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Is nicotine toxic to humans?

Is nicotine toxic to humans?


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More specifically, is nicotine in the concentrations that smokers receive when smoking cigarettes toxic? I know that in great enough concentrations it can be toxic (but then, so can just about anything else, including oxygen) and I know that in plants it is used as a defense against insects and can even be used as an insecticide. However, it has always been my understanding that nicotine is irrelevant as far as the harmful effects of smoking go.

I recently had a conversation with another biologist who had just quit smoking and had done quite a bit of research on the subject. He said that nicotine itself is in fact bad for you and, therefore, that tobacco-less alternatives to cigarettes (such as electronic cigarettes) are still harmful because of the nicotine alone.

Does anyone have any more information on this? Perhaps some references? Or, even better, a detailed explanation of the pathways involved? Again, I stress, not about nicotine's toxicity in general but about its harmful effects on vertebrates (preferably human) at the kinds of concentrations one could expect to ingest when smoking.


I think its useful to say that nicotine is not very toxic to humans - cells don't die or get sick for typical smoking habits. Secondary health effects are possible, but here is a toxicological profiles.

Nicotine is a toxin in large enough quantities and nicotine has an LD50 (lethal dose for 50% of individuals) of 0.5-1 mg Nicotine / kg of body weight. So even a small spill on your skin of the chemical can be life threatening, but for smokers the nicotine itself is not dangerous.

Individuals who smoke intake about 1 mg per cigarette smoked. So a small adult (110 lbs) can smoke 25 cigarettes in a short period of time (or all at once!) and just barely get to the bottom end of that limit. Nicotine is water soluble and clears out through the urine at a fast rate though - half of the nicotine from a cigarette is cleared from your system within 2 hours, which means that 4-5 pack a day smokers are not really killing themselves (from nicotine).

That being said, children are about 5-10 times more sensitive than adults, so even 5-6 cigarettes in an hour can be toxic. That's quite a bit of smoking though.

Not all animals have the same relationship to the nicotinic acetylcholine receptors as humans do. Nicotine is toxic to insects and will kill an insect in a matter of minutes or hours. Rats are about 50x less sensitive than people.

I think its comparable to the question of whether caffeine is harmful to people. In the amount we consume it, sometimes up to grams a day, there is no obvious common side effect, but you figure that decades later it will show up as a problem - a difficult connection to prove.


Nicotine acts as a ligand for nicotinic acetycholine receptors (nAChRs), which are ligand-gated ion channels normally activated by acetylcholine. This family of receptors is expressed in every mammalian cell (Schuller, 2009). A priori, at least to me, I'd suggest that it's a bad idea to chronically introduce a foreign substance that mimics the activity of an essential signaling molecule like acetylcholine.

Directly to your question of toxicity, nicotine appears to be linked to many forms of cancer (Schuller, 2009). Cancer promoting signaling pathways are stimulated as a result of calcium entry through nAChRs. Also, interactions of nAChRs with other signalling systems, such as those based on stress hormones, GABA, and dopamine, can lead to cancer.

Nicotine also has important effects in the brain. Chronic exposure to nicotine induces a homeostatic mechanism that upregulates nAChR expression in the brain to maintain responsiveness to endogenous acetylcholine. This effect partially underlies nicotine addiction (Penton and Lester, 2009). As @Armatus notes, nicotine appears to have some neuroprotective properties against neurodegenerative diseases like Parkinson's (Quik, M., Wonnacott, S., 2011) and Alzheimer's (Mehta et al, 2012).


Schuller, H.M., 2009. Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nature Reviews Cancer 9, 195-205.

Penton, R.E., Lester, R.A.J., 2009. Cellular events in nicotine addiction. Seminars in Cell & Developmental Biology 20, 418-431.

Quik, M., Wonnacott, S., 2011. α6β2* and α4β2* nicotinic acetylcholine receptors as drug targets for Parkinson's disease. Pharmacol. Rev. 63, 938-966.

Mehta, M., Adem, A., Kahlon, M.S., Sabbagh, M.N., 2012. The nicotinic acetylcholine receptor: smoking and Alzheimer's disease revisited. Front Biosci (Elite Ed) 4, 169-180.


When exploring whether nicotine is toxic to humans, the discussion isn't complete without the inclusion of non-adult humans / humans-in-development. Nicotine is toxic to humans beginning at conception. Nicotine has adverse effects on sperm, making them malformed, less likely to fertilize eggs, and making the embryos they do create less likely to survive. Mohamad Eid Hammadeh, PhD, professor of obstetrics and gynecology a the University of the Saarland, Homburg/Saar, Germany, in an interview with WebMD, is quoted as saying,

"The DNA alphabet of these sperm has one or two letters missing. And this cannot be repaired. When we inject these damaged sperm into an egg cell, the sperm is not capable of fertilizing the cell. And even if it does, the [miscarriage] rate is very high."

This paper talks about the abnormalities seen in sperm exposed to nicotine, whether sperm can recover, and after how long.

This paper links the nicotine consumption of fathers to their children's likelihood of developing childhood cancer, citing one possible explanation that smoking causes genetic damage to sperm cells. The sperm cell mutations then become inborn cancer-causing mutations in the offspring.

They jury may be out on the extremity of nicotine's impact on adult health, but it's clear that it's deleterious to the next generation.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880486/

Suggesting that the LD50 is an oral LD50 of 6.5-13 mg/kg.


Nicotine

Elimination

Nicotine has an elimination half-life ( t1/2) of approximately 2 h in humans, but this value varies from 1 to 4 h among people. This relatively short t1/2, and the relative pharmacological inactivity of nicotine’s metabolites contribute to frequent smoking by people who are addicted to nicotine. The t1/2 for cotinine is 17 h, and cotinine clearance is highly correlated with nicotine clearance. Concentrations of cotinine in the saliva, plasma, and urine are correlated, so salivary cotinine serves as a good biomarker for tobacco or nicotine exposure.

The major site of elimination for nicotine and its metabolites is in the urine, through the kidneys. Approximately 10% of nicotine and 10% of cotinine are excreted unmetabolized in the urine, although the process is pH dependent. When the pH of urine is acidic, then nicotine reabsorption from the kidney decreases which results in increased renal clearance of nicotine. Certain foodstuffs as well as physical and psychological stress can acidify the urine and may thereby contribute pharmacokinetically to increased nicotine intake through cigarette smoking.

Trace amounts of nicotine and its metabolites remain in other body fluids, such as the saliva. Nursing mothers also secrete nicotine in breast milk which can expose nursing children to nicotine.


Is the universe a graveyard? This theory suggests humanity may be alone.

Ever since we've had the technology, we've looked to the stars in search of alien life. It's assumed that we're looking because we want to find other life in the universe, but what if we're looking to make sure there isn't any?

Here's an equation, and a rather distressing one at that: N = R* × fP × ne × f1 × fi × fc × L. It's the Drake equation, and it describes the number of alien civilizations in our galaxy with whom we might be able to communicate. Its terms correspond to values such as the fraction of stars with planets, the fraction of planets on which life could emerge, the fraction of planets that can support intelligent life, and so on. Using conservative estimates, the minimum result of this equation is 20. There ought to be 20 intelligent alien civilizations in the Milky Way that we can contact and who can contact us. But there aren't any.

The Drake equation is an example of a broader issue in the scientific community—considering the sheer size of the universe and our knowledge that intelligence life has evolved at least once, there should be evidence for alien life. This is generally referred to as the Fermi paradox, after the physicist Enrico Fermi who first examined the contradiction between high probability of alien civilizations and their apparent absence. Fermi summed this up rather succinctly when he asked, “Where is everybody"?

But maybe this was the wrong question. A better question, albeit a more troubling one, might be “What happened to everybody?" Unlike asking where life exists in the universe, there's a clearer potential answer to this question: the Great Filter.


Results/Discussion

IRpmt Constructs Silence Nicotine Production

Nicotine accumulation was not reduced in most of the independent lines transformed with antisense pmt constructs (25 lines of pNATPMT1 and six lines of pCAMPMT1) compared to WT (Figure 1A). None of the five lines with lower nicotine accumulation in the T1 screen had nicotine levels lower than those of WT in the homozygous T2 generation. In contrast, 29 of 34 independently transformed lines with the IRpmt construct pRESC5PMT had dramatically reduced constitutive and MeJA-induced nicotine accumulations (Figure 1B). The suppression of nicotine accumulation was stable during plant development and when plants were grown in the glasshouse or in the field in Utah. Clearly, inverted-repeat constructs are more efficient at silencing the expression of endogenous genes, as has been previously described (Wesley et al. 2001).

