Safety of electronic cigarettes

Graphic from the January 2015 California Department of Public Health's State Health Officer's Report on E-Cigarettes warning about harmful substances in e-cigarette vapor.[47]

Reviews on the safety of electronic cigarettes, evaluating roughly the same studies, have reached significantly different conclusions.[6] Broad-ranging statements regarding their safety cannot be reached because of the vast differences of devices and e-liquids available.[48] A consensus has not been established for the effects as well as the benefits related to their use.[49] Due to various methodological issues, severe conflicts of interest, and inconsistent research, no definite conclusions can be determined regarding the safety of e-cigarettes.[50] However, e-cigarettes cannot be regarded as a harmless alternative to traditional cigarettes.[50] Guidelines for the design, manufacture or assessment of their safety has not been established.[51]

Repeated exposure over a long time to e-cigarette vapor poses substantial potential risk.[16] Although companies state that e-cigarettes are safe, there is no scientific evidence to support this view.[52] Long-term data showing that vaping is a "healthier alternative" than cigarette smoking does not exist.[8] There is little data about their safety, and considerable variability among vaporizers and in their liquid ingredients[4] and thus the contents of the aerosol delivered to the user.[5] The health community, pharmaceutical industry, and other groups have raised concerns about the emerging phenomenon of e-cigarettes, including the unknown health risks from their long-term use.[43] A 2017 review found "There is a justifiable concern that any broad statement promoting e-cig safety may be unfounded considering the lack of inhalational toxicity data on the vast majority of the constituents in e-cigs. This is particularly true for individuals with existing lung disease such as asthma."[53] A 2014 review has stated, there are "Many unanswered questions about their safety, efficacy for harm reduction and cessation, and total impact on public health."[5] There is concern that e-cigarettes may result in many smokers rejecting historically effective quitting smoking methods.[54] 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.[55]

A policy statement by the American Association for Cancer Research and the American Society of Clinical Oncology has reported that "The benefits and harms must be evaluated with respect to the population as a whole, taking into account the effect on youth, adults, nonsmokers, and smokers."[24] The widespread availability and popularity of flavored e-cigarettes is a key concern regarding the potential public health implications of the products.[57] It is assumed that vaping leads to serious health concerns due to the levels of various toxicants such as nicotine.[58] A 2016 Surgeon General of the United States report stated e-cigarettes typically contain nicotine as well as other chemicals that are known to damage health.[59] For example, users risk exposing their respiratory systems to potentially harmful chemicals in e-cigarettes.[59] E-cigarettes are not safe for youth, young adults, pregnant women, or adults who do not currently use tobacco products.[60] A July 2014 World Health Organization (WHO) report cautioned about the potential risks to children and adolescents, pregnant women, and women of reproductive age regarding e-cigarette use.[7] E-cigarettes are an increasing public health concern due to the rapid rise among adolescents and the uncertainty of potential health consequences.[61] 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.[62] Concerns exist in respect to adolescence vaping due to studies indicating nicotine may potentially have harmful effects on the brain.[63]

General information on what are e-cigarettes.[64]

It is recommended the precautionary principle be used for e-cigarettes because of the long history of the tobacco crisis, in order to assess their benefits and long-term effects and to avoid another nicotine crisis.[65] A 2015 review suggested that e-cigarettes could be regulated in a similar way as inhalation therapeutic medicine, meaning, they would regulated based on toxicology and safety clinical trials.[26] A 2014 review recommended that e-cigarettes could be adequately regulated for consumer safety with existing regulations on the design of electronic products.[43] Regulation of the production and promotion of e-cigarettes may help lower some of the adverse effects associated with tobacco use.[41] 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.[66] 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.[66] Furthermore, vaping in public places, coupled with recent e-cigarette commercials on national television, could possibly undermine or weaken current antismoking regulations.[66] 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.[67] Public health professionals voiced concerns regarding vaping while using other tobacco products, particularly combustible products.[68] 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.[69] 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.[69] It is argued to implement the precautionary principle because dual use could end up being an additional risk.[6] The industry could also lead vapers to tobacco products, which would increase instead of decrease overall addiction.[69] Concerns exist that the emergence of e-cigarettes may benefit Big Tobacco to sustain an industry for tobacco.[70] 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."[68] E-cigarettes are expanding the tobacco epidemic by bringing lower-risk youth into the market, many of whom then transition to smoking cigarettes.[71]

E-cigarettes have the potential for benefit and harm, the nature and scale of each being uncertain in the absence of much evidence.[72] The health effects related to e-cigarette use is mostly unknown.[73] The health effects on intensive e-cigarette users are unknown.[32] The effect on population health from e-cigarettes is unknown.[8] Smokefree.gov, a website run by the Tobacco Control Research Branch of the National Cancer Institute to provide information to help quit smoking, stated that "Since e-cigs aren't regulated yet, there's no way of knowing how much nicotine is in them or what other chemicals they contain. These two things make the safety of e-cigs unclear."[74] The chemical characteristics of the short-lived free radicals and long-lived free radicals produced from e-cigarettes is unclear.[75] The English National Health Service has stated in 2014, "While e-cigarettes may be safer than conventional cigarettes, we don't yet know the long-term effects of vaping on the body."[76] While quitting smoking may be firmly recommended for smokers who have asthma, it is not clear whether replacing e-cigarettes for cigarettes is a universally safer alternative.[53] The American Diabetes Association states "There is no evidence that e-cigarettes are a healthier alternative to smoking."[77] In August 2014, the Forum of International Respiratory Societies stated that e-cigarettes have not been demonstrated to be safe.[78] Health Canada has stated that, "their safety, quality, and efficacy remain unknown."[79] The National Institute on Drug Abuse stated that "There are currently no accepted measures to confirm their purity or safety, and the long-term health consequence of e-cigarette use remain unknown."[80] There is insufficient data regarding the health benefits of vaping.[81] Vaping requires more forceful sucking than smoking, and this action is still unclear on increased absorption of harmful substances and the user's health.[82] Sucking more forcefully from e-cigarette use may be adverse to human health.[83] The risks from long-term use of nicotine as well as other toxicants that are unique to e-cigarettes are uncertain.[84] The long-term consequences from e-cigarette use on death and disease are unclear.[85] There is limited available research regarding their effects to vulnerable groups such as minors.[86]

