to its
metabolites did not differ from those in saline controls on either the right or left side
of any of the regions examined.
The effects of short term cigarette smoking abstinence and nicotine
polacrilex (Nicorette) in chewing gum, on theophylline metabolism in 14 smoking
volunteers, aged 22-61 yr, who received an intravenous injection of aminophylline /SRP: a
water-soluble salt complex of theophylline/ were studied. Seven subjects received
aminophylline, equivalent to 0.2 mg/kg of theophylline while smoking, then the same dose
14 days later after 6 days of abstinence, and again 8 days later after smoking was
resumed. In the others, nicotine gum was given
during the abstinence period, and the same schedule of aminophylline administration was
followed. The clearance rate of theophylline was elevated and half life decreased in the
subjects while smoking, but approached normal at the end of the abstinence period.
The administration of nicotine during the
prenatal stages of life resulted in a significant decrease in tumors occurring after
transplacental induction by N-methylnitrosourea. The overall tumor incidence following
oral application of N-methylnitrosourea to dams was 85% in the rats of the F1 generation,
the main occurrence being related to the neurogenic system (62% of the animals). Regular
injections of nicotine before or after birth
resulted in a reduction of malignancies by 17% and 22%, respectively. The difference in
the incidence of neurogenic tumors proved to be highly significant in rats of either sex,
when nicotine was applied over 26 wk following
birth.
Nicotine (20-60 ug/kg) produced an initial
vasodepressor response followed by a vasopressor response in anaesthetized cats, the
mechanism of which was investigated. The vasodepressor response was antagonized by
atropine or by vagotomy and was potentiated by physostigmine or neostigmine. Nicotine increased the single unit activity of
different peripheral sympathetic nerves and evoked contraction of nictitating membrane and
spleen along with vasopressor response. The vasopressor response was antagonized by
phentolamine, prazosin, guanethidine, bretylium, 6-OHDA, hemicholinium-3 or hexamethonium.
Propranolol or atenolol pretreatment potentiated the vasodepressor response and was
antagonized by atropine. Desensitization by salbutamol did not modify the response to nicotine. The biphasic response to nicotine
remained unaltered in yohimbine pretreated, in adrenalectomized, and in acute spinal as
well as in decapitated animals; intracarotid or intracerbroventricular administration of nicotine did not produce any response. The biphasic
response to nicotine does not involve the
stimulation of the central vasomotor centre.
This study evaluated superoxide anion generation evoked by phorbol myristate acetate
and chemotactic responses to formylmethionylleucylphenylaniline in polymorphonuclear
leukocytes isolated from rats treated acutely or subchronically with nicotine
and from rats chronically exposed to cigarette smoke. Acute or subchronic (twice daily for
7 days) intraperitoneal injection of 0.2 or 0.02 mg nicotine/kg
potentiated phorbol myristate acetate induced superoxide anion generation by
polymorphonuclear leukocytes. Similarily, acute intraperitoneal injections of 0.2 mg nicotine/kg or subchronic treatment with 0.02 mg nicotine/kg potentiated
formylmethionylleucylphenylaniline induced chemotaxis. Subchronic treatment with 0.2 mg nicotine/kg blunted formylmethionylleucylphenylaniline
induced chemotaxis, in contrast to the potentiating actions of the lower dose. Treatment
with nicotine mimicked the effects of tobacco
smoke exposure. A 15 week exposure regimen to either sidestream and mainstream smoke from
cigarettes potentiated phorbol myristate acetate induced superoxide anion generation.
Mainstream but not sidestream smoke also enhanced chemotactic responses to
formylmethionylleucylphenylaniline.
Ethanol (2.5 g/kg, 15% v/v in a 0.9% NaCl soln) was admin to male Long-Evans rats via
bilateral ip injections to facilitate distribution. Immediately after ethanol injection,
rats were injected with nicotine (0.05 mg/kg in
a 0.9% NaCl solution, sc intrascapular). Vehicle injections were 0.9% NaCl, equivalent in
volume to appropriate ethanol or nicotine
injections. For 11 days a colonic temp was taken, both drugs were injected and rats were
tested for locomotor activity for 45 min, after which a final colonic temp was taken. Nicotine significantly enhanced the rate of tolerance
development to the hypothermic effects of ethanol and blocked a degree of the sedative
effects. On days 12 to 17, rats in all groups received vehicle injections to extinguish
tolerance. There were significant group and time effects on changes of colonic temp during
days 0-11. While there were no differences between control groups, there was a significant
time effect between exptl groups, as well as a group & time interaction, with the
colonic temp of rats receiving ethanol and nicotine
returning toward control values at a faster rate over test days than those receiving
ethanol and vehicle.
S-(-)-Nicotine competitively inhibits the
metabolism of histamine to its N-methylated derivative in guinea pig lung homogenates.
S-(-)-Nicotine exhibited a dissociation constant
of the enzyme: inhibitor complex, Ki, of 9.4X10-5M compared with Km's for histamine and
co-factor, S-adenosylmethionine, of 4.74X10-5M and 1.76X10-5M, respectively.
Cytotoxic neutrophil derived oxygen radicals were implicated in the pathogenesis of a
variety of cardiovascular, pulmonary, and neoplastic disorders for which cigarette smoking
is a prominent risk factor. Although nicotine
alone failed to provoke neutrophil oxidative metabolism, the alkaloid caused dose
dependent (0.1 to 10 uM) potentiation of superoxide anion release induced by TPA or
N-formylmethionylleucylphenylalanine. The potentiating effect of nicotine
was not attenuated by atropine or hexamethonium nor was it mimicked by acetylcholine
suggesting involvement of noncholinergic receptors or a membrane fluidizing effect of the
alkaloid.
Pharmacology:
Therapeutic Uses:
Ganglionic Stimulants; Nicotinic Agonists
MEDICATION (VET): ectoparasiticide; has been used as an anthelmintic
In a double blind randomized trial to aid smoking cessation a 2 mg nicotine
gum (n= 101) was compared with a 4 mg gum (n= 98), in smokers of at least 15
cigarettes/day. The trial involved blue and white collar workers and took place at their
working place (industrial setting). Intervention during the one year follow-up period was
minimal. At 3 months 36.2% of the 2 mg nicotine
gum group reported to have stopped smoking, against 44.8% in the 4 mg group
(non-significant difference). At one year in the 2 mg and 4 mg groups respectively 22.3
and 32.2% reported smoking abstinence (non-significant difference).
A meta-analysis was made of fourteen randomized controlled trials that evaluated the
efficacy of nicotine chewing-gum in stopping
patients smoking. The combined success rates in specialized cessation clinics are
significantly higher with nicotine gum (27%)
than with placebo gum (18%) at 6 months (n= 734), and 23% and 13% at 12 months,
respectively. In contrast, success rates in general medical practices are similar with nicotine gum (11.4%) and with placebo gum (11.7%) at 6
months (n= 1022). However, in general practices, the success rates are 17% for nicotine gum and 13% for the no gum control at 4-6
months, and 9% and 5% at 12 months, a significant difference between the treatments at
each time (n= 2238).
Drug Warnings:
Drugs of Abuse: Contraindicated during Breast-Feeding: Nicotine
(smoking): Shock, vomiting, diarrhea, rapid heart rate, restlessness; decreased milk
production. (The Committee on Drugs strongly believes that nursing mothers should not
ingest any compounds listed /drugs of abuse/ ... Not only are they hazardous to the
nursing infant, but they are also detrimental to the physical and mental health of the
mother ... No drug of abuse should be ingested by nursing mothers even though adverse
reports are not in the literature.) /from Table 2/ [Report of the American Academy of
Pediatrics Committee on Drugs in Pediatrics 93 (1): 138 (1994)]
Allergic contact sensitization to nicotine,
confirmed by rechallenge in some patients, has been reported in 2-3% of patients receiving
the drug via a transdermal system...
Intranasal administration of nicotine
solution commonly produces local nasopharyngeal and ocular irritation. During the initial
2 days of intranasal nicotine therapy, nearly
all patients experience nasal irritation, which usually is moderate to severe. Both the
incidence and severity of nasal irritation decrease with continued intranasal therapy, but
it still is experienced by about 80% of patients after 3 weeks of therapy...
Patients with cardiac disease, recent myocardial infarction, or irregular heart rate
should consult their clinician before initiating self-medication with nicotine
preparations. A clinician also should be consulted prior to self-medication if the patient
has peptic ulcer disease, is receiving insulin for the management of diabetes mellitus, or
has uncontrolled hypertension or if they are receiving drug therapy for depression or
asthma...and, for the transdermal systems, if they are allergic to adhesive tape or have a
dermatologic condition.
Adverse GI effects occur frequently during the first week of therapy with nicotine polacrilex. The most frequent adverse
systemic effects...are indigestion and nausea, which reportedly occur in about 20-40% of
patients receiving the drug.
Adverse nervous system effect of nicotine
polacrilex include dizziness and lightheadedness, headache, insomnia, and irritability,
which reportedly occur in 1-25% of patients. Euphoria reportedly occurs in less than 1% of
patients.
Patients receiving nicotine polacrilex should
be warned that chewing the gum too rapidly may result in effects similar to those
associated with smoking a cigarette too rapidly or those experienced by nonsmokers when
they inhale a cigarette for the first time.
Interactions:
THE DELETERIOUS EFFECTS (INCR IN GESTATIONAL PERIOD & DECR IN FETAL NUMBER &
WT) CAUSED BY INJECTION OF NICOTINE INTO
PREGNANT RATS WERE PREVENTED AFTER SIMULTANEOUS ADMIN OF PHENTOLAMINE.
PRETREATMENT OF RATS WITH NICOTINE DECR
BENZOPYRENE HYDROXYLASE ACTIVITY IN VITRO. FINDINGS SHOW THAT NICOTINE
INHIBITS THE METABOLISM OF 3,4-BENZOPYRENE IN VIVO & IN VITRO.