Nicotine content (mean of 5–6 plants/line) normalized to mean of WT of unelicited (control) N. attenuata plants and plants 5 d after elicitation with 150 μg of MeJA per plant from independent lines transformed with (A) antisense pmt constructs and (B) an IRpmt construct. In contrast to the 31 lines transformed with the antisense pmt construct, 29 of the 34 IRpmt lines had dramatically reduced constitutive and MeJA-induced nicotine levels. T, terminator P, promoter I, spliceable intron arrow, 950-bp consensus fragment of pmt1 and pmt2. For details of transformation constructs see Protocol S1.

Genomic and Transcriptional Characterization

Two homozygous T2 IRpmt lines (108 and 145) with reduced nicotine levels were further characterized. Southern blot analysis using a probe hybridizing to the selective marker in the IRpmt construct demonstrated that both lines contained a single insertion (Figure S1). Transformation with a pRESC transformation vector allowed the transferred DNA (T-DNA) and flanking DNA at the insertion site to be recovered from the plant genomic DNA. These experiments demonstrated that the T-DNA integrated into the N. attenuata genome at a single site in each line, since all sequenced clones from a line (108, n = 4 145, n = 5) contained the same flanking sequence (see Figure S1 and Protocol S1).

Transcripts of the pmt genes in the two lines were significantly reduced to approximately 10% of the constitutive and MeJA-induced WT mRNA levels (Figure 2A), demonstrating that the targeted genes were successfully silenced.

Mean (± SE) relative PMT mRNA transcript levels in the roots (A), and leaf levels of (B) nicotine and (C) anatabine, in two independent lines of IRpmt-transformed (108 and 145) and WT N. attenuata plants. Elicited (150 μg of MeJA) and unelicited (control) plants were harvested at 10 h for transcript (A) and at 4 d for alkaloid (B and C) quantification. Both IRpmt lines had significantly reduced PMT transcript and nicotine but featured anatabine not present in WT plants. Lowercase letters signify differences at p ≤ 0.01, Bonferroni corrected ([A] n = 3, ANOVA: F2,12 = 12.55 [B] n = 8–10, ANOVA: F2,50 = 135.4 [C] n = 8–10, ANOVA: F2,50 = 39.611]. n.d., not detected.

Metabolic Consequences of pmt Silencing in N. attenuata

Consistent with the observed silencing of pmt transcripts, the constitutive and induced nicotine levels in transformed plants of both lines were dramatically reduced to 3%–4% of the levels found in WT plants (Figure 2B). All 29 IRpmt lines with reduced nicotine levels accumulated the alkaloid anatabine, which was not detected in WT plants. Constitutive and MeJA-induced total (nicotine, anabasine, and anatabine) alkaloid contents of the two IRpmt lines were about one-half and one-third of the WT levels, respectively, of which anatabine comprised 30% and 23% (Figure 2C). Levels of anabasine representing 20% of the constitutive and 8% of the MeJA-elicited total alkaloid contents in WT plants were unchanged in IRpmt plants (Figure S2). Elevated anatabine levels were also found in recently published studies with antisense pmt transformation of N. tabacum elevated anatabine levels did not affect transcript levels of other genes encoding enzymes involved in alkaloid metabolism (Chintapakorn and Hamill 2003).

Anatabine consists of a pyridine and a piperideine ring. Both are likely derived from NA, which is also the precursor of the pyridine ring of nicotine (Leete and Slattery 1976). Disrupting nicotine biosynthesis at the formation of the pyrrolidine ring by silencing PMT activity might cause an oversupply of the NA used in the biosynthesis of anatabine. Feeding the roots of hydroponically grown MeJA-elicited WT plants with NA ethyl ester resulted in formation of anatabine at levels of about a third of the total alkaloids (nicotine and anatabine) (Figure 3) in the IRpmt lines, anatabine constitutes 98% of the total alkaloids. Feeding plants with D4-NA ethyl ester results in the formation not only of D4-nicotine and D4-anatabine but also of D8-anatabine, demonstrating that the last integrates two D4-NA units. When these experiments are conducted with WT plants, about half of the anatabine is labeled, suggesting that the unlabeled half was formed from endogenous unlabeled NA. In addition, about one-fourth of the WT nicotine was D4-nicotine. In IRpmt plants, in contrast, only traces of D4-nicotine were found, but one-third of the anatabine was either D4- or D8-labeled. In summary, exogenously supplied NA is taken up by the roots of N. attenuata plants and used in alkaloid biosynthesis, and an oversupply of NA results in the formation of anatabine. These results support the hypothesis that the silencing of pmt disrupts nicotine biosynthesis, causing an oversupply of NA and the subsequent formation of anatabine.

Biosynthesis scheme and proportion of unlabeled (M + ) and labeled (M + +4, M + +8) nicotine and anatabine in the leaves of two independently transformed N. attenuata IRpmt lines (108 and 145) and WT plants 5 d after elicitation with 150 μg of MeJA per plant. Plants were grown in hydroponic solutions and supplied with either unlabeled or D4-ring-labeled NA ethyl ester (1 mM) 24 h after elicitation (n = 3 or 4). The oversupply of NA resulted in the formation of anatabine even in WT plants from both labeled exogenous and unlabeled endogenous NA pools.

IRpmt plants did not differ from WT plants in any other measured secondary metabolite or growth parameter. Constitutive or MeJA-induced levels of caffeoylputrescine, chlorogenic aid, rutin (Figure S2), TPI activity, or the release of cis-α-bergamotene (Figure S3) in IRpmt-transformed plants did not differ from those of WT plants. Rosette-stage and elongation-stage growth in individual pots in both the glasshouse and the field (Figure S4) did not differ between WT and IRpmt lines, and transformed lines were not visually or morphologically distinguishable from WT plants. Hence, the IRpmt plants represent an ideal construct with which to examine the ecological consequences of nicotine production.

Effects of Nicotine Silencing on N. attenuata Herbivores

M. sexta larvae reared on IRpmt plants in the glasshouse gained significantly more mass and changed instars faster than larvae reared on WT plants (n = 17–20 ANOVA: p < 0.01, pWT-PMT108 < 0.02, pWT-PMT145 < 0.01). The differences were comparable to those observed for M. sexta larvae reared on nicotine-enriched artificial diets (Parr and Thurston 1972 Appel and Martin 1992) or on nicotine-enhanced WT (Baldwin 1988) or antisense-pmt–transformed N. sylvestris plants (Voelckel et al. 2001). Two-thirds of freshly eclosed M. sexta larvae, given the choice between leaf material from WT or IRpmt (108) plants, preferred to initiate feeding on the latter (n = 43 Chi 2 = 6.7, p < 0.01). Such behavior suggests that nicotine plays an important role in determining feeding sites of M. sexta larvae, as has been suggested in a study with cultivated tobacco (Kester et al. 2002). While the relative toxic effects of anatabine and nicotine remain unstudied, these results are likely to underestimate the influence of nicotine on M. sexta choice and performance, because IRpmt plants had enhanced levels of anatabine.

Since secondary metabolism is known to be sensitive to environmental parameters that differ between glasshouse and field conditions (e.g., UV-B influence Caldwell et al. 1983), nicotine, anatabine, and TPI levels of WT and IRpmt plants grown in the field plantation were analyzed: they were found not to differ from plants grown under laboratory conditions (Figure 4A). A M. sexta feeding choice test evaluating the larvae's choice between field-grown WT and IRpmt plants (n = 57 Chi 2 = 7.74, p < 0.01) verified the results described above for the same experiment conducted with glasshouse-grown plants. Thus, the phenotype of glasshouse-grown IRpmt plants was not altered by growth under field conditions. In addition, choice tests with field-collected D. undecimpunctata, which was observed colonizing only IRpmt plants in the field plantation, revealed that 77% of these beetles preferred the nicotine-deficient IRpmt leaf material over WT (n = 35 Chi 2 = 10.31, p < 0.001). Another beetle species observed occasionally on WT plants, Trichobarus mucorea, does not distinguish between WT and IRpmt leaf material in choice tests (n = 19 Chi 2 = 0.05, p = 0.8).

(A) Leaf alkaloids (nicotine and anatabine) and TPIs 7 wk after transplantation (n = 6). Mean (± SE) percentage total leaf area damaged by (B) all herbivores and (C) only by Spodoptera exigua on WT N. attenuata plants and plants transformed with an IRpmt construct (108) that were either untreated (solid lines) or elicited (dotted lines asterisk) with MeJA 7 d after plants were transplanted into a field plot in a native habitat. Differences between 108 and WT, 108*, and WT* are significant at p ≤ 0.05 (nPMT = 36, nWT = 50, nPMT* = 28, nWT* = 27 [B] ANOVA: F3,822 = 5.73, p = 0.001 [C] ANOVA: F3,822 = 4.6, p = 0.004). Plants of the nicotine-deficient transformed line 108 suffered significantly higher leaf area damage than did WT plants, but when line 108 was elicited, leaf damage by all herbivores was reduced to WT levels.

