National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

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. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-313]**PEER REVIEWED**
  
• 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. [Haddad, L.M. and Winchester, J.F. Clinical Management of Poisoning and Drug Overdosage. Philadelphia, PA: W.B. Saunders Co., 1983., p. 513]**PEER REVIEWED**
  
• ... SPLASH OF PURE NICOTINE BASE IN PT EYE CAUSED SEVERE PAIN, MUCH CONJUNCTIVAL REACTION & CORNEAL INFILTRATION. EVENTUALLY, EYE HEALED WITH PARTIAL OPACIFICATION OF CORNEA. [Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 747]**PEER REVIEWED**
  
• CLINICAL FINDINGS: PRINCIPAL MANIFESTATIONS OF NICOTINE POISONING ARE RESPIRATORY STIMULATION & GI HYPERACTIVITY. [Dreisbach, R.H. Handbook of Poisoning. 12th ed. Norwalk, CT: Appleton and Lange, 1987., p. 131]**PEER REVIEWED**
  
• NICOTINE CAUSES INITIAL STIMULATION OF SALIVARY & BRONCHIAL SECRETIONS THAT IS FOLLOWED BY INHIBITION. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 192]**PEER REVIEWED**
  
• ... 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. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 192]**PEER REVIEWED**
  
• 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. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 192]**PEER REVIEWED**
  
• CARDIOVASCULAR RESPONSES ... ARE DUE TO STIMULATION OF SYMPATHETIC GANGLIA & ADRENAL MEDULLA ... WHICH ... RESULTS IN VASOCONSTRICTION, TACHYCARDIA, & ELEVATED BLOOD PRESSURE. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 192]**PEER REVIEWED**
  
• 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. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 193]**PEER REVIEWED**
  
• 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. [Benowitz NL et al; N Engl J Med 315: 1310-13 (1986)]**PEER REVIEWED**
  
• 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. [Lee BL et al; Clin Pharmacol Ther 41 (4): 474-9 (1987)]**PEER REVIEWED**
  
• 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. [Lindblad A, Marsal K; J Perinat Med 15 (1): 13-9 (1987)]**PEER REVIEWED**
  
• NICOTINE IS OF CONSIDERABLE MEDICAL IMPORTANCE BECAUSE OF ITS TOXICITY, PRESENCE IN TOBACCO, AND PROPENSITY FOR CONFERRING A DEPENDENCE ON ITS USERS. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 192]**PEER REVIEWED**
  
• ACUTELY FATAL DOSE OF NICOTINE FOR AN ADULT IS PROBABLY ABOUT 60 MG OF BASE. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 193]**PEER REVIEWED**
  
• ... Toxic by inhalation and by skin absorption. [Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987., p. 485]**PEER REVIEWED**
  
• NICOTINE MAY BE RESPONSIBLE FOR THE HIGHER INCIDENCE OF PEPTIC ULCER AMONG SMOKERS. [ROBERT A; PROC SOC EXP BIOL MED 139 (1): 319 (1972)]**PEER REVIEWED**
  
• 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. [Stjarne P et al; Br J Pharmacol 96 (3): 693-701 (1989)]**PEER REVIEWED**
  
• 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. [Perkins KA et al; New Engl J Med 320 (14): 898-903 (1989)]**PEER REVIEWED**
  
• 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. [Crandall LA et al; Fertil Steril 51 (4): 722-4 (1989)]**PEER REVIEWED**
  
• 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. [Perkins KA et al; Psycopharmacology 97 (4): 529-34 (1989)]**PEER REVIEWED**
  
• 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. [Quensel M et al; Scand J Clin Lab Invest 49 (2): 149-53 (1989)]**PEER REVIEWED**
  
• 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. [Cherek DR et al; Pharmacol Biochem Behav 32 (3): 677-81 (1989)]**PEER REVIEWED**
  
• 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. [Gilbert DG et al; Psychophysiology 26 (3): 311-20 (1989)]**PEER REVIEWED**
  
• 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. [Benowitz NL et al; Ann Intern Med 111 (2): 112-6 (1989)]**PEER REVIEWED**
  
• 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. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1084]**PEER REVIEWED**
  
• 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. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3378]**PEER REVIEWED**
  
