How much nicotine kills a human Tracing back the

Authors: Bernd Mayer

Publish Date: 2013/10/04

Volume: 88, Issue: 1, Pages: 5-7

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Abstract

The human toxicity of nicotine has become increasingly relevant in the past couple of years through marketing of new nicotinecontaining products such as smokeless tobacco and liquids for electronic nicotine delivery systems electronic cigarettes that are freely available in most countries Standard textbooks databases and safety sheets consistently state that the lethal dose for adults is 60 mg or less 30–60 mg leading to safety warnings that ingestion of five cigarettes or 10 ml of a dilute nicotinecontaining solution could kill an adult The 60mg dose would correspond to an oral LD50 of around 08 mg/kg a dose that is considerably smaller than the values determined for laboratory animals which are ranging from 33 mice to more than 50 mg/kg rats Hayes 1982Although an LD50 of 08 mg/kg would implicate that the toxicity of nicotine is similar to or even higher than that of cyanide fatal nicotine intoxications are relatively rare and there are countless records of subjects who survived consumption of nicotine in amounts far higher than 60 mg Larson et al 1961 The most drastic example is probably survival of a suicide attempt with 4 g of pure nicotine Schmidt 1931 While this is certainly an exceptional case in which the amount of bioavailable nicotine was markedly reduced by vomiting ingestion of tobacco or nicotine gums at doses up to 6 mg/kg nicotine was reported to evoke symptoms of intoxication without causing death Malizia et al 1983 Smolinske et al 1988 These and many other literature reports on nonfatal nicotine intoxications are hardly compatible with a lethal dose of 60 mg or lessSeveral detailed reviews are available on fatal nicotine intoxications caused by either suicidal intent or accidents latter mainly resulting from misusage of nicotinecontaining solutions marketed as pesticides Esser and Kühn 1933 Larson et al 1961 Maehly and Bonnichsen 1963 Tiess and Nagel 1966 Hayes 1982 Corkery et al 2010 Solarino et al 2010 The postmortem data reviewed by Maehly and Bonnichsen 1963 and more recently by Corkery et al 2010 and Solarino et al 2010 revealed minimal nicotine blood levels of 2 mg/L but rapid decline of blood nicotine after death Sanchez et al 1996 may have led to underestimation of the actual lethal concentration in delayed autopsiesDespite these uncertainties and the complex pharmacokinetics of nicotine Hukkanen et al 2005 a rough estimate of the amount of ingested nicotine from postmortem analyses of blood levels appears feasible Smoking a cigarette results in uptake of approximately 2 mg of nicotine and gives rise to mean arterial plasma concentrations of about 003 mg/L 30 ng/ml Gourlay and Benowitz 1997 Based on 20  oral bioavailability of nicotine Hukkanen et al 2005 and assuming linear kinetics an oral dose of 60 mg would give rise to a plasma concentration of about 018 mg/L The literature reports on fatal nicotine intoxications suggest that the lower limit of lethal nicotine blood concentrations is about 2 mg/L corresponding to 4 mg/L plasma a concentration that is around 20fold higher than that caused by intake of 60 mg nicotine Thus a careful estimate suggests that the lower limit causing fatal outcomes is 05–1 g of ingested nicotine corresponding to an oral LD50 of 65–13 mg/kg This dose agrees well with nicotine toxicity in dogs which exhibit responses to nicotine similar to humans Matsushima et al 1995Vom reinen Nik ist die lethale Dosis ebenfalls schwer zu bestimmen da es sich an der Luft leicht etwas zersetzt und andererseits meistens mehr oder weniger wasserhaltig ist doch nach den üblen Zufällen sic die bei mehreren Experimentatoren schon 0002–0004 g hervorbrachten ist sie wohl sicher nicht höher als 006 gThe lethal dose of pure nicotine is also difficult to determine because it easily decomposes a bit and on the other hand mostly contains more or less water however in accordance with the severe symptoms evoked in several experimenters by 0002–0004 g it is certainly not going to be higher than 006 gDie Sympt sind durch Selbstversuche von Reil und später von