Effects of vaping, compared to tobacco smoking.[87]

A 2018 Public Health England (PHE) report stated, "The previous estimate that, based on current knowledge, vaping is at least 95% less harmful than smoking remains a good way to communicate the large difference in relative risk unambiguously so that more smokers are encouraged to make the switch from smoking to vaping. It should be noted that this does not mean EC [e-cigarettes] are safe."[88] A 2015 PHE report stated that e-cigarettes are estimated to be 95% less harmful than smoking,[89] but the studies used to support this estimate were viewed as having a weak methodology.[90] It has been extensively disputed in the literature.[91] Many vigorously criticized the validity of the estimate that vaping is 95% less harmful than smoking.[68] It was also criticized by the journal The Lancet for constructing its conclusions on 'flimsy' evidence, which included citing literature with apparent conflicts of interest.[92] It was later discovered that many of the authors who came up with the "95% safer" assertion have ties to the tobacco industry.[90] Some consider that the PHE report's specific number is flawed and confusing, by making opinions at odds with existing knowledge.[93] Despite this, most other health organizations have been more cautious in their public statements on the safety of e-cigarettes.[94] For example, the Food and Drug Administration (FDA) reported that the potential health risks of using e-cigarettes are unclear.[94]

Possible adverse effects of vaping.[95]

Influential health organizations in England, including Public Health England, the Royal College of Physicians, the Royal Society for Public Health, and the National Health Service, have unequivocally stated that e-cigarettes are 95% safer than traditional cigarettes.[71] This claim originated from a single consensus meeting of 12 people convened by D.J. Nutt in 2014.[71] They reached this conclusion without citing any specific evidence.[71] The Nutt et al. paper did include this caveat: "A limitation of this study is the lack of hard evidence for the harms of most products on most of the criteria", which has generally been ignored by those quoting this report.[71] A 2015 editorial in The Lancet identified financial conflicts of interest associated with Nutt et al., noting that "there was no formal criterion for the recruitment of the experts."[71] The Nutt et al. meeting was funded by Euroswiss Health and Lega Italiana Anti Fumo (LIAF).[71] EuroSwiss Health is one of several companies registered at the same address in a village outside Geneva with the same chief executive, who was reported to have received funding from British American Tobacco (BAT) for writing a book on nicotine as a means of harm reduction and who also endorsed BAT's public health credentials.[71] Another of Nutt's coauthors, Riccardio Polosa, was Chief Scientific Advisor to LIAF, received funding from LIAF, and reported serving as a consultant to Arbi Group Srl, an e-cigarette distributor.[71] He also received funding from Philip Morris International.[71] Later in 2015, The BMJ published an investigative report that raised broader issues surrounding potential conflicts of interest between individuals involved in the Nutt et al. paper.[71] The BMJ provided an infographic illuminating undisclosed connections between key people involved in the paper and the tobacco and e-cigarette industries as well as links between the paper and Public Health England via one of the coauthors.[71] Even so, as of June 2017, the "95% safer" figure remains widely quoted, despite the fact that evidence of the dangers of e-cigarette use has rapidly accumulated since 2014.[71] This new evidence indicates that the true risk of e-cigarette use is much higher than the "95% safer" claim would indicate.[71]

In June 2014, the Royal College of Physicians stated that, "On the basis of available evidence, the RCP believes that e-cigarettes could lead to significant falls in the prevalence of smoking in the UK, prevent many deaths and episodes of serious illness, and help to reduce the social inequalities in health that tobacco smoking currently exacerbates."[96] Since vapor does not contain tobacco and does not involve combustion, users may avoid several harmful constituents usually found in tobacco smoke,[13] such as ash, tar, and carbon monoxide.[14] A 2014 review found that e-cigarette aerosol contains far fewer carcinogens than tobacco smoke, and concluded that e-cigarettes "impart a lower potential disease burden" than traditional cigarettes.[54] The public health community is divided, even polarized, over how the use of these devices will impact the tobacco epidemic.[97] Some tobacco control advocates predict that e-cigarettes will increase rates of cigarette uptake, especially among youth.[97] Others envision that these devices have potential for aiding cessation efforts, or reducing harm among people who continue to smoke.[97] Scientific studies advocate caution before designating e-cigarettes as beneficial but vapers continue to believe they are beneficial.[98] It is estimated their safety risk is similar to that of smokeless tobacco, which has about 1% of the mortality risk of traditional cigarettes.[99] The risk of early death is anticipated to be similar to that of smokeless tobacco.[12]

Basic information on harmfulness of e-cigarettes.[100]

Opinions that e-cigarettes are a safe substitute to traditional cigarettes may compromise tobacco control efforts.[101] The American Cancer Society has stated, "The makers of e-cigarettes say that the ingredients are "safe," but this only means the ingredients have been found to be safe to eat. Inhaling a substance is not the same as swallowing it. There are questions about how safe it is to inhale some substances in the e-cigarette vapor into the lungs."[102] The Canadian Cancer Society has stated that, "A few studies have shown that there may be low levels of harmful substances in some e-cigarettes, even if they don't have nicotine."[103] In the UK a National Institute for Health and Care Excellence (NICE) guideline did not recommend e-cigarettes as there are questions regarding the safety, efficacy, and quality of these products.[104] The US National Association of County and City Health Officials has stated, "Public health experts have expressed concern that e-cigarettes may increase nicotine addiction and tobacco use in young people."[105] No long-term studies have evaluated future tobacco use as a result of e-cigarette use.[106] E-cigarette vapor potentially contains harmful substances not found in tobacco smoke.[38] There is no benefit for vaping among youth.[107]