NICOTINE ... FOUND TO ACT AS COCARCINOGEN
WHEN APPLIED TO MOUSE SKIN WITH BENZO(A)PYRENE &
12-0-TETRADECANOLYLPHORBOL-13-ACETATE.
The effects of acute administration of ethanol and nicotine
either singly or in combination, have been studied on the plasma amino acids levels and
certain biochemical and hematological parameters in the rats. Both ethanol and its
combination with nicotine produced significant
reduction in the levels of a number of amino acids and the total amino acid pool. Only the
levels of taurine and hydroxyproline were increased in the ethanol treated rats, whereas
its combination with nicotine resulted in
markedly elevated levels of hydroxyproline, ornithine, and taurine. These changes were
also accompanied by a significant rise in blood glucose, ALT, AST, blood urea and uric
acid and a significant reduction in the total protein and triglycerides level.
Rats with unilateral 6-hydroxydopamine lesions of the substantia nigra became briefly
sedated and hypothermic after the acute injection of nicotine
sc (0.4 or 0.8 mg/kg free base). When nicotine
was repeated 5 days/wk there was a rapid tolerance for the sedation and slower tolerance
for the hypothermia and the lesioned animals began to rotate ipsiversively after each
injection. Stereotypic behavior was also noted. Rats injected with nicotine
5 days/wk and nigrally lesioned on the 24th day rotated promptly on their 1st
postoperative injection of nicotine. The
nicotinic antagonist, mecamylamine (1.0 mg/kg, ip), completely blocked the induced
rotation. The appearance of rotation did not seem to depend on tolerance to sedation. The
direction of rotation indicated enhancement of activity in the intact nigrostriatal
system. However, 10 min after the acute injection of 0.8 mg/kg nicotine
no change was found in the ratios of dopamine to its metabolites DOPAC and homovanillic
acid in the substantia nigra, caudate-putamen, nucleus accumbens, olfactory tubercle,
frontal cortex, or ventral tegmental area. Rats given 0.4 or 0.8 mg/kg nicotine
5 days/wk either lesioned prior to nicotine or
lesioned during the 3rd wk rotated during the 6th week without any sign of tolerance. One
day after the 30th injection in intact or lesioned rats the ratios of dopamine to its
metabolites did not differ from those in saline controls on either the right or left side
of any of the regions examined.
The effects of short term cigarette smoking abstinence and nicotine
polacrilex (Nicorette) in chewing gum, on theophylline metabolism in 14 smoking
volunteers, aged 22-61 yr, who received an intravenous injection of aminophylline /SRP: a
water-soluble salt complex of theophylline/ were studied. Seven subjects received
aminophylline, equivalent to 0.2 mg/kg of theophylline while smoking, then the same dose
14 days later after 6 days of abstinence, and again 8 days later after smoking was
resumed. In the others, nicotine gum was given
during the abstinence period, and the same schedule of aminophylline administration was
followed. The clearance rate of theophylline was elevated and half life decreased in the
subjects while smoking, but approached normal at the end of the abstinence period.
The administration of nicotine during the
prenatal stages of life resulted in a significant decrease in tumors occurring after
transplacental induction by N-methylnitrosourea. The overall tumor incidence following
oral application of N-methylnitrosourea to dams was 85% in the rats of the F1 generation,
the main occurrence being related to the neurogenic system (62% of the animals). Regular
injections of nicotine before or after birth
resulted in a reduction of malignancies by 17% and 22%, respectively. The difference in
the incidence of neurogenic tumors proved to be highly significant in rats of either sex,
when nicotine was applied over 26 wk following
birth.
Nicotine (20-60 ug/kg) produced an initial
vasodepressor response followed by a vasopressor response in anaesthetized cats, the
mechanism of which was investigated. The vasodepressor response was antagonized by
atropine or by vagotomy and was potentiated by physostigmine or neostigmine. Nicotine increased the single unit activity of
different peripheral sympathetic nerves and evoked contraction of nictitating membrane and
spleen along with vasopressor response. The vasopressor response was antagonized by
phentolamine, prazosin, guanethidine, bretylium, 6-OHDA, hemicholinium-3 or hexamethonium.
Propranolol or atenolol pretreatment potentiated the vasodepressor response and was
antagonized by atropine. Desensitization by salbutamol did not modify the response to nicotine. The biphasic response to nicotine
remained unaltered in yohimbine pretreated, in adrenalectomized, and in acute spinal as
well as in decapitated animals; intracarotid or intracerbroventricular administration of nicotine did not produce any response. The biphasic
response to nicotine does not involve the
stimulation of the central vasomotor centre.
This study evaluated superoxide anion generation evoked by phorbol myristate acetate
and chemotactic responses to formylmethionylleucylphenylaniline in polymorphonuclear
leukocytes isolated from rats treated acutely or subchronically with nicotine
and from rats chronically exposed to cigarette smoke. Acute or subchronic (twice daily for
7 days) intraperitoneal injection of 0.2 or 0.02 mg nicotine/kg
potentiated phorbol myristate acetate induced superoxide anion generation by
polymorphonuclear leukocytes. Similarily, acute intraperitoneal injections of 0.2 mg nicotine/kg or subchronic treatment with 0.02 mg nicotine/kg potentiated
formylmethionylleucylphenylaniline induced chemotaxis. Subchronic treatment with 0.2 mg nicotine/kg blunted formylmethionylleucylphenylaniline
induced chemotaxis, in contrast to the potentiating actions of the lower dose. Treatment
with nicotine mimicked the effects of tobacco
smoke exposure. A 15 week exposure regimen to either sidestream and mainstream smoke from
cigarettes potentiated phorbol myristate acetate induced superoxide anion generation.
Mainstream but not sidestream smoke also enhanced chemotactic responses to
formylmethionylleucylphenylaniline.
Ethanol (2.5 g/kg, 15% v/v in a 0.9% NaCl soln) was admin to male Long-Evans rats via
bilateral ip injections to facilitate distribution. Immediately after ethanol injection,
rats were injected with nicotine (0.05 mg/kg in
a 0.9% NaCl solution, sc intrascapular). Vehicle injections were 0.9% NaCl, equivalent in
volume to appropriate ethanol or nicotine
injections. For 11 days a colonic temp was taken, both drugs were injected and rats were
tested for locomotor activity for 45 min, after which a final colonic temp was taken. Nicotine significantly enhanced the rate of tolerance
development to the hypothermic effects of ethanol and blocked a degree of the sedative
effects. On days 12 to 17, rats in all groups received vehicle injections to extinguish
tolerance. There were significant group and time effects on changes of colonic temp during
days 0-11. While there were no differences between control groups, there was a significant
time effect between exptl groups, as well as a group & time interaction, with the
colonic temp of rats receiving ethanol and nicotine
returning toward control values at a faster rate over test days than those receiving
ethanol and vehicle.
S-(-)-Nicotine competitively inhibits the
metabolism of histamine to its N-methylated derivative in guinea pig lung homogenates.
S-(-)-Nicotine exhibited a dissociation constant
of the enzyme: inhibitor complex, Ki, of 9.4X10-5M compared with Km's for histamine and
co-factor, S-adenosylmethionine, of 4.74X10-5M and 1.76X10-5M, respectively.
Cytotoxic neutrophil derived oxygen radicals were implicated in the pathogenesis of a
variety of cardiovascular, pulmonary, and neoplastic disorders for which cigarette smoking
is a prominent risk factor. Although nicotine
alone failed to provoke neutrophil oxidative metabolism, the alkaloid caused dose
dependent (0.1 to 10 uM) potentiation of superoxide anion release induced by TPA or
N-formylmethionylleucylphenylalanine. The potentiating effect of nicotine
was not attenuated by atropine or hexamethonium nor was it mimicked by acetylcholine
suggesting involvement of noncholinergic receptors or a membrane fluidizing effect of the
alkaloid.
Minimum Fatal Dose Level:
The fatal adult dose is 60 mg.
Environmental Fate & Exposure:
Environmental Fate/Exposure Summary:
Nicotine is a natural constituent of the
tobacco plants Nicotiana tabacum and N. rustica and it is released in the vapor (98.3%)
and particulate phase of tobacco smoke. Nicotine
may have been directly released to the environment due to its former use as an
insecticide. If released to air, a vapor pressure of 0.038 mm Hg at 25 deg C indicates nicotine will exist solely as a vapor in the ambient
atmosphere. Vapor-phase nicotine will be
degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals;
the half-life for this reaction in air is estimated to be 4 hours. If released to soil, nicotine is expected to have high mobility based upon
an estimated Koc of 100. However, nicotine is a
base and protonation under neutral and acidic conditions may result in greater adsorption
and less mobility than its estimated Koc or water solubility indicate. Volatilization from
moist soil surfaces is not expected to be an important fate process based upon an
estimated Henry's Law constant of 3.0X10-9 atm-cu m/mole. Based on limited data,
biodegradation of nicotine may occur in both
soil and water with the formation of oxynicotine, 3-pyridylmethyl ketone, 2,3'-dipyridyl,
N-methylmyosmine and an unknown purple crystalline pigment as reaction products. If
released into water, nicotine is not expected to
adsorb to suspended solids and sediment in water based on its estimated Koc value.
However, in neutral to acidic waters, adsorption may occur. Volatilization from water
surfaces is not expected to be an important fate process based on its estimated Henry's
Law constant. An estimated BCF of 5 suggests the potential for bioconcentration in aquatic
organisms is low. The most probable route of human exposure is by inhalation of tobacco
smoke. Some people may also be exposed to nicotine
in drinking water. Infants breast fed by women who smoke are exposed to nicotine
in mother's milk. Worker exposure may occur during processing and extraction of tobacco.