Dworzack und Heinrich unter D Schroff genau festgestellt worden Die letztgenannten Autoren empfanden nach 1–4 mg Nik Brennen im Munde Kratzen im Rachen vermehrte SPEIchelabsonderung dann vom Magen ausgehend ein Gefühl von Wärme die sich über die Brust und den Kopf bis in die Zehen und Fingerspitzen verbreitete Nachher wurden die Genannten aufgeregt litten an Kopfschmerz Schwindel Betäubung undeutlichem Sehen und Hören an Lichtscheu Beklommenheit Trockenheit im Schlunde Kälte in den Extremitäten Ructus Flatulenz Nausea Erbrechen und Stuhldrang Die Atmung wurde beschleunigt und angestrengt die Pulsfrequenz nahm anfänglich zu und zwar umso mehr je größer die Dosis war später aber wechselte reglos Zunahme und Abnahme derselben Nach Verlauf von 45 Minuten wurden die Experimentatoren ohnmächtig Bei dem einen kam es zu 2 Stunden anhaltenden klonischen Krämpfen besonders der Atemmuskeln zu Zittern der Extremitäten und Schütteln des ganzen Körpers Nach eingetretener Besserung blieb doch Abgeschlagenheit Schläfrigkeit und trostlose Stimmung noch 3 Tage lang zurückThe symptoms were determined exactly in selfexperiments by Reil and later by Dworzack and Heinrich under D Schroff After 1–4 mg of nicotine these authors felt a burning sensation in the mouth scratchy throat increased saliva excretion followed by a feeling of warmness emanating from the stomach which spread over the chest and from the head to the toes and fingertips Afterwards the subjects became agitated suffered from headache dizziness numbness cloudy vision and hearing light sensitivity anxiety dryness of the throat coldness of the limbs ructus belch flatulence nausea vomiting and rectal tenesmus Respiration was accelerated and labored pulse rate increased initially and rose directly with the increasing dose but later rose and fell erratically After 45 min the experimenters lost consciousness One of them suffered clonic seizures for 2 h particularly of the respiratory muscles also tremors of the limbs and shivering over the whole body After the initial recovery feelings of exhaustion drowsiness and bleakness remained for 3 daysSome of these effects resemble typical symptoms of nicotine overdosing but 1–4 mg of oral nicotine will certainly not evoke the severe adverse effects described such as clonic seizures and loss of consciousness Curiously Kobert mentioned the Pharmacologist Wilhelm Reil but ignored Reil’s account on very mild symptoms caused by selfingestion of up to around 75 mg of nicotine 15 drops of a solution of 1 drop of nicotine in 100 drops of alcohol Reil 1857 Indeed more recent studies have shown that intravenous administration of up to 5 mg of nicotine corresponding to 25 mg oral ie 50  of the allegedly lethal dose led to only minor adverse effects such as coughing and nausea Henningfield et al 1983 Gourlay and Benowitz 1997 Thus Kobert estimated the lethal dose of nicotine on the basis of highly dubious selfexperiments performed in the mid of the nineteenth century while ignoring conflicting data His excellent reputation as a leading scholar in toxicology has apparently led to uncritical acceptance and citation of the 60mg dose by contemporary fellows and successive researchersThe discrepancy between the 60mg dose and published cases of nicotine intoxication has been noted previously Matsushima et al 1995 Metzler et al 2005 but nonetheless this value is still accepted without scrutiny and taken as the basis for worldwide safety regulations of tobacco and other nicotinecontaining products Nicotine is a toxic compound that should be handled with care but the frequent warnings of potential fatalities caused by ingestion of small amounts of tobacco products or diluted nicotinecontaining solutions are unjustified and need to be revised in light of overwhelming data indicating that more than 05 g of oral nicotine is required to kill an adultI thank Christa Kern from my department for invaluable assistance in literature search and Dr Ellen Zechner Department of Molecular Biosciences KarlFranzens University Graz Austria for her help with the translation of the antiquated German text Support from the Austrian Science Fund P24005 and P24946 is gratefully acknowledged

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