How Toxic is Nicotine?

Thanks to some scientific sleuthing courtesy of a dedicated toxicologist, nicotine may have to surrender its infamous position.

This article originally appeared in the Newton blog on RealClearScience. You can read the original here


Nicotine, the addictive ingredient in cigarettes, can be quite a lethal compound. It's widely recognized to be deadly at doses between 30 and 60 milligrams, making it more dangerous than both arsenic and cyanide. But thanks to some scientific sleuthing courtesy of a dedicated toxicologist, nicotine may have to surrender its infamous position.

Dealing with toxins by trade, Bernd Mayer at Karl-Franzens University in Austria was well acquainted with nicotine's standing, but also irked by the lack of evidence for it. So he took it upon himself to trace the estimate's source. At first, his quest stalled.

"Literature and Internet searches provided circular and often misleading references to databases or textbooks, which either simply stated the dose without reference or referred to another textbook and so on," he lamented. Even the Centers for Disease Control cited dubious sources, Mayer found.

Persistent, Mayer began screening German scientific literature published before World War II, and soon started noticing references to a compendium of intoxicants assembled by prominent German pharmacologist Rudolf Kobert in 1906. It was in the dusty pages of a chapter on nicotine that Mayer found his biggest clue yet:

"The lethal dose of pure nicotine is... difficult to determine," Kobert wrote, "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 0.002-0.004 g it is certainly not going to be higher than 0.06 g."

Mayer knew he was on the right track.

"It is beyond any doubt that this short, not particularly convincing paragraph represents the genuine origin of the lethal nicotine dose we still refer to more than 100 years later," he said. Clue in mind, Mayer further unraveled the mystery, uncovering the experiments Kobert referred to in his textbook. 

Sometime in the 1850s, two German experimenters, known only as Dworzack and Heinrich, took it upon themselves to discover what would happen if they directly consumed nicotine. Here's what happened, as described by Austrian pharmacologist Carl Damian von Schroff in 1856:

"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."

The account is remarkably consistent with what we now know of severe nicotine poisoning, but it deviated from the facts in one key respect. By the self-experimenters' reports, this deleterious chain of symptoms was set in motion after they ingested a mere 4 milligrams of nicotine. For comparison, that's roughly equivalent to the amount absorbed after smoking just four cigarettes! That can't be right. With 43.8 million regular smokers in the United States, we should be seeing a terrifying outbreak of seizures and tremors. We're not. This shoddy account is obviously incorrect, yet it appears to be the sole basis for nicotine's estimated toxic dose! 

Nicotine is, without a doubt, one murderous compound. When concentrated, it's corrosive to soft tissues, and targets the nervous system with frightening speed. But despite it's deadliness, common knowledge needs revision. Citing studies conducted in dogs, Mayer recommends updating nicotine's lethal dose to between 0.5 and 1 gram for the average person -- approximately 15 times the previous value -- but urges that new studies be completed to cement correct information into the scientific literature.

Source: Bernd Mayer. "How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self‐experiments in the nineteenth century." Archives of Toxicology. Oct. 2013. DOI 10.1007/s00204-013-1127-0

(Image: Cigarettes via Shutterstock)

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Homo sapiens have been on earth for 200,000 years — give or take a few ten-thousand-year stretches. Much of that time is shrouded in the fog of prehistory. What we do know has been pieced together by deciphering the fossil record through the principles of evolutionary theory. Yet new discoveries contain the potential to refashion that knowledge and lead scientists to new, previously unconsidered conclusions.

A set of 8-million-year-old teeth may have done just that. Researchers recently inspected the upper and lower jaw of an ancient European ape. Their conclusions suggest that humanity's forebearers may have arisen in Europe before migrating to Africa, potentially upending a scientific consensus that has stood since Darwin's day.

Rethinking humanity's origin story

The frontispiece of Thomas Huxley's Evidence as to Man's Place in Nature (1863) sketched by natural history artist Benjamin Waterhouse Hawkins. (Photo: Wikimedia Commons)

As reported in New Scientist, the 8- to 9-million-year-old hominin jaw bones were found at Nikiti, northern Greece, in the '90s. Scientists originally pegged the chompers as belonging to a member of Ouranopithecus, an genus of extinct Eurasian ape.

David Begun, an anthropologist at the University of Toronto, and his team recently reexamined the jaw bones. They argue that the original identification was incorrect. Based on the fossil's hominin-like canines and premolar roots, they identify that the ape belongs to a previously unknown proto-hominin.

The researchers hypothesize that these proto-hominins were the evolutionary ancestors of another European great ape Graecopithecus, which the same team tentatively identified as an early hominin in 2017. Graecopithecus lived in south-east Europe 7.2 million years ago. If the premise is correct, these hominins would have migrated to Africa 7 million years ago, after undergoing much of their evolutionary development in Europe.

Begun points out that south-east Europe was once occupied by the ancestors of animals like the giraffe and rhino, too. "It's widely agreed that this was the found fauna of most of what we see in Africa today," he told New Scientists. "If the antelopes and giraffes could get into Africa 7 million years ago, why not the apes?"

He recently outlined this idea at a conference of the American Association of Physical Anthropologists.

It's worth noting that Begun has made similar hypotheses before. Writing for the Journal of Human Evolution in 2002, Begun and Elmar Heizmann of the Natural history Museum of Stuttgart discussed a great ape fossil found in Germany that they argued could be the ancestor (broadly speaking) of all living great apes and humans.

"Found in Germany 20 years ago, this specimen is about 16.5 million years old, some 1.5 million years older than similar species from East Africa," Begun said in a statement then. "It suggests that the great ape and human lineage first appeared in Eurasia and not Africa."

Migrating out of Africa

In the Descent of Man, Charles Darwin proposed that hominins descended out of Africa. Considering the relatively few fossils available at the time, it is a testament to Darwin's astuteness that his hypothesis remains the leading theory.

Since Darwin's time, we have unearthed many more fossils and discovered new evidence in genetics. As such, our African-origin story has undergone many updates and revisions since 1871. Today, it has splintered into two theories: the "out of Africa" theory and the "multi-regional" theory.

The out of Africa theory suggests that the cradle of all humanity was Africa. Homo sapiens evolved exclusively and recently on that continent. At some point in prehistory, our ancestors migrated from Africa to Eurasia and replaced other subspecies of the genus Homo, such as Neanderthals. This is the dominant theory among scientists, and current evidence seems to support it best — though, say that in some circles and be prepared for a late-night debate that goes well past last call.

The multi-regional theory suggests that humans evolved in parallel across various regions. According to this model, the hominins Homo erectus left Africa to settle across Eurasia and (maybe) Australia. These disparate populations eventually evolved into modern humans thanks to a helping dollop of gene flow.

Of course, there are the broad strokes of very nuanced models, and we're leaving a lot of discussion out. There is, for example, a debate as to whether African Homo erectus fossils should be considered alongside Asian ones or should be labeled as a different subspecies, Homo ergaster.

Proponents of the out-of-Africa model aren't sure whether non-African humans descended from a single migration out of Africa or at least two major waves of migration followed by a lot of interbreeding.

Did we head east or south of Eden?

Not all anthropologists agree with Begun and his team's conclusions. As noted by New Scientist, it is possible that the Nikiti ape is not related to hominins at all. It may have evolved similar features independently, developing teeth to eat similar foods or chew in a similar manner as early hominins.

Ultimately, Nikiti ape alone doesn't offer enough evidence to upend the out of Africa model, which is supported by a more robust fossil record and DNA evidence. But additional evidence may be uncovered to lend further credence to Begun's hypothesis or lead us to yet unconsidered ideas about humanity's evolution.