Safety of electronic cigarettes

A serious concern regarding vaping is that they could entice children to initiate smoking, either by the argument that nicotine leads to smoking or by making smoking appear more acceptable again.[45] Concerns exist in respect to adolescence vaping due to studies indicating nicotine may potentially have harmful effects on the brain.[46]

The medical community is concerned that increased availability of e-cigarettes could increase worldwide nicotine dependence, especially among the young as they are enticed by the various flavor options e-cigarettes have to offer.[47] Since vaping does not produce smoke from burning tobacco, the opponents of e-cigarettes fear that traditional smokers will substitute vaping for smoking in settings where smoking is not permitted without any real intention of quitting traditional cigarettes.[47] Furthermore, vaping in public places, coupled with recent e-cigarette commercials on national television, could possibly undermine or weaken current antismoking regulations.[47] Fear exists that wide-scale promotion and use of e-cigarettes, fuelled by an increase in the advertising of these products, may carry substantial public health risks.[48] Public health professionals voiced concerns regarding vaping while using other tobacco products, particularly combustible products.[49] The entrance of large US tobacco manufacturers, which are Altria Group, Reynolds American, and Lorillard, into the e-cigarette sector raises many potential public health issues.[50] Instead of encouraging quitting, the tobacco industry could market e-cigarettes as a way to get around clean indoor air laws, which promotes dual use.[50] The industry could also lead vapers to tobacco products, which would increase instead of decrease overall addiction.[50] Concerns exist that the emergence of e-cigarettes may benefit Big Tobacco to sustain an industry for tobacco.[51] A 2017 review states that the "Increased concentration of the ENDS market in the hands of the transnational tobacco companies is concerning to the public health community, given the industry's legacy of obfuscating many fundamental truths about their products and misleading the public with false claims, including that low-tar and so-called "light" cigarettes would reduce the harms associated with smoking. Although industry representatives are claiming interest in ENDS because of their harm-reduction potential, many observers believe that profit remains the dominant motivation."[49] E-cigarettes are expanding the tobacco epidemic by bringing lower-risk youth into the market, many of whom then transition to smoking cigarettes.[52]

There is concern that e-cigarettes may result in many smokers rejecting historically effective quitting smoking methods.[32] Concern exists that the majority of smokers attempting to quit by vaping may stop smoking but maintain nicotine intake because their long-term effects are not clear.[53] Since e-cigarettes are intended to be used repeatedly, they can conveniently be used for an extended period of time, which may contribute to increased adverse effects.[54]

The most frequently reported less harmful effects of vaping compared to smoking were reduced shortness of breath, reduced cough, reduced spitting, and reduced sore throat.[34] Many health benefits are associated with switching from tobacco products to e-cigarettes including decreased weight gain after smoking cessation and improved exercise tolerance.[55] Vaping is possibly harmful by virtue of putting off quitting smoking, serving as a gateway to tobacco use in never-smokers or causing a return to smoking in former smokers.[56] Many people use e-cigarettes to quit smoking, but few succeed.[57] They frequently use both, which increases their health risks by using both products.[57]

Vaping can hinder smokers from trying to quit, resulting in increased tobacco use and associated health problems.[58] Quitting smoking entirely would probably have much greater beneficial effects to overall health than vaping to decrease the number of cigarettes smoked.[3] A 2017 review found "Because the brain does not reach full maturity until the mid-20s, restricting sales of electronic cigarettes and all tobacco products to individuals aged at least 21 years and older could have positive health benefits for adolescents and young adults."[59] Adverse effects to the health of children is mostly not known.[60] E-cigarettes are a source of potential developmental toxicants.[61] Children subjected to e-cigarettes had a higher likelihood of having more than one adverse effect and effects were more significant, than with children subjected to traditional cigarettes.[60] Significant harmful effects were cyanosis, nausea, and coma, among others.[60]

More serious adverse effects frequently related with smoking cessation including depression, insomnia, and anxiety are uncommon with e-cigarette use.[62]

E-cigarettes were associated with fewer adverse effects than nicotine patches.[63] Contact dermatitis from nickel exposure has been reported, following e-cigarette use.[64]

The degree of relative safety of the same amount of use of electronic versus conventional cigarettes is disputed. 2015[65] and 2018 Public Health England (PHE) reports claimed that vaping is "at least 95% less harmful than smoking", while pointing out that this does not mean vaping is safe.[66] This claim has been widely repeated, including by the Royal College of Physicians, the Royal Society for Public Health, and the National Health Service.[52] The original paper making the claim pointed out that the accuracy of the estimate was limited by "lack of hard evidence for the harms of most products on most of the criteria".[52] The group that produced the estimate in a 2014 meeting was funded by EuroSwiss Health and has been criticized as using a weak methodology,[67] not citing specific evidence,[52] and for having financial ties to the tobacco industry.[67][52]

The estimate has been extensively disputed in medical journals.[68] Many vigorously criticized the validity of the estimate that vaping is 95% less harmful than smoking.[49] Some researchers claim in more recent papers that the harm from electronic cigarettes is known to be higher than the 95% figure.[69][52]

A government review by Public Health England[70] finds that e-cigarettes sold in England (which are regulated to a nicotine strength[71] of no more than 20 mg/ml[72]) are unlikely to exceed 5% of the harm of cigarettes for non-pregnant adults. This claim is consistent with the view of the National Academies of Sciences, Engineering, and Medicine[73] of the United States, which argues that e-cigarettes are not without risk, but compared to combustible tobacco cigarettes, they contain fewer toxicants. Furthermore, e-cigarette is not only a harm reduction alternative to smoking; but it is also a smoking cessation product, at least to the same extent to other Food and Drug Administration-approved nicotine replacement therapies.[74]

Frequent vaping among middle and high school students has been correlated with cracked or broken teeth and tongue or cheek pain in a 2017 study relying on self-reporting.[95] There is fair evidence that coughing and wheezing is higher in adolescents who vape.[96]

The US Food and Drug Administration Center for Tobacco Products reported between 2008 and the beginning of 2012, 47 cases of adverse effects associated with e-cigarettes, of which eight were considered serious.[19] Two peer-reviewed reports of lipoid pneumonia were related to e-cigarette use, as well as two reports in the media in Spain and the UK.[97] The man from the UK reportedly died from severe lipoid pneumonia in 2011.[97] In August 2019, the Illinois Department of Public Health (IDPH) reported the first death in the US linked to vaping.[98] The person who had died had been recently using an e-cigarette and was hospitalized with serious respiratory problems.[98]

Symptoms of nicotine poisoning related to e-cigarette calls to US poison control centers.[99]

Nicotine poisoning related to e-cigarettes include ingestion, inhalation, or absorption via the skin or eyes.[24] Accidental poisoning can result from using undiluted concentrated nicotine when mistakenly used as prepared e-liquids.[83] E-cigarettes involve accidental nicotine exposure in children.[25] Accidental exposures in pediatric patients include ingesting of e-liquids and inhaling of e-cigarette vapors.[25] Choking on e-cigarette components is a potential risk.[25] It was stated in 2014 that an infant died from choking on an e-cigarette component.[100] It is recommended that youth access to e-cigarettes be prohibited.[notes 3][101] Concerns exist regarding poisoning, considering they may appeal to children.[100] E-liquid presents a poisoning risk, particularly for small children, who may see the colorful bottles as toys or candy.[102]

The e-liquid can be toxic if swallowed, especially among small children.[19] Four adults died in the US and Europe, after intentionally ingesting liquid.[97] Two children, one in the US in 2014 and another in Israel in 2013, died after ingesting liquid nicotine.[103] A two-year-old girl in the UK in 2014 was hospitalized after licking an e-cigarette liquid refill.[104] Death from accidental nicotine poisoning is very uncommon.[105]

Calls to US poison control centers related to e-cigarette exposures involved inhalations, eye exposures, skin exposures, and ingestion, in both adults and young children.[106] Minor, moderate, and serious adverse effects involved adults and young children.[107] Minor effects correlated with e-cigarette liquid poisoning were tachycardia, tremor, chest pain and hypertension.[108] More serious effects were bradycardia, hypotension, nausea, respiratory paralysis, atrial fibrillation and dyspnea.[108] The exact correlation is not fully known between these effects and e-cigarettes.[108] The initial symptoms of nicotine poisoning may include rapid heart rate, sweating, feeling sick, and throwing up, and delayed symptoms include low blood pressure, seizures, and hypoventilation.[109] Rare serious effects included coma, seizure, trouble breathing trouble breathing, and heart attack.[110] Since June 2018, the US FDA observed a slight but noticeable increase in reports of seizures.[111] After examining poison control centers' reports between 2010 and early 2019, the FDA determined that, between the poison control centers and the US FDA, there were a total of 35 reported cases of seizures mentioning use of e-cigarettes within that timeframe.[111] Due to the voluntary nature of these case reports, there may be more instances of seizure in e-cigarette users than have been reported.[111]