(SRC)
Probable Routes of Human Exposure:
NIOSH (NOES Survey 1981-1983) has statistically estimated that 4737 workers (861 of
these are female) are potentially exposed to nicotine
in the US(1). The most probable route of human exposure to nicotine
is by inhalation of tobacco smoke and in indoor air where smoking is allowed(2). Some
segments of the general population may also be exposed to nicotine
in drinking water. Infants breast fed by woman who smoke will tend to be exposed to nicotine in the mother's milk. Worker exposure to nicotine may occur during processing and extraction of
tobacco(SRC).
Exposure of individuals to ambient nicotine
in households, offices, pubs, restaurants, coffee shops, cars, trains, and airplanes was
estimated. An estimate of the amount of nicotine
inhaled was calculated by multiplying nicotine
concentration from the personal monitor by respiratory volume (0.48 cu m/hr). Nicotine exposure was converted to an equivalent of
cigarettes smoked (representing passive smoking) by dividing the inhaled nicotine
values by the known nicotine exposure (1 mg)
from active smoking of one cigarette. Three individual offices yielded nicotine
exposure values ranging from 5.9 to 19.8 ug/cu m. The nicotine
inhaled was estimated to be 2.8 to 9.5 ug/hr, which is equivalent to active smoking of
0.003 to 0.010 cigarettes/hr. In one office where 28 to 48 cigarettes were smoked per day,
an estimated weekly nicotine exposure of 3.0 to
10.2 ug/cu m was calculated. Average nicotine
exposure levels in several public places ranged from 31.5 to 43.2 ug/cu m, with a passive
smoking exposure equivalent to no more than 50 ug nicotine/hr
(0.05 cigarettes/hr). Nicotine exposure levels
in smoking seats of trains and airplanes was 48.6 and 28.8 ug/cu m, respectively. These
values were equivalent to smoking 0.023 and 0.014 cigarettes/hr. Nicotine
intake was particularly high for individuals exposed at the workplace and at home. Daily nicotine inhaled by non-smokers (passive smoking) is
significantly less than that inhaled by active smokers.
Body Burden:
Breast milk from heavy smokers may contain 0.5 mg/l(1). Nicotine
was detected in breast milk from smokers and nonsmokers at a mean concentration of 91 and
0 ppb, respectively(2). Detected (0.2-1.6 ng/ml) in serum of newborn infants nursed by
smoking mothers(3).
Nicotine concns in hair samples taken from a
non-smoker ranged from 1.3 to 2.8 ug/g and in hair samples from a smoker ranged from 36 to
60 ug/g(1).
Urine samples of 2 groups of children (Group A: 10 mo old, 55 children; Group B: 4 yr
old, 54 children) were analyzed for nicotine and
cotinine to study the effects of exposure to environmental tobacco smoke. Twenty of Group
A and 19 of Group B children had not been exposed to environmental tobacco smoke while the
remaining children had been exposed during the last three days. The differences in urinary
nicotine and cotinine levels between the
"exposed" and "unexposed" children were statistically significant in
both age groups. Median urinary nicotine levels
in "exposed" and "unexposed" children were 2.7 ug/l and 1.3 ug/l
respectively in Group A and 2.2 ug/l and 1.1 ug/l respectively in Group B.
Average Daily Intake:
Using sidestream/mainstream ratios of nicotine
and assuming a 10 L/min respiratory rate, the recent Surgeon General's Report estimates
that from 0.6 to 30 ug of nicotine is inhaled in
one hour by passive smoking(1). As a result of all-day monitoring, it was found that the
highest amount of nicotine inhaled in a day was
estimated to be up to 310 ug, equivalent to actively smoking 0.31 ordinary cigarettes(2).
Natural Pollution Sources:
N. glauca (burley tobacco, wild tobacco, wild tree tobacco) and N. tabacum (tobacco
plant) contain the alkaloid nicotine.
SMOKING TOBACCO USUALLY CONTAINS 1-2% NICOTINE.
Nicotine is an alkaloid contained in the
leaves of the tobacco plants Nicotiana tabacum and N rustica(1,2).
... /Nicotine/ is found in ... Aesclepias
syriaca.
Artificial Pollution Sources:
Nicotine's former use as an insecticide(1)
may have resulted in its direct release to the environment(SRC). Nicotine
is no longer produced in the United States, although limited supplies are imported from
India(2). Nicotine is also directly released to
air in the vapor(98.3%) and particulate phase of tobacco smoke(3).
Chemical characterization was made of gas-phase components of environmental tobacco
smoke in a 30 cu m Teflon chamber from smoking 1R1 Kentucky reference cigarettes. Nicotine was the most abundant particulate compound
identified by collection with either the annular denuder/filter pack system or the high
vol samplers (467 + or - 144 umol/g), regardless of whether fresh or aged environmental
tobacco smoke particles were collected on the filter. Using the denuder system, the concn
of particulate phase nicotine (nmol/cu m) in the
30 cu m teflon chamber was 50, 56, 32, and 10 when 1, 2, 3, and 4 cigarettes were burned,
respectively. These values were 636, 218, 111 and 35 when calculated as umol/mol of carbon
monoxide (CO). The mole ratio of particulate nicotine
to carbon monoxide (CO) was the same for both fresh and aged samples. After 4 cigarettes
were burned and chambers were exposed to ultraviolet light during the second and fourth hr
of the expt, the nicotine concn during hr 1, hr
3 and hr 5 were 154, 581, and 632 umol/g, respectively.
Environmental Fate:
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of
100(SRC), determined from a log Kow value(2) and a regression-derived equation(3),
indicates that nicotine is expected to have high
mobility in soil(SRC). However, nicotine is a
base, pKb1= 6.16; pKb2= 10.96(4), and protonation under neutral and acidic conditions may
result in greater adsorption and less mobility than its estimated Koc or water
solubility(9) indicate(5,SRC). Volatilization of nicotine
from moist soil surfaces is not expected to be important(SRC) given an estimated Henry's
Law constant of 3.0X10-9 atm-cu m/mole(SRC), using a fragment constant estimation
method(6). Nicotine is not expected to
volatilize from dry soil surfaces based on a vapor pressure of 0.038 mm Hg(7). Based on
limited data, biodegradation of nicotine may
occur with the formation of oxynicotine, 3-pyridylmethyl ketone, 2,3'-dipyridyl,
N-methylmyosmine and an unknown purple crystalline pigment as reaction products(8).
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 100(SRC),
determined from a log Kow value(2) and a regression-derived equation(3), indicates that nicotine is not expected to adsorb to suspended solids
and sediment in water(SRC). However, nicotine is
a base, pKb1= 6.16; pKb2= 10.96(4), and protonation under neutral and acidic conditions
may result in greater adsorption than its estimated Koc value may indicate(5,SRC). Based
on limited data, biodegradation of nicotine may
occur with the formation of oxynicotine, 3-pyridylmethyl ketone, 2,3'-dipyridyl,
N-methylmyosmine and an unknown purple crystalline pigment as reaction products(6). Nicotine is not expected to volatilize from water
surfaces(3,SRC) based on an estimated Henry's Law constant of 3.0X10-9 atm-cu m/mole(SRC),
developed using a fragment constant estimation method(7). According to a classification
scheme(8), an estimated BCF of 5(3,SRC), from a log Kow value(2), suggests the potential
for bioconcentration in aquatic organisms is low(SRC).
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile
organic compounds in the atmosphere(1), nicotine,
which has a vapor pressure of 0.038 mm Hg at 25 deg C(2), is expected to exist solely as a
vapor in the ambient atmosphere. Vapor-phase nicotine
is degraded in the atmosphere by reaction with photochemically-produced hydroxyl
radicals(SRC); the half-life for this reaction in air is estimated to be 4 hours(3,SRC).
Environmental Biodegradation:
BACTERIAL STRAIN, ISOLATED FROM TOBACCO LEAVES, OXIDIZED NICOTINE
TO GAMMA-AMINOBUTYRIC ACID ... ARTHROBACTER OXYDANS, ADAPTED TO L-, D-, DL-NICOTINE, CONVERTED BOTH ... ISOMERS INITIALLY TO
6-HYDROXY NICOTINE. THESE ... THEN METABOLIZED
TO ... 6-HYDROXY-N-METHYLMYOSMIN.
Several organisms capable of degrading nicotine
have been isolated from leaves and seeds of tobacco and from soil(1). A wide variety of
transformation products have been identified from bacterial fermentation media, tobacco
seed infusions and fermented tobacco leaves. These products include oxynicotine,
3-pyridylmethyl ketone, 2,3'-dipyridyl, N-methylmyosmine and a purple crystalline
pigment(1). A variety of different degradation pathways have been proposed(1).
Environmental Abiotic Degradation:
NICOTINE DECOMP WAS ACCELERATED BY UV
RADIATION. RATE WAS GREATER IN SOLN @ PH 9.5 THAN @ ACID PH OF 6.2 OR 2.1. SULFATE FORM
WAS MORE STABLE THAN FREE NICOTINE ... .
The concn of gas-phase nicotine from
environmental tobacco smoke generated from cigarettes in a Teflon chamber decr
significantly (-70%) as a result of exposure of the tobacco smoke to 1 hr of ultraviolet
radiation.
The rate constant for the vapor-phase reaction of nicotine
with photochemically-produced hydroxyl radicals has been estimated as 9.7X10-11 cu
cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This
corresponds to an atmospheric half-life of about 4 hours at an atmospheric concn of 5X10+5
hydroxyl radicals per cu cm(1,SRC). Nicotine is
not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable
functional groups(2). Nicotine in cyclohexane
exhibits weak absorption of UV light greater than 290 nm, suggesting that nicotine has slight potential for photolysis by
sunlight in water or air(3,SRC). Nicotine
decomposes rather quickly under the influence of light and air and resinous products are
formed(4).
