Nicotine lethal dose in humans: a common argument by regulatory authorities, based on poor science

By Dr Farsalinos

I am sure everyone has heard the “magic number”: 60mg is the nicotine lethal dose in adults. Τhis is a very low level, which would categorize nicotine as one of the most toxic substances available. It is a very common and strong argument of the regulatory authorities and of several anti-smokers activists who support very strict regulation on e-cigarettes and criticize the high levels of nicotine present mostly in refillable liquid bottles. Special concerns are usually raised for children, because lethal dose is expected to be much lower at this age group.

I always wondered how the lethal dose level was defined, because everyone mentioned that the lethal dose was just theoretical and was never really tested. In animals the lethal dose may be from 3mg/kg in mice to 50mg/kg in rats, while a 60mg dose means a 0.8mg/kg in humans. A brief search of the literature revealed some reports that cigarette ingestion in children has a benign prognosis CDC 1997, Kubo 2008), making it hard to understand how a 60mg lethal dose is realistic and accurate.

Yesterday however, a very important review was published in Archives of Toxicology. Professor Bernd Mayer from the University of Gratz performed an extensive review of available literature in an effort to identify the existing proof for defining the nicotine lethal dose in humans. He has also found several references mentioning that the acute lethal dose in humans has been estimated to be 50-60mg. However, no proof was provided for such figures. He had to go back to the mid of the 19th century to find that the lethal dose came from self experiments of Austrian pharmacologists, who described really peculiar and unrealistic symptoms after ingesting just 1-4mg of nicotine. Therefore, reports based on dubious experiments and results 150 years ago are still reproduced today…

More interestingly, Prof Mayer reports that the lethal level of nicotine as measured in postmortem exams was 2mg/ml of blood, corresponding to 4mg/ml of plasma. Such levels would correspond to ingesting 500-1000mg of nicotine. This is 10-20 times higher levels that those “accepted” today.

There is no doubt that nicotine is toxic and can be lethal. However, the levels currently mentioned in the literature seem to be extremely low and unrealistic. Nicotine solutions should always be handled with care, but there is no reason to produce excessive fear or accept poor science in order to terrorize the public.

It is worth reading the full review by Prof Mayer. It is available online with free access to everyone.

 

 

Dr Farsalinos is a researcher at Onassis Cardiac Surgery Center in Athens-Greece and at Medical Imaging Research Center, University Hospital Gathuisberg in Leuven-Belgium. He is actively involved in research on e-cigarettes’ safety and risk profile.

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Comments   

 
0 #12 Dr Farsalinos 2013-11-17 01:02
It would be interesting to measure plasma nicotine levels when you were doing that.

Moreover, we should remember that nicotine-naive users have higher sensitivity to nicotine intoxication...
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0 #11 Phoenix.pronik.org 2013-11-17 00:25
Quoting Clive Bates:
It's a great article - but what would you now use as an LD50 in mg/kg or lethal adult dose in mg? And what if the route of accidental administration was absorption through skin due to a liquid spill rather than oral ingestion?

Oral: LD50 6.5–13 mg/kg (Prof. Mayer)

Dermal / absorption through skin:
In Vitro Test of Nicotine's Permeability through Human Skin. Risk Evaluation and Safety Aspects
SARA ZORIN, FREDRIK KUYLENSTIERNA and HANS THULIN http://annhyg.oxfordjournals.org/content/43/6/405.full.pdf

We at pronik.org tested nicotine absorption using our own skin with e-liquids. Up to 300 mg as long as 20 min showed no remarkable effect but reduced "craving for nicotine".

We would not recommend to dilute the e-liquid with water because this mix will be absorbed much quicker (what the article says).
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0 #10 Dr Farsalinos 2013-11-16 15:07
Bernd Mayer mentioned in his paper that according too postmortem exams the lethal dose should be about 500-1000mg. This was based on the nicotine levels in whole blood found in suicide victims. So, vomiting is excluded from this calculation.
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0 #9 Clive Bates 2013-11-16 14:48
It's a great article - but what would you now use as an LD50 in mg/kg or lethal adult dose in mg? And what if the route of accidental administration was absorption through skin due to a liquid spill rather than oral ingestion?
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0 #8 Dr Farsalinos 2013-10-17 18:25
Quoting Dr M. Melvin:
Thanks for the head-up about this article Dr.F. Quite a good read even for the non-scientific. I've often wondered how rat and mice data could be used to extrapolate human toxicity. It is well known that nicotine is rapidly metabolized to cotinine in humans presumably through CYP-2D6. Thus lowering the bioavailability of nicotine. Rats and mice do not have the same 2D6 metabilizing pathways and would have much higher nicotine plasma levels. Just my reasoning... Matt



I agree with that, but remember that this study evaluated isolated cells. Nicotine metabolism occurs in the liver.
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0 #7 Dr M. Melvin 2013-10-17 18:12
Thanks for the head-up about this article Dr.F. Quite a good read even for the non-scientific. I've often wondered how rat and mice data could be used to extrapolate human toxicity. It is well known that nicotine is rapidly metabolized to cotinine in humans presumably through CYP-2D6. Thus lowering the bioavailability of nicotine. Rats and mice do not have the same 2D6 metabilizing pathways and would have much higher nicotine plasma levels. Just my reasoning... Matt
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+3 #6 David Moger 2013-10-05 11:55
I too would like to thank Dr Farsalinos for bringing "real science" to these discussions.
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+3 #5 Orb Skewer 2013-10-05 09:29
I ,as a long term user and advocate of E-cigarettes, owe you a debt of gratitude Dr Farsalinos, for your tireless work to dispel myths, right wrongs and 'deal in facts'.

I look forward to catching up on your future work.
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0 #4 Dr. J. H. Lauterbach 2013-10-05 07:35
Cigarette tobacco is acidic and much of the nicotine is tied up as salts. The classic paper on cigarette ingestion by children is: Hum Toxicol. 1988 Jan;7(1):27-31.
Cigarette and nicotine chewing gum toxicity in children.
Smolinske SC, Spoerke DG, Spiller SK, Wruk KM, Kulig K, Rumack BH..
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+2 #3 Dr Farsalinos 2013-10-04 22:52
Thank you for the feedback!!
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