In the field plantation, IRpmt plants lost significantly more leaf area to herbivores than did WT plants (Figure 4B), demonstrating that nicotine indeed functions as a direct resistance trait of N. attenuata in its native habitat. Over a period of 16 d, IRpmt plants exposed to naturally occurring herbivores lost 16% of their total leaf area to herbivores, an amount that is more than double the amount of damage incurred by WT plants. In order to meet compliance requirements described in the Code of Federal Regulations (7CFR340.3c) for the introduction of organisms altered through genetic engineering, flowers were removed as they matured, and therefore we could not directly measure the fitness consequences of this greater herbivore load. However, in other experiments with N. attenuata plants grown in natural populations, leaf area damage is negatively correlated with capsule number (Baldwin 1998 Kessler and Baldwin 2004), suggesting that the strongly enhanced herbivore damage of the nicotine-deficient IRpmt plants translates into a fitness loss.

IRpmt plants were attacked by a variety of insect herbivores. About half of the total herbivore damage resulted from S. exigua feeding (Figure 4C). One-third of the total herbivore damage was damage from grasshoppers of the genus Trimerotropis, which followed the same general pattern of distribution as S. exigua damage, but the differences between unelicited IRpmt and WT plants were not significant. The damage caused by Epetrix hirtipennis was variable but significantly higher for unelicited IRpmt compared to WT plants (ANOVA: F = 2.81, df = 3, p = 0.04, pPMT-WT < 0.05).

MeJA elicitation significantly reduced the damage of IRpmt plants to levels found on WT plants, suggesting that MeJA treatment elicits defense traits that are as efficient as the constitutive levels of nicotine in protecting plants. MeJA elicitation of N. attenuata plants is known to induce a diverse suite of transcriptional responses and secondary metabolites including TPIs, phenolics, flavonoids, phenolic putrescine conjugates, diterpene sugar esters, and volatile organic compounds (Halitschke and Baldwin 2003 Roda and Baldwin 2003), some of which apparently function as resistance traits. Which component of this complex suite of elicited metabolites is as effective as nicotine remains to be determined. It should be noted that the overall amounts of leaf area lost to herbivores was relatively low during the field experiments. Only 5% of the canopy area was lost from control and MeJA-elicited WT plants. In previous experiments (Baldwin 1998), fitness differences were observed between control and MeJA-elicited WT plants in populations that had lost approximately 40% of their canopy area to herbivores.

Altogether, these results provide direct evidence for the defensive value of nicotine. In a field trial, we established that a native tobacco, which produces large amounts of nicotine, is better defended against its natural herbivores than are nicotine-deficient transformants of the same genetic background. This is likely mediated by the reduction of herbivore performance and by the fact that these phytophagous insects prefer low-nicotine diets. In contrast to studies demonstrating genetic correlations between the production of secondary metabolites and herbivore resistance (Berenbaum et al. 1986 Shonle and Bergelson 2000), the resistance effects established in this study can be directly attributed to the altered traits. The fact that the silencing of one enzyme in the nicotine biosynthetic pathway redirects metabolite flux, resulting in the accumulation of an apparently less toxic alkaloid, anatabine, underscores the importance of characterizing single-gene transformants for secondary effects.

Conclusion

Plant secondary metabolites are widely accepted as essential components of a plant's direct defenses against its natural enemies, but unambiguous proof has been lacking, mainly because of the difficulty of altering the expression of single traits in plants and testing the consequences of these manipulations under natural conditions. Transformation technology has provided biologists with the ability to manipulate and study the ecological consequences of single-gene manipulations. To date, the technology has largely been used for the heterologous expression of resistance genes (e.g., Bacillus thuringiensis d-endotoxin) in agricultural systems (see Tian et al. [2003] for an elegant exception), and therefore has provided little evidence for the defensive value of endogenously expressed traits against a plant's native herbivore community. The scientific value of transgenically silencing endogenous genes in native plants to understand the ecological function of particular genes has been undermined by the polarized attitudes towards the use of genetically modified organisms in agriculture. Transgenic down-regulation of nicotine demonstrates that N. attenuata is under relentless herbivore pressure. Disabling this resistance trait, even in a year of low herbivore abundance, results in a large increase in opportunistic herbivory and supports the conclusion that secondary metabolites play an important role in explaining why the earth is largely green (Hairston et al. 1960).


Can you overdose on too much nicotine?

Nicotine, found naturally in tobacco plants, is the chemical responsible for the addictive nature of cigarettes, cigars, and many e-cigarettes.

Until recent years, nicotine poisoning was a relatively rare occurrence and tended to be linked to exposure to insecticides containing the chemical. However, the popularity of vaping or e-cigarettes has seen an increase in reported cases.

Both adults and children can be affected by nicotine, with over 50 percent of cases of nicotine exposure reported to the American Association of Poison Control Centers (AAPCC) in 2014 occurring in children under 6 years of age.

Share on Pinterest Cigarettes and nicotine gum both contain nicotine, which in large doses may cause nicotine poisoning.

  • cigarettes
  • cigars
  • e-cigarettes (vaping)
  • liquid nicotine
  • nicotine gum
  • nicotine patches
  • nicotine lozenges
  • chewing tobacco
  • pipe tobacco
  • snuff
  • some insecticides
  • tobacco plants

Nicotine poisoning tends to occur in 2 stages.

Within the first 15 to 60 minutes following exposure, symptoms are related to the stimulatory effects of nicotine and include:

  • excess saliva in the mouth
  • feeling nauseous
  • stomach ache
  • vomiting
  • loss of appetite
  • eye irritation
  • dizziness
  • tremors and restlessness
  • confusion
  • sweating
  • cough
  • rapid breathing
  • increased heart rate
  • elevated blood pressure

Following this stage, the body begins to wind down. Nicotine’s depressor effects appear within a few hours. These include:

  • low blood pressure
  • slow heart rate
  • shallow breathing
  • weakness
  • pale skin

In extreme cases, symptoms include:

Serious or fatal nicotine overdoses can occur but are rare.

Nicotine poisoning is essentially caused by overexposure to nicotine.

This is causes either through inhalation, ingestion, or absorption through the skin or eyes.

E-cigarettes and liquid nicotine are responsible for the majority of cases of nicotine poisoning.

How commonly is nicotine poisoning reported?

According to research by the Centers for Disease Control and Prevention (CDC), the number of calls to poison centers involving nicotine poisoning from these sources rose from 1 per month in September 2010 to 215 per month in February 2014. The number of calls regarding nicotine poisoning from traditional cigarettes did not change.

What forms of nicotine are most dangerous?

Children are most at risk of nicotine poisoning through eating cigarettes or nicotine-containing products, or drinking or touching liquid nicotine. Nicotine from e-cigarettes may be especially hazardous, as these products are not required to be childproof, and are available in flavors that appeal to children.

Adults who are unaccustomed to smoking and who try vaping are at greater risk of nicotine poisoning than adults who smoke regularly. Using a nicotine patch or chewing gum containing nicotine while smoking at the same time can also lead to nicotine overdose. Chewing or snorting tobacco tends to release more nicotine into the body than smoking.

Third-hand nicotine poisoning may also be an issue for adults, children, and pets. Vapors from e-cigarettes can stick to fabrics or other surfaces and then transfer to those who touch them.

A form of nicotine poisoning, known as Green Tobacco Sickness (GTS), can occur in those who harvest tobacco or work in tobacco processing factories.

Nicotine overdose depends on factors such as body weight and the source of the nicotine.

Researchers have frequently indicated that the lethal dose of nicotine for adults is 50 to 60 milligrams (mg), which prompted safety warnings stating that approximately five cigarettes or 10 milliliters (ml) of a nicotine-containing solution could be fatal.

However, the mortality rate from nicotine poisoning is extremely low, and some research suggests that it takes 500-1000 mg of oral nicotine to kill an adult.

Children are much more susceptible to the effects of nicotine, with consumption of a single cigarette shown to be enough to cause illness.

Nicotine affects the body in a variety of ways. It is both a sedative and a stimulant that impacts the heart, hormones, and digestive system.

Aside from the risk of nicotine poisoning, the primary risk associated with nicotine use is its addictive qualities. It is at least as difficult to quit nicotine as it is heroin. One study reports that consuming nicotine makes cocaine more addictive.

Many people who quit nicotine will experience withdrawal symptoms such as:

Nicotine is most harmful when taken in quantities larger than those recommended (leading to nicotine poisoning) and when consumed in cigarettes or other products that contain a variety of chemicals that are detrimental to health including cigars.

Treatment for nicotine poisoning is usually carried out at a hospital. The treatments administered will depend on the amount of nicotine ingested and the symptoms experienced.

