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Nicotiana tabacum L

1. NAME
   1.1 Scientific name
   1.2 Family
   1.3 Common name(s)
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
   2.5 Poisonous parts
   2.6 Main toxins
3. CHARACTERISTICS
   3.1 Description of the plant
      3.1.1 Special identification features
      3.1.2 Habitat
      3.1.3 Distribution
   3.2 Poisonous parts of the plant
   3.3 The toxin(s)
      3.3.1 Name(s)
      3.3.2 Description, chemical structure, stability
      3.3.3 Other physico-chemical characteristics
   3.4 Other chemical contents of the plant
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
   4.2 High risk circumstances
   4.3 High risk geographical areas
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological/toxinological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote/antitoxin treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes/antitoxins
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
   13.1 Clinical and toxicological
   13.2 Botanical
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)


    POISONOUS PLANTS
    1. NAME
     1.1 Scientific name
       Nicotiana Tabacum L
     1.2 Family
       Solanaceae
     1.3 Common name(s)
       Fumo
       Petume
       Petina
       Pitura
       etum
       Tabaco (Brazil)
       Tabaco (Argentina)
       Tobacco (USA).
    2. SUMMARY
     2.1 Main risks and target organs
       Nicotianas are highly toxic plants due to their nicotine 
       alkaloid content.  The effects of nicotine alkaloid are a 
       result of the summation of actions at ganglionic sites, motor 
       end plates and smooth muscle.  The central nervous system is 
       affected, initially by stimulation, resulting in tremors and 
       convulsions, progressing to depression.  Death occurs from 
       respiratory failure.  Vomiting is a result of stimulation of 
       the emetic chemoreceptor trigger zone.
       
       The cardiovascular responses are generally due to stimulation 
       of sympathetic ganglia and adrenal medulla combined with 
       discharge of catecholamines.  The target organs are nervous 
       system and heart.
     2.2 Summary of clinical effects
       The onset of symptoms in acute nicotine alkaloid poisoning is
       usually rapid.  In the case of ingestion of leaves and other 
       parts of the plant there is a delay in the onset of the 
       symptoms due to slower gastric absorption of the alkaloid.  
       Symptoms following a relatively small dose are transient and 
       consist of salivation, nausea, vomiting, diarrhoea, 
       bradycardia and dizziness.
       
       In severe poisoning with pure alkaloid, the patient may 
       collapse and die within minutes from overwhelming paralysis.  
       Where death is delayed, abdominal pain is marked with severe 
       diarrhoea and a cold sweat. Mental confusion, giddiness, 
       restlessness, muscular weakness and disturbed vision and 
       hearing are followed by a loss of coordination, and 
       unconsciousness.  Blood pressure may initially be raised and 
       respiration stimulated, but is soon followed by a fall in 
       blood pressure, a rapid irregular pulse and laboured 
       breathing.  Clonic convulsions are followed by collapse and
       complete muscle relaxation.  Reflexes disappear and 
       respiration becomes slow and weak, followed by respiratory 
       arrest.
     2.3 Diagnosis
       At low doses, symptoms are transient and consist of salivation,
        nausea, vomiting, diarrhoea, bradycardia and dizziness.
                 

       At higher doses, abdominal pain is marked with severe 
       diarrhoea and a cold sweat. Mental confusion, giddiness, 
       restlessness, muscular weakness and disturbed vision and 
       hearing are followed by a loss of coordination, and 
       unconsciousness. Respiration is stimulated, he pulse is rapid 
       and irregular and breathing is laboured.  Clonic convulsions 
       are followed by collapse and  complete muscle relaxation.  
       Reflexes disappear and respiration  becomes slow and weak, 
       followed by respiratory arrest.
       
       In severe poisoning with pure alkaloid, collapse and death may 
       be rapid.
       
       Standard biomedical tests as indicated.
       
       Sample collection: Collect remnants of plant and vomitus in 
       clean bottles.
     2.4 First-aid measures and management principles
       If the plant has been swallowed, the stomach should be emptied 
       and a purgative administered.
       
       There is no specific antidote.  Convulsions should be 
       controlled with diazepam, and airway ensured and respiration 
       maintained.
     2.5 Poisonous parts
       Leaves, stems, roots and flowers.
     2.6 Main toxins
       Nicotine.
    3. CHARACTERISTICS
     3.1 Description of the plant
       3.1.1 Special identification features
             Annual herb, shrub or small tree; from 0.90 to 1.50 m 
             tall according to the variety.  The leaves are elliptic 
             or oblanceolate; flowers clustered at the end of the 
             branches; have a cylindrical calyx and are greenish or 
             reddish in the upper part.  Fruit has different forms 
             with globular seeds.
       3.1.2 Habitat
             N. tabacum is sensitive to temperature, air, ground 
             humidity and the type of land.  Temperatures of 20 to 30 
             °C are best for adequate growth; an atmospheric humidity 
             of 80 to 85% and soil without a high level of nitrogen 
             are also necessary.
       3.1.3 Distribution
             N. tabacum is a native of tropical and subtropical 
             America but it is now commercially cultivated worldwide. 
              Other varieties are cultivated as ornamental plants or 
             grow as a weed.
     3.2 Poisonous parts of the plant
       Every part of the plant except the seed contains nicotine, but 
       the concentration is related to different factors such as 
       species, type of land, culture or weather conditions.
       