Since 2011, accidental poisoning from e-liquids that contain nicotine have grown rapidly in the US.[112] From September 1, 2010, to December 31, 2014, 58% of e-cigarette calls to US poison control centers were related to children 5 years old or less.[107] Exposures for children below the age of 6 is a concern because a small dose of nicotine e-liquid may be fatal.[110] A 2014 Centers for Disease Control and Prevention report found 51.1% of the calls to US poison centers due to e-cigarettes were related to children under age 5, and about 42% of the US poison center calls were related to people age 20 and older.[113] E-cigarette calls had a greater chance to report an adverse effect and a greater chance to report a moderate or major adverse effect than traditional cigarette calls.[107] Most of the e-cigarette and traditional cigarette calls were a minor effect.[107] Severe outcomes were more than 2.5 times more frequent in children exposed to e-cigarettes and nicotine e-liquid than with traditional cigarettes.[114] E-cigarette sales were roughly equivalent to just 3.5% of traditional cigarette sales, but e-cigarettes represented 44% of the total number of e-cigarette and traditional cigarette calls to US poison control centers in December 2014.[107]

Poison control center calls in the US related to e-cigarettes was one call per month in September 2010 to over 200 calls per month in February 2014.[113]

The US poison control centers reported 92.5% of children coming in contact with liquid nicotine was from swallowing during the period from January 2012 to April 2017.[110] From September 1, 2010 to December 31, 2014, the most frequent adverse effects to e-cigarettes and e-liquid reported to US poison control centers were: Ingestion exposure resulted in vomiting, nausea, drowsy, tachycardia, or agitation;[107] inhalation/nasal exposure resulted in nausea, vomiting, dizziness, agitated, or headache;[107] ocular exposure resulted in eye irritation or pain, red eye or conjunctivitis, blurred vision, headache, or corneal abrasion;[107] multiple routes of exposure resulted in eye irritation or pain, vomiting, red eye or conjunctivitis, nausea, or cough;[107] and dermal exposure that resulted in nausea, dizziness, vomiting, headache, or tachycardia.[107] The ten most frequent adverse effects to e-cigarettes and e-liquid reported to US poison control centers were vomiting (40.4%), eye irritation or pain (20.3%), nausea (16.8%), red eye or conjunctivitis (10.5%), dizziness (7.5%), tachycardia (7.1%), drowsiness (7.1%), agitation (6.3%), headache (4.8%), and cough (4.5%).[107] In nine reported calls, exposed individuals stated the device leaked.[107] In five reported calls, individuals used e-liquid for their eyes rather than use eye drops.[107] In one reported call, an infant was given the e-liquid by an adult who thought it was the infant's medication.[107] There were also reports of choking on e-cigarette components.[25]

From January 1, 2016, and April 30, 2016, the American Association of Poison Control Centers (AAPCC) reported 623 exposures related to e-cigarettes.[57] In 2016 AAPCC reported there were a total of 2,907 exposures regarding e-cigarettes and liquid nicotine.[115] The yearly nicotine exposure rate in the US involving children went up by 1398.2% from 2012 to 2015, and later dropped by 19.8% from 2015 to 2016.[110] The AAPCC reported 3,067 exposures relating to e-cigarettes and liquid nicotine in 2015, and 3,783 in 2014.[116] As of October 31, 2018, there were a total of 2,555 exposures regarding e-cigarettes and liquid nicotine in 2018.[115] The US National Poison Control database showed that in 2015 more than 1000 needed medical attention from being exposed to nicotine e-liquid.[64] Most exposures in 2015 were related to children under the age of 5.[64] The reported e-cigarette poisonings to medical centres in the UK most often happen in children under the age of five.[117] Toxic effects for children under the age of five in the UK are typically short in length and not severe.[117] From September 1, 2010 to December 31, 2014, there were at least 5,970 e-cigarette calls to US poison control centers.[107] Calls to US poison control centers related to e-cigarettes increased between September 2010 to February 2014, and of the total number of cigarettes and e-cigarettes calls, e-cigarette calls increased from 0.3% to 41.7%.[63] Calls to US poison controls centers related to e-cigarette liquid poisoning increased from 1 in September 2010 to 215 for the month of February 2014.[108] E-cigarette calls was 401 for the month of April 2014.[107] The National Poison Data System stated that exposures to e-cigarettes and liquid nicotine among young children is rising significantly.[118] The California Poison Control System reported 35 cases of e-cigarette contact from 2010 to 2012, 14 were in children and 25 were from accidental contact.[10] Calls associated with e-cigarette poisoning in Texas found that 57% was associated with children under the age of 5.[89] They were accidental with 96% where they lived, 85% from swallowing, and 11% from skin contact.[89]

In 2017, the US Food and Drug Administration states that the e-cigarette aerosol can still cause problems for the user and their pets.[119] Some studies have shown that the aerosol made by these devices may expose the user and, therefore, their pets to higher-than-normal amounts of nicotine and other toxic chemicals, like formaldehyde.[119] E-cigarettes use capsules that can contain nicotine.[119] Some of these capsules can be re-filled using a special liquid.[119] Sometimes, pets—mainly dogs—find the capsules and bite them or get into the liquid refilling solution.[119] In a March 15, 2016, letter to the editor of the Journal of the American Veterinary Medical Association, the Texas Poison Center Network reported 11 cases of dogs being exposed to e-cigarettes or refills.[119] Moreover, there is no antidote for nicotine poisoning.[119] If someone's pet gets into an e-cigarette, nicotine capsule, or the liquid refilling solution, it is an emergency, according to the FDA.[119] Get him or her to the veterinarian or to a veterinary emergency clinic as quickly as possible, according to the FDA.[119] The Animal Poison Control Center states that all the nicotine toxicity cases in 2012 included 4.6% of e-cigarettes causes and it increased to 13.6% in 2013.[120]

Fruit flavored e-liquids.

There is a possibility that inhalation, ingestion, or skin contact can expose people to high levels of nicotine.[17] Concerns with exposure to the e-liquids include leaks or spills and contact with contaminants in the e-liquid.[84] This may be especially risky to children, pregnant women, and nursing mothers.[17] The FDA intends to develop product standards around concerns about children's exposure to liquid nicotine.[121] E-liquid exposure whether intentional or unintentional from ingestion, eye contact, or skin contact can cause adverse effects such as seizures, anoxic brain trauma, throwing up, and lactic acidosis.[122] The liquid does quickly absorb into the skin.[123] Local irritation can be induced by skin or mucosal nicotine exposure.[124] The nicotine in e-liquid can be hazardous to infants.[125] Even a portion of e-liquid may be lethal to a little child.[126] An excessive amount of nicotine for a child that is capable of being fatal is 0.1–0.2 mg/kg of body weight.[17] Less than a 1 tablespoon of contact or ingestion of e-liquid can cause nausea, vomiting, cardiac arrest, seizures, or coma.[127] An accidental ingestion of only 6 mg may be lethal to children.[53][128]

Children are susceptible to ingestion due to their curiosity and desire for oral exploration.[114] Children could confuse the fruity or sweet flavored e-liquid bottles for fruit juices.[89] E-liquids are packed in colorful containers[107] and children may be attracted to the flavored liquids.[39] More youth-oriented flavors include "My Birthday Cake" or "Tutti Frutti Gumballs".[103] Many nicotine cartridges and bottles of liquid are not child-resistant to stop contact or accidental ingestion of nicotine by children.[88] "Open" e-cigarette devices, with a refillable tank for e-liquids, are believed to be the biggest risk to young children.[127] If flavored e-cigarettes are let alone, pets and children could be attracted to them.[129] The FDA states that children are curious and put all sorts of things in their mouths.[130] Even if you turn away for a few seconds, they can quickly get into things that could harm them.[130] The FDA recommends that adults can help prevent accidental exposure to e-liquids by always putting their e-cigarettes and e-liquids up and away—and out of kids' and pets' reach and sight—every time you use them.[130] The FDA recommends to also ask family members, house guests, and other visitors who vape to keep bags or coats that hold e-cigarettes or e-liquids up and away and out of reach and sight of children and pets.[130] They recommend for children old enough to understand, explain to them that these products can be dangerous and should not be touched.[130] The FDA states to tell kids that adults are the only people who should handle these products.[130]

As part of ongoing efforts to protect youth from the dangers of nicotine and tobacco products, the US FDA and the Federal Trade Commission announced on May 1, 2018, they issued 13 warning letters to manufacturers, distributors, and retailers for selling e-liquids used in e-cigarettes with labeling and/or advertising that cause them to resemble kid-friendly food products, such as juice boxes, candy or cookies, some of them with cartoon-like imagery.[131] Several of the companies receiving warning letters were also cited for illegally selling the products to minors.[131] "No child should be using any tobacco product, and no tobacco products should be marketed in a way that endangers kids – especially by using imagery that misleads them into thinking the products are things they would eat or drink. Looking at these side-to-side comparisons is alarming. It is easy to see how a child could confuse these e-liquid products for something they believe they have consumed before – like a juice box. These are preventable accidents that have the potential to result in serious harm or even death. Companies selling these products have a responsibility to ensure they are not putting children in harm's way or enticing youth use, and we'll continue to take action against those who sell tobacco products to youth and market products in this egregious fashion," the FDA Commissioner Dr. Scott Gottlieb, said in 2018.[131] E-liquids have been sold in packaging that looks similar to Tree Top-brand juice boxes, Reddi-wip whipped cream, and Sour Patch Kids gummy candy.[132]