Activated charcoal may be used to bind with the nicotine in the stomach and take it out of the body.

If the person is experiencing breathing difficulties, a ventilator will be used to deliver oxygen.

Other supportive treatments, including medications, are used to manage seizures, low blood pressure, and abnormal heart rates.

If someone is experiencing nicotine poisoning symptoms, it is important to seek emergency medical attention.

Follow the directions of the medical personnel and do not force the person to vomit or give them any food or liquids.

For nicotine that was absorbed through the skin, rinse the affected area immediately with water for 15 minutes.

The most effective way to prevent nicotine poisoning is to stop using cigarettes and other nicotine-containing products.

Other preventative measures include:

  • protecting the skin, especially when using liquids containing nicotine
  • safely storing nicotine products away from children and pets
  • correctly disposing of nicotine products – including cigarette butts and empty nicotine cartridges

People who wish to quit smoking or use of other nicotine products should consult their doctor for further information.

The outlook for those with nicotine poisoning depends on how much nicotine they have ingested and how quickly they seek treatment. With rapid medical treatment, most people make a full recovery without any long-term effects.


Contents

The dominant paradigm of drug abuse focuses on human neurobiology and suggests that drug use is the result of reward-related behavior and that drug addiction is a consequence of drug interference with natural reward systems. [1] Specifically, this tradition postulates that the chemical compounds humans seek out increase brain dopamine levels and thereby effectively usurp the mesolimbic pathway, a system originally intended to motivate/reward fitness enhancing behaviors such as those that increase access to food and sex. [2]

History Edit

Ideas concerning the neural bases of motivation and reinforcement in behavior can be traced back to the 1950s. In 1953, Olds and Milner [3] published findings implicating a brain region, specifically a cluster of dopamine neurons, with reward-based learning. Addictive substances were later discovered to increase dopamine in the region of the brain associated with reward-based-learning (see: brain stimulation reward).

Proximate mechanisms Edit

Molecular pathways Edit

Research on the molecular pathways of addiction suggests that addictive substances, despite their diverse chemical substrates, converge on a common circuitry in the brain's limbic system. Specifically, drugs are thought to activate the mesolimbic dopamine pathway, facilitating dopamine transmission in the nucleus accumbens, via disinhibition, excitation, uptake blockade, etc. [4] to produce a dopamine-like, yet dopamine independent effect. [5]

Emotional pathways Edit

The hijack model of substance addiction explains that drugs that elicit positive emotion mediate incentive motivation in the nucleus accumbens of the brain. Put another way, addictive substances act on ancient and evolutionarily conserved neural mechanisms associated with positive emotions that evolved to mediate incentive behavior. [6] [7] Psychoactive drugs induce emotions that in human evolutionary history signaled increases in fitness. [8] Positive emotions such as euphoria and excitation are tools chosen by natural selection to help direct the behavior and physiology of an individual towards an increase in Darwinian fitness. [6] [9] For example, in the environment of evolutionary adaptation, humans would feel positive euphoric emotions in response to a successful foraging session or in the event of a successful breeding. Many psychoactive substances provide this same feeling and yet do not produce fitness benefits.

Example: Alcohol Edit

Researchers [9] [10] have shown how emotional disposition is correlated with problematic use of alcohol, wherein if the reason for alcohol consumption is positive, the user is thought to drink to enhance positive feelings with greater control of the substance than if the user's emotional disposition prior to alcoholic consumption was negative. In these cases, the individual is drinking to cope and is shown to have less control over his/her own use. Alcohol mediates negative feelings by their suppression but also encourages the habituated continuance of positive emotion. Recovering alcoholics often report that the reason for relapse is often related to the impulse to compensate for negative feelings, resulting in a motivation to cope and therefore drink.

Evolutionary mismatch Edit

Drugs such as nicotine, cocaine, alcohol, THC, and opium artificially stimulate the emotions and neural circuits involved in the mesolimbic reward system, thus encouraging drug consumption despite any negative side-effects. [11] Drugs of abuse are harmful, why do they increase dopamine like sugar and sex do? The hijack hypothesis suggests that drugs are effective hijackers of neural reward circuitry (e.g. the mesolimbic dopamine system) because they are evolutionarily novel. [6] Specifically proposing that modern-day drug concentrations, methods of delivery, and the existence of certain drugs themselves were not available until recently on an evolutionary time scale, and thus human biology has been slow to adapt and is presently mismatched and susceptible.

To explain how drugs increase dopamine and cause positive emotions while at the same time lowering reproductive fitness, researchers posited that evolutionarily novel drugs hijack the brain's mesolimbic dopamine system and generate a false positive signal of a fitness benefit as well as inhibiting negative effects, to signal a lack of negative fitness consequences. [6] [12] Modern drug addiction fundamentally indicates a false increase of fitness, leading to increasing substance addiction to continue gain, even if the gain is realized as being false. [13] That these drugs create a signal in the brain that indicates, falsely, the arrival of a huge fitness benefit which changes behavioral propensities so that drug-seeking increases in frequency and displaces adaptive behaviors. [11] Proponents of the hijack hypothesis suggest that the paradox of drug reward is due to this evolutionary mismatch, that extant access to psychoactive drug concentrations and products are unmatched by those that existed in the past.

Why do humans seek out and consume drugs that harm them? The paradox of drug reward refers to the puzzling ability of drugs to induce both aversive and rewarding effects. [14] Despite contention on the particulars of dopamine-induced reward and behavior, there is agreement that dopamine plays an instrumental role in the processing of reward-related stimuli and that drug-induced dopamine stimulation explains at least some part of substance use phenomena. And still, almost all major recreational drugs are plant secondary metabolites or a close chemical analog. [12] The secondary plant compounds from which psychoactive drugs are derived are a form of interspecies defense chemicals that evolved to deter and/or mitigate consumption of the plant soma by herbivores/insects. The compounds from which psychoactive drugs are derived evolved to punish herbivore consumption, not reward it. [15]

Human-plant co-evolutionary history Edit

Animals evolved to exploit plant tissues and energy stores and in response, plants developed a number of defenses, including neurotoxins. The presence and concentration of these toxins vary by plant tissue, with leaves and organs central to reproduction and energy conservation displaying high toxin concentrations (e.g. pistils/stamens and storage organs) and absent in tissue central to seed dispersion (e.g. fruit). [16] The power and effectiveness of plant neurotoxic substances has been shaped by

400 million years of evolution. [17] Plant-derived neurotoxins are not evolutionarily novel and human neurophysiology recognizes plant toxins and activates specialized xenobiotic defenses that involve genes, tissue barriers, neural circuits, organ systems, and behaviors to protect against them. [17]

Herbivore defense mechanisms Edit

Drug toxicity and aversion exist in humans and are at odds with the theory of drug reward. Chronic drug use is harmful in humans and the human brain has evolved defenses to prevent, not reinforce substance use. In response to the evolution of plant chemical defenses, herbivores have co-evolved a number of countermeasures, [18] including (1) compounds that prevent or attenuate induction of plant chemical defenses (2) detoxification mechanisms, including enzymes and symbiotic relationships with microbes to detoxify or extract nutrients from plant defenses, and cellular membrane carrier proteins for toxin transport and (3) chemosensors and aversive learning mechanisms that permit selective feeding on less toxic tissues.

Human defense mechanisms Edit

Human and plant neurotoxin coevolution is evidenced by features of the xenobiotic defense network. Tobacco activates defense mechanisms which researchers suggests it is recognized as toxic not a reward. Nicotine activates bitter taste receptors in the mouth and gut. [19] Ingesting 4–8 mg of nicotine causes burning of the mouth and throat, nausea, aversion, vomiting and diarrhea. In higher doses the effects are more robust and can result in weakness, confusion, dizziness, convulsions, and coma. If consumed in high enough amounts, acute nicotine toxicity can trigger failure of the respiratory system and induce death in human adults within minutes. [17] First-time users of tobacco especially report a variety of unpleasant effects upon administration of nicotine, including nausea, vomiting, gastrointestinal distress, headache, and sweating. [ citation needed ] This, when taken with the fact that nicotine is a plant toxin that evolved to deter herbivores, [20] suggests instead that the human body naturally recognizes tobacco as a toxic substance, and not a reward. [21]

In addition, research has found genetic evidence that humans have had a long evolutionary history to plant neurotoxins. Sullivan et al. (2008) [12] has noted that humans, like other mammals, have ‘inherited’ the cytochrome P450 system, which functions to detoxify chemicals found in the environment, including plant neurotoxins. The ubiquity of CYP genes in humans worldwide, including CYP2A6 and CYP2B6, which metabolize nicotine, as well as other drugs, might suggest an evolutionary history with humans and plant neurotoxins. [12] The mammalian body has also evolved to develop defenses against over toxicity, such as exogenous substance metabolism and vomiting reflexes. [17]