       The concentration of nicotine increases with the age of the 
       plant.  Tobacco leaves contain 2 to 8% of nicotine combined as 
       malate or citrate.  The distribution of the nicotine in the 

       mature plant is widely variable: 64% of the total nicotine 
       exists in the leaves; 18% in the stem, 13% in the root, and 5% 
       in the flowers.
     3.3 The toxin(s)
       3.3.1 Name(s)
             Nicotine
       3.3.2 Description, chemical structure, stability
             Nicotine is a tertiary amine composed of a pyridine and 
             pyrrolidine ring.
             
             Chemical name: 3-(1-methyl-2-pyrrolidyl) pyridine.
             
             Chemical structure:
             
             CAS No:   54-11-5
             
             Molecular weight:        162.2
       3.3.3 Other physico-chemical characteristics
             Nicotine is a colourless to pale yellow, very 
             hygroscopic, oily liquid with an unpleasant pungent 
             odour and sharp burning persistent taste.  It gradually 
             becomes brown on exposure to air or light.
             
             Soluble in water, alcohol, chloroform, ether, kerosene, 
             light petroleum and fixed oils.  Store in airtight 
             containers.  Protect from light.
     3.4 Other chemical contents of the plant
       Anabasine: alkaloid similar to the nicotine but less active.  
       
       Glucosides: tabacinine, tabacine.
    4. USES/CIRCUMSTANCES OF POISONING
     4.1 Uses
       The nicotine of tobacco is used as an insecticide.
       Instillation of tobacco enemas for treatment of 
       intestinal worms or constipation.
       Dried tobacco leaves for chewing, snuffing or smoking.
     4.2 High risk circumstances
       Poisoning has been reported from percutaneous absorption in 
       tobacco harvesters, during manufacture and the workers in the 
       tobacco industry.
       
       Death has followed the use of tobacco infusions as enemas in 
       the treatment of intestinal parasites in children.
       
       Fatal cases have been reported after ingestion of tobacco's
       infusions in attempted suicide or mistaking wild tobacco for 
       and edible plant.
     4.3 High risk geographical areas
       Cultivated areas of N. tabacum or in places where different
       varieties of nicotianas are cultivated as an ornamental or 
       grown as a weed.
       
       In Argentina, the cultivated area of tobacco is in the north-
       west or the country (Salta, Jujuy).
       
       Rio Grande do Sul is the most important area for tobacco

       cultivation in Brazil.
    5. ROUTES OF ENTRY
     5.1 Oral
       Chewing tobacco leaves, sucking the flowers, eating as cooked
       greens, or ingesting infusion of tobacco leaves.
     5.2 Inhalation
       Smoking or snuffing dried tobacco leaves.
     5.3 Dermal
       Acute nicotine poisonings have been reported from percutaneous
       absorption in tobacco harvesters (green tobacco sickness).
     5.4 Eye
       No data available.
     5.5 Parenteral
       No data available.
     5.6 Others
       Instillation of tobacco enemas for treatment of worms or
       constipation.
    6. KINETICS
     6.1 Absorption by route of exposure
       Nicotine is readily absorbed from the respiratory tract, 
       buccal, vaginal and rectal mucosae and skin.  Severe poisoning 
       has resulted from percutaneous absorption.  Being a relatively 
       strong base, its absorption from the stomach is minimal unless 
       intragastric pH is raised.  Intestinal absorption is far more 
       efficient.
       
       Nicotine is not readily absorbed in the stomach from ingested
       tobacco, as when children swallow cigarettes, and the initial
       stimulus to vomiting usually removes most of it before much 
       harm is done by an otherwise serious dose.
       
       Chewed or sniffed tobacco is buffered to an alkaline pH to
       facilitate the absorption of nicotine through mucous 
       membranes.
       
       When the smoke of burning tobacco reaches the small airways 
       and alveoli of the lung the nicotine is absorbed rapidly, 
       regardless of the pH of the smoke.  Presumably the rapid 
       absorption of nicotine from tobacco smoke through the lung is 
       the result of the huge surface area of the alveoli and small 
       airways, and the dissolution of nicotine into fluid or 
       physiologic pH, which facilitates transfer across cell 
       membranes.
     6.2 Distribution by route of exposure
       Smoking is a unique form of systemic drug administration, in 
       that nicotine enters the circulation through the pulmonary 
       rather than the portal or system venous circulation.  The lag 
       time between smoking and the entry of nicotine into the brain 
       is shorter than that observed when nicotine is injected 
       intravenously.
       