Concerns about the carcinogenicity of e-cigarettes arise from both nicotine[36] and from other chemicals that may be in the vapor.[31] 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.[36] 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".[121] 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".[121] Nicotine in the form of nicotine replacement products is less of a cancer risk than with smoking,[37] and they have not been shown to be associated with cancer in the real world.[36] Nicotine promotes metastasis by causing cell cycle progression, epithelial-to-mesenchymal transition, migration, invasion, angiogenesis, and avoidance of apoptosis in a number of systems.[122] Nicotine does promote the growth of blood vessels that supply tumors and it speeds tumor growth.[71] Whether long-term vaping can raise the chance for malignancy in individuals with a susceptibility for tumor growth is unknown.[123] The effects of nicotine on the sympathoadrenal system could stimulate the advancement of cancer in people who have cancer.[124]

Nicotine has been shown to induce DNA damage in the Escherichia colipol A+/pol− test.[125] Low concentrations of nicotine stimulate cell proliferation, while high concentrations are cytotoxic.[125] Nicotine decreases the tumor suppressor Chk2, which is activated by DNA damage.[125] 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.[125] There is strong evidence that some substances found in e-cigarette vapors such as formaldehyde and acrolein can induce DNA damage and mutagenesis.[126]

Nicotine promotes endothelial cell migration, proliferation, survival, tube formation, and nitric oxide (NO) production in vitro, mimicking the effect of other angiogenic growth factors.[125] 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.[125] Effects of nicotine on angiogenesis have been demonstrated for a number of tumor cells, such as breast, colon, and lung.[125] 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.[125]

A 2014 study suggested that e-cigarette use may be a risk factor for lung cancer.[67] 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.[125] These effects were partially reverted by exposure to α-bungarotoxin (α-BTX), an inhibitor of α7-nAChR.[125] In the case of radiotherapy (RT), nicotine administration increased survival of H460 and A549 lung cancer cells.[125] This effect was likewise reduced by addition of α-BTX prior to nicotine addition and radiation.[125] 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.[125]

Endogenous formation of tobacco-specific nitrosamines (TSNAs) may occur after absorption of nicotine.[125]

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.[125] Nicotine acts primarily by activation of nicotine acetylcholine receptors and nicotine binds to these receptors with a higher affinity than acetylcholine.[125] 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.[125] E-cigarettes deliver the potent lung carcinogen NNK.[71] Some evidence indicates that the NNK dose-response curve for cancer is highly nonlinear, with substantial increases in risk at low doses.[71] Known bladder carcinogens have been detected in the urine of e-cigarette users but not in non-users.[71] 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.[125] 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.[125] Thus, the toxicokinetics of nicotine may depend on the route of administration.[125] 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.[125]

Nicotine has been shown to induce chromosomal aberration, chromatid exchange, single-strand DNA strand breaks, and micronuclei in vitro.[125] Oxidative stress is probably involved since the effects are reduced in the presence of antioxidants.[125] 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.[125]

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.[125] Although nicotinic acetylcholine receptors are the primary receptors, binding of nicotine to β-ARs and EGFRs may also be important.[125] Nicotine induces epithelial–mesenchymal transition, which is one of the vital steps for the acquisition of malignant phenotype.[125] This transition allows the cell to acquire migratory properties, which may facilitate cancer metastases.[125] Moreover, nicotine induces changes that mimic the effects of angiogenic growth factors.[125]

At present, it is not possible to draw a conclusion whether nicotine itself may act as a complete carcinogen.[125] In mice studies with NNK as an initiator, nicotine acts as a promoter after injection or dermal absorption, but not after oral administration.[125] In drinking water experiments, there is considerable first-pass metabolism of nicotine before nicotine enters the systemic circulation.[125] As a result, serum concentration is much lower after ingestion than after intraperitoneal injection administration.[125] Nicotine enhanced tumor growth and progression after injection of malignant cells in mice.[125] Enhancements were found both after exposure of nicotine by intraperitoneal injection, oral, and skin administration.[125] Moreover, cotinine did also enhance tumor growth.[125] Nicotine may inhibit antitumor immune response.[125] It has also been reported that exposure to nicotine adversely affects dendritic cells, a cell type that has an important role in anticancer immunosurveillance.[125] Moreover, in studies on xenograft in mice, nicotine has been found to reduce the effect of radiotherapy and chemoradiotherapy.[125]

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.[8] Their long-term effect on risk of developing cancer is not known.[32] Their long-term use is anticipated to raise the risk of developing lung cancer.[127] 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.[128] Vaping is associated with a possible risk of developing head and neck cancers.[129] 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."[116] The e-cigarette vapors triggered DNA strand breaks and lowered cell survival in vitro,[73] regardless of nicotine content.[39] 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.[10] 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.[130] 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."[131]

Chart showing various toxicants as measured in cigarette smoke and e-cigarette aerosol.[132]

Since nicotine-containing e-liquids are made from tobacco they may contain impurities like cotinine, anabasine, anatabine, myosmine and beta-nicotyrine.[23] The health implications of nicotine-related impurities are not known.[57] 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."[109] The majority of e-cigarettes evaluated included carcinogenic TSNAs; heavy metals such as cadmium, nickel, and lead; and the carcinogen toluene.[41] However, in comparison to traditional cigarette smoke, the toxic substance levels identified in e-cigarette vapor were 9- to 450-fold less.[41] E-liquid with tin was cytotoxic.[50] E-cigarettes cannot be considered absolutely safe because there is no safe level for carcinogens.[133]

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.[8] 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."[134]

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."[31] Few of the methods used to analyze the chemistry of e-cigarettes in the studies the review evaluated were validated.[31] Many variables affect the levels of toxicants in the e-cigarette vapor, including the design, the type of liquid, and user behavior.[135] The FDA in 2009 analyzed e-liquid cartridge samples[36] from two brands of e-cigarettes,[136] which were NJOY and Smoking Everywhere.[133] 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.[137] Diethylene glycol was detected in one cartridge at approximately 1%.[137] Diethylene glycol, an ingredient used in antifreeze, is toxic to humans.[137] The source of the diethylene glycol contamination is not clear but could reflect the use of non-pharmaceutical grade propylene glycol.[66] On July 22, 2009,[136] the FDA warned that e-cigarettes may present a health risk.[8]

The propylene glycol molecule.

