Nicotine Poisoning

Nicotine (C10H14N2), a naturally occurring alkaloid is a Solanaceae family member, which also house tobacco, tomato, green pepper, potato and eggplant. It was first isolated and identified as a major component of tobacco plant in 1828 [1]. Cigarettes, cigars, other tobacco items and their smoke contain nicotine. When warm it emits a fishy odor. Workers processing and extracting tobacco have a higher chance of exposure. Formerly it was used as a fumigant and insecticide in the United States, but has been discontinued from use now. The nervous system and cardiac functions are affected by nicotine and even a small amount of exposure may prove fatal.

The disease is related to the following processes:  Poison and has an incidence of about  3 / 100.000.

Overview

Nicotine is the major alkaloid (95 % of the total content) present in commercial tobacco [2]. It is a central nervous system stimulant and is highly addictive. Over 4.9 million tobacco-associated deaths are reported annually. It is the major cause of death in present day and is more dangerous and fatal than any other consumer products [3]. 95% of cigarette toxicity reported is either symptom less (70%) or mild (25%). The recent reports of severe nicotine toxicity are from workers who are accidentally exposed to the animal control agents. Appropriate respiratory and cardiovascular aid will help patients suffering from delayed effects of exposure to recover without any lasting effects (sequelae). 

The modern versions of cigarettes like battery powered devices (electronic cigarettes, or e-cigarettes) provide nicotine doses as aerosol. E-cigarette cartridges generally contain nicotine, aerosol producing component (e.g. glycerol or propylene glycol) and flavorings (e.g. fruit, chocolate or mint). Presence of potentially dangerous components like irritants, genotoxins, and animal carcinogen has also been reported. Food and Drug Administration poses no regulation for non therapeutic uses of such e-cigarettes and is thus legally available to minors in many states. Recent reports suggest an increase in the usage of e-cigarettes among the present and former smokers in the United States. The popularity of e-cigarettes among young adults is yet to be ascertained [4]. Nicotine is a known teratogen (causative agent of birth defects) but their potential for carcinogenesis, developmental and reproductive toxicity is yet to be studied.

Etiology

The use of nicotine is illegal for minors owning to its addictive nature and the potential for overdose. Taking large quantities of nicotine through cigarettes, gum, e-liquid and patches may result in an overdose. Recommendations to prevent overdosing and fatality include quitting e-liquid drinking and avoiding the use of patches, gum, combinations of recreational products containing nicotine while smoking.

Nicotine is capable of contaminating water and food. It contaminates the indoor and outdoor air as fine particles or as spray (aerosol). In case of outdoor contamination it may result in contamination of agricultural products also. The route of exposure to nicotine include absorption through inhalation, ingestion, mucous membranes and skin. Nicotine induced toxicity through skin contact have been reported in nicotine containing pesticides handlers [5] and tobacco field workers [6].

Based on the route of nicotine administration and the particular type used, the LD50 (concentration lethal to 50 % of test subjects) varies in experimental animals. The variation in nicotine sensitivity observed in rodents is assumed to be genetically acquired [7].

Epidemiology

Oral exposure of nicotine leads to acute toxic effects [8]. The major symptoms of toxicity upon subjection (2 mg to 5 mg) include nausea. In case of adults, ingestion of large quantities (40 mg to 60 mg) of nicotine may lead to death. A sizable number of human poisoning and deaths have been reported from exposure to nicotine-containing pesticides [6].

Dermal exposure from accidental spilling, purposeful application of nicotine-containing insecticides on skin, contact with tobacco leaves on clothes will all result in poisoning [9]. Children may suffer from acute intoxication by ingesting tobacco containing supplies. One particular case was reported where four children developed salivation, vomiting, diarrhoea, tachycardia, tachypnoea and hypertension within 30 minutes of ingestion of two cigarettes each. Symptoms of depressed respiration and cardiac arrhythmia followed within 40 minutes  and convulsions were observed within 60 minutes [10]. Prolonged exposure to nicotine in smaller quantities (e.g. smoking) will result in chronic toxicity [11]. Increased chance of low birth weight and spontaneous abortion are reported in expectant mother smokers [6]. Short term skin contact with pharmaceutical and insecticidal nicotine products leads to serious toxicity. Green tobacco sickness as the name implies is caused by occupational tobacco plant handling. Second hand smoking resulted in 49,000 of the total 440,000 deaths in America related by chronic cigarette smoking [12].