       Nicotine enters the brain quickly, but levels decline rapidly.
       
       Nicotine crosses the placenta freely and has been found in 
       amniotic fluid and the umbilical-cord blood of neonates.
       

       It is found in breast milk and in the breast fluid of 
       nonlactating women.
       
       Its concentration in breast milk is so low that the dose of
       nicotine consumed by an infant is small and unlikely to be of
       physiologic consequence. The milk of lactating women who are 
       heavy smokers would contain 0.5 mg/litre of nicotine.  The 
       volume of distribution is 2.6 l/kg and the percentage of serum 
       binding of nicotine is 4.9%.
     6.3 Biological half-life by route of exposure
       The half-life of nicotine averages 2 h, although there is
       considerable variability among people (range: 1 to 4 h).
     6.4 Metabolism
       Nicotine is rapidly and extensively metabolized (80 to 90%),
       primarily in the liver, but also to a small extent in the 
       lungs and kidneys.
       
       Nicotine's primary metabolites are cotinine and nicotine-N-
       oxide, neither of which appears to be pharmacologically 
       active.  Their formation involves oxidation, demethylation and 
       pyridine N-methylation.
       
       Cotinine, because of its long half-life (16 to 20 h), is 
       commonly used in surveys and treatment studies as a marker of 
       nicotine intake.  The most abundant metabolite in the urine is 
       3'-hydroxycotinine, which could also prove to be a useful 
       indicator of nicotine exposure.
     6.5 Elimination by route of exposure
    7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY
     7.1 Mode of action
       Nicotine binds stereospecifically to acetylcholine receptors 
       at autonomic ganglia, the adrenal medulla, neuromuscular 
       junction and the brain.
       
       As a consequence of the stimulation of nicotinic receptors,
       possibly located on presynaptic sites, short-term exposure to
       nicotine results in the activation of several central nervous
       system neurohumoral pathways, leading to the release of
       acetylcholine, norepinephrine, dopamine, serotonin, 
       vasopressin, growth hormone, and ACTH.
       
       Most of the effects of nicotine on the central nervous system 
       are due to the direct action on brain receptors, although 
       activation of the brain through afferent nerves of 
       chemoreceptors in the carotid bodies or the lung may also 
       contribute.
       
       Nicotine excites nicotinic receptors in the spinal cord, 
       autonomic ganglia, and adrenal medulla, the last of which 
       causes the release of epinephrine.  Nicotine evokes the 
       release of catecholamines and facilitates the release of 
       electrical stimulation-evoked neurotransmitters from 
       sympathetic nerves in blood vessels. 
       
       In experimental preparations, nicotine in low doses causes
       ganglionic stimulation but in high doses it causes ganglionic

       blockade after brief stimulation.  This biphasic response 
       pattern is observed in the intact organism as well, although 
       the mechanism is far more complex:
       
       At very low doses, similar to those seen during cigarette 
       smoking, the cardiovascular effects appear to be mediated by 
       the central nervous system, either through the activation of 
       chemoreceptor afferent pathways or by direct effects on the 
       brain stem.  The net result is sympathetic neural discharge, 
       with an increase in blood pressure and heart rate.
       
       At higher doses, nicotine may act directly on the peripheral
       nervous system, producing ganglionic stimulation and the 
       release of adrenal catecholamines.
       
       At extremely high doses, nicotine produces hypotension and 
       slowing of the heart rate, mediated by either peripheral 
       ganglionic blockade, vagal afferent nerve stimulation, or 
       direct depressor effects mediated by action on the brain.
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     Lethal doses of nicotine may be estimated in 0.5 
                     mg to 1 mg/kg body weight (about 40 to 60 mg).
                     
                     Two to four drops pure nicotine can prove lethal 
                     (each drop: 23-33 mg).  There was death with the 
                     ingestion of 30 g of tobacco or infusion of 15 to 
                     20 g of tobacco or with administration of enemas to
                     8 g or inhalation of 0.8 g of tobacco as snuff.
             7.2.1.2 Children
                     The lethal dose is considered to be about 10 mg 
                     of nicotine. (Arena, 1974)
       7.2.2 Animal data
             LD50 dog:      1 mg/kg
             LD50 horse:    200 to 300 mg
             LD50 rat p.o.: 55 mg/kg
             LD50 rat IV:   1 mg/kg.       (RTECS, 1986)
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       Smoking of cigarettes is causally related to cancer of the
       respiratory tract, the upper digestive tract, pancreas, renal
       pelvis and bladder; cigarette smokers also face an increased 
       risk for cancer of the cervix (USDHHS 1982; IARC 1986). Many
       carcinogenic agents have been identified in cigarette smoke 
       but no single component nor chemical group(s) of component is 
       solely responsible for the carcinogenic activity of cigarette 
       smoke in the various organs. Laboratory bioassay suggest that 
       polynuclear aromatic hydrocarbons and N-nitrosamines play 
       significant roles in the induction of cancer in smokers 
       (USDHHS 1989, IARC 1986).
     7.4 Teratogenicity
       Whether cigarette smoking is associated with increased rates 
       of congenital malformations in humans is controversial. 
       Several studies show no association or a lower incidence of 