The US FDA announced on August 23, 2018 that all 17 manufacturers, distributors and retailers that were warned by the agency in May, have stopped selling the nicotine-containing e-liquids used in e-cigarettes with labeling or advertising resembling kid-friendly food products, such as juice boxes, candy or cookies that were identified through warning letters as being false or misleading.[133] Following the warning letters in May, the FDA worked to ensure the companies took appropriate corrective action – such as no longer selling the products with the misleading labeling or advertising – and issued close-out letters to the firms. The agency expects some of the companies may sell the products with revised labeling that addresses the concerns expressed in the warning letters.[133] "Removing these products from the market was a critical step toward protecting our kids. We can all agree no kid should ever start using any tobacco or nicotine-containing product, and companies that sell them have a responsibility to ensure they aren’t enticing youth use. When companies market these products using imagery that misleads a child into thinking they’re things they’ve consumed before, like a juice box or candy, that can create an imminent risk of harm to a child who may confuse the product for something safe and familiar," said FDA Commissioner Scott Gottlieb.[133]

There is growing evidence that vaping is hazardous to your health including depression which increases the risk of suicidal thoughts and suicide.[134] Nicotine toxicity is of concern when e-cigarette solutions are swallowed intentionally by adults as a suicidal overdose.[50] Seizures or convulsions are known potential side effects of nicotine toxicity and have been reported in the scientific literature in relation to intentional or accidental swallowing of e-liquid.[111] Six people attempted suicide by injecting e-liquid.[97] One adolescent attempted suicide by swallowing the e-liquid.[25] Three deaths were reported to have resulted from swallowing or injecting e-liquid containing nicotine.[97] An excessive amount of nicotine for an adult that is capable of being fatal is 0.5–1 mg/kg of body weight.[17] An oral lethal dose for adults is about 30–60 mg.[34] However the widely used human LD₅₀ estimate of around 0.8 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit resulting in fatal events is 500–1000 mg of ingested nicotine, which is equivalent to 6.5–13 mg/kg orally.[135] Reports of serious adverse effects associated with acute nicotine toxicity that resulting in hospitalization were very uncommon.[136] Death from intentional nicotine poisoning is very uncommon.[105] Clear labeling of devices and e-liquid could reduce unintentional exposures.[107] Child-proof packaging and directions for safe handling of e-liquids could minimize some of the risks.[125] Some vaping companies willingly used child-proof packaging in response to the public danger.[100] In January 2016, the Child Nicotine Poisoning Prevention Act of 2015 was passed into law in the US,[137] which requires child-proof packaging.[138] The nicotine exposure rate in the US has since dropped by 18.9% from August 2016 to April 2017, following the Child Nicotine Poisoning Prevention Act of 2015, a federal law mandating child-resistant packaging for e-liquid, came into effect, on July 26, 2016.[110] The states in the US that did not already have a law, experienced a notable decline in the average number of exposures during the 9 months after the Child Nicotine Poisoning Prevention Act of 2015 came into effect compared to before it became law.[110] E-liquids have been observed in 2016 to include a press-and-turn feature similar to what is used for aspirin.[100] E-liquids that were normally available in bottles that were not regarded as child-resistant, have been reported in 2016.[100]

There was inconsistent labeling of the actual nicotine content on e-liquid cartridges from some brands,[3] and some nicotine has been found in "no nicotine" liquids.[21] A 2015 PHE report noted overall the labelling accuracy has improved.[139] Most inaccurately-labelled examples contained less nicotine than stated.[139] Due to nicotine content inconstancy, it is recommended that e-cigarette companies develop quality standards with respect to nicotine content.[4]

Because of the lack of production standards and controls, the pureness of e-liquid are generally not dependable, and testing of some products has shown the existence of harmful substances.[125] The German Cancer Research Center in Germany released a report stating that e-cigarettes cannot be considered safe, in part due to technical flaws that have been found.[53] This includes leaking cartridges, accidental contact with nicotine when changing cartridges, and potential of unintended overdose.[53] The Therapeutic Goods Administration (TGA) of Australia has stated that, "Some overseas studies suggest that electronic cigarettes containing nicotine may be dangerous, delivering unreliable doses of nicotine (above or below the stated quantity), or containing toxic chemicals or carcinogens, or leaking nicotine. Leaked nicotine is a poisoning hazard for the user of electronic cigarettes, as well as others around them, particularly children."[140]

Cannabinoid-enriched e-liquids require lengthy, complex processing, some being readily available online despite lack of quality control, expiry date, conditions of preservation, or any toxicological and clinical assessment.[141] It is assumed that vaporizing cannabinoids at lower temperatures is safer because it produces smaller amounts of toxicants than the hot combustion of a cannabis cigarette.[141] The health effects specific to vaping these cannabis preparations is largely unknown.[141]

Concerns about the carcinogenicity of e-cigarettes arise from both nicotine[20] and from other chemicals that may be in the vapor.[4] As regards nicotine, there is evidence from in vitro and animal research that nicotine may have a role as a tumor promoter, but carcinogenicity has not been demonstrated in vivo.[20] A 2014 Surgeon General of the United States report stated that the single relevant randomized trial "does not indicate a strong role for nicotine in promoting carcinogenesis in humans".[150] They concluded that "There is insufficient data to conclude that nicotine causes or contributes to cancer in humans, but there is evidence showing possible oral, esophageal, or pancreatic cancer risks".[150] Nicotine in the form of nicotine replacement products is less of a cancer risk than with smoking,[151] and they have not been shown to be associated with cancer in the real world.[20] Nicotine promotes metastasis by causing cell cycle progression, epithelial-to-mesenchymal transition, migration, invasion, angiogenesis, and avoidance of apoptosis in a number of systems.[152] Nicotine does promote the growth of blood vessels that supply tumors and it speeds tumor growth.[52] Whether long-term vaping can raise the chance for malignancy in individuals with a susceptibility for tumor growth is unknown.[153] The effects of nicotine on the sympathoadrenal system could stimulate the advancement of cancer in people who have cancer.[154]

The cancer risk from vaping is 0.5% of the risk from smoking

Nicotine has been shown to induce DNA damage in the Escherichia colipol A+/pol− test.[155] Low concentrations of nicotine stimulate cell proliferation, while high concentrations are cytotoxic.[155] Nicotine decreases the tumor suppressor Chk2, which is activated by DNA damage.[155] The decrease in Chk2 in cells exposed to nicotine suggests that nicotine may be capable of overriding DNA damage checkpoint activation, disrupting genetic surveillance, and increasing the risk of oncogenesis.[155] There is strong evidence that some substances found in e-cigarette vapors such as formaldehyde and acrolein can induce DNA damage and mutagenesis.[156]

Nicotine promotes endothelial cell migration, proliferation, survival, tube formation, and nitric oxide (NO) production in vitro, mimicking the effect of other angiogenic growth factors.[155] In 2001, it was found that nicotine was a potent angiogenic agent at tissue and plasma concentrations similar to those induced by light to moderate smoking.[155] Effects of nicotine on angiogenesis have been demonstrated for a number of tumor cells, such as breast, colon, and lung.[155] Similar results have also been demonstrated in in vivo mouse models of lung cancer, where nicotine significantly increased the size and number of tumors in the lung, and enhanced metastasis.[155]

A 2014 study suggested that e-cigarette use may be a risk factor for lung cancer.[48] In several in vitro experiments, it has been found that nicotine in concentrations as low as 1 μM decreased the anti-proliferative and pro-apoptotic effects exerted by chemotherapeutics on several different malignant cell lines.[155] These effects were partially reverted by exposure to α-bungarotoxin (α-BTX), an inhibitor of α7-nAChR.[155] In the case of radiotherapy (RT), nicotine administration increased survival of H460 and A549 lung cancer cells.[155] This effect was likewise reduced by addition of α-BTX prior to nicotine addition and radiation.[155] On this basis, it is expected that use of nicotine products during cancer treatment may reduce the effects due to reactions following interaction of nicotine with α7-nAChR.[155]

Endogenous formation of tobacco-specific nitrosamines (TSNAs) may occur after absorption of nicotine.[155]

Evidence from experimental in vitro studies on cell cultures, in vivo studies on rodents as well as studies on humans inclusive of epidemiological studies indicate that nicotine may contribute in cancer development by stimulating a number of important processes.[155] Nicotine acts primarily by activation of nicotine acetylcholine receptors and nicotine binds to these receptors with a higher affinity than acetylcholine.[155] Furthermore, the tobacco-specific nitrosamines (TSNAs) NNN (N′-nitrosonornicotine) and NNK (4-(metylnitrosamino)-1-(3-pyridyl)-1-butanon) may be formed from nicotine after oral administration.[155] E-cigarettes deliver the potent lung carcinogen NNK.[52] Some evidence indicates that the NNK dose-response curve for cancer is highly nonlinear, with substantial increases in risk at low doses.[52] Known bladder carcinogens have been detected in the urine of e-cigarette users but not in non-users.[52] A 2015 study reported that the urine from users of e-cigarettes had very low levels of NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol), which may suggest that endogenous formation of TSNA after nicotine inhalation is negligible.[155] The data does indicate that TSNA may be formed internally after absorption of nicotine through the mucous membranes in the oral cavity and through the skin, while formation after lung absorption may be negligible.[155] Thus, the toxicokinetics of nicotine may depend on the route of administration.[155] The role of nicotine in carcinogenesis is of great importance in the evaluation of potentially harmful effects from non-tobacco related sources of nicotine, such as e-cigarettes.[155]