Environmental Bioconcentration:
An estimated BCF of 5 was calculated for nicotine(SRC),
using a log Kow value of 1.17(1) and a regression-derived equation(2). According to a
classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic
organisms is low(SRC).
Soil Adsorption/Mobility:
The Koc of nicotine is estimated as
approximately 100(SRC), using a log Kow value of 1.17(1) and a regression-derived
equation(2,SRC). According to a classification scheme(3), this estimated Koc value
suggests that nicotine is expected to have high
mobility in soil(SRC). However, nicotine is a
base, pKb1= 6.16; pKb2= 10.96(4), and protonation under neutral and acidic conditions may
result in greater adsorption and less mobility than its estimated Koc value
indicates(SRC). Adsorption of nicotine, under
more acidic conditions, can be represented as a high-affinity type isotherm, indicating
that nicotine has a high affinity for humic
acids in soil as a result of protonation of the pyrrolidine nitrogen atom of nicotine(5).
Volatilization from Water/Soil:
The Henry's Law constant for nicotine is
estimated as 3.0X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1).
This Henry's Law constant indicates that nicotine
is expected to be essentially nonvolatile and thus volatilization from water surfaces is
not expected(2,SRC). Nicotine's Henry's Law
constant(1,SRC) indicates that volatilization from moist soil surfaces is not
expected(SRC). Nicotine is not expected to
volatilize from dry soil surfaces based on a vapor pressure of 0.0380 mm Hg(3).
Environmental Water Concentrations:
OF 10 WATER UTILITIES SURVEYED BY EPA (1975A), ONLY FINISHED WATER OF MIAMI CONTAINED NICOTINE @ 3 UG/L.
DRINKING WATER: Nicotine was positively
idenified in drinking water from: Cincinnati, OH - Oct 1978 and Jan 1980; Ottumva, IA -
Sept 1976; and Seattle, WA - Nov 1976(1). During the 1975 US EPA National Organics
Reconnaissance Survey (NORS) nicotine was
detected in 1/10 finished water supplies(2). Finished water from Miami, FL contained 3
ug/l nicotine(2).
SURFACE WATER: Nicotine was measured in
samples collected from the Rhine river in 1989 and 1991 at several locations including
Lobith (not detected to 0.032 ug/l), Werkendam (0.022 ug/l), Maasluis (0.02 ug/l), and
Haringvliet (0.019 ug/l), The Netherlands(1).
Effluent Concentrations:
Nicotine was tentatively identified in the
final effluent, sampled during May 1980, from the Roselle, IL municipal wastewater
treatment plant(1). During Nov 1980, 0.12 ug/l nicotine
was identified in the secondary effluent from the Fort Polk, LA rapid infiltration
site(2). Nicotine has been detected in the final
effluent from one plant in each of the following industries: pulp and paper, auto and
other laundries and mechanical products(3). Nicotine
was detected in 1 of 3 publicly owned treatment works in New Jersey at a concn of 0.9
ppb(4).
Atmospheric Concentrations:
Air samples taken from offices in Wichita, KS and Lubbock, TX contained 0.3 and 0.6
ng/cu m, respectively, of nicotine in
particulate form(1). Nicotine was not detected
in samples of ambient air taken from Wichita, KS during 1981/82 and Lubbock, TX during
1982(1).
INDOOR AIR: Reported concns range from approximately 1 ug/cu m for a highly ventilated
low-frequency smoking environment to approximately 1000 ug/cu m for the extreme case of a
non-ventillated artificially high-frequency smoking environment. More typical exposures
such as those occurring under actual smoking conditions in offices, restaurants, and
common-access facilities range from 3 to 30 ug/cu m of nicotine(1).
Vapor-phase nicotine was measured over 1 week in
the main living area in 96 residences; nicotine
was detected in 47 residences and was strongly correlated with the number of cigarettes
smoked in that location(2). Air samples collected from an apartment where smoking was
occurring in the living room contained nicotine
at 33, 22, and 8.7 ug/cu m in the living room, bedroom, and study room, respectively(3).
Air samples collected from a 3-story house where smoking was occurring in the living room
contained nicotine at 75, 26, 10, and 10 ug/cu m
in the living room, kitchen, bedroom, and attic, respectively(3). Nicotine
was present at 27 ug/cu m in a small smoking room with a high ventilation rate during
working hours(3). The exposure level to nicotine
in three offices was from 5.9 to 19.8 ug/cu m; in coffee shops, pubs and cars an average
exposure level of 31.5 to 43.2 ug/cu m was measured; in smoking seats and no-smoking seats
of trains and airplanes nicotine concns were
16.7 and 1.3, and 13.5 and 5.3 ug/cu m, respectively(4). The mean nicotine
concn measured in passenger cabins of airplanes was 5.5 ug/cu m and 9.2 ug/cu m for
non-smoking and smoking sections, respectively(5). Nicotine
concns measured in a tavern ranged from 60-71 ug/cu m(6).
INDOOR AIR: Nicotine concns at a bar and at 2
bar/restaurants, where smoking was permitted, ranged from 1.1-7 ug/cu m to 2 to 13.1 ug/cu
m, respectively(1). Nicotine concns of 1.0, 1.6,
17.1, and 0.6 to 4.3 ug/cu m were reported for a subway station, hospital, clinic (smoking
area), and in 5 office buildings, respectively(1). Nicotine
concns in a billiard parlor(34 cigarettes smoked , 2 hr period), in 2 homes (6 cigarettes
smoked each home, 4 hr period), in a department store (0 cigarettes smoked, 4 hr period),
and in an automobile (0 cigarettes smokes, 8 hr period) were 19.4, 12.1 to 14.4, 0.6, and
0.4 ug/cu m, respectively(2). Nicotine concns
measured in an office receiving recirculated air from smoking designated areas were
similar to nonsmoking offices receiving "clean" air (about 1 ug/cu m)(3). The
mean concn of nicotine from 57 offices was 3
ug/cu m with a minimum of <1 ug/cu m and a maximum value of 21 ug/cu m(4). Indoor air
was sampled in 8 residential homes in Columbus, OH where a wide range of cigarettes were
smoked(5). concns of nicotine averaged 4700
ug/cu m in the kitchen (minimum=45; maximum=25000 ug/cu m) and 9400 ug/cu m in the living
room (minimum=24; maximum=45000 ug/cu m), but only 9.6 ug/cu m in outdoor samples(5).
Average indoor air concns of nicotine in
non-smoking households ranged from 60 to 110 ug/cu m and in smoking households from
1600-20000 ug/cu m(5).
Environmental tobacco smoke was analyzed after smoking of research cigarettes by a
machine in an experimental chamber 13.6 cu m in volume. The ventilation rate was 3.55 air
changes per hour. Air removed for sampling added about 0.5 air changes per hour. One
cigarette was lit every 30 min and was smoked with a 35 ml puff of 2 sec every minute
until extinguished after about 12 min. Mainstream smoke was vented to the outside of the
chamber. Additional tests were performed with one cigarette smoked every 15 min and with
several commercial cigarette brands. Nicotine
concentrations and yields were lower during the first series than during the second
series, with concentrations of 29 + or - 7 ug/cu m and 127 + or - 23 ug/cu m,
respectively, and yields of 800 ug/cigarette and 3300 ug/cigarette, respectively. There
were several differences in the two series. In the first series, the chamber contained
more adsorbent surfaces: two persons, television set, crib, chair, and a curtain, all of
which were absent in the second series. The relative humidity was 50 to 60% in the first
series but only about 30% in the second series. Concentrations of nicotine
using commercial brands of cigarettes in the chamber and in a tavern setting were similar
to those produced by the research cigarettes.
Food Survey Values:
Gum containing nicotine (Nicorette) is
available in boxes of 96 pieces, each of which contains 2 mg nicotine
bound to an ion-exchange resin.
Nicotine was detected in the fiscal year
period of 1983-1986 during regulatory monitoring for the FDA pesticide residue monitoring
program at unreported concns and in an unreported number of samples(1).
Other Environmental Concentrations:
Nicotine is found in cigarettes, cigars and
other tobacco products and in the particulate phase of tobacco smoke(1,2). The nicotine content of tobacco can vary between 0.2 to
5%, but typically ranges between 1 and 2% in smoking tobaccos(2). Cigarettes currently
manufactured in the USA deliver 0.05 to 2.0 mg nicotine
per cigarette and averaged 1.0 mg nicotine per
cigarette in 1982(2). It is present in the protonated form in almost all cigarette
tobaccos and is present in the more readily absorbed, unprotonated form in cigars and pipe
tobaccos(2). Nicotine was present in cigarette
smoke at 1000-2500 ug/cigarette(3). Nicotine
concns were measured in 10 different brands of cigarettes; from 0.1 to 1.3 mg nicotine/cigarette was measured in mainstream
emissions(4). Nine experimental cigarettes without filter tips were prepared with 70% of a
defined blend of laminae and 30% of various types of stems, resulting in nicotine
concns from 9.9 to 13.9 mg/g tobacco(5).
Environmental Standards & Regulations:
FIFRA Requirements:
Tolerances are established for residues of the insecticide nicotine
(3-1-methyl-2-pyrrolidyl)pyridine) in the raw agricultural commodities eggs and the meat,
fat, and meat byproducts of poultry.