California Poison Control System received reports of 557 nicotine exposure in 2004. Majority of the victims were children under five years (85%). Recreational tobacco products (e.g.cigarettes, chewing tobacco), pharmaceutical preparations (e.g.patches, gum, lozenges) and nicotine-containing plants resulted in 481 (86%), 72(13%) and 4 cases (1%) respectively. Fortunately patients involved did not suffer any serious toxicity despite the former reports of lethal poisonings  and deaths associated with exposure and ingestion of raw plants, nicotine insecticides, pharmaceutical preparations and commercially prepared recreational products [6] [12].

Sex distribution
Age distribution

Pathophysiology

The quantity of nicotine required to produce lethal effects in human is 60 mg or less corresponding to an oral LD50 of 0.8 mg per kg [13].  Nicotine poisoning does not produce any specific histological changes however evidence of caustic effect of nicotine has been observed in the gastrointestinal tract (GIT) after ingestion. Skin along with mucosal membranes of lungs, mouth, GIT and rectum absorb nicotine upon exposure. The elimination half-life of nicotine is 2 hours and has a distribution volume of approximately 1 L/kg. Immediately dangerous to life or health concentration (IDLH) is not determined for nicotine due to lack of inhalation toxicity data. The updated IDLH value for nicotine is given as  5 mg per m3 of skin surface. The value is derived from the acute oral toxicity figures in humans and animals [14].

Nicotine acts by  stimulating the nicotinic acetylcholine receptors of  -

  1. Autonomic nervous system - Adrenal medulla exhibits a "biphasic action" upon nicotine toxicity. Nicotine poisoning at lower doses result in  catecholamine release and  at higher doses result in inhibition in catecholamine release
  2. Central nervous system -  Low dose exposure to nicotine result in mild insentience and respiratory stimulation and  higher doses may lead to seizures and respiratory depression
  3. Neuromuscular junction - Fasciculations due to neuromuscular stimulation is ensued by neuromuscular blockade manifested as frailty and respiratory arrest

Time to attain peak serum levels differs widely depending upon the type and quantity of nicotine consumed. In case of chewing nicotine gum, nicotine serum concentration peaks around 30 minutes. Mean steady-state levels of 11.8ng /ml of serum concentration is  observed after consumption of 2 mg of gum. 5 to 10 minutes is the time required to attain maximum nicotine levels in case of cigarette smoking.

Prognosis

Clinical symptoms on acute exposure present within 15-90 minutes after exposure and mainly include nausea, salivation, vomiting, dizziness, confusion and diaphoresis. Hypertension, tachycardia and hyperpnea are the cardiopulmonary symptoms presented. These manifestations are considered as cases of minor toxicity or temporary early symptoms of  severe poisoning. In such cases, condition can quickly deteriorate to more serious symptoms like muscle twitching, weakness, seizures, bradycardia, hypotension, hypoventilation, coma and paralysis.

Recommended exposure limit (REL) and threshold limit value (TLV) for nicotine is 500 µg per m3 as per recommendations of the National Institute for Occupational Safety and Health (NIOSH) and the American Conference of Governmental Industrial Hygienists’ (ACGIH) respectively. Time-weighted average subjection to 2.3 µg per m3 of nicotine for 8 hours  was shown to result in three lung cancer induced deaths per 10,000 people exposed to nicotine over a working lifetime by a model used to determine the health-based standard for environmental tobacco smoke [15].

Clinical manifestations of nicotine toxicity last for about 1-2 hours in case of minor poisoning and to about 24 hours in severe cases. Paralysis of respiratory muscles and circulatory collapse results in demise within 1 hour after acute exposure. Skin contact to wet tobacco plant lead to green tobacco sickness with symptoms like nausea, vomiting, headaches, giddiness and diaphoresis within 3 to 17 hours from exposure that may last up to three days.