The primary base ingredients of the liquid solution is propylene glycol and glycerin.[5] About 20% to 27% of propylene glycol and glycerin-based liquid particles are inhaled.[138] A 2016 study found that 6% of nicotine, 8% of propylene glycol, and 16% of glycerin was breathed out by e-cigarette users.[139] The long-term effects of inhaled propylene glycol has not been studied,[106] and is unknown.[140] The effects of inhaled glycerin are unknown.[141] Being exposed to propylene glycol may cause irritation to the eyes and respiratory tract.[5] 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.[5][39] The risk from the inhalation of propylene glycol and glycerin is probably low.[23] Propylene glycol and glycerin have not been shown to be safe.[141] Some research states that propylene glycol emissions may cause respiratory irritation and raise the likelihood to develop asthma.[54] Long-term inhalation of propylene glycol indoors could increase risk to children to develop asthma.[55] To lessen the risks, most e-cigarettes companies began to use water and glycerin as replacement for propylene glycol.[54] The inhaled glycerin could cause lipoid pneumonia.[142] Propylene glycol and glycerin had increased the amount of hydrogen peroxide.[143]

Some e-cigarette products had acrolein identified in the aerosol.[23] It may be generated when glycerin is heated to higher temperatures.[23] Acrolein may induce irritation to the upper respiratory tract,[5] and harm the lining of the lungs.[29] Acrolein induces oxidative stress and inflammation, leading to a disruption in the function of the endothelial cell barrier in the lung.[143] Acrolein may lead to chronic obstructive pulmonary disease.[143] Acrolein levels were reduced by 60% in dual users and 80% for those that completely switched to e-cigarettes when compared to traditional cigarettes.[23] 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."[128] E-cigarettes vapor have been found to create oxidants and reactive oxygen species (OX/ROS).[26] OX/ROS could react with other substances in the e-cigarette vapor because they are highly reactive.[26] 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.[26] 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.[144]

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.[117] 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.[11] The short-term toxicity of e-cigarette use appears to be low, with the exception for some people with reactive airways.[28]

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.[28] Health effects of e-cigarette flavorings are not entirely known.[145] There is very limited toxicological data on inhaling flavoring additives.[53] Flavorings can be a significant part of toxicants in the e-cigarette vapor.[146] Each flavor has a different chemical composition, and therefore, probably, a distinct composition of toxicant emissions.[146] The cytotoxicity of e-liquids varies,[27] and contamination with various chemicals have been detected in the liquid.[28] Some liquids were very toxic and others had little or no cytotoxicity.[27] The cytotoxicity is mostly due to the amount and number of flavors added.[27] Since nicotine has a bitter taste, nicotine e-liquids contain chemicals to cover up the nicotine taste.[26] The liquids contain aromatic substances like tobacco, fruit, vanilla, caramel, and coffee.[28] Generally, these additives are imprecisely described, using terms such as "vegetable flavoring".[28] Although they are approved for human consumption there are no studies on the short-term or long-term effects of inhaling them.[28] The safety of inhaling flavors is mostly unknown,[114] and their safety has not been determined by the Flavor and Extract Manufacturers Association.[73] The majority of flavorings in e-liquids have not been investigated for toxicity by means of inhalation.[147] 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)."[53] 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."[148]

The extensive and unregulated use of flavoring additives may pose health concerns.[53] Many flavors are irritants.[127] 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.[83] In some cases e-liquids contain very large amounts of flavorings, which may cause irritation and inflammation on respiratory and cardiovascular systems.[111] 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).[149] Some flavors are regarded as toxic and a number of them resemble known carcinogens.[28] The cytotoxicity of some flavors such as strawberry seems to be greater than others.[150] 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.[149] Some artificial flavors are known to be cytotoxic.[28] Unflavored vapor is less cytotoxic than flavored vapor.[30] 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.[151] The caffeine exposures from vaping are approximately at amounts considerably less than in comparison with consuming caffeinated beverages.[152] There is very limited information available regarding the effects of breathing in caffeine.[152] 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.[153]

Cinnamaldehyde has been described as a highly cytotoxic material in vitro in cinnamon-flavored refill liquids.[1] Cinnamaldehyde has also been detected in tobacco flavors, sweet flavors (e.g. caramel), and fruit flavors.[154] 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.[13] Compared to other flavors, coffee and cinnamon flavor are the most toxic.[155] The four most commonly found flavor additives were vanillin, ethyl maltol, ethyl vanillin and menthol.[143] They are carcinogenic or toxic, which contribute to causing cardiopulmonary diseases and neurodegenerative disorders.[143] 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.[156] 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.[156] There is limited information on the effects of inhaling menthol.[53] Many flavoring additives likely cause respiratory effects not typically seen in cigarette smokers.[53] The evidence is sparse to directly associate inhalations of cinnamon with developing or aggravating asthma.[53] Some flavorings could cause lung inflammation.[157] Fruity, sweet, and traditional tobacco flavorings may result in lung toxicity.[148] Flavorings can harm lung cells by producing free radicals and inflammation.[39] Some e-liquids containing cinnamaldehyde stimulate TRPA1, which might induce effects on the lung.[26] In human lung fibroblasts, cinnamon roll flavoring resulted in a noticeable rise in the amount of inflammatory cytokine IL-8.[143] E-liquids contain possibly toxic aldehydes and reactive oxygen species (ROS).[26] Many flavors are known aldehydes, such as anisaldehyde, cinnamaldehyde, and isovaleraldehyde.[26] Saccharides in sweet e-liquid flavors break down and generate furans and aldehydes when vaporized.[158] The consequences of aldehyde-containing flavors on pulmonary surfaces are unknown.[26] A 2012 study found butterscotch flavor was highly toxic with one liquid and two others had a low toxicity.[69] A 2014 in vitro study showed that menthol flavors have a damaging effect on human periodontal ligament fibroblast growth.[138] Methanol had increased the amount of hydrogen peroxide.[143] 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.[157] 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.[41] Some additives may be added to reduce the irritation on the pharynx.[141] The long-term toxicity is subject to the additives and contaminants in the e-liquid.[28] 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.[146]