The neurotoxin regulation model of human drug use proposes that during the course of human evolution, plant consumption played a key role. The hypothesis suggests that the compulsory consumption of both the nutrients and neurotoxins in plants selected for a system capable of maximizing the benefits of plant energy extraction while mitigating the cost of plant toxicity. [22] [12] To do this, humans evolved a defense system in which plant consumption is mediated by cues of toxicity in a manner sensitive to the individual's toxicity threshold, maintaining blood toxin concentrations below a critical level. [17]

Evidence for toxin regulation Edit

Research on herbivores supports the notion of a regulation pathway. Plant toxin concentration informs mammalian herbivore food choices, with herbivores moderating toxicity by capping daily plant intake to accommodate blood toxin concentrations. This mechanism exists across herbivore species and remains static in response to a range of plant toxins, even those that are evolutionarily novel. [23] Similarly, in laboratory conditions, mice have been shown to moderate administration of drugs regardless of dose per injection or the number of lever presses required. [24]

Example: Nicotine Edit

Evidence of toxin regulation exists across drug types and is present in the case of nicotine. In humans, self-administration of nicotine is moderated such that steady blood concentrations of the toxin are maintained. [25] [17] Moreover, though nicotine is a potent neurotoxin, lethal overdoses are rare and smoking behavior is couched around titration, with number of cigarettes smoked directly tied to changes in nicotine blood concentration. [26] In addition, although typical doses of recreational drugs are often only marginally below the lethal dose, overdose remains rare. [27] For the most part, drug consumption is metered. Thus, proponents of the neurotoxin regulation model of drug use suggest it is highly unlikely that toxin consumption is controlled by the system that motivates and rewards the consumption of macronutrients. Arguing that If drugs and sugar (and other energetically dense foods) stimulate dopamine in the mesolimbic reward system with the same degree of efficiency, then, the drug overdose rates should be comparable in scale to the incidence of obesity.

Evidence of human brain and plant neurotoxin co-evolution Edit

The neurotoxin regulation hypothesis proposes that drug use is not novel because human brains and plant neurotoxins coevolved. Genetic evidence suggests that humans have had regular exposure to plant drugs throughout our evolutionary history. [28] Archeological evidence indicates the presence of psychoactive plants and drug use in early hominid species about 2 million years ago. [9] Paleogenetic evidence suggests that the first time human ancestors were exposed and adapted to substantial amount of dietary ethanol, was approximately 10 million years ago. [29] Neurobiological evidence appears to corroborate this story. The fit of allelochemicals within the CNS indicates some coevolutionary activity between mammalian brains and psychoactive plants, meaning they interacted ecologically and therefore responded to one another evolutionarily. [9] This would have only been possible with mammalian CNS exposure to these allelochemicals, therefore to ancient mammalian psychotropic substance use. For example, the mammalian brain has evolved receptor systems for plant substances, such as the opioid receptor system, not available to the mammalian body itself.

Neurotoxin regulation hypothesis versus hijack hypothesis Edit

The neurotoxin regulation model of drug use is a response to proponents of the hijack hypothesis. [12] Largely this is because the neurobiological reward model of drug use sees interactions between plant neurotoxins and human reward systems as novel and rewarding. [6] [2]

The neurotoxin regulation hypothesis emphasizes the evolutionary biology of plant-human coevolution and maintains that secondary plant metabolites, including alkaloids like nicotine, morphine, and cocaine, are potent neurotoxins that evolved to deter and punish herbivore consumption of the plant soma not encourage/reward it. Researchers highlight that it is evolutionarily disadvantageous for plants to produce toxins that plant predators (e.g. humans) are attracted to, and that it runs contrary to evolutionary logic that plant predators (e.g. humans) would evolve neurobiological systems unprotected from plant toxin consumption. [17] [22]

Proponents of the hijack hypothesis outline a path to addiction that involves drugs co-opting neural reward systems intended for food. However, research on murine models has shown that when the concentration is sufficiently high, sugar operates as a more robust reward than even cocaine. In laboratory conditions, where rats are presented with both a sugar and cocaine sipper, they choose sugar. [24] Researchers use [24] these findings to suggest that sugar reward might generate a stronger dopamine stimulation than cocaine and also may make use of neural mechanisms beyond dopamine stimulation.

Alternative mechanisms explain continued tobacco use: The majority of first time users of cigarettes report adverse reactions, including nausea, dizziness, sickness, and headache. [30] A study by DiFranza et al. (2004) [31] found that 69% of subjects rated inhaling their first cigarette as bad, and nearly three-quarters (72%) reported that their first cigarette made them not want to smoke again. Given the above, opponents of the reward model of drug use suggest it is likely that a mechanism other than a false perception of an increased fitness benefit via hijacking of the brain's mesolimbic dopamine system, is leading to continued tobacco use.

Throughout the course of human evolution, the importance of psychoactive plant substances for health has been enormous. Since our earliest ancestors chewed on certain herbs to relieve pain, or wrapped leaves around wounds to improve healing, natural products have often been the only ways of treating disease and injury. [32] Plants provide fitness benefits. Upwards of 25% of all pharmaceutical drugs are from plant-derived sources. [33] The US National Cancer Institute has identified over 3,000 plants that are effective against cancer cells. Almost all major recreational drugs are secondary plant compounds or a close chemical analog. [12] It is well established that in both present and past contexts plants have been used for medicinal purposes. [12]

A core premise of evolutionary theory is that a trait cannot evolve unless it contributes to an individual's reproductive fitness. Proponents of the pharmacophagy hypothesis/medicinal model of drug use suggest that pharmacophagy, the consumption of pharmacological substances for medicinal purposes, evolved in the backdrop of human-plant coevolution as a means of self-medication. Theorists propose that the reason humans learned to ignore the cues of plant toxicity (e.g. bitter taste) and consumed potentially lethal substances with little to no energetic content because ingesting the bioactive compounds of plants in small amounts was therapeutic. [25] [17]

Though the long-term health costs of drug use are undeniable, proponents of the medicinal model of drug use suggest it is possible that regulated consumption of plant neurotoxins was selected. In this regard, researchers have argued that the human brain evolved to control and regulate the intake of psychoactive plant toxins in order to promote reproductive fitness. Broadly, theorists suggest that plant toxins were deliberately ingested by human ancestors to combat macroparasites (e.g. parasitic worms) and/or to ward off disease-carrying vectors (e.g. mosquitos).

Nicotine as an anthelminthic Edit

For example, researchers have recently sought to understand why humans began using tobacco in spite of the consequences and adverse reactions commonly associated with its use. Hagen and colleagues [17] [22] propose that, as in other species, [34] humans began using tobacco and other plant toxins as a way of controlling infection by parasitic diseases, including helminths. Tobacco, as well as arecoline and cannabis, two other plant neurotoxins that are widely used as recreational drugs in humans, have been found to be toxic to parasitic worms that affect humans and other mammals, as well as plants. [35] Modern anthelminthics function as well by targeting nicotinic acetylcholine receptors (nAChRs) on somatic muscle cells of parasites, producing paralysis and expelling the parasite, [36] the same receptors which are targeted by nicotine (Roulette et al., 2014). Moreover, it has also been found that nicotine is equally or more effective than commercial anthelmintics at killing leeches, including those that infect humans. [37] Similarly, Roulette et al. (2014) [35] found in a study comparing male smoking prevalence and parasite load among Aka hunter-gatherers that treatment with commercial anthelmintics was associated with a decrease in cotinine concentrations (a measure of current tobacco use), thereby supporting their theory that humans regulate the amount of tobacco used in response to current helminth infection. The study also found that men with higher initial tobacco use also had lower worm burdens one year later, suggesting that nicotine not only eliminates parasites, but also protects from reinfection.

Some evolutionary psychological theories concerning drug use suggest individuals consume drugs to increase reproductive opportunities. Drug use can increase reproductive fitness because drug use can (1) advertise biological quality, sexual maturity, or availability, (2) decrease inhibitions in mating contexts, and/or (3) enhance associative learning behaviors that in turn increase mating opportunities. See Richardson et al., 2017 [38] for a review.