• Farm workers who hand-harvest tobacco are at risk of developing "green tobacco sickness" /SRP: from nicotine exposure/. [Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992., p. 1218]**PEER REVIEWED**
  

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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. [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 130]**PEER REVIEWED**
  
• NICOTINE WAS TERATOGENIC IN MICE WHEN INJECTED @ 25 MG/KG ON DAYS 9-11 OF GESTATION. SKELETAL DEFECTS & OCCASIONAL CLEFT PALATES WERE PRODUCED. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 749]**PEER REVIEWED**
  
• ... 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. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 410]**PEER REVIEWED**
  
• In the rat ... used 0.05 mg per ml of drinking water and found a reduced size in the newborn. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 410]**PEER REVIEWED**
  
• 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. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3376]**PEER REVIEWED**
  
• 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. [Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 747]**PEER REVIEWED**
  
• 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. [STALHANDSKE T ET AL; ACTA PHARMACOL TOXICOL 27 (5): 363-80 (1969)]**PEER REVIEWED**
  
• DEFORMITIES WERE FOUND IN SOME RABBIT FETUSES WHOSE DAMS WERE ADMIN 20 MG/KG, 5 TIMES DURING PREGNANCY. [CROWE MW; TOB HEALTH WORKSHOP CONF (PROC 3RD) 256-66 (1972)]**PEER REVIEWED**
  
• INJECTION OF 0.07-0.09 MG NICOTINE INTO MICE RESULTED IN GROSS CHROMOSOMAL ABERRATIONS IN BONE MARROW CELLS. [BISHUN NP ET AL; ACTA BIOL (BUDAPEST) 23 (2): 175-80 (1972)]**PEER REVIEWED**
  
• PREGNANT SWINE FED AQUEOUS LEAF EXTRACTS OF TOBACCO AT RATE OF 16 & 32 MG/KG NICOTINE PRODUCED ARTHROGRYPOTIC NEWBORN PIGS. [CROWE MW; PROCEEDINGS OF THE TOBACCO AND HEALTH WORKSHOP CONF, 4TH: 198-202 (1973)]**PEER REVIEWED**
  
• 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. [UPSHALL DG; TERATOLOGY 5 (3): 287-94 (1972)]**PEER REVIEWED**
  
• 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. [HUDSON DB, TIMIRAS PS; BIOL REPROD 7 (2): 247-53 (1972)]**PEER REVIEWED**
  
• 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. [MCGRATH JJ, SMITH D; DRUG & CHEMICAL TOXICOLOGY 7 (1): 1-10 (1984)]**PEER REVIEWED**
  
• Toxic to bees but has a repellent effect. [Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987., p. A298/AUG 87]**PEER REVIEWED**
  
• 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. [Cheeke, P.R. and Shull, L.R. Natural Toxicants in Feeds and Poisonous Plants. Westport, CT: AVI Publishing Company, Inc. 1985., p. 119]**PEER REVIEWED**
  
• 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. [Aceto MD et al; NIDA Res Monogr 76 (1): 327-33 (1987)]**PEER REVIEWED**
  
• 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. [Forrest CR et al; Br J Plast Surg 40 (3): 295-9 (1987)]**PEER REVIEWED**
  
• 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). [Freeman GB et al; Pharmacol Biochem Behav 26 (2): 305-12 (1987)]**PEER REVIEWED**
  
• 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. [Fukuma M et al; J Toxicol Sci 11 (3): 169-77 (1986)]**PEER REVIEWED**
  
• 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. [Maritz GS; Respir 51 (3): 232-40 (1987)]**PEER REVIEWED**
  
• ... 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. [Sharp BM et al; J Pharmacol Exp Ther 241 (2): 438-42 (1987)]**PEER REVIEWED**
  
• 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. [Riesenfeld A, Oliva H; Acta Anat 128 (1): 45-50 (1987)]**PEER REVIEWED**
  
• 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. [Meyer DC, Carr LA; Neurobehav Toxicol Teratol 9 (2): 95-8 (1987)]**PEER REVIEWED**
  
• 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. [Marks MJ et al; Pharmacol Biochem Behav 27 (3): 505-12 (1987)]**PEER REVIEWED**
  
• 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. [Levin ED et al; Physiol Behav 39 (4): 441-4 (1987)]**PEER REVIEWED**
  