       malformations in the offspring of smoking mothers, but others 
       report positive associations. Smoking is associated with 
       impaired fetal growth and development.
     7.5 Mutagenicity
       In the Ames Salmonella typhimurium mutagenesis and mammalian 
       cell cytogenic essays nicotine did not posses any genotoxicity 
       although it induced reparable DNA damage in the Escherichia 
       coli. prl. A +/A-system  (USDHH, 1988).
     7.6 Interactions
       Several pharmacodynamic interactions arise from hemodynamic 
       effects of nicotine in cigarette smoke.  For example, by 
       reducing the blood flow to the skin and subcutaneous tissue, 
       cigarette smoking may slow the absorption of insulin from 
       subcutaneous sites. Smoking may impair the efficacy of beta-
       blockers and calcium antagonists in patients with hypertension 
       or angina pectoris.
       
       Cigarette smoking and oral contraceptives may interact
       synergistically to increase the risk of stroke and premature
       myocardial infarction in women. Cigarette smoking appears to
       enhance the procoagulant effects of oestrogens.  For this 
       reason, oral contraceptives should be used only with care in 
       women who smoke cigarettes.
       
       Cigarette smokers experience less sedation than nonsmokers 
       from several drugs that act on the central nervous system, 
       including diazepam, chlordiazepoxide, and chlorpromazine.  
       Smoking probably acts by producing arousal of the central 
       nervous system rather than by accelerating metabolism and 
       reducing the brain levels of these drugs.  
       
       The efficacy of analgesics such as propoxyphene, may be 
       reduced in cigarette smokers, even in the absence of 
       pharmacokinetics interaction.  Cigarette smoking is a major 
       risk factor for the recurrence of peptic ulcer disease and the 
       failure of treatment with antacids or H2 blockers.  Sucralfate,
        which acts on the gastric mucous barrier, seems to be equally 
       effective in smokers and nonsmokers and may be the drug of 
       choice for peptic ulcer disease in cigarette smokers (Laurence,
       1980).
    8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
                     The plant or tobacco can be identified in 
                     specimens of vomitus or gastric lavage.
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses

       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Tobacco leaves have caused severe poisoning when eaten 
             as cooked greens.  The plant has been the cause of 
             illness in children sucking the flowers.
             
             Gastric absorption of nicotine from tobacco taken by 
             mouth is delayed because of slowed gastric emptying; 
             vomiting caused by the central effect of the fraction 
             initially absorbed may therefore remove much of the 
             tobacco remaining in the stomach. 
             
             The onset of symptoms of acute nicotine poisoning is 
             rapid; they include nausea, salivation, abdominal pain, 
             vomiting, diarrhoea, cold sweat, headache, dizziness, 
             disturbed hearing and vision, mental confusion, and 
             marked weakness.  Faintness and prostration ensue; the 
             blood pressure falls;
             breathing is difficult; the pulse is weak, rapid and
             irregular - and collapse may be followed by terminal
             convulsions.  Death may result within a few minutes from 
             respiratory failure caused by paralysis of the muscles 
             of respiration.

       9.1.2 Inhalation
             Poisoning by inhalation occurs through smoking tobacco 
             or inhaled snuff.
             
             In naive subjects, cigarette smoking commonly produces
             dizziness, nausea, vomiting and pallor as a result of 
             mild intoxication.
       9.1.3 Skin exposure
             Green-tobacco sickness, in which tobacco harvesters are 
             exposed to dew containing nicotine, results in nausea, 
             vomiting, pallor, weakness, dizziness, light-headedness, 
             headache  and sweating.  Less common symptoms are 
             abdominal pain, chills and excessive salivation.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             No data available.
       9.1.6 Other
             Acute poisoning has been reported when tobacco was used 
             as a parasiticide and when administered by enema as an 
             anthelmintic in children (Arena, 1974).
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Chewing leaves of tobacco (see monograph on nicotine).
       9.2.2 Inhalation
             Smoking tobacco (see monograph on nicotine)
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Nicotine is a highly toxic substance and death may occur 
       within a few minutes in acute poisoning due to respiratory 
       failure arising from paralysis of the muscles of respiration. 
       If supportive care can be instituted early, the prognosis is 
       good.  Tobacco is much less toxic than is anticipated from its 
       nicotine content.  Apparently, the intestinal absorption of 
       nicotine from tobacco is so slow that metabolic inactivation 
       sometimes keeps pace with absorption. Spontaneous vomiting may 
       also remove many unabsorbed alkaloids. On the other hand, 
       serious poisonings and deaths have occurred following 
       contamination of infant formula feeds with tobacco. (Gosselin, 
       1988).
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             The ultimate response of any one structure or system
             represents the summation of the several different and
             opposing effects of nicotine.  For example, the drug 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 
             simulation of parasympathetic cardiac ganglia.  In 

             addition, the effects of the drug of the chemoreceptors 
             of the carotid and aortic bodies and on medullary 
             centres influence heart rate, as do the cardiovascular 
             compensatory reflexes resulting from changes in blood 
             pressure caused by nicotine. 
             