Costly signaling Edit

Advertising biological quality Edit

Researchers [39] suggest that because variation in drug use susceptibility is in part due to genetic factors, drug consumption could potentially be a costly and honest signal of biological quality. [40] [41] The hypothesis being that humans engage in substance use despite health costs in part to evidence that they can afford to do so. To test the effects substance use had on indicators of mating success researchers tested the effect an individual's fluctuating asymmetry had on the propensity/likelihood to use drugs and found no significant results. [40]

Advertising sexual maturity Edit

Hagen et al. (2013) [17] suggest that individuals use drug substances to signal maturity. They point out that sexually selected cues of quality often emerge in adolescence (e.g. the peacock's tail) and reliably signal developmental maturity. The teratogenic effects of addictive substances are well documented, as is the fact that psychoactive substances are most harmful to individuals who are developmentally immature. Although this hypothesis remains untested, evidence in support comes from age at onset of drug use. Unequivocally, tobacco consumption does not occur prior to age 11 and in almost all cases, this aligns with age at onset of drug use, as cigarette addicts report having first smoked in adolescence. Hagen et al. suggest the reason drug use most often occurs in adolescent populations is due to the developmental maturity of the adolescent nervous system as well as the increased competition to compete for mates. Consistent with these notions, researchers have found that adolescents with alcohol use disorders were more sexually active, had more sexual partners, and initiated sexual activity at slightly albeit younger ages. [42]

Decreasing inhibitions Edit

Another possible explanation to the prevalence of substance use is that it contributes to mating success by altering brain functions that lower inhibitions. Generally, people seem to believe substance use will enhance their social behaviors in ways conducive to mating success. [43] Research has shown that many drug types inhibit prefrontal cortex neural activity, the area of the brain responsible conducting long term gains and short term costs. Alcohol myopia theory suggest alcohol lowers inhibitions [44] and amplifies the pre-drinking intention to have sex. [45] Research has also shown that alcohol stimulates dopamine activity in the mesolimbic-dopamine system, which amplifies the salience of natural rewards (e.g. finding food and mates) in the present environment and boost associative learning. [46]

Drug use is not evenly distributed in the population. Research has shown that the prevalence of substance use problems varies in fairly reliable ways according to age, sex, and sociodemographic characteristics. Overall, and across drug categories—including alcohol, coffee, cannabis, and nicotine—men make up the primary drug demographic. [47] Research has also shown that the prevalence of substance use disorders is highest among young adults (ages 18–29), [48] and among individuals of low socioeconomic status.

Application of evolutionary theory to patterns of drug use suggest patterns can be explained in terms of the fundamental trade-offs that occur during different developmental periods [49] as well as gender differences arising from reproductive asymmetry. [50] According to life history theory, individuals have finite energetic resources and thus face energetic allocation decisions concerning investment in maintenance, growth, and reproduction. [51] How resources are allocated to these different tasks in order to most effectively maximize reproductive fitness will depend on the age and sex of the individual and the environmental context the individual exists in.

Sex differences Edit

Life history predicts that men, especially if they are young, are most likely to engage in drug use because they are most likely to engage in risky behavior and discount the future. Young men have the most to gain from risk-taking behavior because competition for mates, status, and resources is greatest during late adolescence and young adulthood. As men age, they are more likely to develop long-term pair-bonds, accrue status, and have children, thus as men age life-history theory predicts a decrease in risk-taking behavior and a reallocation of energy to parenting rather than mating. The average age at drug initiation occurs in adolescence (ages 15–25) and supports this shift. In contrast, life-history theory predicts that women are less prone to engage in risk-taking behavior because they experience less variance in reproductive success and have more to lose from risk-taking and more to gain from focusing effort on parenting. [52]

The fetal protection hypothesis: Edit

Almost all major recreational drugs are secondary plant compounds or a close chemical analog [14] and are thus teratogenic, substances known to cause congenital abnormalities and other reproductive harms (e.g. nicotine, carbon monoxide, hydrogen cyanide). Give sex-specific vulnerabilities and fitness costs, the fetal protection hypothesis proposes that selection for increased drug avoidance could have evolved in women to protect them from harming their developing fetuses and nursing infants. [49]

Ancestral women and conditions: In the environment of evolutionary adaptation (EEA), selection pressures shaping avoidance of or defenses against teratogenic substances would have been high. Evidence from evolutionary anthropology suggest ancestral women, similar to women in extant hunter gatherer populations, experienced high fertility and high infant mortality. [53] Importantly, high fertility is characterized by short inter-birth intervals, early age at first birth, and periods of breastfeeding spanning upwards of two years. [54] Given such high reproductive costs, it is likely the fitness cost of ingesting neurotoxins is higher for women than men. One such hunter-gatherer population, the Aka, have incredibly high smoking prevalence rates among men (95%), but very low rates among women (5%). [55]

Drugs and negative fertility endpoints: Studies have shown that fetal exposure to nicotine is associated with a range of negative outcomes before and during parturition as well as for the baby early and later in life. [56] It has also been shown that cigarette smoking has a significant negative effect on the clinical outcome of assisted reproduction treatments, with smokers requiring higher mean gonadotropin doses for ovarian stimulation and requiring nearly twice the number of in vitro fertilization cycles to conceive. [57] [58]


Nicotine may harm human embryos at the single-cell level

Nicotine induces widespread adverse effects on human embryonic development at the level of individual cells, researchers report February 28th in the journal Stem Cell Reports. Single-cell RNA sequencing of human embryonic stem cell (hESC)-derived embryoid bodies revealed that 3 weeks of nicotine exposure disrupts cell-to-cell communication, decreases cell survival, and alters the expression of genes that regulate critical functions such as heart muscle-cell contractions.

The authors say this stem-cell model offers new insights into the effects of nicotine on individual organs and cells within the developing fetus and can be used to optimize drug and environmental toxicity screening.

"These results are especially important in that they provide a scientific basis for educating the public, especially young women, to keep away from smoking when they are pregnant or considering having a family," says senior author Joseph C. Wu (@StanfordCVI) of the Stanford University School of Medicine. "Nicotine found in products such as tobacco, e-cigarettes, and nicotine gums may have wide-ranging, harmful effects on different organs of a developing embryo during pregnancy."

Maternal smoking during pregnancy is an established risk factor for birth defects such as miscarriage, growth restriction, and premature birth. It is closely associated with long-term adverse neurobehavioral, cardiovascular, respiratory, endocrine, and metabolic outcomes in offspring. Nicotine, the main chemical constituent of tobacco smoking, is primarily responsible for the elevated risk. Unfortunately, the introduction and spread of new tobacco products containing nicotine, such as e-cigarettes, is reversing recent progress toward the reduction of tobacco use.

A large body of research has elucidated the negative effects of nicotine in animals, mainly in rodent models. Animal studies have demonstrated that nicotine exposure during pregnancy has detrimental effects on fetal development. But due to interspecies differences, it remains questionable whether this research can be translated to humans. While other studies have examined nicotine toxicity using human cells through bulk RNA-sequencing analysis, these conventional studies did not allow researchers to investigate effects at the single-cell level. As a result, the effects of nicotine on human embryonic development and the underlying molecular mechanisms remain poorly understood.

To address these limitations, Wu and his collaborators used single-cell RNA sequencing to analyze the effects of 21 days of nicotine exposure on the transcriptomes of a total of 12,500 cells generated from hESC-derived embryoid bodies, which are 3D aggregates of different types of pluripotent cells that give rise to the brain, heart, liver, blood vessels, muscles, and other organs. They found that cell survival decreased, suggesting that nicotine can affect embryo development as early as the preimplantation stage.

Nicotine exposure also decreased the size of the embryoid bodies, increased the level of damaging molecules called reactive oxygen species, and resulted in the aberrant formation and differentiation of the embryoid bodies. Moreover, nicotine exposure altered cell cycling in a broad range of progenitor cells differentiated from hESCs and caused dysregulated cell-to-cell communication, another adverse effect that has not been well studied.

"This is important because we know that smoking and nicotine have been shown to increase the pathological risk in endocrine, reproductive, respiratory, cardiovascular, and neurologic systems that rely on intricate and dynamic interactions amongst multiple cell types for homeostasis and function," Wu says.

The researchers also found that nicotine exposure leads to altered expression of genes implicated in metal toxicity and mitochondrial function, brain malformations and intellectual disability, muscle development and disease, lung disease, and Ca2+-associated arrhythmias that affect the contractility of heart muscle cells.

"A major implication of our study is that we now have validated a new method for evaluating the effect of drugs and environmental toxicity on human embryonic development," Wu says. "But one major limitation is that we are not able to recapitulate the whole-body physiology of a pregnant woman using differentiation of hESCs into embryoid bodies. For example, the influence of exercise, stress, food, or hormonal changes are not captured in this model."

In the future, the researchers plan to further investigate the mechanisms of nicotine-induced fetal birth defects. "We hope this will lead to the discovery of novel biomarkers that can help doctors better prevent, diagnose, and treat these diseases," Wu says. "In addition, we plan to utilize our hESC-derived embryoid body model and single-cell-sequencing technology to investigate the wider effects of other harmful conditions such as air pollution on human embryonic development."


Nicotine

Description of substance: Pale-yellow to dark-brown liquid with a fish-like odor when warm.