• 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. [Ksir C et al; Psychopharmacol 92 (1): 25-9 (1987)]**PEER REVIEWED**
  
• 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. [Goldberg SR et al; Psychopharmacology 97 (3): 295-302 (1989)]**PEER REVIEWED**
  
• 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. [Flynn FW et al; Behav Neurosci 103 (2): 356-64 (1989)]**PEER REVIEWED**
  
• 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. [Prasad C et al; Biochem Biophys Res Commun 159 (1): 48-52 (1989)]**PEER REVIEWED**
  
• 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. [Haikala H; Pharmacol Toxicol 64 (4): 334-9 (1989)]**PEER REVIEWED**
  
• 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. [Walter S, Kuschinsky K; Naunyn-Schmiedebergs Arch Pharmacol 339 (1-2): 208-213 (1989)]**PEER REVIEWED**
  
• 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. [Smith DC, Priola DV; European J Pharmacol 161 (2/3): 249-253 (1989)]**PEER REVIEWED**
  
• 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. [Savino JR, Tanabe LL; Bull Environ Contam Toxicol 42 (4): 778-8 (1989)]**PEER REVIEWED**
  
• 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. [Franco-Cereceda A et al; Acta Physiol Scand 135 (2): 173-87 (1989)]**PEER REVIEWED**
  
• 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. [Malaveille C et al; Carcinogenesis 10 (3): 577-86 (1989)]**PEER REVIEWED**
  
• 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. [Malaveille C et al; Carcinogenesis 10 (3): 577-86 (1989)]**PEER REVIEWED**
  
• 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. [Clark GC; Arch Toxicol 63 (1): 1-6 (1989)]**PEER REVIEWED**
  
• 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. [Ogungiyi PO, Misra HP; Toxicol Appl Pharmacol 98 (1): 25-30 (1989)]**PEER REVIEWED**
  
• 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. [Ikegami H et al; Nutr Res 9 (6): 635-43 (1989)]**PEER REVIEWED**
  
• 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. [Lapin EP et al; Eur J Pharmacol 160 (1): 53-9 (1989)]**PEER REVIEWED**
  
• 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). [Sobey CG et al; Naunyn Schmiedebergs Arch Pharmacol 339 (4): 464-8 (1989)]**PEER REVIEWED**
  
• 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. [Fung YK, Lau YS; Pharmacol Biochem Behav 33 (1): 1-6 (1989)]**PEER REVIEWED**
  
• 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. [Costall B et al; Pharmacol Biochem Behav 33 (1): 197-203 (1989)]**PEER REVIEWED**
  
• 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. [Carroll ME et al; Life Sci 45 (15): 1381-8 (1989)]**PEER REVIEWED**
  
• 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. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 604]**PEER REVIEWED**
  
• ...toxicity depends very much on the species; sheep and goats appear to tolerate high amounts in comparison to other mammals. [Harvey, A.L. (ed.). Natural and Synthetic Neurotoxins. London, England: Academic Press 1993., p. 261]**PEER REVIEWED**
  
• 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. [ANDERSSON K ET AL; ACTA PHYSIOL SCAND 118 (1): 35-40 (1983)]**PEER REVIEWED**
  
• 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/ [American Medical Association, Department of Drugs. Drug Evaluations. 6th ed. Chicago, Ill: American Medical Association, 1986., p. 158]**PEER REVIEWED**
  
• 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. [Gruenwald F et al; Brain Res 400 (2): 232-8 (1987)]**PEER REVIEWED**
  
• 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. [Kirch DG et al; Clin Neuropharmacol 10 (4): 376-83 (1987)]**PEER REVIEWED**
  
• 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. [Yamanaka K et al; Pharmacol Biochem Behav 26 (2): 259-63 (1987)]**PEER REVIEWED**
  
• 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. [Stotkin TA et al; J Pharmacol Exp Ther 242 (1): 232-7 (1987)]**PEER REVIEWED**
  
• 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. [Marks MJ et al; Mol Pharmacol 30 (5): 427-36 (1986)]**PEER REVIEWED**
  
• 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. [Hexum TD, Russet LR; Brain Res 406 (1-2): 370-2 (1987)]**PEER REVIEWED**
  