             
             Finally, nicotine causes a discharge of epinephrine from 
             the adrenal medulla, and this hormone accelerates the 
             cardiac rate and raises blood pressure.
             
             On the cardiovascular system the effects are those of
             sympathetic stimulation.  There is vasoconstriction in 
             the skin and vasodilatation in the muscles, tachycardia 
             and a rise in blood pressure of about 15 mm Hg systolic 
             and 10 mm Hg diastolic.  Ventricular extrasystole may 
             occur.  Cardiac output, work and oxygen consumption 
             increase. Coronary vascular resistance decreases and 
             blood flow increases in men aged 20 to 50 years.  However, 
             if the resistance is fixed by atherosclerosis, flow does 
             not increase, though work and oxygen consumption do.  This 
             may be the mechanism of tobacco-induced angina pectoris.  
             It is possible that nicotine stimulates the myocardium by 
             releasing noradrenaline stored in it, but at present it 
             seems likely that this effect only occurs with higher 
             doses.
       9.4.2 Respiratory
             Cigarette smoking is the major cause of chronic 
             obstructive lung disease.  Nicotine may directly or 
             indirectly influence the development of emphysema in 
             smokers.  It rapidly accumulates in the pulmonary 
             epithelial cells and some of its metabolites are 
             retained in the lung for a long period (USDHHS, 1988).
       9.4.3 Neurological
             9.4.3.1 CNS
                     Nicotine markedly stimulates the central nervous 
                     system (CNS).  Moderate doses produce tremors in 
                     both man and laboratory animals, with somewhat 
                     larger doses, the tremor is followed by 
                     convulsions.  The excitation of respiration is a 
                     particularly prominent action of nicotine.  Although 
                     large doses act directly on the medulla oblongata, 
                     smaller doses augment respiration reflexly by 
                     excitation of the chemoreceptors of the carotid and 
                     aortic bodies.  Stimulation of the CNS is followed by 
                     depression, and death results from failure of 
                     respiration due to both central paralysis and 
                     peripheral blockade of muscles of respiration.
                     
                     Nicotine causes vomiting by a complex of central 
                     and peripheral actions.  The central component 
                     of the vomiting response is due to stimulation 
                     of the emetic chemoreceptor trigger zone in the 
                     area postrema of the medulla oblongata.
                     
                     In addition, nicotine activates a number of 

                     vagal and spinal afferent nerves that form the 
                     sensory input of the reflex pathways involved in 
                     the act of vomiting.
                     
                     Nicotine exerts an antidiuretic action as the 
                     result of stimulation of the hypothalamic - 
                     neurohypophyseal system with the consequent 
                     release of antidiuretic hormone (ADH).
             9.4.3.2 Peripheral nervous system
                     The effects of nicotine on the neuromuscular 
                     junction are similar to those on ganglia.  
                     However, with the exception of avian and 
                     denervated mammalian muscle, the stimulant phase 
                     is largely obscured by the rapidly developing 
                     paralysis.  In the latter stage, nicotine also 
                     produces neuromuscular blockade due to receptor 
                     desensitization.  In contrast to autonomic ganglia, 
                     where lobeline causes depolarization and acts like 
                     nicotine, the end-plate of skeletal muscle fibres is
                     blocked but not depolarized by lobeline.
                     
                     Nicotine, like acetylcholine, is known to 
                     stimulate a number of sensory receptors.  These 
                     include  mechanoreceptors that respond to 
                     stretch or pressure of the skin, mesentery, 
                     tongue, lung, and stomach; chemoreceptors of the 
                     carotid body; thermal receptors of the skin and 
                     tongue; and pain receptors.  Prior administration 
                     of hexamethonium prevents the stimulation of the 
                     sensory receptors by nicotine, but has little effect 
                     on physiological stimuli.  The explanation of these 
                     observations is controversial.
             9.4.3.3 Autonomic nervous system
                     The major action of nicotine consists initially 
                     in transient stimulation and subsequently a more 
                     persistent depression of all autonomic ganglia.  
                     Small doses of nicotine stimulate the ganglion 
                     cells directly and facilitate neuronal transmission. 
                     At larger doses of the drug, the initial 
                     stimulation is followed very quickly by a 
                     blockade of transmission, whereas stimulation of 
                     the ganglion cells coincides with their 
                     depolarization. Depression of transmission
                     by adequate doses of nicotine occurs both during 
                     the depolarization and after it has subsided.  
                     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 also causes the release of techolamines 
                     in a number of isolated organs.  This action 
                     results in a sympathomimetic response to 
                     nicotine that is blocked by drugs known to 
                     prevent the effects of catecholamines.