Certain flavorings contain diacetyl and acetyl propionyl which give a buttery taste.[38] Some sweet flavors containing diacetyl and acetyl propionyl include butter, chocolate, milk, or toffee.[155] Diacetyl occurs in a variety of e-cigarette flavorings such as caramel, butterscotch, watermelon, pina colada, and strawberry.[157] A 2016 Harvard detected 39 of the 51 flavored e-cigarettes tested contained diacetyl.[159] The American Lung Association recommended in 2016 that the FDA require that diacetyl and other unsafe chemicals be omitted from e-cigarettes.[159] Menthol flavorings could also contain diacetyl.[157] Diacetyl and acetyl propionyl are associated with bronchiolitis obliterans.[38] A 2018 PHE report stated that the e-cigarette flavorings containing diacetyl is not likely to present a considerable risk.[160] 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.[6] Being exposed to diacetyl produces morphological alterations in the liver according to animal studies.[109] Both diacetyl and acetyl-propionyl have been found in concentrations above those recommended by the US National Institute for Occupational Safety and Health.[38] Diacetyl is normally found at lower levels in e-cigarettes than in traditional cigarettes.[38] 2, 3-pentanedione, is a α-diketone that is chemically and structurally similar to diacetyl.[57] 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.[57] Some liquids use butyric acid instead of diacetyl and acetyl propionyl, but it could have negative health effects.[161] Concerns exist that the flavors and additives in e-cigarettes might lead to diseases, including the popcorn lung.[93] The cardiovascular effects, including a vast range of flavorings and fragrances, is unknown.[162] Compared to other flavors, cherry contains a greater amount of benzaldehyde,[155] a main ingredient for a variety of fruit flavors.[157] 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.[163] 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.[164] The precise ingredients of e-cigarettes are not known.[165] A 2010 study found rimonabant when examining e-liquids.[166] This weight loss drug has been linked to seizures and suicide.[166] The same study also determined e-liquid can contain amino-tadalafil which is a component of Cialis, used for erectile dysfunction.[166] Users are at risk of encountering negative health outcomes from the small possibility of being exposed to pharmacologic compounds in some e-liquids.[166]

The Centers for Disease Control tested in 2015 36 e-cigarette products for 10 flavor compounds commonly used as additives in tobacco products.[57] Measurable levels of eucalyptol and pulegone were found in the menthol-flavored varieties for all manufacturers.[57] 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.[57] Interestingly, menthol was found at low concentrations in 40% of the tobacco-flavored nonmenthol products tested.[57] Other flavor compounds found were camphor, methyl, salicylate, pulegone, cinnamaldehyde (CAD), and eugenol.[57] 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.[57] Among the chemicals identified were aldehydes (e.g., benzaldehyde and vanillin), which are categorized as primary irritants of the respiratory tract.[57] 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.[57] Various candy and fruit flavor e-liquids that are enticing to youth exhibit in cell culture cytotoxic or mutagenic effects.[167]

The IARC has categorized formaldehyde as a human carcinogen, and acetaldehyde is categorized as a potential carcinogenic to humans.[29] Formaldehyde induced DNA damage and inhibited DNA repair.[168] Acetaldehyde generated crosslinking of DNA-protein which impede with DNA metabolic functions, including replication, repair, recombination, transcription and chromatin remodeling.[168] Aldehydes may cause harmful health effects; though, in the majority of cases, the amounts inhaled are less than with traditional cigarettes.[29] 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.[169] 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,[29] to high temperatures.[41] These compounds are frequently identified in e-cigarette aerosols.[29] Potentially hazardous carbonyls have been identified in e-cigarette aerosols produced at temperatures above 200 °C.[53] The propylene glycol-containing liquids produced the most amounts of carbonyls in e-cigarette aerosols.[29] 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.[5] Nearly all e-cigarettes evaluated, toxic and irritation-causing carbonyls were identified.[41] Reports regarding the levels of toxic chemicals were inconsistent.[41] This includes a study showing that the levels of toxicants in e-cigarettes may be higher than with cigarette smoke.[41]

Battery output voltage influences the level of the carbonyl substances in the e-cigarette vapor.[29] Some newer e-cigarette models let users boost the amount of vapor and nicotine provided by modifying the battery output voltage.[29] E-cigarettes that were modified to boost the vapor production are more dangerous to use.[51] High-voltage e-cigarettes could subject users to large amounts of carbonyls.[29] E-cigarettes with higher voltages (5.0 V[27]) can emit carcinogens including formaldehyde at levels comparable to cigarette smoke,[123] while reduced voltages (3.0 V[31]) generate aerosol with levels of formaldehyde and acetaldehyde roughly 13 and 807-fold less than in cigarette smoke.[29] The average amount of formaldehyde in vapor from high-voltage devices is higher than the average amount of formaldehyde released from cigarettes.[170] "Dripping", where the liquid is dripped directly onto the atomizer, can create carbonyls including formaldehyde.[171]