• 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. [Arregui-Aguirre A et al; Pharmacol Biochem Behav 27 (1): 15-20 (1987)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat oral 188 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 604]**PEER REVIEWED**
  
• LD50 Rat ip 30 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 604]**PEER REVIEWED**
  
• LD50 Mouse oral 24 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 604]**PEER REVIEWED**
  
• LD50 Rat oral 50-60 mg/kg [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 669]**PEER REVIEWED**
  
• LD50 Rat skin 140 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2410]**PEER REVIEWED**
  
• LD50 Rat iv 1 mg/kg [Gossel, T.A., J.D. Bricker. Principles of Clinical Toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 1994., p. 5]**PEER REVIEWED**
  
• LD50 Rat scu 25 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2410]**PEER REVIEWED**
  

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Absorption, Distribution and 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. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 192]**PEER REVIEWED**
  
• IN MICE, DOGS, & GUINEA PIGS, EXPOSURE TO NICOTINE SMOKE PERMITS ... DETECTION IN VISCERAL STORAGE COMPARTMENTS, INCL LIVER, KIDNEYS, LUNG, & BRAIN. ... [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 747]**PEER REVIEWED**
  
• ... 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. [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 144]**PEER REVIEWED**
  
• 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 ... [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 157]**PEER REVIEWED**
  
• 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. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 156]**PEER REVIEWED**
  
• 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 ... [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 270]**PEER REVIEWED**
  
• 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. [MOSIER HD JR, JANSONS RA; TERATOLOGY 6 (3): 303-11 (1972)]**PEER REVIEWED**
  
• FREE ALKALOID IS ABSORBED RAPIDLY THROUGH SKIN AND GASTROINTESTINAL AND RESPIRATORY TRACTS, BUT ABSORPTION OF ITS ACID SALTS IS LESS COMPLETE. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3378]**PEER REVIEWED**
  
• 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. [Broussolle EP et al; Life Sci 44 (16): 1123-32 (1989)]**PEER REVIEWED**
  
• 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. [Malaveille C et al; Carcinogenesis 10 (3): 577-86 (1989)]**PEER REVIEWED**
  
• ...more slowly absorbed from acidic than alkaline smoke. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 605]**PEER REVIEWED**
  
• 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. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 605]**PEER REVIEWED**
  
• 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. [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1051]**PEER REVIEWED**
  
• ...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. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1084]**PEER REVIEWED**
  
• 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. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1084]**PEER REVIEWED**
  
• 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. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1084]**PEER REVIEWED**
  

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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. [Menzie, C.M. Metabolism of Pesticides. U.S. Department of the Interior, Bureau of Sport Fisheries and Wildlife, Publication 127. Washington, DC: U.S. Government Printing Office, 1969., p. 258]**PEER REVIEWED**
  
• 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 ... [Menzie, C.M. Metabolism of Pesticides. U.S. Department of the Interior, Bureau of Sport Fisheries and Wildlife, Publication 127. Washington, DC: U.S. Government Printing Office, 1969., p. 258]**PEER REVIEWED**
  
• 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. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 566]**PEER REVIEWED**
  
• 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/. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 469]**PEER REVIEWED**
  
• ... BASIC AMINES, EG NICOTINE ... ARE N-OXIDIZED BY NON-CYTOCHROME P-450-DEPENDENT SYSTEM ... [Testa, B. and P. Jenner. Drug Metabolism: Chemical & Biochemical Aspects. New York: Marcel Dekker, Inc., 1976., p. 308]**PEER REVIEWED**
  
• ... 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/ [Matsumura, F. Toxicology of Insecticides. 2nd ed. New York, NY: Plenum Press, 1985., p. 282]**PEER REVIEWED**
  
• ... 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. [Kyerematen GA et al; J Chromatogr 419: 191-203 (1987)]**PEER REVIEWED**
  
• 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. [Peterson LA et al; J Med Chem 30 (2): 249-54 (1987)]**PEER REVIEWED**
  
• 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. [Hodgson E, Levi PE; A Textbook of Modern Toxicology 2nd ed p.74 (1997)]**PEER REVIEWED**
  
• 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. [Hines RN et al; Toxicol and Applied Pharmacology 125: 1-6 (1994)]**PEER REVIEWED**
  

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TSCA Test Submissions

• None found

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.