Nicotine has been shown to induce chromosomal aberration, chromatid exchange, single-strand DNA strand breaks, and micronuclei in vitro.[155] Oxidative stress is probably involved since the effects are reduced in the presence of antioxidants.[155] The finding that the effects decrease after co-incubation with a nicotinic acetylcholine receptor antagonist indicates a receptor-dependent pathway for induction of oxidative stress.[155]

The interaction of nicotine with nicotinic acetylcholine receptors activates signaling pathways that result in a number of reactions, such as increased cell proliferation and cell survival.[155] Although nicotinic acetylcholine receptors are the primary receptors, binding of nicotine to β-ARs and EGFRs may also be important.[155] Nicotine induces epithelial–mesenchymal transition, which is one of the vital steps for the acquisition of malignant phenotype.[155] This transition allows the cell to acquire migratory properties, which may facilitate cancer metastases.[155] Moreover, nicotine induces changes that mimic the effects of angiogenic growth factors.[155]

At present, it is not possible to draw a conclusion whether nicotine itself may act as a complete carcinogen.[155] In mice studies with NNK as an initiator, nicotine acts as a promoter after injection or dermal absorption, but not after oral administration.[155] In drinking water experiments, there is considerable first-pass metabolism of nicotine before nicotine enters the systemic circulation.[155] As a result, serum concentration is much lower after ingestion than after intraperitoneal injection administration.[155] Nicotine enhanced tumor growth and progression after injection of malignant cells in mice.[155] Enhancements were found both after exposure of nicotine by intraperitoneal injection, oral, and skin administration.[155] Moreover, cotinine did also enhance tumor growth.[155] Nicotine may inhibit antitumor immune response.[155] It has also been reported that exposure to nicotine adversely affects dendritic cells, a cell type that has an important role in anticancer immunosurveillance.[155] Moreover, in studies on xenograft in mice, nicotine has been found to reduce the effect of radiotherapy and chemoradiotherapy.[155]

There is no long-term research concerning the cancer risk related to the potentially small level of exposure to the identified carcinogens in the e-cigarette vapor.[16] Their long-term effect on risk of developing cancer is not known.[22] Their long-term use is anticipated to raise the risk of developing lung cancer.[157] A 2015 study found carcinogenicity was mainly evident in the lungs, mouth, and throat, which may be associated with nitrosamines, propylene glycol and some flavoring additives.[92] Vaping is associated with a possible risk of developing head and neck cancers.[158] In May 2014, Cancer Research UK stated that there are "very preliminary unpublished results that suggest that e-cigarettes promote tumour growth in human cells."[144] The e-cigarette vapors triggered DNA strand breaks and lowered cell survival in vitro,[97] regardless of nicotine content.[104] A 2013 study found some samples of e-cigarette vapors had cytotoxic effects on cardiac muscle cells, though the effects were less than with cigarette smoke.[6] Studies demonstrate that e-cigarette vapor have adverse effects on primary airway epithelial cells and tumor cell lines, and other epithelial cell lines, that ranged from reducing viability, an increase in production of inflammatory mediators and oxidative stress, to reducing antimicrobial defences and pro-carcinogenic events.[159] In October 2012, the World Medical Association stated, "Manufacturers and marketers of e-cigarettes often claim that use of their products is a safe alternative to smoking, particularly since they do not produce carcinogenic smoke. However, no studies have been conducted to determine that the vapor is not carcinogenic, and there are other potential risks associated with these devices."[160]

Chart showing various toxicants as measured in cigarette smoke and e-cigarette aerosol.[161]

Since nicotine-containing e-liquids are made from tobacco they may contain impurities like cotinine, anabasine, anatabine, myosmine and beta-nicotyrine.[19] The health implications of nicotine-related impurities are not known.[162] A 2016 review found "Some studies have demonstrated that impurities and nicotine degradation products such as nicotine-cis-N-oxide, nicotine-trans-N-oxide, myosmine, anabasine, and anatabine, which are very carcinogenic, can be found in e-cigarette refill liquids. The molecules can lead to mutations in genes such as Ras (vital function in signal transduction of cell proliferation), p53 and Retinoblastoma (with roles as tumour suppressors) as these molecules can form adducts with cellular DNA."[89] The majority of e-cigarettes evaluated included carcinogenic TSNAs; heavy metals such as cadmium, nickel, and lead; and the carcinogen toluene.[17] However, in comparison to traditional cigarette smoke, the toxic substance levels identified in e-cigarette vapor were 9- to 450-fold less.[17] E-liquid with tin was cytotoxic.[163] E-cigarettes cannot be considered absolutely safe because there is no safe level for carcinogens.[164]

A 2014 review found higher levels of carcinogens and toxicants than in an FDA regulated nicotine inhaler, suggesting that regulated FDA devices may deliver nicotine more safely.[16] In 2014, the World Lung Foundation (now known as Vital Strategies) stated that "Researchers find that many e-cigarettes contain toxins, contaminants and carcinogens that conflict with the industry's portrayal of its products as purer, healthier alternatives. They also find considerable variations in the amount of nicotine delivered by different brands. None of this information is made available to consumers so they really don't know what they are ingesting, or how much."[165]

A 2014 review found "Various chemical substances and ultrafine particles known to be toxic, carcinogenic and/or to cause respiratory and heart distress have been identified in e-cigarette aerosols, cartridges, refill liquids and environmental emissions."[4] Few of the methods used to analyze the chemistry of e-cigarettes in the studies the review evaluated were validated.[4] Many variables affect the levels of toxicants in the e-cigarette vapor, including the design, the type of liquid, and user behavior.[136] The FDA in 2009 analyzed e-liquid cartridge samples[20] from two brands of e-cigarettes,[166] which were NJOY and Smoking Everywhere.[164] Their analysis of the e-cigarette samples showed that the products contained detectable levels of known carcinogens and toxic chemicals to which users could potentially be exposed.[167] Diethylene glycol was detected in one cartridge at approximately 1%.[167] Diethylene glycol, an ingredient used in antifreeze, is toxic to humans.[167] The source of the diethylene glycol contamination is not clear but could reflect the use of non-pharmaceutical grade propylene glycol.[47] On July 22, 2009,[166] the FDA warned that e-cigarettes may present a health risk.[16]

Other chemicals in vapor on the California Prop 65 list of chemicals known to cause cancer or reproductive harm include benzenene and isoprene.[168]

The propylene glycol molecule.

The primary base ingredients of the liquid solution is propylene glycol and glycerin.[3] About 20% to 27% of propylene glycol and glycerin-based liquid particles are inhaled.[169] A 2016 study found that 6% of nicotine, 8% of propylene glycol, and 16% of glycerin was breathed out by e-cigarette users.[170] The long-term effects of inhaled propylene glycol has not been studied,[39] and is unknown.[171] The effects of inhaled glycerin are unknown.[128] Being exposed to propylene glycol may cause irritation to the eyes and respiratory tract.[3] When propylene glycol is heated and aerosolized, it could turn into propylene oxide, which the International Agency for Research on Cancer (IARC) states is possibly carcinogenic to humans.[3][104] The risk from the inhalation of propylene glycol and glycerin is probably low.[19] Propylene glycol and glycerin have not been shown to be safe.[128] Some research states that propylene glycol emissions may cause respiratory irritation and raise the likelihood to develop asthma.[32] Long-term inhalation of propylene glycol indoors could increase risk to children to develop asthma.[53] To lessen the risks, most e-cigarettes companies began to use water and glycerin as replacement for propylene glycol.[32] The inhaled glycerin could cause lipoid pneumonia.[172] Propylene glycol and glycerin had increased the amount of hydrogen peroxide.[173]

Some e-cigarette products had acrolein identified in the aerosol.[19] It may be generated when glycerin is heated to higher temperatures.[19] Acrolein may induce irritation to the upper respiratory tract,[3] and harm the lining of the lungs.[174] Acrolein induces oxidative stress and inflammation, leading to a disruption in the function of the endothelial cell barrier in the lung.[173] Acrolein may lead to chronic obstructive pulmonary disease.[173] Acrolein levels were reduced by 60% in dual users and 80% for those that completely switched to e-cigarettes when compared to traditional cigarettes.[19] A 2017 review stated that "based on the average of 120 puffs/day reported in the literature, our calculated levels of acrolein emitted by e‐cigarette users per day were found to vary between 0.00792 and 8.94 ppm/day."[92] E-cigarettes vapor have been found to create oxidants and reactive oxygen species (OX/ROS).[76] OX/ROS could react with other substances in the e-cigarette vapor because they are highly reactive.[76] Although e-cigarettes have been found to contain OX/ROS at about 100 times less than in cigarette smoke, they probably induce meaningful biological effects.[76] A 2014 study showed that e-liquids from a specific manufacturer contained greater amounts of ethylene glycol than glycerin or propylene glycol, but ethylene glycol has not been permitted for use in products meant for human consumption.[11]

The toxicity of e-cigarettes and e-liquid can vary greatly, as there are differences in construction and materials in the delivery device, kind and origin of ingredients in the e-liquid, and the use or non-use of good manufacturing practices and quality control approaches.[145] If exposure of aerosols to propylene glycol and glycerin rises to levels that one would consider the exposure in association with a workplace setting, it would be sensible to investigate the health of exposed persons.[7] The short-term toxicity of e-cigarette use appears to be low, with the exception for some people with reactive airways.[21]

The ingredients in an e-cigarette cartridge: Distilled water, Nicotine, FCC Grade Vegetable Glycerin, Natural Flavors, Artificial Flavors, Citric Acid. Nicotine content 6-8 mg per cartridge.