LEL: . . . 0.7% (10% LEL, 4,700 mg/m 3 )

Original (SCP) IDLH: 35 mg/m 3

Basis for original (SCP) IDLH: No data on acute inhalation toxicity are available on which to base the IDLH for nicotine. The chosen IDLH, therefore, has been estimated from the human oral lethal dose of 60 mg [Lehman 1938 cited by Patty 1963 and ACGIH 1971].

Short-term exposure guidelines: None developed

ACUTE TOXICITY DATA:

Lethal dose data:

Human data: The fatal human dose has been estimated to be about 50 to 60 mg [Lazutka et al. 1969]. [Note: An oral dose of 50 to 60 mg/kg is equivalent to a 70-kg worker being exposed to about 30 to 40 mg/m 3 for 30 minutes, assuming a breathing rate of 50 liters per minute and 100% absorption.]

Basis for revised IDLH: No inhalation toxicity data are available on which to base an IDLH for nicotine. Therefore, the revised IDLH for nicotine is 5 mg/m 3 based on acute oral toxicity data in humans [Lazutka et al. 1969] and animals [Franke and Thomas 1932 Lazutka et al. 1969].

REFERENCES:

1. ACGIH [1971]. Nicotine. In: Documentation of the threshold limit values for substances in workroom air. 3rd ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, p. 181.

2. Franke FE, Thomas JE [1932]. A note on the minimal fatal dose of nicotine for unanesthetized dogs. Proc Soc Exp Biol Med 29:1177-1179.

3. Lazutka FA, Vasilyauskene AD, Gefen SG [1969]. Toxicological evaluation of the insecticide nicotine sulfate. Gig Sanit 34(5):30-33 (translated).

4. Lehman AJ [1938]. Pharmacological considerations of insecticides. Q Bulletin Assoc Food Drug Off U.S. 13(2):65-70.

5. Patty FA, ed. [1963]. Industrial hygiene and toxicology. 2nd rev. ed. Vol. II. Toxicology. New York, NY: Interscience Publishers, Inc., p. 2196.

6. Sine C, ed. [1993]. Nicotine. In: Farm chemicals handbook &rsquo93, p. C245.


E-cigarettes don’t need nicotine to be toxic

Liquids for electronic cigarettes come in a variety of flavors — with and without nicotine. A new study finds that vapors from even those without nicotine can still poison cells.

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Think electronic cigarettes without nicotine are harmless? Think again. A new study shows that the flavorings in e-cigs can harm human infection-fighting cells.

E-cigarettes work by heating a flavored liquid to make a mist that users inhale, or “vape.” These flavored liquids, called e-liquids, usually contain nicotine. But not always. Manufacturers add nicotine for vapers who want a buzz from their e-cigarettes. It’s the same stimulant that true cigarettes deliver. That nicotine — made from tobacco — qualifies most e-cigs as “tobacco products.”

The nicotine may be useful for adults who are addicted to cigarettes and want to wean themselves off. But nicotine can harm children and teens. That’s why some young people may choose to vape instead of smoke, and use nicotine-free products. But the new data suggest that e-cigs can still be toxic, even without nicotine.

“We know these flavors are really attractive to teens,” says Irfan Rahman. He works at the University of Rochester in New York. He says studies have shown that one reason many teens try e-cigarettes is an interest in fruity and candy-flavored products.

Explainer: What are e-cigarettes?

As a toxicologist, Rahman studies whether various materials can poison the body’s cells or tissues. His team decided to test whether certain flavored e-liquids are toxic (meaning poisonous). They tested several common e-liquid flavorings. These included cinnamon roll, cotton candy, melon, pineapple, coconut and cherry.

Such flavorings are considered safe in foods. That’s because after a person swallows them, they’re broken down in the gut. But that doesn’t mean these same chemicals are safe to breathe in. They could harm parts of the respiratory tract, such as the lungs.

Rahman’s team didn’t expose people to these flavorings, in case they were harmful. Instead, they tested e-liquid chemicals on human cells in a dish. This helped them judge whether the chemicals might also harm cells inside the body.

The answer: Some of the vaped flavorings did prove toxic to those cells. The researchers published their findings in the January Frontiers in Physiology.

Cells vs. cinnamon

After a person vapes, e-liquid chemicals could pass through the walls of small vessels in the lungs to enter the blood, says Thivanka Muthumalage. He’s a researcher in Rahman’s lab.

Rahman’s team wanted to know what would happen when these chemicals encountered blood cells. In one set of tests, the researchers exposed blood cells directly to the flavorings. They chose a type of white blood cell called a macrophage (MAK-roh-fayj). These cells are part of the immune system, which fights disease. Macrophages hunt down and “eat” particles that shouldn’t be in the blood stream. Those foreign particles could be germs or other things that might make people sick.

The team used doses of flavoring chemicals similar to what are in the e-liquids that you can buy at a store, says Muthumalage. The doses in the experiment might even have been lower than what people would vape.

To measure how toxic each chemical was, the researchers looked for signs of stress in the cells, or even cell death. A number of e-liquid flavoring chemicals caused high levels of cell stress or death. Those included flavorings that taste buttery (these contain the chemicals pentanedione and acetoin). They also included flavorings that taste like vanilla (O-vanillin), cotton candy, caramel (maltol) and cinnamon (cinnamaldehyde).

That last one, cinnamaldehyde (Sih-nuh-MAAL-duh-hide), killed the most cells. And that’s bad. Dead immune cells can’t fight infection, explains Muthumalage.

His team’s findings are backed up by a study in the March 27 PLOS Biology. Researchers at the University of North Carolina School of Medicine in Chapel Hill tested the effects of 148 e-liquids on human cells. When exposed to vapors of some e-liquid flavors, it showed, fewer of these cells grew. The worst culprits? Cinnamaldehyde and vanillin.

A vaping machine

In a second set of tests, the researchers used a “vaping machine” to suck e-liquids through an e-cigarette. Afterward, they measured what vapors had entered the air. These mists are what an e-cig user would ordinarily inhale. The researchers then exposed human cells to these vapors.

Researchers used this machine to mechanically “vape” e-liquids. The researchers then measured harmful chemicals that had been released into the air. Irfan Rahman

They showed that heating each flavoring in an e-cigarette created harmful levels of molecules that can damage cells. What’s more, mixing two or more flavors together caused even higher levels of these damaging molecules than did heating each on its own.

This suggests that breathing in multiple e-liquid flavors could be more dangerous than exposure to just one at a time.

That’s concerning, says Melanie Prinz. She’s a college student who worked on the study in Rahman’s lab. “Teens at parties often pass their [e-cig] devices around,” she notes. That means they could be “sharing and inhaling a lot of different flavors.”

The findings from Rahman’s lab agree with the findings from another study. It looked at vapors from nicotine-free e-cigs. Here, researchers at the University of California San Francisco studied the urine of teens who had vaped e-liquids without nicotine. The researchers looked for toxic chemicals that form when e-liquids are heated. The teens had up to three times the levels of five potentially cancer-causing chemicals in their bodies as did those who didn’t vape. These findings appear in the April Pediatrics.

That was the first study to measure the toxic chemicals that can get into the bodies of teens vaping nicotine-free e-liquids.

Cause for concern

Maciej Goniewicz works at the Roswell Park Comprehensive Cancer Center in Buffalo, N.Y. There he, too, studies the health effects of e-cig vapors. Testing the toxicity of e-liquid flavoring on cells is extremely important, he says. It helps identify which chemicals may be “bad actors,” he explains.

If these tests show strong toxicity, they could help government agencies decide which products to regulate — or even ban. Such data, he adds, could also help manufacturers create safer vape products.

Explainer: The nico-teen brain

One benefit of studying cells in a dish, rather than studying actual people, is that you can limit variables, Goniewicz says. For instance, the Rochester team could omit nicotine, a known bad actor. But in real life, people might vape a liquid with nicotine one day and another without nicotine the next day. This could make it harder for scientists to tease apart the effects of flavorings and nicotine.

But cell studies are just one piece of the puzzle. They’re good for identifying potentially toxic chemicals. They don’t, however, tell us about the long-term effects of exposure to them. Human studies will — but they take far longer. A disease may not show up for years or decades after a toxic exposure.

In fact, a large review found that the long-term health effects of vaping are not yet clear. A review is a research paper that gathers the results of other studies. This paper included more than 800 scientific studies — and found cause for concern.

For instance, it found “moderate evidence” that vaping led to more coughing and wheezing in teens, and worse asthma. There is also moderate evidence linking vaping to a short-term rise in blood pressure, and to harmful stiffening of blood vessels. And the review authors found “substantial evidence” that e-cig vapors can damage DNA and cells.

This massive report, released January 23, was issued by the U.S. National Academies of Sciences, Engineering and Medicine.