Controversy exists regarding the specific amount of formaldehyde expected to be breathed in by the user.[146] A 2015 PHE report found that normal e-cigarette use generates very low levels of aldehydes.[33] Normal usage of e-cigarettes generates very low levels of formaldehyde,[30] and at normal settings they generate very low levels of formaldehyde.[33] A 2018 PHE report found that at normal usage temperatures, aldehyde in the e-cigarette vapor is at negligible amounts in comparison with smoking.[172] Later-generation and "hotter" e-cigarettes may generate equal or higher levels of formaldehyde compared to smoking.[32] 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.[27] This was estimated to be a lifetime cancer risk of 5 to 15 times greater than compared with long-term smoking.[27] 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.[30] 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.[71] 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.[33] Users detect the "dry puff" (also known as a "dry hit"[34]) and avoid it, and they concluded that "There is no indication that EC users are exposed to dangerous levels of aldehydes."[35] However, e-cigarette users may learn to overcome the unpleasant taste due to elevated aldehyde formation, when the nicotine craving is high enough.[26]

Possible side effects of nicotine.[173]

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.[174] Shown above is the MOE for daily drug use from the analysis.[174]

Pregnant women, breastfeeding mothers, and the elderly are more sensitive to nicotine than other individuals.[114] There are safety issues with the nicotine exposure from e-cigarettes, which may cause addiction and other adverse effects.[31] 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.[114] At sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradyarrhythmia, and possibly seizures and hypoventilation.[42] High doses can induce deleterious effects on the growth of osteoblasts.[175] Higher-doses leads to loss of nicotinic receptor specificity and induces cholinergic toxicity.[176] The highest-doses can lead to coma.[176] 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.[42]

E-cigarettes provide nicotine to the blood quicker than nicotine inhalers.[98] 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.[177] How efficiently different e-cigarettes give nicotine is unclear.[24] Serum cotinine levels are comparable to that of traditional cigarettes,[178] but are inharmonious and rely upon the user and the device.[8] Blood nicotine levels raised more gradually and took more time to get to peak concentration with e-cigarettes than with traditional cigarettes.[179] Vaping was found to have comparable levels of nicotine urinary metabolites to those who were tobacco and smokeless tobacco product users.[148] Though, the oxidative nicotine metabolites were less in those who were vaping.[148] Evidence indicates that some vaping products may deliver the same amount of nicotine as traditional cigarettes.[180] 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.[181] It not clear the level of addictiveness of e-cigarettes, compared with traditional cigarettes, according to a 2018 PHE report.[182] 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."[183] Users vaping without using nicotine exhibited symptoms of dependence, according to a 2015 study.[184] E-cigarette packages and advertisements require health warnings under US law, stating "WARNING: This product contains nicotine. Nicotine is an addictive chemical."[180]

E-cigarettes resembling cigarettes typically produce much less blood nicotine levels.[145] 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.[82] This is due to the minute nicotine particles in the e-cigarette vapor, which permit quick delivery into the bloodstream.[82] The nicotine delivered from e-cigarettes enters the body slower than traditional cigarettes.[45] Studies suggest that inexperienced users obtain moderate amounts of nicotine from e-cigarettes.[185] Concerns were raised over inconsistent amounts of nicotine delivered when drawing on the device.[186]

Tank or adjustable e-cigarettes can raise nicotine levels as high as traditional cigarettes.[145] Later-generation e-cigarettes give nicotine more effectively than first-generation e-cigarettes.[1] 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.[69] 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.[162] Later-generation devices delivery 35% to 72% more nicotine than compared with first‐generation devices.[128] Second-generation e-cigarettes raised the heart rate and blood pressure similar to traditional cigarettes.[187] 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.[83] Such devices may largely reshape the effects on cardiac safety, misuse, and addiction.[83] There is not much research on fourth-generation devices.[68]

The reinforcing effects of drugs of abuse, such as nicotine, is associated with its ability to excite the mesolimbic and dopaminergic systems.[188]
How do e-cigarettes affect the brain?[189] The nicotine in e-liquids readily absorbs into the bloodstream when a person uses an e-cigarette.[189] Upon entering the blood, nicotine stimulates the adrenal glands to release the hormone epinephrine (adrenaline).[189] Epinephrine stimulates the central nervous system and increases blood pressure, breathing, and heart rate.[189] 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).[189] These feelings motivate some people to use nicotine again and again, despite possible risks to their health and well-being.[189]

The health effects of long-term nicotine use is unknown.[140] It may be decades before the long-term health effects of nicotine vapor inhalation is known.[190] It is not recommended for non-smokers.[13] Public health authorities do not recommend nicotine use for non-smokers.[191] The pureness of the nicotine differs by grade and producer.[192] The impurities associated with nicotine are not as toxic as nicotine.[192] The health effects of vaping tobacco alkaloids that stem from nicotine impurities in e-liquids is not known.[192] Nicotine affects practically every cell in the body.[114] The complex effects of nicotine are not entirely understood.[36] It poses several health risks.[193] Short-term nicotine use excites the autonomic ganglia nerves and autonomic nerves, but chronic use seems to induce negative effects on endothelial cells.[194] Nicotine may have a profound impact on sleep.[195] The effects on sleep vary after being intoxicated, during withdrawal, and from long-term use.[195] Nicotine may result in arousal and wakefulness, mainly via incitement in the basal forebrain.[196] Nicotine withdrawal, after abstaining from nicotine use in non-smokers, was linked with longer overall length of sleep and REM rebound.[195] 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."[197]