The essential propylene glycol and/or glycerin mixture may consist of natural or artificial substances to provide it flavor.[21] Health effects of e-cigarette flavorings are not entirely known.[175] There is very limited toxicological data on inhaling flavoring additives.[176] Flavorings can be a significant part of toxicants in the e-cigarette vapor.[177] Each flavor has a different chemical composition, and therefore, probably, a distinct composition of toxicant emissions.[177] The cytotoxicity of e-liquids varies,[18] and contamination with various chemicals have been detected in the liquid.[21] Some liquids were very toxic and others had little or no cytotoxicity.[18] The cytotoxicity is mostly due to the amount and number of flavors added.[18] Since nicotine has a bitter taste, nicotine e-liquids contain chemicals to cover up the nicotine taste.[76] The liquids contain aromatic substances like tobacco, fruit, vanilla, caramel, and coffee.[21] Generally, these additives are imprecisely described, using terms such as "vegetable flavoring".[21] Although they are approved for human consumption there are no studies on the short-term or long-term effects of inhaling them.[21] The safety of inhaling flavors is mostly unknown,[85] and their safety has not been determined by the Flavor and Extract Manufacturers Association.[97] The majority of flavorings in e-liquids have not been investigated for toxicity by means of inhalation.[178] A 2017 review found "The Flavor and Extract Manufacturers Association (FEMA) of the USA, a trade association of flavor ingredient manufacturers which evaluates the safety of food flavorings, has identified 1037 flavoring agents as potential respiratory hazards due to possible volatility and respiratory irritant properties. Common e-cig flavoring agents on this list include, but are not limited to: diacetyl, acetoin, 2,3-pentanedione (buttery flavors), camphor and cyclohexanone (minty flavors), benzaldehyde (cherry or almond flavors), cinnamaldehyde (cinnamon flavor), cresol (leathery or medicinal flavor), butyraldehyde (chocolate flavor), and isoamyl acetate (banana flavor)."[176] A 2017 review stated, "the implication by manufacturers that flavor ingredients used in e-cigarettes and related devices (e.g. hookahs) are safe for inhalation because they have FEMA GRAS™ status for use in food has been stated to be 'false and misleading' by FEMA."[61]

The extensive and unregulated use of flavoring additives may pose health concerns.[176] Many flavors are irritants.[157] The limited data available on their flavoring agents suggest that the majority of flavorings could lead to significant health risks from long-term use, particularly the ones that are sweet.[80] In some cases e-liquids contain very large amounts of flavorings, which may cause irritation and inflammation on respiratory and cardiovascular systems.[83] A 2016 study of 30 e-cigarette products in the US market found that 13 were more than 1% flavor chemicals by weight, some of which were of potential toxicological concern (e.g., cause respiratory irritation).[179] Some flavors are regarded as toxic and a number of them resemble known carcinogens.[21] The cytotoxicity of some flavors such as strawberry seems to be greater than others.[180] A 2016 study of five flavors across six types of e-cigarettes found that flavors significantly affected the in vitro toxicity profile and the strawberry-flavored product was the most toxic.[179] Some artificial flavors are known to be cytotoxic.[21] Unflavored vapor is less cytotoxic than flavored vapor.[181] A 2012 study demonstrated that in embryonic and adult cellular models, some substances of the e-cigarette vapor such as flavoring not found in tobacco smoke were cytotoxic.[182] The caffeine exposures from vaping are approximately at amounts considerably less than in comparison with consuming caffeinated beverages.[183] There is very limited information available regarding the effects of breathing in caffeine.[183] The evidence is unclear that particular flavorings carry health risks, though there are indications that breathing in some may be a source of avoidable risks.[184]

Cinnamaldehyde has been described as a highly cytotoxic material in vitro in cinnamon-flavored refill liquids.[82] Cinnamaldehyde has also been detected in tobacco flavors, sweet flavors (e.g. caramel), and fruit flavors.[185] Cinnamaldehyde have been identified as cytotoxic at the amount of about 400 times less than those allowed for use by the US Environmental Protection Agency.[10] Compared to other flavors, coffee and cinnamon flavor are the most toxic.[186] The four most commonly found flavor additives were vanillin, ethyl maltol, ethyl vanillin and menthol.[173] They are carcinogenic or toxic, which contribute to causing cardiopulmonary diseases and neurodegenerative disorders.[173] An 18-year-old patient reported using a Juul device with mint flavored pods in the days leading to episodes of pneumothorax in January 2019.[187] In sampling multiple e-cigarette delivery systems, a 2019 study found Juul pods were the only product to demonstrate in vitro cytotoxicity from both nicotine and flavor chemical content, in particular ethyl maltol.[187] There is limited information on the effects of inhaling menthol.[176] Many flavoring additives likely cause respiratory effects not typically seen in cigarette smokers.[176] The evidence is sparse to directly associate inhalations of cinnamon with developing or aggravating asthma.[176] Some flavorings could cause lung inflammation.[188] Fruity, sweet, and traditional tobacco flavorings may result in lung toxicity.[61] Flavorings can harm lung cells by producing free radicals and inflammation.[104] Some e-liquids containing cinnamaldehyde stimulate TRPA1, which might induce effects on the lung.[76] In human lung fibroblasts, cinnamon roll flavoring resulted in a noticeable rise in the amount of inflammatory cytokine IL-8.[173] E-liquids contain possibly toxic aldehydes and reactive oxygen species (ROS).[76] Many flavors are known aldehydes, such as anisaldehyde, cinnamaldehyde, and isovaleraldehyde.[76] Saccharides in sweet e-liquid flavors break down and generate furans and aldehydes when vaporized.[189] The consequences of aldehyde-containing flavors on pulmonary surfaces are unknown.[76] A 2012 study found butterscotch flavor was highly toxic with one liquid and two others had a low toxicity.[50] A 2014 in vitro study showed that menthol flavors have a damaging effect on human periodontal ligament fibroblast growth.[169] Methanol had increased the amount of hydrogen peroxide.[173] A 2017 study found a variety of flavoring initiated inflammatory cytokines in lung cell cultures, of which acetoin and maltol were among the most strongest.[188] A 2014 in vitro study demonstrated that e-cigarette use of a "balsamic" flavor with no nicotine can activate the release of proinflammatory cytokine in lung epithelial cells and keratinocytes.[17] Some additives may be added to reduce the irritation on the pharynx.[128] The long-term toxicity is subject to the additives and contaminants in the e-liquid.[21] It is possible that flavors may worsen some of harmful effects in various cell types such as diminished cell viability, escalated rates of apoptosis, escalated DNA strand breaks, alterations in cell morphology and intensified inflammatory mediator production.[177]

Certain flavorings contain diacetyl and acetyl propionyl which give a buttery taste.[40] Some sweet flavors containing diacetyl and acetyl propionyl include butter, chocolate, milk, or toffee.[186] Diacetyl occurs in a variety of e-cigarette flavorings such as caramel, butterscotch, watermelon, pina colada, and strawberry.[188] A 2016 Harvard detected 39 of the 51 flavored e-cigarettes tested contained diacetyl.[190] The American Lung Association recommended in 2016 that the FDA require that diacetyl and other unsafe chemicals be omitted from e-cigarettes.[190] Menthol flavorings could also contain diacetyl.[188] Diacetyl and acetyl propionyl are associated with bronchiolitis obliterans.[40] A 2018 PHE report stated that the e-cigarette flavorings containing diacetyl is not likely to present a considerable risk.[191] A 2015 review recommended for specific regulation of diacetyl and acetyl propionyl in e-liquid, which are safe when ingested but have been associated with respiratory harm when inhaled.[192] Being exposed to diacetyl produces morphological alterations in the liver according to animal studies.[89] Both diacetyl and acetyl-propionyl have been found in concentrations above those recommended by the US National Institute for Occupational Safety and Health.[40] Diacetyl is normally found at lower levels in e-cigarettes than in traditional cigarettes.[40] 2, 3-pentanedione, is a α-diketone that is chemically and structurally similar to diacetyl.[162] Although it has become a popular replacement for diacetyl, acute inhalation exposure to 2, 3-pentanedione has been shown to cause airway epithelial damage similar to diacetyl.[162] Some liquids use butyric acid instead of diacetyl and acetyl propionyl, but it could have negative health effects.[193] Concerns exist that the flavors and additives in e-cigarettes might lead to diseases, including the popcorn lung.[69] The cardiovascular effects, including a vast range of flavorings and fragrances, is unknown.[194] Compared to other flavors, cherry contains a greater amount of benzaldehyde,[186] a main ingredient for a variety of fruit flavors.[188] Because benzaldehyde can irritate the eyes and mucous membranes of the respiratory tracts with workplace exposure, concerns have been expressed regarding the toxicity of flavored e-cigarette vapor.[195] The irritants butyl acetate, diethyl carbonate, benzoic acid, quinoline, bis(2-ethylhexyl) phthalate, and 2,6-dimethyl phenol were present as undeclared ingredients in the e-liquid.[55] The precise ingredients of e-cigarettes are not known.[196] A 2010 study found rimonabant when examining e-liquids.[197] This weight loss drug has been linked to seizures and suicide.[197] The same study also determined e-liquid can contain amino-tadalafil which is a component of Cialis, used for erectile dysfunction.[197] Users are at risk of encountering negative health outcomes from the small possibility of being exposed to pharmacologic compounds in some e-liquids.[197]