A tolerance is established for residues of nicotine-containing
compounds used as insecticides in or on the following raw agricultural commodities:
apples, apricots, artichokes, asparagus, avocados, beans, beets, (with or without tops) or
beet greens alone, blackberries, boysenberries, broccoli, brussels sprouts, cabbage,
cauliflower, celery, cherries, citrus fruits, collards, corn, cranberries, cucumbers,
currants, dewberries, eggplants, gooseberries, grapes, kale, kohlrabi, lettuce,
loganberries, melons, mushrooms, mustard greens, nectarines, okra, onions, parsley,
parsnips (with or without tops) or parsnip greens alone, peaches, pears, peas, peppers,
plums (fresh prunes), pumpkins, quinces, radishes (with or without tops) or radish tops,
raspberries, rutabagas (with or without tops) or rutabaga tops, spinach, squash,
strawberries, summer squash, Swiss chard, tomatoes, turnips (with or without tops) or
turnip greens, youngberries. /Nicotine-containing
compounds/
Classified for restricted use, limited to use by or under the direct supervision of a
certified applicator. FORMULATION: liquid and dry formulations 14% and above; USE PATTERN:
indoor (greenhouse); CLASSIFICATION: restricted; CRITERIA INFLUENCING RESTRICTION: acute
inhalation toxicity. /Nicotine (alkaloid)/
Classified for restricted use, limited to use by or under the direct supervision of a
certified applicator. FORMULATION: all formulations; USE PATTERN: applications to
cranberries; CLASSIFICATION: restricted; CRITERIA INFLUENCING RESTRICTION: effects on
aquatic organisms. /Nicotine (alkaloid)/
Classified for restricted use, limited to use by or under the direct supervision of a
certified applicator. FORMULATION: liquid and dry formulations 1.5% and less; USE PATTERN:
all uses (domestic and nondomestic); CLASSIFICATION: unclassified. /Nicotine
(alkaloid)/
As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of
older pesticides to consider their health and environmental effects and make decisions
about their future use. Under this pesticide reregistration program, EPA examines health
and safety data for pesticide active ingredients initially registered before November 1,
1984, and determines whether they are eligible for reregistration. In addition, all
pesticides must meet the new safety standard of the Food Quality Protection Act of 1996.
Pesticides for which EPA had not issued Registration Standards prior to the effective date
of FIFRA, as amended in 1988, were divided into three lists based upon their potential for
human exposure and other factors, with List B containing pesticides of greater concern and
List D pesticides of less concern. Nicotine is
found on List B. Case No: 2460; Pesticide type: insecticide, rodenticide (repellent); Case
Status: OPP is reviewing data from the pesticide's producers regarding its human health
and/or environmental effects, or OPP is determining the pesticide's eligibility for
reregistration and developing the Reregistration Eligibility Decision (RED) document.;
Active ingredient (AI): Nicotine; Data Call-in
(DCI) Date(s): 03/27/91, 03/24/93; AI Status: The producers of the pesticide has made
commitments to conduct the studies and pay the fees required for reregistration, and are
meeting those commitments in a timely manner.
CERCLA Reportable Quantities:
Persons in charge of vessels or facilities are required to notify the National Response
Center (NRC) immediately, when there is a release of this designated hazardous substance,
in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The
toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area
(202) 426-2675. The rule for determining when notification is required is stated in 40 CFR
302.4 (section IV. D.3.b). /Nicotine and salts/
Releases of CERCLA hazardous substances are subject to the release reporting
requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the
requirements of 40 CFR part 355. Nicotine is an
extremely hazardous substance (EHS) subject to reporting requirements when stored in
amounts in excess of its threshold planning quantity (TPQ) of 100 lbs.
RCRA Requirements:
P075; As stipulated in 40 CFR 261.33, when nicotine
and salts, as a commercial chemical product or manufacturing chemical intermediate or an
off-specification commercial chemical product or a manufacturing chemical intermediate,
becomes a waste, it must be managed according to federal and/or state hazardous waste
regulations. Also defined as a hazardous waste is any container or inner liner used to
hold this waste or any residue, contaminated soil, water, or other debris resulting from
the cleanup of a spill, into water or on dry land, of this waste. Generators of small
quantities of this waste may qualify for partial exclusion from hazardous waste
regulations (40 CFR 261.5(e)). /Nicotine and
salts/
Allowable Tolerances:
Tolerances of 1 ppm are established for residues of the insecticide nicotine
(3-1-methyl-2-pyrrolidyl)pyridine) in the raw agricultural commodities eggs and the meat,
fat, and meat byproducts of poultry.
A tolerance of 2 ppm is established for residues of nicotine-containing
compounds used as insecticides in or on the following raw agricultural commodities:
apples, apricots, artichokes, asparagus, avocados, beans, beets, (with or without tops) or
beet greens alone, blackberries, boysenberries, broccoli, brussels sprouts, cabbage,
cauliflower, celery, cherries, citrus fruits, collards, corn, cranberries, cucumbers,
currants, dewberries, eggplants, gooseberries, grapes, kale, kohlrabi, lettuce,
loganberries, melons, mushrooms, mustard greens, nectarines, okra, onions, parsley,
parsnips (with or without tops) or parsnip greens alone, peaches, pears, peas, peppers,
plums (fresh prunes), pumpkins, quinces, radishes (with or without tops) or radish tops,
raspberries, rutabagas (with or without tops) or rutabaga tops, spinach, squash,
strawberries, summer squash, Swiss chard, tomatoes, turnips (with or without tops) or
turnip greens, youngberries. /Nicotine-containing
compounds/
Chemical/Physical Properties:
Molecular Formula:
C10-H14-N2
Molecular Weight:
162.23
Color/Form:
COLORLESS TO PALE YELLOW, OILY LIQUID
Thick, water-white, oil turning brown on exposure to air
Pale-yellow to dark brown liquid.
Odor:
Slightly fishy
Fish-like odor when warm.
Taste:
ACRID, BURNING
Boiling Point:
247 DEG C
Melting Point:
-79 DEG C
Corrosivity:
Nicotine will attack some forms of plastics,
rubber, and coatings.
Density/Specific Gravity:
1.0097 @ 20 DEG C/4 DEG C
Dissociation Constants:
pKb1= 6.16 @ 15 deg C; pKb2= 10.96
Heat of Combustion:
-15.836 BTU/LB= -8.798 CAL/G= -368.1X10+5 JOULES
Octanol/Water Partition Coefficient:
log Kow= 1.17
pH:
10.2 (0.05 MOLAR SOLN)
Solubilities:
MISCIBLE WITH WATER BELOW 60 DEG C; VERY SOL IN ALCOHOL, CHLOROFORM, ETHER, PETROLEUM
ETHER, KEROSENE, OILS
Spectral Properties:
Index of refraction: 1.5282 @ 20 deg C/D
SADTLER REF NUMBER: 1355 (IR, PRISM); 8148 (IR, GRATING); 401 (UV); V269 (NMR); MAX
ABSORPTION (ALC): 262 NM (LOG E= 3.47); SPECIFIC OPTICAL ROTATION: -169 DEG @ 20 DEG C/D
Intense mass spectral peaks: 84 m/z (100%), 133 m/z (31%), 162 m/z (30%), 161 m/z (20%)
IR: 8148 (Sadtler Research Laboratories IR Grating Collection)
MASS: 1039 (Atlas of Mass Spectral Data, John Wiley & Sons, New York)
Surface Tension:
38.61 DYNES/CM= 0.03861 N/M @ 20 DEG C
Vapor Density:
5.61 (AIR= 1)
Vapor Pressure:
0.038 mm Hg at 25 deg C
Viscosity:
Becomes viscous on exposure to air
Other Chemical/Physical Properties:
FORMS SALTS WITH ALMOST ANY ACID & DOUBLE SALTS WITH MANY METALS & ACIDS; ON
MIXING NICOTINE WITH WATER VOL CONTRACTS; VERY
HYGROSCOPIC
LIQUID-WATER INTERFACIAL TENSION: 20 DYNES/CM= 0.020 N/M @ 20 DEG C (EST)
Darkens rapidly on exposure to light and air; highly basic and readily forms salts with
acids and many metals
Vapor pressure: 1 MM HG @ 61.8 DEG C
MASS: 642 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /Nicotine hydrochloride (d)/
MASS: 1039 (Atlas of Mass Spectral Data, John Wiley & Sons, New York) /Nicotine (d)/
UV: 401 (Sadtler Research Laboratories Spectral Collection) /Nicotine
(dl)/
NMR: 269 (Varian Associates NMR Spectra Catalogue) /Nicotine
(dl)/
MASS: 1039 (Atlas of Mass Spectral Data, John Wiley & Sons, New York) /Nicotine (dl)/
Chemical Safety & Handling:
DOT Emergency Guidelines:
Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin.
Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce
irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may
be corrosive and/or toxic and cause pollution.
Fire or explosion: Non-combustible, substance itself does not burn but may decompose
upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated.
Runoff may pollute waterways.
Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area
immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep
unauthorized personnel away. Stay upwind. Keep out of low areas.
Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA).
Wear chemical protective clothing which is specifically recommended by the manufacturer.
Structural firefighters' protective clothing is recommended for fire situations ONLY; it
is not effective in spill situations.
Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE
for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800
meters (1/2 mile) in all directions.
Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or
regular foam. Move containers from fire area if you can do it without risk. Dike fire
control water for later disposal; do not scatter the material. Do not use straight
streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or
use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool
containers with flooding quantities of water until well after fire is out. Withdraw
immediately in case of rising sound from venting safety devices or discoloration of tank.
ALWAYS stay away from the ends of tanks. For massive fire, use unmanned hose holders or
monitor nozzles; if this is impossible withdraw from area and let fire burn.
Spill or leak: Do not touch damaged containers or spilled material unless wearing
appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry
into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent
spreading. Absorb or cover with dry earth, sand or other non-combustible material and
transfer to containers. DO NOT GET WATER INSIDE CONTAINERS.
First aid: Move victim to fresh air. Call emergency medical care. Apply artificial
respiration if victim is not breathing. Do not use mouth-to-mouth method if victim
ingested or inhaled the substance; induce artificial respiration with the aid of a pocket
mask equipped with a one-way valve or other proper respiratory medical device. Administer
oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In
case of contact with substance, immediately flush skin or eyes with running water for at
least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin.
Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to
substance may be delayed. Ensure that medical personnel are aware of the material(s)
involved, and take precautions to protect themselves.
Odor Threshold:
1.90x10-5 moles/l taste detection in water (purity not specified)
3.00x10-3 g/l taste detection in water (purity not specified)
Fire Potential:
COMBUSTIBLE WHEN EXPOSED TO HEAT OR FLAME.
NFPA Hazard Classification:
HEALTH 4. 4= MATERIALS TOO DANGEROUS TO HEALTH TO EXPOSE FIRE FIGHTERS. A FEW WHIFFS OF
THE VAPOR COULD CAUSE DEATH OR VAPOR OR LIQ COULD BE FATAL ON PENETRATING FIRE FIGHTER'S
NORMAL FULL PROTECTIVE CLOTHING. NORMAL FULL PROTECTIVE CLOTHING & BREATHING APPARATUS
AVAIL TO AVERAGE FIRE DEPARTMENT WILL NOT PROVIDE ADEQUATE PROTECTION AGAINST INHALATION
OR SKIN CONTACT WITH THESE MATERIALS.
FLAMMABILITY: 1. 1= MATERIALS THAT MUST BE PREHEATED BEFORE IGNITION CAN OCCUR. WATER
MAY CAUSE FROTHING IF IT GETS BELOW SURFACE OF LIQ & TURNS TO STEAM. HOWEVER, WATER
FOG GENTLY APPLIED TO SURFACE WILL CAUSE FROTHING WHICH WILL EXTINGUISH THE FIRE.
REACTIVITY 0. 0= MATERIALS WHICH (IN THEMSELVES) ARE NORMALLY STABLE EVEN UNDER FIRE
CONDITIONS & WHICH ARE NOT REACTIVE WITH WATER. NORMAL FIRE FIGHTING PROCEDURES MAY BE
USED.
Flammable Limits:
LOWER 0.7% BY VOL; UPPER 4.0% BY VOL
Autoignition Temperature:
471 DEG F; 244 DEG C
Fire Fighting Procedures:
ALCOHOL FOAM, DRY CHEMICAL, CARBON DIOXIDE.
If material is on fire or involved in a fire: Do not extinguish fire unless flow can be
stopped. Use water in flooding quantities as fog. Solid streams of water may be
ineffective. Cool all affected containers with flooding quantities of water. Apply water
from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon
dioxide.
Toxic Combustion Products:
... WHEN HEATED, EMITS HIGHLY TOXIC FUMES ...
Toxic oxides of nitrogen are produced during combustion of material.
Explosive Limits & Potential:
MODERATE, WHEN EXPOSED TO HEAT OR FLAME.
Hazardous Reactivities & Incompatibilities:
... CAN REACT WITH OXIDIZING MATERIALS.
Strong oxidizers, strong acids.
Hazardous Decomposition:
When heated to decomp it emits /nitrogen oxides, carbon monoxide/ and other highly
toxic fumes. ...
Immediately Dangerous to Life or Health:
5 mg/cu m
Protective Equipment & Clothing:
GOGGLES OR FACE SHIELD; RUBBER GLOVES; PROTECTIVE CLOTHING.
PERSONAL PROTECTIVE EQUIPMENT SHOULD BE WORN DURING PREPN & APPLICATION OF NICOTINE SOLN. IF ... APPLIED AS SPRAY OR AS VAPOR,
RESP PROTECTIVE EQUIPMENT SHOULD BE WORN. ... WASHING FACILITIES ... TO ENSURE IMMEDIATE
REMOVAL OF NICOTINE THAT HAS COME IN CONTACT
WITH ... SKIN. CONTAMINATED CLOTHING SHOULD BE REMOVED BEFORE NICOTINE
PENETRATES TO THE BODIES OF THE WEARERS.
Employees should be provided with and required to use impervious clothing, gloves,
face-shields (eight-inch minimum), and other appropriate protective clothing necessary to
prevent any possibility of skin contact with nicotine.
Employees should be provided with and required to use splash-proof goggles where there is
any possibility of liquid nicotine contacting
the eyes.
Particulate or vapor concn: 5 mg/cu m or less: Any supplied-air respirator or any
self-contained breathing apparatus. 25 mg/cu m or less: Any supplied-air respirator with a
full facepiece, helmet, or hood, or any self-contained breathing apparatus with a full
facepiece. 35 mg/cu m or less: A type C supplied-air respirator operated in
pressure-demand or other positive-pressure or continuous-flow mode. Greater than 35 mg/cu
m or entry and escape from unknown concentrations: Self-contained breathing apparatus with
a full facepiece operated in pressure-demand or other positive-pressure mode, or a
combination respirator which includes a type C supplied-air respirator with a full
facepiece operated in pressure-demand or other positive pressure or continuous-flow mode
and an auxillary self-contained breathing apparatus operated in pressure-demand or other
positive-pressure mode. Escape: Any gas mask providing protection against organic vapors
and particulates, including pesticide respirators which meet the requirements of this
class, or any escape self-contained breathing apparatus.
Wear appropriate personal protective clothing to prevent skin contact.
Wear appropriate eye protection to prevent eye contact.
Eyewash fountains should be provided in areas where there is any possibility that
workers could be exposed to the substance; this is irrespective of the recommendation
involving the wearing of eye protection.
Facilities for quickly drenching the body should be provided within the immediate work
area for emergency use where there is a possibility of exposure. (Note: It is intended
that these facilities provide a sufficient quantity or flow of water to quickly remove the
substance from any body areas likely to be exposed. The actual determination of what
constitutes an adequate quick drench facility depends on the specific circumstances. In
certain instances, a deluge shower should be readily available, whereas in others, the
availability of water from a sink or hose could be considered adequate.)
Recommendations for respirator selection. Max concn for use: 5 mg/cu m. Respirator
Class(es): Any supplied-air respirator. Any self-contained breathing apparatus with a full
facepiece.
Recommendations for respirator selection. Condition: Emergency or planned entry into
unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing
apparatus that has a full facepiece and is operated in a pressure-demand or other positive
pressure mode. Any supplied-air respirator that has a full facepiece and is operated in
pressure-demand or other positive pressure mode in combination with an auxiliary
self-contained breathing apparatus operated in pressure-demand or other positive pressure
mode.
Recommendations for respirator selection. Condition: Escape from suddenly occurring
respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator
(gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any
appropriate escape-type, self-contained breathing apparatus.
Preventive Measures:
Contact lenses should not be worn when working with this chemical.
SRP: The scientific literature for the use of contact lenses in industry is
conflicting. The benefit or detrimental effects of wearing contact lenses depend not only
upon the substance, but also on factors including the form of the substance,
characteristics and duration of the exposure, the uses of other eye protection equipment,
and the hygiene of the lenses. However, there may be individual substances whose
irritating or corrosive properties are such that the wearing of contact lenses would be
harmful to the eye. In those specific cases, contact lenses should not be worn. In any
event, the usual eye protection equipment should be worn even when contact lenses are in
place.
In addition to respirator selection, a complete respiratory protection program should
be instituted which includes regular training, maintenance, inspection, cleaning, and
evaluation.
Clothing contaminated with liquid nicotine
should be placed in closed containers for storage until it can be discarded or until
provision is made for the removal of nicotine
from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the nicotine, the person performing the operation should
be informed of nicotine's hazardous properties.
Non-impervious clothing which becomes contaminated with liquid nicotine
should be removed immediately and not reworn until the nicotine
is removed from the clothing.
Where there is any possibility of exposure of an employee's body to liquid nicotine, facilities for quick drenching of the body
should be provided within the immediate work area for emergency use.
Where there is any possibility that employees' eyes may be exposed to liquid nicotine, an eye-wash fountain should be provided
within the immediate work area for emergency use.
Employees who handle liquid nicotine should
wash their hands thoroughly with soap or mild detergent and water before eating, smoking,
or using toilet facilities.
Eating and smoking should not be permitted in areas where liquid nicotine
is handled, processed, or stored.
Skin that becomes contaminated with liquid nicotine
should be immediately washed or showered with soap or mild detergent and water to remove
any nicotine.
If material is not on fire and not involved in a fire: Keep sparks, flames and other
sources of ignition away. Keep material out of water sources and sewers. Build dikes to
contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use
water spray to knock-down vapors.
Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. Do not
handle broken packages unless wearing appropriate personal protective equipment. Wash away
any material which may have contacted the body with copious amounts of water or soap and
water.
Evacuation: If material is leaking and not on fire, consider evacuation from downwind
area based on the amount spilled, location and weather conditions.
The worker should immediately wash the skin when it becomes contaminated.
Work clothing that becomes wet or significantly contaminated should be removed and
replaced.
Land spill - Dig a pit, pond, lagoon, holding area to contain liquid or solid material.
/SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed
with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags,
foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash or cement powder.
/Nicotine compounds, n.o.s. or nicotine
preparations, n.o.s., liquids/
Water spill - Use natural barriers or oil spill control booms to limit spill travel.
Remove trapped material with suction hoses. /Nicotine
compounds, n.o.s. or nicotine preparations,
n.o.s., liquids/
Air spill - Apply water spray or mist to knock down vapors. Combustion products include
corrosive or toxic vapors. /Nicotine compounds,
n.o.s. or nicotine preparations, n.o.s.,
liquids/
SRP: Contaminated protective clothing should be segregated in such a manner so that
there is no direct personal contact by personnel who handle, dispose, or clean the
clothing. Quality assurance to ascertain the completeness of the cleaning procedures
should be implemented before the decontaminated protective clothing is returned for reuse
by the workers. Contaminated clothing should not be taken home at end of shift, but should
remain at employee's place of work for cleaning.
Stability/Shelf Life:
Nicotine is photosensitive and will gradually
turn brown when exposed to light or air.