Nicotine can weaken antibacterial defenses and modify macrophage activation.[135] Nicotine can cause tremors,[39] high blood pressure, abnormal heart rhythms,[134] and lower coronary blood flow.[162] Nicotine constricts blood vessels.[75] This includes coronary blood vessels and those in the skin.[198] However, blood vessels in the skeletal muscle dilate as a result of nicotine.[198] It can also cause nausea, sweating, and diarrhea.[83] In reaction to nitric oxide, it hinders endothelial-dependent widening of blood vessels.[36] It is associated with stroke, peripheral vascular disease, delayed wound healing, peptic ulcer disease, and esophageal reflux.[170] Vapers that get a higher amount of blood nicotine are probably correlated with increased heart rates.[135] 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.[57] Nicotine is correlated with lung inflammation in adults, which may be as a result of it chemotactic effects.[68] Nicotine may have adverse effects on lipids,[199] cause insulin resistance,[69] and may cause pro-inflammatory effects that could impact beta cell function.[200] Nicotine lowers activity of free radical scavenging enzymes, resulting in more production of hydroxyl free radicals.[200] Nicotine impairs glucose homeostasis, indicating a major role in the development of diabetes mellitus type 2.[200] Osseointegration is a pertinent part of the survival of implants.[201] Nicotine considerably impedes the regenerative capability of mesenchymal stem cells.[58] This includes impeding their proliferation, migration, and differentiation.[58] Nicotine has been correlated with vasoconstriction and a weakened ability to heal at the cellular level.[201] Thus, it apparently compromises implant osseointegration.[201] Nicotine lowers estrogen levels and has been associated with early menopause in women.[134] Nicotine is negatively associated with total sperm motility.[150] Nicotine causes dysfunction of NO synthesis.[193] This may result in inability to get penile erections and erectile dysfunction.[193]

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."[202] The consequence of nicotine use in autoimmunity has been conflicting.[203] Nicotine could have cancer-promoting properties, therefore long-term use may not be harmless.[204] Nicotine may result in neuroplasticity variations in the brain.[205] Nicotine has been demonstrated to alter the amounts of brain-derived neurotrophic factor in humans.[206] Nicotine could make cancer therapies less effective.[20] 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.[125] Nicotine can suppress appetite.[15] Nicotine users will probably gain weight after using less nicotine.[207] A long-term risk from vaping a base containing nicotine is nicotine dependence.[167]

Children are more sensitive to nicotine than adults.[114] The use of products containing nicotine in any form among youth, including in e-cigarettes, is unsafe.[57] Nicotine has more significant and durable damaging effects on adolescent brains compared to adult brains, the former suffering more harmful effects.[57] Animal research offers strong evidence that the limbic system is particularly vulnerable to the long lasting effects of nicotine.[208] In youth, nicotine may result in cognitive impairment[208] as well as the chance of nicotine addiction for life.[134] The adolescent's developing brain is especially sensitive to the harmful effects of nicotine.[209] A short period of regular or occasional nicotine exposure in adolescence exerts long-term neurobehavioral damage.[209] Risks of exposing the developing brain to nicotine include mood disorders and permanent lowering of impulse control.[210] 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[42] Nicotine exposure during brain development may hamper growth of neurons and brain circuits, effecting brain architecture, chemistry, and neurobehavioral activity.[42]

Nicotine changes the way synapses are formed, which can harm the parts of the brain that control attention and learning.[210] 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.[212] Each e-cigarette brand differs in the exact amount of ingredients and nicotine in each product.[212] Therefore, little is known regarding the health consequences of each brand to the growing brains of youth.[212] In August 2014, the American Heart Association noted that "e-cigarettes could fuel and promote nicotine addiction, especially in children."[69] Whether there are subgroups of adolescents who are at greater risk of developing a nicotine dependence from vaping is not known.[167] 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."[213] 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.[57]

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.[130] The results showed that nicotine-containing e-cigarette vapor induces addiction-related neurochemical, physiological and behavioral changes.[130] A 2015 study on the offspring of the pregnant mice, which were exposed to nicotine-containing e-cigarette liquid, showed significant behavioral alterations.[130] This indicated that exposure to e-cigarette components in a susceptible time period of brain development could induce persistent behavioral changes.[130] 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.[214] The FDA stated in 2019 that some people who use e-cigarettes have experienced seizures, with most reports involving youth or young adult users.[215]

Graphic from the 2018 Centers for Disease Control and Prevention's report entitled Why Is Nicotine Unsafe for Kids, Teens, and Young Adults?[216]

There is limited evidence on the long-term exposure of metals.[13] Exposure to the levels and kinds of metals found in the aerosol relies upon the material and other manufacturing designs of the heating element.[69] 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.[13] According to a 2018 PHE report, metals emissions no matter how small, are not needed.[153] They further stated, "EC [e-cigarettes] that generate minimal metal emissions should become an industry standard."[139] The device itself could contribute to the toxicity from the small amounts of silicate and heavy metals found in the liquid and vapor,[171] because they have metal parts that come in contact with the e-liquid.[13] Low levels of possibly harmful chromium, lead, and nickel metals have been found in the emissions.[69] Chromium and nickel nanoparticles have also been found.[5] Copper nanoparticles can induce mitochondrial and DNA injury in lung fibroblasts.[217] DNA repair can be impeded by titanium dioxide nanoparticles from the e-cigarette vapor.[86] This was demonstrated that the titanium dioxide nanoparticles induced single-strand breaks and produced oxidative stress in the DNA of A549 cells.[86] The risk of inhaling nanoparticles is an area of concern.[218] The toxicity of nanoparticles is unknown.[219] Metals including nickel, cadmium, lead and silicate can found in the e-cigarette vapors, and are thought to be carcinogenic, nephrotoxic, neurotoxic, and hemotoxic.[109] Heavy metals are correlated with serious health issues.[14] Inhaling lead can induce serious neurologic injury, notably to the growing brains of children.[14]

Metals may adversely affect the nervous system.[220] Metals found in the e-cigarette vapor may induce cell damage and initiate inflammatory cytokine such as in human lung fibroblasts.[157] 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."[143] A 2013 review found metallic and nanoparticles are associated with respiratory distress and disease.[221] 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.[41] A 2013 study found metal particles in the aerosol were at levels 10-50 times less than permitted in inhalation medicines.[23] A 2014 review suggested that there is no evidence of contamination of the aerosol with metals that justifies a health concern.[11] Cadmium that have been found in the e-cigarette vapor is linked to low sperm density.[150]

Abbreviations: μg, microgram; ng, nanogram; ND, not detected.[27]
∗Fifteen puffs were chosen to estimate the nicotine delivery of one traditional cigarette.[27]