The Centers for Disease Control tested in 2015 36 e-cigarette products for 10 flavor compounds commonly used as additives in tobacco products.[162] Measurable levels of eucalyptol and pulegone were found in the menthol-flavored varieties for all manufacturers.[162] Menthol concentrations ranged from 3,700 to 12,000 μg/g in flavored e-liquids, levels similar to those found in the filler of traditional cigarettes.[162] Interestingly, menthol was found at low concentrations in 40% of the tobacco-flavored nonmenthol products tested.[162] Other flavor compounds found were camphor, methyl, salicylate, pulegone, cinnamaldehyde (CAD), and eugenol.[162] Tierney and colleagues in 2016 analyzed 30 e-cigarette products on the U.S. market and found 13 products contained more than 1% flavor chemicals by weight.[162] Among the chemicals identified were aldehydes (e.g., benzaldehyde and vanillin), which are categorized as primary irritants of the respiratory tract.[162] Tierney and colleagues also found that tobacco-flavored e-liquids were derived from confection-flavored chemicals (e.g., bubble gum and cotton candy flavoring) rather than tobacco extract.[162] Various candy and fruit flavor e-liquids that are enticing to youth exhibit in cell culture cytotoxic or mutagenic effects.[95]

The IARC has categorized formaldehyde as a human carcinogen, and acetaldehyde is categorized as a potential carcinogenic to humans.[174] Formaldehyde induced DNA damage and inhibited DNA repair.[198] Acetaldehyde generated crosslinking of DNA-protein which impede with DNA metabolic functions, including replication, repair, recombination, transcription and chromatin remodeling.[198] Aldehydes may cause harmful health effects; though, in the majority of cases, the amounts inhaled are less than with traditional cigarettes.[174] A 2016 study found that e-liquids without flavoring generated no aldehydes, which indicated that the flavors were causing the creation of aldehydes, according to a 2018 PHE report.[199] Many chemical compounds can inadvertently be produced from e-cigarettes, especially carbonyl compounds like formaldehyde, acetaldehyde, acrolein, and glyoxal by the chemical reaction of the e-liquid when the nichrome wire (heating element) is heated,[174] to high temperatures.[17] These compounds are frequently identified in e-cigarette aerosols.[174] Potentially hazardous carbonyls have been identified in e-cigarette aerosols produced at temperatures above 200 °C.[176] The propylene glycol-containing liquids produced the most amounts of carbonyls in e-cigarette aerosols.[174] The levels of toxic chemicals in the e-cigarette vapor were found to be 1 to 2 orders of magnitude smaller than with cigarette smoke but greater than from a nicotine inhaler.[3] Nearly all e-cigarettes evaluated, toxic and irritation-causing carbonyls were identified.[17] Reports regarding the levels of toxic chemicals were inconsistent.[17] This includes a study showing that the levels of toxicants in e-cigarettes may be higher than with cigarette smoke.[17]

Battery output voltage influences the level of the carbonyl substances in the e-cigarette vapor.[174] Some newer e-cigarette models let users boost the amount of vapor and nicotine provided by modifying the battery output voltage.[174] E-cigarettes that were modified to boost the vapor production are more dangerous to use.[75] High-voltage e-cigarettes could subject users to large amounts of carbonyls.[174] E-cigarettes with higher voltages (5.0 V[18]) can emit carcinogens including formaldehyde at levels comparable to cigarette smoke,[153] while reduced voltages (3.0 V[4]) generate aerosol with levels of formaldehyde and acetaldehyde roughly 13 and 807-fold less than in cigarette smoke.[174] The average amount of formaldehyde in vapor from high-voltage devices is higher than the average amount of formaldehyde released from cigarettes.[58] "Dripping", where the liquid is dripped directly onto the atomizer, can create carbonyls including formaldehyde.[200]

Controversy exists regarding the specific amount of formaldehyde expected to be breathed in by the user.[177] A 2015 PHE report found that normal e-cigarette use generates very low levels of aldehydes.[23] Normal usage of e-cigarettes generates very low levels of formaldehyde,[181] and at normal settings they generate very low levels of formaldehyde.[23] A 2018 PHE report found that at normal usage temperatures, aldehyde in the e-cigarette vapor is at negligible amounts in comparison with smoking.[201] Later-generation and "hotter" e-cigarettes may generate equal or higher levels of formaldehyde compared to smoking.[22] A 2015 study analyzing 10 puffs found that vaping at a high voltage (5.0 V) generates formaldehyde in e-cigarette vapor; they inferred from the finding that the user vaping at high voltage with 3 ml of e-liquid daily would inhale 14.4±3.3 mg of formaldehyde daily in formaldehyde-emitting chemicals.[18] This was estimated to be a lifetime cancer risk of 5 to 15 times greater than compared with long-term smoking.[18] A 2015 study using a third-generation device, very low levels of formaldehyde were produced on lower power, although, when adjusted to a maximum power setting, levels were greater than with cigarette smoke.[181] Running at a higher power (temperature) not only increases nicotine delivery, but also increases the amount of formaldehyde and other aldehydes that are naturally produced by heating up propylene glycol or glycerin and other toxicants produced in the e-cigarette aerosol.[52] A 2015 PHE report found that by applying maximum power and increasing the time the device is used on a puffing machine, e-liquids can thermally degrade and produce high levels of formaldehyde.[23] Users detect the "dry puff" (also known as a "dry hit"[202]) and avoid it, and they concluded that "There is no indication that EC users are exposed to dangerous levels of aldehydes."[203] However, e-cigarette users may learn to overcome the unpleasant taste due to elevated aldehyde formation, when the nicotine craving is high enough.[76]

Possible side effects of nicotine.[204]

A 2015 comparative risk analysis of drugs found the nicotine's margin of exposure (MOE) values were in a lower risk range than cocaine, heroin, and alcohol, whereas its MOE values was in a higher risk range than MDMA, methamphetamine, and methadone.[205] Shown above is the MOE for daily drug use from the analysis.[205]

Pregnant women, breastfeeding mothers, and the elderly are more sensitive to nicotine than other individuals.[85] There are safety issues with the nicotine exposure from e-cigarettes, which may cause addiction and other adverse effects.[4] Nicotine is regarded as a potentially lethal poison.[24] Concerns exist that vaping can be harmful by exposing users to toxic levels of nicotine.[24] At low amounts, it has a mild analgesic effect.[85] At sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradyarrhythmia, and possibly seizures and hypoventilation.[206] High doses can induce deleterious effects on the growth of osteoblasts.[207] Higher-doses leads to loss of nicotinic receptor specificity and induces cholinergic toxicity.[124] The highest-doses can lead to coma.[124] However, at the low amount of nicotine provided by e-cigarettes fatal overdose from use is unlikely; in contrast, the potent amount of nicotine in e-cigarettes liquids may be toxic if it is accidentally ingested or absorbed via the skin.[24] The health effects of nicotine in infants and children are unclear.[206]

E-cigarettes provide nicotine to the blood quicker than nicotine inhalers.[34] The levels were above that of nicotine replacement product users.[24] E-cigarettes seem to have a pharmacokinetic nicotine profile closer to nicotine replacement products than with traditional cigarettes.[208] How efficiently different e-cigarettes give nicotine is unclear.[24] Serum cotinine levels are comparable to that of traditional cigarettes,[209] but are inharmonious and rely upon the user and the device.[16] Blood nicotine levels raised more gradually and took more time to get to peak concentration with e-cigarettes than with traditional cigarettes.[210] Vaping was found to have comparable levels of nicotine urinary metabolites to those who were tobacco and smokeless tobacco product users.[61] Though, the oxidative nicotine metabolites were less in those who were vaping.[61] Evidence indicates that some vaping products may deliver the same amount of nicotine as traditional cigarettes.[59] There is fair evidence that chance and degree of dependence are less for e-cigarettes than traditional cigarettes, according to a 2018 National Academies of Sciences, Engineering, and Medicine report.[211] It not clear the level of addictiveness of e-cigarettes, compared with traditional cigarettes, according to a 2018 PHE report.[212] The report also stated "nicotine addictiveness depends on a number of factors including presence of other chemicals, speed of delivery, pH, rate of absorption, the dose, and other aspects of the nicotine delivery system, environment and behaviour."[213] Users vaping without using nicotine exhibited symptoms of dependence, according to a 2015 study.[214] E-cigarette packages and advertisements require health warnings under US law, stating "WARNING: This product contains nicotine. Nicotine is an addictive chemical."[59][215][216]