Power Words

asthma A disease affecting the body’s airways, which are the tubes through which animals breathe. Asthma obstructs these airways through swelling, the production of too much mucus or a tightening of the tubes. As a result, the body can expand to breathe in air, but loses the ability to exhale appropriately. The most common cause of asthma is an allergy. Asthma is a leading cause of hospitalization and the top chronic disease responsible for kids missing school.

blood pressure The force exerted against vessel walls by blood moving through the body. Usually this pressure refers to blood moving specifically through the body’s arteries. That pressure allows blood to circulate to our heads and keeps the fluid moving so that it can deliver oxygen to all tissues. Blood pressure can vary based on physical activity and the body’s position. High blood pressure can put someone at risk for heart attacks or stroke. Low blood pressure may leave people dizzy, or faint, as the pressure becomes too low to supply enough blood to the brain.

blood vessel A tubular structure that carries blood through the tissues and organs.

cancer Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.

cell The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall.

chemical A substance formed from two or more atoms that unite (bond) in a fixed proportion and structure. For example, water is a chemical made when two hydrogen atoms bond to one oxygen atom. Its chemical formula is H2O. Chemical also can be an adjective to describe properties of materials that are the result of various reactions between different compounds.

chronic A condition, such as an illness (or its symptoms, including pain), that lasts for a long time.

DNA (short for deoxyribonucleic acid) A long, double-stranded and spiral-shaped molecule inside most living cells that carries genetic instructions. It is built on a backbone of phosphorus, oxygen, and carbon atoms. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.

e-cigarette (short for electronic cigarette) Battery-powered device that disperses nicotine and other chemicals as tiny airborne particles that users can inhale. They were originally developed as a safer alternative to cigarettes that users could use as they tried to slowly break their addiction to the nicotine in tobacco products. These devices heat up a flavored liquid until it evaporates, producing vapors. People use these devices are known as vapers.

e-liquid A term for the solutions heated to the evaporation point in an electronic cigarette. These solutions are the basis of the vapors that will be inhaled. The liquid typically contains a solvent into which flavorings and nicotine have been dissolved.

flavor The particular taste associated with something that is eaten or drunk. This is based largely on how it is sensed by cells in the mouth. It can also be influenced, to some extent, by its smell.

germ Any one-celled microorganism, such as a bacterium or fungal species, or a virus particle. Some germs cause disease. Others can promote the health of more complex organisms, including birds and mammals. The health effects of most germs, however, remain unknown.

gut An informal term for the gastrointestinal tract, especially the intestines.

immune system The collection of cells and their responses that help the body fight off infections and deal with foreign substances that may provoke allergies.

infection A disease that can spread from one organism to another. It’s usually caused by some type of germ.

macrophage A type of white blood cell dispatched by the immune system. Like janitors of the body, they gobble up germs, wastes and debris for disposal. These cells also stimulate other immune cells by exposing them to small bits of the invaders.

nicotine A colorless, oily chemical produced in tobacco and certain other plants. It creates the “buzz” associated with smoking. Highly addictive, nicotine is the substance that makes it hard for smokers to give up their use of cigarettes. The chemical is also a poison, sometimes used as a pesticide to kill insects and even some invasive snakes or frogs.

oxidation (adj. oxidative) A process that involves one molecule’s theft of an electron from another. The victim of that reaction is said to have been “oxidized,” and the oxidizing agent (the thief) is “reduced.” The oxidized molecule makes itself whole again by robbing an electron from another molecule. Oxidation reactions with molecules in living cells are so violent that they can cause cell death. Oxidation often involves oxygen atoms — but not always.

particle A minute amount of something.

respiratory Of or referring to parts of the body involved in breathing (called the respiratory system). It includes the lungs, nose, sinuses, throat and other large airways.

respiratory tract Parts of the body involved in breathing (also called the respiratory system). It includes the lungs, nose, sinuses, throat and other large airways.

stimulant Something that triggers an action. (in medicine) Drugs that can stimulate the brain, triggering a feeling of more energy and alertness. Caffeine, for instance, is a mild stimulant that for a short while enhances alertness and helps fight drowsiness. Other stimulants, including some dangerous illegal drugs — such as cocaine — have stronger or longer-lasting effects.

tissue Made of cells, any of the distinct types of materials that make up animals, plants or fungi. Cells within a tissue work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues.

tobacco A plant cultivated for its leaves, which many people burn in cigars, cigarettes, and pipes. Tobacco leaves also are sometimes chewed. The main active drug in tobacco leaves is nicotine, a powerful stimulant (and poison).

toxic Poisonous or able to harm or kill cells, tissues or whole organisms. The measure of risk posed by such a poison is its toxicity.

toxicologist A scientist who investigates the potential harm posed by physical agents in the environment. These may include materials to which we may be intentionally exposed, such as chemicals, cigarette smoke and foods, or materials to which we are exposed without choice, such as air and water pollutants. Toxicologists may study the risks such exposures cause, how they produce harm or how they move throughout the environment.

tract A particular, well-defined area. It can be a patch of land, such as the area on which a house is located. Or it can be a bit of real estate in the body. For instance, important parts of an animal’s body will include its respiratory tract (lungs and airways), reproductive tract (gonads and hormone systems important to reproduction) and gastro-intestinal tract (the stomach and intestines — or organs responsible for moving food, digesting it, absorbing it and eliminating wastes).

vaping (v. to vape) A slang term for the use of e-cigarettes because these devices emit vapor, not smoke. People who do this are referred to as vapers.

vapors Fumes released when a liquid transforms to a gas, usually as a result of heating.

Citations

Journal: M.L. Rubinstein et al. Adolescent exposure to toxic volatile organic chemicals from e-cigarettes. Pediatrics. Vol. 141, April 2018, p. e20173557. doi: 10.1542/peds.2017-3557.

Journal: M.F. Sassano et al. Evaluation of e-liquid toxicity using an open-source high-throughput screening assay. PLoS Biology. Vol 16, March 27, 2018, p. e2003904. doi: 10.1371/journal.pbio.2003904.

Report: Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems. Public Health Consequences of E-Cigarettes. The National Academies of Sciences, Engineering, and Medicine. Published online January 23, 2018. doi: 10.17226/24952.

Journal: T. Muthumalage et al. Inflammatory and oxidative responses induced by exposure to commonly used e-cigarette flavoring chemicals and flavored e-liquids without nicotine. Frontiers in Physiology. Vol. 8, Article No. 1130, published online January 11, 2018. doi: 10.3389/fphys.2017.01130.

About Lindsey Konkel

Lindsey Konkel likes to write stories about the environment and health for Science News for Students . She has degrees in biology and journalism. She has three cats, Misty, Trumpet and Charlotte, and one dog, Lucky.

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How Smoking Encourages Infection

Smokers are often more prone to bacterial infections and inflammatory diseases than the rest of us, thanks to hundreds of toxic components in their cigarettes. Now new research shows that nicotine affects neutrophils, the short-lived white blood cells that defend against infection, by reducing their ability to seek and destroy bacteria.

Neutrophils are generated by our bone marrow, which they leave as terminally differentiated cells. Although nicotine is known to affect neutrophils, there has been no study until now of the mechanisms at work when nicotine is present during neutrophil differentiation. David Scott from the Oral Health and Systemic Disease Research Group at the University of Louisville School of Dentistry, Kentucky, USA, along with a team of international colleagues decided to investigate how nicotine influenced the differentiation process.

The authors suggest the processes they observed as contributing to impaired neutrophil function partially explain chronic tobacco users' increased susceptibility to bacterial infection and inflammatory diseases. A better understanding of this relationship could pave the way for specific therapeutic strategies to treat a number of important tobacco-associated inflammatory diseases and conditions.

The team modeled the neutrophil differentiation process beginning with promyelocytic HL-60 cells, which differentiated into neutrophils following dimethylsulfoxide (DMSO) treatment both with and without nicotine. The researchers found that nicotine increased the percentage of cells in late differentiation phases (metamyelocytes, banded neutrophils and segmented neutrophils) compared to DMSO alone, but did not affect other neutrophil differentiation markers that they examined.

However, the nicotine treated neutrophils were less able to seek and destroy bacteria than nicotine-free neutrophils. The nicotine suppressed the oxidative burst in HL-60 cells, a function that helps kill invading bacteria. Nicotine also increased MMP-9 release, a factor involved in tissue degradation.

"It must be acknowledged that our study model, DMSO-differentiated HL-60 cells, are not entirely similar to normal neutrophils," says Scott. "However, this leukemic human cell line does permit the reproducible study of differentiation while retaining many of the key effector functions of primary neutrophils."

Journal reference: The influence of nicotine on granulocytic differentiation -- inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release. Minqi Xu, James E. Scott, Kan-Zhi Liu, Hannah R. Bishop, Diane E. Renaud, Richard M. Palmer, Abdel Soussi-Gounni, and David A. Scott. BMC Cell Biology (in press)

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