             9.4.3.4 Skeletal and smooth muscle
                     Nicotine stimulates the discharge of Renshaw 
                     cells, which inhibit the motor activity of 
                     anterior horn cells.  Nicotine may also 
                     stimulate the pulmonary afferent nerves, which 
                     in turn inhibit alpha motor neurons that act on 
                     skeletal muscle.
                     
                     As a result, phasic stretch-reflex responses, 
                     such as the patellar reflex, are reduced and 
                     certain muscles are relaxed.
                     
                     However, increased electromyographic activity 
                     and tonicity of the trapezius muscle have been 
                     observed after smoking (Laurence, 1980).
       9.4.4 Gastrointestinal
             In contrast to the cardiovascular actions of nicotine, 
             the effects of the drug on the gastrointestinal tract 
             are due largely to parasympathetic stimulation.  The 
             combined activation of parasympathetic ganglia and 
             cholinergic nerve endings results in increased tone and 
             motor activity of the bowel.
             
             Nausea, vomiting and occasional diarrhoea are observed
             following systemic absorption of nicotine.
             
             Cigarette smoking is a risk factor for peptic ulcer 
             disease and an even stronger risk factor for delayed 
             healing, failure to respond to therapy and relapse 
             (Kikundal, 1984)
       9.4.5 Hepatic
             No data available.
       9.4.6 Urinary
             9.4.6.1 Renal
                     No data available.
             9.4.6.2 Others
                     No data available.
       9.4.7 Endocrine and reproductive systems
             Cigarette smoking has been reported to increase the
             circulating levels of catecholamines, vasopressin, 
             growth hormone, ACTH, cortisol, prolactin, neurophysin 1,
              and beta-endorphin;  these effects are believed to be 
             mediated by nicotine.
             
             Many studies of the effects of smoking on endocrine 
             function have been performed in smokers who have smoked 
             to the point of toxicity (that is, nausea) but the 
             pattern of hormone release observed with nausea may not 
             be representative of nicotine's action at levels more 
             relevant to human smoking.
             
             In studies of more moderate smoking, small increases in 
             vasopressin, beta-endorphin, and cortisol have been 
             found.
             
             However, when cortisol concentrations were measured

             throughout the day, there were no differences whether
             subjects were smoking or not.  It appears that in humans 
             some endocrine responses result from the stress of the 
             experimental situation or from rapid smoking procedures 
             and differ from those that result from smoking at normal 
             rates.  In addition, the development of tolerance to the 
             effects of nicotine may result in hormonal effects being 
             seen after single cigarettes but not with repetitive 
             smoking.  It has been speculated that the release of 
             vasopressin may mediate improvement in memory and the 
             release of beta-endorphin may mediate the nicotine-related
             relief of anxiety and decrease in pain perception.
             
             In women, cigarette smoking is associated with earlier
             menopause and an increased risk of osteoporosis, 
             believed to be associated with lower levels of 
             oestrogens in smokers than in nonsmokers.  In 
             postmenopausal women receiving oestrogens, lower serum 
             oestrogen levels are seen in smokers than in nonsmokers. 
             It has been suspected that smoking acts primarily by 
             accelerating the hydroxylation of oestradiol.  Recent 
             evidence also suggested that nicotine and other alkaloids 
             in tobacco inhibit the formation of oestrogen by inhibiting 
             an enzyme in granulosa cells or placental tissue.  This 
             enzyme is responsible for the conversion of androstenedione 
             or testosterone to oestrogens.
       9.4.8 Dermatological
             No data available.
       9.4.9 Eye, ears, nose, throat:  local effects
             No data available.
       9.4.10 Haematological
              No data available.
       9.4.11 Immunological
              No data available.
       9.4.12 Metabolic
              9.4.12.1 Acid base disturbances
                       No data available.
              9.4.12.2 Fluid and electrolyte disturbances
                       No data available.
              9.4.12.3 Others
                       The body weight of smokers is on average 2.7 
                       to 4.5 kg lower than that of nonsmokers.  When 
                       a smoker stops, he or she typically gains 
                       weight in the subsequent year (to proximately 
                       the level of those who have never smoked).
                       
                       Weight control or the fear of gaining weight 
                       after stopping smoking may be a motive for 
                       continuing to smoke, particularly among women. 
                       Certain cigarette advertisements conspicuously 
                       use slender women to reinforce this 
                       association.  Studies in animals indicate that 
                       weight loss is an effect of nicotine.
                       