E-cigarettes resembling cigarettes typically produce much less blood nicotine levels.[175] When compared to traditional cigarettes older devices usually delivered low amounts of nicotine.[24] E-cigarette use can be associated with a substantial dispersion of nicotine, thus generating a plasma nicotine concentration which can be comparable to that of traditional cigarettes.[79] This is due to the minute nicotine particles in the e-cigarette vapor, which permit quick delivery into the bloodstream.[79] The nicotine delivered from e-cigarettes enters the body slower than traditional cigarettes.[217] Studies suggest that inexperienced users obtain moderate amounts of nicotine from e-cigarettes.[218] Concerns were raised over inconsistent amounts of nicotine delivered when drawing on the device.[219]

Tank or adjustable e-cigarettes can raise nicotine levels as high as traditional cigarettes.[175] Later-generation e-cigarettes give nicotine more effectively than first-generation e-cigarettes.[82] Later-generation models with concentrated nicotine liquids may deliver nicotine at levels similar to traditional cigarettes.[24] Some e-cigarette tank devices with stronger batteries heat solutions to greater temperatures, which may raise levels of nicotine in the blood similar to those of traditional cigarettes.[50] Research suggests that experienced e-cigarettes users are able to get as much nicotine from e-cigarettes as traditional cigarettes.[24] Later-generation e-cigarettes containing sufficient nicotine elevate heart rate comparable to traditional cigarettes.[194] Later-generation devices delivery 35% to 72% more nicotine than compared with first‐generation devices.[92] Second-generation e-cigarettes raised the heart rate and blood pressure similar to traditional cigarettes.[220] As there are design changes, later-generation devices may provide nicotine similar to traditional cigarettes with a highly concentrated amount potential straight to the brain.[80] Such devices may largely reshape the effects on cardiac safety, misuse, and addiction.[80] There is not much research on fourth-generation devices.[49]

The reinforcing effects of drugs of abuse, such as nicotine, is associated with its ability to excite the mesolimbic and dopaminergic systems.[221]
How do e-cigarettes affect the brain?[222] The nicotine in e-liquids readily absorbs into the bloodstream when a person uses an e-cigarette.[222] Upon entering the blood, nicotine stimulates the adrenal glands to release the hormone epinephrine (adrenaline).[222] Epinephrine stimulates the central nervous system and increases blood pressure, breathing, and heart rate.[222] As with most addictive substances, nicotine increases levels of a chemical messenger in the brain called dopamine, which affects parts of the brain that control reward (pleasure from natural behaviors such as eating).[222] These feelings motivate some people to use nicotine again and again, despite possible risks to their health and well-being.[222]

The health effects of long-term nicotine use is unknown.[171] It may be decades before the long-term health effects of nicotine vapor inhalation is known.[223] It is not recommended for non-smokers.[10] Public health authorities do not recommend nicotine use for non-smokers.[224] The pureness of the nicotine differs by grade and producer.[225] The impurities associated with nicotine are not as toxic as nicotine.[225] The health effects of vaping tobacco alkaloids that stem from nicotine impurities in e-liquids is not known.[225] Nicotine affects practically every cell in the body.[85] The complex effects of nicotine are not entirely understood.[20] It poses several health risks.[226] Short-term nicotine use excites the autonomic ganglia nerves and autonomic nerves, but chronic use seems to induce negative effects on endothelial cells.[227] Nicotine may have a profound impact on sleep.[228] The effects on sleep vary after being intoxicated, during withdrawal, and from long-term use.[228] Nicotine may result in arousal and wakefulness, mainly via incitement in the basal forebrain.[229] Nicotine withdrawal, after abstaining from nicotine use in non-smokers, was linked with longer overall length of sleep and REM rebound.[228] A 2016 review states that "Although smokers say they smoke to control stress, studies show a significant increase in cortisol concentrations in daily smokers compared with occasional smokers or nonsmokers. These findings suggest that, despite the subjective effects, smoking may actually worsen the negative emotional states. The effects of nicotine on the sleep-wake cycle through nicotine receptors may have a functional significance. Nicotine receptor stimulation promotes wake time and reduces both total sleep time and rapid eye movement sleep."[230]

Nicotine can weaken antibacterial defenses and modify macrophage activation.[136] Nicotine can cause tremors,[104] high blood pressure, abnormal heart rhythms,[165] and lower coronary blood flow.[194] Nicotine constricts blood vessels.[143] This includes coronary blood vessels and those in the skin.[231] However, blood vessels in the skeletal muscle dilate as a result of nicotine.[231] It can also cause nausea, sweating, and diarrhea.[80] In reaction to nitric oxide, it hinders endothelial-dependent widening of blood vessels.[20] It is associated with stroke, peripheral vascular disease, delayed wound healing, peptic ulcer disease, and esophageal reflux.[58] Vapers that get a higher amount of blood nicotine are probably correlated with increased heart rates.[136] Acute administration of nicotine causes a variety of well-characterized, dose- and route-dependent effects in adults, including cardiovascular effects, such as greater cardiac output, leading to an increase in myocardial oxygen demand.[162] Nicotine is correlated with lung inflammation in adults, which may be as a result of it chemotactic effects.[49] Nicotine may have adverse effects on lipids,[232] cause insulin resistance,[50] and may cause pro-inflammatory effects that could impact beta cell function.[233] Nicotine lowers activity of free radical scavenging enzymes, resulting in more production of hydroxyl free radicals.[233] Nicotine impairs glucose homeostasis, indicating a major role in the development of diabetes mellitus type 2.[233] Osseointegration is a pertinent part of the survival of implants.[234] Nicotine considerably impedes the regenerative capability of mesenchymal stem cells.[235] This includes impeding their proliferation, migration, and differentiation.[235] Nicotine has been correlated with vasoconstriction and a weakened ability to heal at the cellular level.[234] Thus, it apparently compromises implant osseointegration.[234] Nicotine lowers estrogen levels and has been associated with early menopause in women.[165] Nicotine is negatively associated with total sperm motility.[180] Nicotine causes dysfunction of NO synthesis.[226] This may result in inability to get penile erections and erectile dysfunction.[226]

A 2016 review found "Evidence from experimental animal models clearly demonstrate nicotine's ability to enhance existing tissue injury and diseases such as cancer, cardiovascular disease, stroke, pancreatitis, peptic ulcer, renal injury and developmental (e.g. pulmonary, reproductive and central nervous system) abnormalities."[236] The consequence of nicotine use in autoimmunity has been conflicting.[237] Nicotine could have cancer-promoting properties, therefore long-term use may not be harmless.[238] Nicotine may result in neuroplasticity variations in the brain.[123] Nicotine has been demonstrated to alter the amounts of brain-derived neurotrophic factor in humans.[239] Nicotine could make cancer therapies less effective.[62] Based on in vitro and in vivo effects of nicotine, patients should be advised not to use nicotine products during cancer treatment unless it is temporarily needed to stop tobacco smoking.[155] Nicotine can suppress appetite.[240] Nicotine users will probably gain weight after using less nicotine.[241] A long-term risk from vaping a base containing nicotine is nicotine dependence.[95]

Children are more sensitive to nicotine than adults.[85] The use of products containing nicotine in any form among youth, including in e-cigarettes, is unsafe.[162] Nicotine has more significant and durable damaging effects on adolescent brains compared to adult brains, the former suffering more harmful effects.[162] Animal research offers strong evidence that the limbic system is particularly vulnerable to the long lasting effects of nicotine.[242] In youth, nicotine may result in cognitive impairment[242] as well as the chance of nicotine addiction for life.[165] The adolescent's developing brain is especially sensitive to the harmful effects of nicotine.[243] A short period of regular or occasional nicotine exposure in adolescence exerts long-term neurobehavioral damage.[243] Risks of exposing the developing brain to nicotine include mood disorders and permanent lowering of impulse control.[244] The rise in vaping is of great concern because the parts encompassing in greater cognitive activities including the prefrontal cortex of the brain continues to develop into the 20s[206] Nicotine exposure during brain development may hamper growth of neurons and brain circuits, effecting brain architecture, chemistry, and neurobehavioral activity.[206]