Presentation

Toxicity is usually presented in two stages and symptoms presented mainly depend on type of subjection. 

  • Early - stimulation/excitation within 15 minutes to 1 hour and may last up to 1 to 2 hours. The most vital symptom associated with nicotine toxicity is vomiting.
  • Late - inhibition/depression within  30 minutes to 4 hours. Some cases exhibit only late phase symptoms. Symptoms last up to 18 to 24 hours after exposure in serious cases. Severe toxicity may lead to death in 1 hour after exposure.

Major symptoms to look out include:

  • Irritation and redness (erythema) of eye, intense pain and inflammation of conjunctiva in case of direct eye contact with pure nicotine and in severe cases, this may often lead to cornea opacification.
  • Whole-body (systemic) toxicity in case of dermal and mucosal exposure
  • Allergic reactions
  • Green tobacco disease symptoms in occupational handlers

Workup

The best way to diagnosis nicotine toxicity is by correlating clinical findings with history of exposure. Urine toxicology test allows physicians to confirm presence of  nicotine and its metabolite (cotinine), but it may not help in diagnosis owning to its qualitative nature and universality of smoking. Serum levels tests are equally difficult to interpret and is also time consuming rendering it useless in case of acute poisoning management. Patients sufferering from respiratory distress in severe cases should be managed by intubation and mechanical ventilation.

Recommendations for management of nicotine poisoning given by Amy Hanoian-Fontana of Connecticut Poison Control Center include:

  • Patients exhibiting typical symptoms of nicotine toxicity must seek emergency medical treatment.
  • In suspected cases of toxicity with no symptoms, patients after informing the poison control center should stay home and center will follow up every few hours to monitor the progress.
  • Washing of skin with copious amount of lukewarm water for 20 minutes in case of accidental spillage of liquid nicotine. 

Treatment

Treatment options available for nicotine poisoning is directed towards easing the clinical symptoms mainly owning to the lack of specific antidote treatrment for nicotine toxicity. Patients exhibiting toxicity symptoms after nicotine ingestion should be given a gastric lavage with activated charcoal. Nicotine is mainly metabolized in liver by enterohepatic recirculation. Therefore, treatment using activated charcoal (up to 4 times, at 1 to 2 hours interval) will help to effectively detoxify nicotine through nicotine charcoal binding. Charcoal treatment should not be performed in patients suffering from vomiting, seizures or coma. Mecamylamine, a specific nicotine antagonist in the form of tablet can be used for managing nicotine poisoning when the patient is not convulsive, hypotensive or vomiting.

Benzodiazepines are the class of drugs used in managing seizures. Hypotension is managed initially with fluids followed by administration of vasopressors in refractory cases. Patients suffering from respiratory distress is stabilized by intubation and mechanical ventilation. Muscarnic symptoms including bradycardia is treated with atropine. Intravenous administration of atropine is recommended for treating adult patient (2 to 3 mg) and pediatric patients (0.02mg/kg). The procedure must be repeated if necessary.

Nicotine toxicity through skin contact is treated by rigorous cleansing with soap and water. The standard observation time set for oral and skin contact toxicity is 4-6 hours from exposures. Longer periods of observation is required in case of ingestion of intact nicotine patches or tobacco plant materials.

Prevention

First responders entering a nicotine contaminated area should wear a NIOSH-certified chemical, biological, radiological, nuclear (CBRN) self contained breathing apparatus (SCBA) and a level A protective suit. Level A protection must be exercised until the contaminant is identified and its concentration is determined. Training and experience will help responders to use protective clothing and equipment effectively under such circumstances. In an effort to prevent the accidental ingestion of nicotine, Child Nicotine Poisoning Prevention Act (2015) has instructed Consumer Product Safety Commission (CPSC) to implement a mandatory redesigning of liquid nicotine containers to prevent children under age five from opening and consuming its contents. 

Patient Information

Presence of nicotine in the body results in symptoms like nausea, vomiting or seizures.