                       The mechanism of this effect has not been 
                       fully elucidated, but current evidence 

                       suggests that smoking is associated both with 
                       reduced consumption of food, particularly 
                       sweet foods, and with increased energy use.  
                       The magnitude of weight gain after the
                       discontinuation of smoking has been associated 
                       with lipoprotein-lipase activity in adipose 
                       tissue before the smoker stops smoking 
                       suggesting a direct effect on lipid 
                       metabolism.  Studies of the action of nicotine
                       on carbohydrate metabolism have had 
                       conflictive results.  Smoking may increase the 
                       levels of insulin and glucose in the short-
                       term, probably as a result of the stress 
                       reaction.  However, habitual smokers have not 
                       been shown to have abnormal carbohydrate
                       metabolism.
       9.4.13 Allergic reactions
              No data available.
       9.4.14 Other clinical effects
              Studies in animals show the rapid development to 
              tolerance to many effects of nicotine, although 
              tolerance may not be complete.  Smokers know that 
              tolerance develops to some of the effects of smoking.  
              In naive subjects, the first cigarette commonly 
              produces dizziness, nausea and vomiting, effects to 
              which the smoker rapidly becomes tolerant. 
              Tolerance to subjective effects and acceleration of the 
              heart rate develop within a day in regular smokers.  
              Tolerance may develop to toxic effects, such as nausea 
              and vomiting, even during the 8 h course of an 
              accidental nicotine poisoning, despite the persistence 
              of nicotine in the blood in extremely high 
              concentration.
       9.4.15 Special risks
              Nicotine crosses the placenta freely and has been found 
              in amniotic fluid and the umbilical cord blood of 
              neonates.  It is found in breast milk and in breast 
              fluid of nonlactating women.  Its concentration in 
              breast milk is so low that the dose of nicotine 
              consumed by an infant is small and unlikely to be of 
              physiologic consequence. Cigarette smoking during
              pregnancy increases the risk of low birth weight,
              prematurity, spontaneous abortions, and perinatal 
              mortality in humans, which has also been referred to as 
              the fetal tobacco syndrome. (Nieburg, 1985).
     9.5 Others
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         The treatment of acute nicotine poisoning needs to begin 
         quickly. The stomach should be emptied by induced emesis 
         with ipecac syrup or gastric lavage.  Activated charcoal and 
         a cathartic should be administered to prevent further 
         absorption.  Supportive therapy should be directed towards 
         maintaining respiration and blood pressure and control 

         convulsions.
      10.2 Relevant laboratory analyses and other investigations
         10.2.1 Sample collection
                Arterial blood for gases.
                Blood for routine test.
                Urine for routine test.
         10.2.2 Biomedical analysis
                Routine blood and urine tests.
         10.2.3 Toxicological/toxinological analysis
                Investigation of cotinine in urine and/or nicotine in 
                plasma.
         10.2.4 Other investigations
                No data available.
      10.3 Life supportive procedures and symptomatic treatment
         Supportive therapy should be directed toward maintaining 
         respiration and blood pressure and continued for as long as 
         necessary.
         
         Diazepam should be given cautiously to control convulsions.
      10.4 Decontamination
         Prompt treatment of poisoning is essential.  If contact was 
         with the skin, remove contaminated clothing and wash the 
         skin thoroughly with cold water without rubbing.
         
         If the patient has swallowed tobacco, induce emesis with 
         ipecac syrup.  Wash out the stomach with water.  Alkaline 
         solutions should be avoided.  A slurry of activated charcoal 
         should be passed through the tube and left in the stomach.
         
         In a case of use of tobacco enemas, give a cleaning enema 
         with water.
      10.5 Elimination
         Excretion of nicotine decreases when the urine is alkaline.
      10.6 Antidote/antitoxin treatment
         10.6.1 Adults
                No antidote is available.
         10.6.2 Children
                No antidote is available.
      10.7 Management discussion
         No data available.
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
              a.   Green tobacco sickness is a self-limiting 
         occupational illness of tobacco harvesters.  Symptoms 
         characteristically begin with a headache and dizziness 
         during the afternoon of the harvest, and progress to 
         abdominal pain, protracted vomiting and prostration by 
         evening.  The illness lasts only 12 to 24 h but recurs 
         frequently in susceptible workers after repeated harvest 
         exposure.  As many as 12 recurrences have been reported in 8 
         weeks by some workers.  Mortality and long-term sequelae from 
         the illness have not been documented (Gehlbach, 1974).
         
              b.   Early on the day of admission a 76-year-old man 
         had picked a wild green plant that was growing in a vacant 
         lot in south-east San Diego.  He thought the plant was 

         pokeweed (Phytolacca americana) which he had eaten as a 
         child in Arkansas.  Approximately 5 h prior to admission he 
         consumed the plant with dinner.  About 1.5 h later his wife 
         noted him to be ataxic and complaining of feeling "sick and 
         weak".  He then became diaphoretic and semi-responsive and 
         an ambulance was summoned.  Ipecac syrup was administered by 
         the paramedics and vomiting occurred.  Upon arrival in the 
         emergency department, the patient was awake and alert with 
         severe nausea and vomiting.  Shortly after admission he 
         became unresponsive except to deep pain.  Vital signs 
         included BP 210/140, respiration 16/min and shallow, and 
         pulse of 90 min.  There was profuse diaphoresis and muscle 
         twitching.  Because of decreasing depth of respiration,  an 
         endotracheal tube was inserted and mechanical ventilatory 
         assistance was begun.  The patient was admitted to the 
         intensive care unit.  The patient was treated with IV fluids 
         and respiratory support.  His mental status 24 h after 
         ingestion recovered and he was extubated.  He was discharged 
         3 days after admission (Manoguerra, 1982-1983).
         