Nicotine changes the way synapses are formed, which can harm the parts of the brain that control attention and learning.[244] Preclinical studies indicate that teens being exposed to nicotine interferes with the structural development of the brain, inducing lasting alterations in the brain's neural circuits.[129] Each e-cigarette brand differs in the exact amount of ingredients and nicotine in each product.[129] Therefore, little is known regarding the health consequences of each brand to the growing brains of youth.[129] In August 2014, the American Heart Association noted that "e-cigarettes could fuel and promote nicotine addiction, especially in children."[50] Whether there are subgroups of adolescents who are at greater risk of developing a nicotine dependence from vaping is not known.[95] A 2014 policy statement by the UK's Faculty of Public Health has stated, "A key concern for everyone in public health is that children and young people are being targeted by mass advertising of e-cigarettes. There is a danger that e-cigarettes will lead to young people and non-smokers becoming addicted to nicotine and smoking. Evidence from the US backs up this concern."[245] Long-term studies on the safety of nicotine-only exposure (e.g., as with using e-cigarettes rather than smoking traditional cigarettes) among youth have not been conducted.[162]

In 2015 the psychological and behavioral effects of e-cigarettes were studied using whole-body exposure to e-cigarette vapor, followed by a series of biochemical and behavioral studies.[159] The results showed that nicotine-containing e-cigarette vapor induces addiction-related neurochemical, physiological and behavioral changes.[159] A 2015 study on the offspring of the pregnant mice, which were exposed to nicotine-containing e-cigarette liquid, showed significant behavioral alterations.[159] This indicated that exposure to e-cigarette components in a susceptible time period of brain development could induce persistent behavioral changes.[159] As indicated in the limited research from animal studies, there is the potential for induced changes in neurocognitive growth among children who have been subjected to e-cigarette vapors consisting of nicotine.[246] The FDA stated in 2019 that some people who use e-cigarettes have experienced seizures, with most reports involving youth or young adult users.[111]

Graphic from the 2018 Centers for Disease Control and Prevention's report entitled Why Is Nicotine Unsafe for Kids, Teens, and Young Adults?[247]

There is limited evidence on the long-term exposure of metals.[10] Exposure to the levels and kinds of metals found in the aerosol relies upon the material and other manufacturing designs of the heating element.[50] E-cigarettes contain some contamination with small amounts of metals in the emissions but it is not likely that these amounts would cause a serious risk to the health of the user.[10] According to a 2018 PHE report, metals emissions no matter how small, are not needed.[184] They further stated, "EC [e-cigarettes] that generate minimal metal emissions should become an industry standard."[170] The device itself could contribute to the toxicity from the small amounts of silicate and heavy metals found in the liquid and vapor,[200] because they have metal parts that come in contact with the e-liquid.[10] Low levels of possibly harmful chromium, lead, and nickel metals have been found in the emissions.[50] Chromium and nickel nanoparticles have also been found.[3] Copper nanoparticles can induce mitochondrial and DNA injury in lung fibroblasts.[248] DNA repair can be impeded by titanium dioxide nanoparticles from the e-cigarette vapor.[249] This was demonstrated that the titanium dioxide nanoparticles induced single-strand breaks and produced oxidative stress in the DNA of A549 cells.[249] The risk of inhaling nanoparticles is an area of concern.[125] The toxicity of nanoparticles is unknown.[250] Metals including nickel, cadmium, lead and silicate can found in the e-cigarette vapors, and are thought to be carcinogenic, nephrotoxic, neurotoxic, and hemotoxic.[89] Heavy metals are correlated with serious health issues.[12] Inhaling lead can induce serious neurologic injury, notably to the growing brains of children.[12]

Metals may adversely affect the nervous system.[101] Metals found in the e-cigarette vapor may induce cell damage and initiate inflammatory cytokine such as in human lung fibroblasts.[188] A 2017 review found "E-cigarette aerosols and copper nanoparticles induced mitochondrial ROS production, mitochondrial stress (reduced stability of OxPhos electron transport chain (ETC) complex IV subunit) and DNA fragmentation in lung fibroblasts."[173] A 2013 review found metallic and nanoparticles are associated with respiratory distress and disease.[251] A 2014 review found considerable amounts of tin, metals, and silicate particles that came from various components of the e-cigarette were released into the aerosol, which result in exposure that could be higher than with cigarette smoke.[17] A 2013 study found metal particles in the aerosol were at levels 10-50 times less than permitted in inhalation medicines.[19] A 2014 review suggested that there is no evidence of contamination of the aerosol with metals that justifies a health concern.[7] Cadmium that have been found in the e-cigarette vapor is linked to low sperm density.[180]

Abbreviations: μg, microgram; ng, nanogram; ND, not detected.[18]
∗Fifteen puffs were chosen to estimate the nicotine delivery of one traditional cigarette.[18]

Since 2019, an ongoing outbreak of severe vaping-associated lung illness has affected certain users of vaping products in the United States.[notes 4][15] Cases involved in the outbreak of lung illness were first identified in Illinois and Wisconsin in April 2019.[268] Similar cases of vaping-associated lung illness were reported in the UK and Japan before the outbreak occurred.[5] As of January 21, 2020, a total of 2,711 hospitalized cases have been reported to the Centers for Disease Control and Prevention (CDC) from all 50 states, the District of Columbia, and two US territories (Puerto Rico and US Virgin Islands).[15] 60 deaths have been confirmed in 27 states and the District of Columbia in the US, as of January 21, 2020.[15] Based on reports from several states, symptoms typically develop over a period of days but sometimes can manifest over several weeks.[265] The outbreak mainly affected young people, which is the group with the greatest prevalence of cannabis use in the US.[269] The ubiquitous use of e-cigarettes including products that enable THC use likely contributed to the outbreak.[269]

On September 6, 2019, Dr. Dana Meaney-Delman, serving as the incident manager of the Centers for Disease Control and Prevention's (CDC) response to this outbreak, said that "Based on the clinical and laboratory evidence to date, we believe that a chemical exposure is likely associated with these illnesses."[270] Of the 2,506 reported cases, information is available in the three months prior to symptom onset for 1,782 of them as of December 3, 2019.[15] 80% reported THC use, 35% reported exclusive THC use, about 54% reported using nicotine-containing products, and 13% reported exclusive use of nicotine-containing products.[15] Many of the samples tested by the states or by the US Food and Drug Administration (US FDA) as part of the 2019 investigation have been identified as vaping products containing tetrahydrocannabinol (or THC, a psychoactive component of the cannabis plant).[271] Most of those samples with THC tested also contained significant amounts of vitamin E acetate.[271] The CDC reported that their findings suggest vaping products containing THC are linked to most of the cases and play a major role in the outbreak.[15] The CDC stated that the chemical vitamin E acetate is a very strong culprit of concern in the lung illnesses related to THC-based vaping products, but did not rule out other chemicals as possible causes.[notes 5][272]

Thickening agents were used to dilute vape oils.[273] There has been an increase in attention to companies that sell diluent products that are made with vitamin E acetate.[273] Previously, vitamin E was used in low concentrations, or lower than 20% of the formula in vape cartridges.[273] As a result of a limited availability of cannabis in California as well as high demand, illicit sellers had used about 50% or higher of diluent thickeners in their formulas to bulk up tiny potency vape cartridges.[273] In September 2019, New York Governor Andrew Cuomo instructed the state health department to issue subpoenas against three sellers of thickening agents used in illicit vaping products.[274]

The e-cigarette industry is placing the blame on illicit vaping liquids for the lung injuries.[275] Juul Labs stated that some news reports state that several cases of lung illness are associated with vaping THC, found in cannabis, "a Schedule 1, controlled substance that we do not sell."[276] The CDC recommends that the public should consider not using any vaping products during their investigation, particularly those containing THC from informal sources like friends, or family, or in-person or online dealers as of November 20, 2019.[15] The US FDA considers it prudent to avoid inhaling vitamin E acetate.[271] On September 6, 2019, the US FDA stated that because consumers cannot be sure whether any THC vaping products may contain vitamin E acetate, consumers are urged to avoid buying vaping products on the street, and to refrain from using THC oil or modifying/adding any substances to products purchased in stores.[271]

Some of the vaping products analyzed by the Wadsworth Center contained exceedingly high amounts of vitamin E acetate, including those pictured here.[277]

E‐cigarettes can be unsafe to non-users via third-hand exposure, including children, pregnant women, casino employees, housekeeping employees, and vulnerable groups.[92] E-cigarette use by a parent might lead to inadvertent health risks to offspring.[206] E-cigarettes pose many safety concerns to children.[206] For example, indoor surfaces can accumulate nicotine where e-cigarettes were used, which may be inhaled by children, particularly youngsters, long after they were used.[206] A policy statement by the American Association for Cancer Research and the American Society of Clinical Oncology has reported that "Third-hand exposure occurs when nicotine and other chemicals from second-hand aerosol deposit on surfaces, exposing people through touch, ingestion, and inhalation".[24] A 2015 PHE report stated the amount of nicotine deposited was low and that an infant would have to lick 30 square meters to be exposed to 1 mg of nicotine.[306] There are no published studies of third-hand exposure from e-cigarettes, however initial data suggests that nicotine from e-cigarettes may stick to surfaces and would be hard to remove.[24] The extent of third-hand contamination indoors from e-cigarettes in real-world settings has not been established but would be of particular concern for children living in homes of e-cigarette users, as they spend more time indoors, are in proximity to and engage in greater activity in areas where dust collects and may be resuspended (e.g., carpets on the floor), and insert nonfood items in their mouths more frequently.[162]