Shipment Methods and Regulations:
No person may /transport,/ offer or accept a hazardous material for transportation in
commerce unless that person is registered in conformance ... and the hazardous material is
properly classed, described, packaged, marked, labeled, and in condition for shipment as
required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./
The International Air Transport Association (IATA) Dangerous Goods Regulations are
published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and
constitute a manual of industry carrier regulations to be followed by all IATA Member
airlines when transporting hazardous materials.
The International Maritime Dangerous Goods Code lays down basic principles for
transporting hazardous chemicals. Detailed recommendations for individual substances and a
number of recommendations for good practice are included in the classes dealing with such
substances. A general index of technical names has also been compiled. This index should
always be consulted when attempting to locate the appropriate procedures to be used when
shipping any substance or article.
Cleanup Methods:
1. VENTILATE AREA OF SPILL OR LEAK. 2. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS.
EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS
TO COMPLETELY CLEAR HOOD DUCTWORK.
Disposal Methods:
Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant,
EPA hazardous waste number P075, must conform with USEPA regulations in storage,
transportation, treatment and disposal of waste.
1. BY ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL & DISPOSING
IN SECURED SANITARY LANDFILL. 2. BY ATOMIZING IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH
APPROPRIATE EFFLUENT GAS CLEANING DEVICE.
A potential candidate for rotary kiln incineration at a temperature range of 820 to
1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A
potential candidate for fluidized bed incineration at a temperature range of 450 to 980
deg C and residence times of seconds for liquids and gases, and longer for solids.
A) Dissolve in such combustible solvent as alcohols, ... etc. Spray the soln into a
furnace with afterburner and scrubber. B) Pour into a mixture of sand and soda ash (9:1).
After mixing, put into a paper carton stuffed full with packing paper to serve as fuel.
Burn in a furnace. Recommendable method: Incineration.
Occupational Exposure Standards:
OSHA Standards:
Permissible Exposure Limit: 8-hr Time-Weighted Avg: 0.5 mg/cu m, skin
Threshold Limit Values:
8 hr Time Weighted Avg (TWA) 0.5 mg/cu m, skin
Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three
times the TLV-TWA for no more than a total of 30 min during a work day, and under no
circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not
exceeded.
NIOSH Recommendations:
Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.5 mg/cu m, skin.
Immediately Dangerous to Life or Health:
5 mg/cu m
Manufacturing/Use Information:
Major Uses:
Insecticide (former use); fumigant (former use).
MEDICATION
MEDICATION (VET)
IN TANNING
Greenhouse fumigant (former use)
Manufacturers:
Gary-Samuels Chemical MFG Corp, Hq, 91 Carolyn Blvd, Farmingdale, NY 11735-1527 (516)
694-9000
Methods of Manufacturing:
... FROM WASTE TOBACCO, NICOTIANA TABACUM, OR FROM N RUSTICA EITHER BY STEAM
DISTILLATION IN PRESENCE OF ALKALI, OR BY EXTRACTION WITH TRICHLOROETHYLENE IN PRESENCE OF
ALKALI & EXTRACTION FROM SOLVENT BY DIL SULFURIC ACID ...
By distilling tobacco with milk of lime and extracting with ether
General Manufacturing Information:
LITTLE OR NO NICOTINE IS NOW PRODUCED IN
UNITED STATES. LIMITED SUPPLIES ARE IMPORTED FROM INDIA.
NICOTINE IS NON-SYSTEMIC CONTACT INSECTICIDE.
IT IS USED AS FUMIGANT IN CLOSED SPACES, EG IN GLASSHOUSES.
Nicotine sprays commonly contain 0.05-0.06% nicotine, and nicotine
dusts, 1-2% nicotine.
NICOTINE IS MARKETED AS TECHNICAL ALKALOID
(950 G AI/L) OR AS NICOTINE SULFATE (400 G/KG);
THE ADDN OF SOAP OR ALKALI IS REQUIRED TO DILUTIONS OF LATTER TO LIBERATE NICOTINE; ALSO AS DP (30-50 G/KG); [FOR FUMIGATION, NICOTINE IS APPLIED TO HEATED METAL SURFACE OR NICOTINE 'SHREDS' ARE BURNT.]
Organophosphate insecticides have largely replaced nicotine.
Two basic types of nicotine products have been
marketed; alkaloid and sulfate. Had former use in greenhouse as a fumigant.
Formulations/Preparations:
Available as the dihydrochloride, salicylate, sulfate, and bitartrate
Nicorette /nicotine-containing chewing gum/
contains 2 mg of nicotine bound to an
ion-exchange resin /per piece/.
Nicotine alkaloid, 95%; Nicotine
sulfate 40%
...also in form of dust or powder
Available commercially as the (-)-enantiomer sulfate salt
Fumigant; Soluble concentrate
U. S. Production:
(1985) /Nicotine/ is no longer produced in
the USA
U. S. Imports:
(1984) 2.20X10+8 g /Nicotine and its
compounds/
Laboratory Methods:
Clinical Laboratory Methods:
A METHOD IS DESCRIBED FOR RAPID EXTRACTION OF NICOTINE
FROM HUMAN PLASMA & DETERMINATION BY GC UTILIZING THERMOIONIC DETECTION. ENVIRONMENTAL
NICOTINE APPEARS TO LIMIT RELIABLE DETERMINATION
(APPROX 100% ACCURACY) BELOW 5 NG/ML.
CATALYTIC HYDROGENATION OF NICOTINE FOLLOWED
BY COUPLING OF THE RESULTING SECONDARY AMINES WITH PERFLUORO ACIDS WAS USED TO PRODUCE
ELECTRON CAPTURE DERIVATIVES FOR ANALYSIS IN BLOOD & BIOLOGICAL FLUIDS. LIMIT OF
DETECTION WAS 0.0067 NG FOR ELECTRON CAPTURE, COMPARED WITH 1.3 NG FOR FLAME IONIZATION
DETECTION. /Nicotine/
The qualitative direct barbituric acid (DBA) method of detecting urine nicotine metabolites were modified to make it
quantitative. The performance of the quantitative DBA method was compared with the
qualitative method and an established cotinine radioimmunoassay (RIA), using a panel of
urines from 128 reported smokers and 383 reported non-smokers.
Nicotine, cotinine, and 5 unidentified nicotine metabolites were determined in the urine of
human smokers using precolumn derivatization and high performance liquid chromatography
separation. ... Urine samples were subjected to colorimetric assay. The recoveries for nicotine and cotinine were 91-96% and 84-91%
respectively.
A sensitive radiometric high performance liquid chromatography assay was developed to
measure concentrations of nicotine and 12 of its
metabolites in biological fluids.
When using capillary gas chromatography with nitrogen-specific detection for rapid
screening of drugs, to overcome problems associated with the use of retention indices
based on homologous series determined with nitrogen-specific detectors, a retention
indices reference system was developed based on molecular masses and retention times of
nitrogen-containing compounds. The standards chosen are readily available in highly
purified form and can be detected by the unmodified nitrogen-specific detector. By using
temperature programming, a linear relationship can be obtained between the molecular
masses of standards and their retention times. Used in conjunction with microcomputer data
handling, this screening system is rugged and reliable, operating 22 hr/day. Using the
present method the retention time in min for nicotine
standard was 5.351 on DB-1, and 2.836 on DB-17 with retention indices of 1620 (initial
temperature 120 deg C for 1 min, incr by 8 deg C/min and held for 22 min).
SFSAS Method SFSAS_29. Extraction and Analysis of Organics in Biological Tissue.
Analysis by cGC/MS. Limit of quantitation = 2 mg/kg tissue.
Analytic Laboratory Methods:
MACRO: ... BY STEAM DISTILLATION & PRECIPITATION AS SILICOTUNGSTATE (AOAC METHODS,
1955, P 66) ... SILICOTUNGSTATE METHOD SUBJECT TO ERROR IN PRESENCE OF AMMONIUM SALTS ...
AVOIDED IN SPECTROPHOTOMETRIC METHOD OF WILLITS, CO ET AL, ANAL CHEM, 22, 430, 1950. FOR
DETERMINATION ... IN TOBACCO, SEE CUNDIFF RH & MARKUNAS, PC, ANAL CHEM, 27, 1650,
1955.
MATRIX: AIR; ANALYTE: NICOTINE; PROCEDURE:
ADSORPTION WITH ETHYL ACETATE, GC/ALKALI-FLAME IONIZATION DETECTOR. RANGE: 0.30-1.20 MG/CU
M. PRECISION: 0.066
... BY STEAM DISTILLATION & PRECIPITATION AS SILICOTUNGSTATE: AOAC METHODS; MAFF
TECH BULL NO 1: 59 (1958); CIPAC HANDBOOK 1: 543 (1970) ... RESIDUES MAY BE DETERMINED BY
GLC: MARTIN RJ, J ASSOC OFF ANAL CHEM 50 (1967) OR BY COLORIMETRY (AOAC METHODS,
29.162-29.166)
NICOTINE WAS EXTRACTED FROM FRUIT WITH
ACETONE & ANALYZED BY GAS CHROMATOGRAPHY WITH FLAME THERMAL DETECTOR.
THIN-LAYER CHROMATOGRAPHY. DAVIDOW B; PETRI NL; B QUAME, TECH BULL REG MED
TECHNOLOGISTS 38: 298 (1968).
Chemical characterization was made of gas-phase components of environmental tobacco
smoke generated from cigarettes in 10 and 30 cu m Teflon chambers. Nicotine
was determined both by gas chromatography and ion chromatography.
AREAL Method IP-2A. Determination of Nicotine
in Indoor Air Using XAD-4 Sorbent Tubes. Analysis by cGC/NPD. Limit of detection=0.020
ug/cu m.
AREAL Method IP-2B. Determination of Nicotine
in Indoor Air Using Treated Filter Cassettes. Analysis by cGC/NPD. Limit of detection=0.10
ug/cu m.