              c.   An eight month old child swallowed two cigarette 
         butts from an ash-tray.  Rapidly, he developed a states of 
         coma with dyspnoea that needed intubation, ventilation and 
         gastric lavage.  No other causes were found.  He also 
         received atropine for hypersalivation.  This case stresses 
         the higher toxicity of cigarette butts, in which nicotine is 
         concentrated (Borys, 1988).
      11.2 Internally extracted data on cases
      11.3 Internal cases
    12. ADDITIONAL INFORMATION
      12.1 Availability of antidotes/antitoxins
         No antidote is available.
      12.2 Specific preventive measures
         Precautions should be taken when collecting tobacco leaves 
         to avoid their contact with the skin.
      12.3 Other
         No data available.
    13. REFERENCES
      13.1 Clinical and toxicological
         Arena J (1974).  Poisoning 4th Ed. New York. Charles Thomas.
         
         Benowitz NL (1987) In: The Pharmacology of Nicotine - 
         Proceedings, Satellite Symposium of the Tenth International 
         Congress of Pharmacology.  Gold Coast, Queensland, 
         Australia. September 4-6, Edited by Raul M. and Thurau K; 
         IRL Press, Washington D.C. 11-14.
         
         Benowitz NL (1988).  Pharmacologic aspects of cigarette 
         smoking and nicotine addiction.  N Eng J Med 319: 1318-28.
         
         Benowitz NL et al (1982). Interindividual variability in the 
         metabolism and cardiovascular effects of nicotine in man.  J 
         Pharmacol Exp Ther 221:368-372.
         
         Borys DJ, Setzer SC, Ling LJ (1988). CNS depression in an 
         infant after the ingestion of tobacco. Vet Hum Toxicol 30:20-22.

         
         Gehlbach SH et al (1974). Green tobacco sickness. An illness 
         of tobacco harvesters. J Am Med Assoc 229:1880-83.
         
         Goodman & Gilman (1986).  Las Bases Farmacologicas de la 
         Terapéutica.  d. Médica Panamericana S.A. 220.
         
         Gosselin RE (1988).  Clinical Toxicology of Commercial 
         Products. 6th ed. Baltimore, Williams & Wilkins, 311-313.
         
         Hardin JW, Arena JM (1974).  Human poisoning from native and 
         cultivated plants.  Durham, North Carolina, Duke University 
         Press: 140.
         
         IARC (1986). International Agency for Research on Cancer. 
         Tobacco Smoking. IARC monographs on the evaluation of the 
         carcinogenic risk of chemicals to humans. Volume 38, 
         WHO/IARC.
         
         Jouglard J (1977).  Intoxications d'origine végétale in 
         Encyclopédie Médico-Chirurgicale, Paris.  Editions 
         Techniques - 16.065 A 20.
         
         Kikendall JW et al (1984). Effect of cigarette smoking on
         gastrointestinal physiology and non-neoplastic digestive 
         disease. Journal of Clinical Gastroenterology 6:65-79.
         
         Laurence DR, Benett ON (1980).  Clinical pharmacology.  
         London, Churchill Livingstone. 465-72.
         
         Nieburg P et al (1985).  The fetal tobacco syndrome. J Am 
         Med Assoc 253:2998-99.
         
         Reynolds JEF (1982). Martindale, The Extra Pharmacopoeia 
         28th ed. London, UK. The Pharmaceutical Press.
         
         RTECS (1986).  Registry of Toxic effects of Chemical 
         Substances. NIOSH (vol 3A). 3060-424.
         
         Schvartsman S (1979).  Plantas venenosas.  Sao Paulo.  
         Sarvier Ed.  143-46.
         
         USDHHS (1982).  US Department of Health and Human Services. 
         The Health consequences of smoking:  Cancer.  A Report of 
         the Surgeon General US Department of Health and Human 
         Services.  Public Health Service.  Office on Smoking and 
         Health.  DHHS Publications N°(PHS). 82-50179.
         
         USDHHS (1988). US Department of Health and Human Services. 
         Nicotine addiction.  The health consequences of smoking. A 
         report of the Surgeon
              General. 32-33: 601-602.
      13.2 Botanical
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)

    Author:        Dr Julia Higa de Landoni
                   Seccion Toxicologia
                   Hospital de Clinicas "José de San Martin"
                   Cordoba 2351
                   1120 Capital Federal
                   Argentina
    
    Date:          March 1990.
         
    Peer Review:   Adelaide, Australia, April 1991