Current statistics on source of nicotine poisoning is as follows:

  • Recreational tobacco supplies (cigarettes, chewing tobacco) -  481 cases (86%)
  • Medical preparations (patches, gum, lozenges) - 72 cases (13%)
  • Tobacco plants -  4 cases (1%)

Even though none of the above cases resulted in serious conditions and death, it is worth while to know that serious and lethal nicotine poisoning do have occurred previously from ingestion of raw plant, insecticides containing insecticides, medicinal preparations and recreational tobacco supplies. Inhalation, absorption (through skin and mucous membranes) and ingestion of liquid nicotine from e-cigarettes will result in nicotine poisoning.

Nicotine poisoning symptoms go through (but not always) two phases:

  1. early phase - stimulation/excitation within 15 minutes to 1 hour of exposure
  2. late phase - inhibition/depression within 30 minutes to 4 hour. Many victims may display late phase only 

Symptoms of poisoning depend on the type and route of exposure. Vomiting is the most important symptom to look out for in case of nicotine poisoning. The symptoms last for approximately 1 to 2 hours after light exposures, but may continue up to 18 to 24 hours in case of severe exposure. Severe cases  may result in death within 1 hour of poisoning. Atropine is the antidote used to treat nicotine toxicity (should only be used when there is no vomiting, convulsions and hypotension). In case of nicotine exposure, seek emergency medical care or inform poison control center (1-800-222-1222).

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References

  1. Schevelbein H. Nicotine, resorption and fate. Pharm Ther. 1982;18:233–248.
  2. Jacob P 3rd, Yu L, Liang G, Shulgin AT, Benowitz NL. Gas chromatographic-mass spectrometric method for determination of anabasine, anatabine and other tobacco alkaloids in urine of smokers and smokeless tobacco users. J Chromatogr. 1993;619:49-61.
  3. WHO. An international treaty for tobacco control. World Health Organization,Geneva. http://www.who.int/features/2003/08/en/
  4. Cobb NK, Byron MJ, Abrams DB, Shields PG. Novel nicotine delivery systems and public health: the rise of the "e-cigarette". Am J Public Health. 2010;100(12):2340-2342.
  5. Yildiz D. Nicotine, its metabolism and an overview of its biological effects. Toxicon. 2004;43:619-632.
  6. Health Council of the Netherlands: Committee on Updating of Occupational Exposure Limits. Nicotine; Health-based Reassessment of Administrative Occupational Exposure Limits. The Hague: Health Council of the Netherlands, 2005.
  7. Marks MH, Burch JB, Collins AC. Genetics of nicotine response in four inbred strains of mice. J Pharmacol Exp Ther. 1983;226:291-302.
  8. ICSC. Nicotine Material Safety Data Sheet. Nicotine ICSC: 0519. International Chemical Safety Cards. https://www.erowid.org/chemicals/nicotine/nicotine_data_sheet1.shtml Published 1993. Accessed September 05, 2015.
  9. Benowitz NL, Lake T, Keller KH, Lee BL. Prolonged absorption with development of tolerance to toxic effects following cutaneous exposure to nicotine. Clin Pharmacol Ther. 1987;42:119-120.
  10. Malizia E, Andreucci G, Alfani F, Smeriglio M, Nicholai P. Acute intoxication with nicotine alkaloids and cannabinoids in children from ingestion of cigarettes. Hum Toxicol. 1983;2:315-316.
  11. US-EPA. Chemical profile: Nicotine. US Environmental Protection Agency; 1987.
  12. Centers for Disease Control and Prevention. Cigarette Smoking in the United States. http://www.cdc.gov/tobacco/campaign/tips/resources/data/cigarette-smoking-in-united-states.html#two. Accessed: ‎February ‎06, ‎2014.
  13. Mayer B. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. Archives of Toxicology. 2014;88(1):5-7.
  14. CDC, NIOSH:Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH). Nicotine. National Institute for Occupational Safety and Health. http://www.cdc.gov/niosh/idlh/intridl4.html. Published 1994, Accessed September 2,2015.
  15. Trout D, Decker J, Mueller C, Bernert JT, Pirkle J. Exposure of casino employees to environmental tobacco smoke. J Occup Environ Med. 1998;40:270-276.

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