NIOSH Method 2544. Determination of Nicotine
by Gas Chromatography with a Nitrogen Phosphorous Detector. Detection of nicotine
in air samples.
OSW Method 8270B. Determination of Semivolatile Organic Compounds by Gas
Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Estimated
Quantitation Limit=20 ug/l.
OSW Method 8270C. Semivolatile Organic Compounds by Gas Chromatography/ Mass
Spectrometry (GC/MS): Capillary Column Technique.
AOAC Method 920.35. Nicotine in Tobacco
Products by Silicotungstic Acid Method.
AOAC Method 964.20. Nicotine Residues by
Spectrophotometric Method.
EPA-B Method PMD-NIC. Determination of Nicotine
by High Performance Liquid Chromatography. UV detection.
Sampling Procedures:
A known volume of air is drawn through a tube containing XAD-2 resin to absorb the nicotine present.
Measurements to determine employee exposure are best taken so that the eight hour
exposure is based on a single eight hour sample or on two four hour samples. Several
short-time interval samples (up to 30 minutes) may also be used to determine the average
exposure level. Air samples should be taken in the employee's breathing zone (air that
would most nearly represent that inhaled by the employee).
Personal monitors (Pyrex glass tubes containing Uniport-S with adsorbed silicone OV-17,
and an MDA Scientific Inc sampling pump) were used to measure ambient nicotine
as an indicator for exposure to environmental tobacco smoke (ETS). Nicotine
content of the monitors was quantitated by gas chromatography.
A personal monitoring system for the determination of exposure to nicotine
from sidestream cigarette smoke was developed. The system consists of a sampling cartridge
packed with 200 mg of Tenax GC and a small, constant-flow, personal sampling pump. After
sampling, the cartridges are analyzed by triethylamine-assisted thermal desorption gas
chromatography with nitrogen-selective detection. The limit of detection of the device was
equivalent to 0.07 ug/m3 nicotine, and the limit
of quantitation was 0.17 ug/cu m. The system has been evaluated in controlled-atmosphere
chambers, and applied in a variety of work sites, and in 36 restaurants, where measured
concentrations of nicotine ranged from 0.5 to
37.2 ug/cu m.
Special References:
Special Reports:
EDWARDS JA, WARBURTON DM; SMOKING, NICOTINE
AND ELECTROCORTICAL ACTIVITY; PHARMACOL THER 19 (2): 147-64 (1983). A REVIEW &
DISCUSSION WITH 76 REFERENCES ON SMOKING, NICOTINE,
& ELECTROCORTICAL ACTIVITY IN HUMAN & ANIMAL STUDIES.
Synonyms and Identifiers:
Related HSDB Records:
805 [NICOTINE SULFATE]
806 [NICOTINE TARTRATE]
1261 [NICOTINE HYDROCHLORIDE]
Synonyms:
Black Leaf 40
**PEER REVIEWED**
Caswell No 597
**PEER REVIEWED**
DESTRUXOL ORCHID SPRAY
**PEER REVIEWED**
ORTHO N-4 DUST
**PEER REVIEWED**
ORTHO N-5 DUST
**PEER REVIEWED**
EMO-NIK
**PEER REVIEWED**
ENT 3,424
**PEER REVIEWED**
FLUX MAAG
**PEER REVIEWED**
MACH-NIC
**PEER REVIEWED**
1-METHYL-2-(3-PYRIDYL)PYRROLIDINE
**PEER REVIEWED**
3-(N-METHYLPYROLLIDINO)PYRIDINE
**PEER REVIEWED**
L-3-(1-METHYL-2-PYRROLIDYL)PYRIDINE
**PEER REVIEWED**
3-(1-Methyl-2-pyrrolidyl)pyridine
**PEER REVIEWED**
NIAGARA P.A. DUST
**PEER REVIEWED**
NICOCIDE
**PEER REVIEWED**
NICO-DUST
**PEER REVIEWED**
NICO-FUME
**PEER REVIEWED**
NICOTIN
**PEER REVIEWED**
NICOTINA (ITALIAN)
**PEER REVIEWED**
(-)-NICOTINE
**PEER REVIEWED**
L-NICOTINE
**PEER REVIEWED**
(S)-Nicotine
**PEER REVIEWED**
NICOTINE ALKALOID
**PEER REVIEWED**
NIKOTIN (GERMAN)
**PEER REVIEWED**
NIKOTYNA (POLISH)
**PEER REVIEWED**
PYRIDINE, 3-(1-METHYL-2-PYRROLIDINYL)-, (S)-
**PEER REVIEWED**
PYRIDINE, 3-(TETRAHYDRO-1-METHYLPYRROL-2-YL)
**PEER REVIEWED**
BETA-PYRIDYL-ALPHA-N-METHYLPYRROLIDINE
**PEER REVIEWED**
PYRROLIDINE, 1-METHYL-2-(3-PYRIDAL)-
**PEER REVIEWED**
TENDUST
**PEER REVIEWED**
TETRAHYDRONICOTYRINE, DL-
**PEER REVIEWED**
XL All Insecticide
**PEER REVIEWED**
Associated Chemicals:
Nicotine hydrochloride (d);69782-38-3
Nicotine (d);25162-00-9
Nicotine (dl);22083-74-5
Formulations/Preparations:
Available as the dihydrochloride, salicylate, sulfate, and bitartrate
Nicorette /nicotine-containing chewing gum/
contains 2 mg of nicotine bound to an
ion-exchange resin /per piece/.
Nicotine alkaloid, 95%; Nicotine
sulfate 40%
...also in form of dust or powder
Available commercially as the (-)-enantiomer sulfate salt
Fumigant; Soluble concentrate
Shipping Name/ Number DOT/UN/NA/IMO:
UN 1654; NICOTINE LIQUID OR SOLID
IMO 6.1; Nicotine liquid or solid
Standard Transportation Number:
49 214 49; Nicotine, liquid
EPA Hazardous Waste Number:
P075; An acute hazardous waste when a discarded commercial chemical product or
manufacturing chemical intermediate or an off-specification commercial chemical product or
a manufacturing chemical intermediate.
RTECS Number:
NIOSH/QS5250000
Administrative Information:
Hazardous Substances Databank Number: 1107
Last Revision Date: 20010809
Last Review Date: Reviewed by SRP on 5/7/1998
Update History:
Complete Update on 08/09/2001, 1 field added/edited/deleted.
Complete Update on 05/16/2001, 1 field added/edited/deleted.
Complete Update on 06/12/2000, 1 field added/edited/deleted.
Complete Update on 03/09/2000, 1 field added/edited/deleted.
Complete Update on 02/08/2000, 1 field added/edited/deleted.
Complete Update on 02/02/2000, 1 field added/edited/deleted.
Complete Update on 11/18/1999, 1 field added/edited/deleted.
Complete Update on 09/21/1999, 1 field added/edited/deleted.
Complete Update on 08/26/1999, 1 field added/edited/deleted.
Complete Update on 07/27/1999, 5 fields added/edited/deleted.
Complete Update on 06/03/1999, 1 field added/edited/deleted.
Complete Update on 03/19/1999, 1 field added/edited/deleted.
Complete Update on 01/27/1999, 1 field added/edited/deleted.
Complete Update on 11/12/1998, 2 fields added/edited/deleted.
Complete Update on 10/13/1998, 1 field added/edited/deleted.
Complete Update on 08/17/1998, 82 fields added/edited/deleted.
Field Update on 06/02/1998, 1 field added/edited/deleted.
Field Update on 02/25/1998, 1 field added/edited/deleted.
Complete Update on 10/20/1997, 1 field added/edited/deleted.
Complete Update on 06/11/1997, 4 fields added/edited/deleted.
Field Update on 05/08/1997, 1 field added/edited/deleted.
Complete Update on 03/12/1997, 2 fields added/edited/deleted.
Complete Update on 02/27/1997, 1 field added/edited/deleted.
Complete Update on 01/24/1997, 1 field added/edited/deleted.
Complete Update on 10/13/1996, 1 field added/edited/deleted.
Complete Update on 06/06/1996, 2 fields added/edited/deleted.
Field Update on 06/06/1996, 1 field added/edited/deleted.
Complete Update on 05/10/1996, 1 field added/edited/deleted.
Complete Update on 04/09/1996, 8 fields added/edited/deleted.
Field Update on 01/21/1996, 1 field added/edited/deleted.
Complete Update on 11/10/1995, 1 field added/edited/deleted.
Complete Update on 01/23/1995, 1 field added/edited/deleted.
Complete Update on 12/22/1994, 1 field added/edited/deleted.
Complete Update on 08/02/1994, 1 field added/edited/deleted.
Complete Update on 06/07/1994, 1 field added/edited/deleted.
Complete Update on 03/25/1994, 1 field added/edited/deleted.
Complete Update on 08/07/1993, 1 field added/edited/deleted.
Complete Update on 05/25/1993, 1 field added/edited/deleted.
Field update on 12/19/1992, 1 field added/edited/deleted.
Complete Update on 12/02/1992, 1 field added/edited/deleted.
Complete Update on 11/05/1992, 1 field added/edited/deleted.
Complete Update on 09/03/1992, 1 field added/edited/deleted.
Complete Update on 04/27/1992, 1 field added/edited/deleted.
Complete Update on 01/23/1992, 1 field added/edited/deleted.
Complete Update on 01/07/1991, 20 fields added/edited/deleted.
Field Update on 05/14/1990, 1 field added/edited/deleted.
Field Update on 03/06/1990, 1 field added/edited/deleted.
Complete Update on 06/19/1989, 2 fields added/edited/deleted.
Complete Update on 04/13/1989, 1 field added/edited/deleted.
Complete Update on 12/28/1988, 95 fields added/edited/deleted.
Complete Update on 04/24/1987
Record Length: 227492