In 2019, an outbreak of severe vaping-associated lung illness affected users in most states in the US.[notes 3][22] Cases involved in the outbreak of lung illness were first identified in Illinois and Wisconsin in April 2019.[240] Similar cases of vaping-associated lung illness were reported in the UK and Japan before the outbreak occurred.[9] 2,051 cases have been reported from 49 states, the District of Columbia, and one US territory, as of November 5, 2019.[22] 47 deaths have been confirmed in the US, as of November 20, 2019.[22] Based on reports from several states, symptoms typically develop over a period of days but sometimes can manifest over several weeks.[237]

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."[241] Of the 2,051 reported cases, information is available in the three months prior to symptom onset for 867 as of October 15, 2019.[22] 86% reported THC use, 34% reported exclusive THC use, about 64% reported using nicotine-containing products, and 11% reported exclusive use of nicotine-containing products.[22] 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).[242] Most of those samples with THC tested also contained significant amounts of Vitamin E acetate.[242] On October 17, 2019, 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.[22] 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 4][243]

Thickening agents were used to dilute vape oils.[244] There has been an increase in attention to companies that sell diluent products that are made with Vitamin E acetate.[244] Previously, Vitamin E was used in low concentrations, or lower than 20% of the formula in vape cartridges.[244] 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.[244] 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.[245]

The e-cigarette industry is placing the blame on illicit vaping liquids for the lung injuries.[246] 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."[247] The CDC recommends that the public should consider not using vaping products until more is known.[22] They also recommend against vaping any THC products as of November 5, 2019.[22] The US FDA considers it prudent to avoid inhaling Vitamin E acetate.[242] 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.[242]

Some of the vaping products analyzed by the Wadsworth Center contained exceedingly high amounts of vitamin E acetate, including those pictured here.[248]

The chemical composition of the e-cigarette aerosol varies across and within manufacturers.[31] Limited data exists regarding their chemistry.[31] The aerosol of e-cigarettes is generated when the e-liquid reaches a temperature of roughly 100–250 °C within a chamber, which is thought to cause pyrolysis of the e-liquid and could also lead to decomposition of other liquid ingredients.[26] The vapor usually contains propylene glycol, glycerin, nicotine, flavors, aroma transporters, and other substances.[23] The levels of nicotine, TSNAs, aldehydes, metals, volatile organic compounds (VOCs), flavors, and tobacco alkaloids in e-cigarette vapors vary greatly.[31] The yield of chemicals found in the e-cigarette vapor varies depending on, several factors, including the e-liquid contents, puffing rate, and the battery voltage.[39]

E-cigarettes consist of fine and ultrafine particles of particulate matter,[5] in the form of an aerosol.[32][31] The aerosol (mist[28]) produced by an e-cigarette is commonly but inaccurately called vapor.[31] In physics, a vapor is a substance in the gas phase whereas an aerosol is a suspension of tiny particles of liquid, solid or both within a gas.[31] The word "vaping" is not technically accurate when applied to e-cigarettes.[262] The aerosol is made-up of liquid sub-micron particles of condensed vapor; thus, the users of these devices are rather "aerosolizing."[262] This aerosol that is produces looks like cigarette smoke to some extent.[263] After a puff, inhalation of the aerosol travels from the device into the mouth and lungs.[31] The composition of e-liquids varies widely due to the extensive range of nicotine levels and flavoring additives used in these products, which result in a hugely great number of different chemical vapor combinations potentially breathed in by the user.[53]

The particles produced from vaping are comparable in particle-size distribution and number of particles to cigarette smoke, with the majority of them in the ultrafine range.[5] Some e-cigarettes released more particles than cigarette smoke.[5] A 2014 review found that fine particles can be chemically intricate and not uniform, and what a particle is made of, the exact harmful elements, and the importance of the size of the particle is mostly unknown.[5] They found that because these things are uncertain, it is not clear whether the ultrafine particles in e-cigarette vapor have health effects similar to those produced by traditional cigarettes.[5] A 2014 WHO report found e-cigarettes release a lower concentration of particles than traditional cigarettes.[7]

After the aerosol is inhaled, it is exhaled.[31] Emissions from e-cigarettes are not comparable to environmental pollution or cigarette smoke as their nature and chemical composition are completely different.[13] The particles are larger, with the mean size being 600 nm in inhaled aerosol and 300 nm in exhaled aerosol.[28] The exhaled aerosol particle concentration is 5 times lower from an e-cigarette than from a traditional cigarette.[8] The density of particles in the e-cigarette vapor is lower than in cigarette smoke by a factor of between 6 and 880 times lower.[13]

For particulate matter emissions, e-cigarettes slightly exceeded the WHO guidelines, but emissions were 15 times less than traditional cigarette use.[264] In January 2014, the International Union Against Tuberculosis and Lung Disease stated "Adverse health effects for exposed third parties (second-hand exposure) cannot be excluded because the use of electronic cigarettes leads to emission of fine and ultrafine inhalable liquid particles, nicotine and cancer-causing substances into indoor air."[265] The dense vapor consists of liquid sub-micron droplets.[262] Substantial levels of particulate matter with a diameter of 2.5 μm are exhaled by vapers.[128]

Aerosol (vapor) exhaled by an e-cigarette user may expose non-users to second-hand vapor.[266]

Since e-cigarettes have not been widely used long enough for evaluation, the long-term health effects from the second-hand vapor are not known.[5] The short-term health effects from the second-hand vapor is also not known.[40] There is insufficient data to determine the impact on public health from e-cigarettes.[178] The potential harm to bystanders from e-cigarettes is unknown.[267] This is because no long-term data is available.[23] There are limited information on the health effects for children inhaling second-hand vapor.[167] Long-term effects for children inhaling second-hand vapor is not known.[167] Vaping has quickly gained public awareness with greater use among adolescents and adults, resulting in greater inhaled second-hand vapor for adolescents, children, and infants.[167] Second-hand vapor does vary depending on the e-liquid, the device and in the way it is used.[268] There is an array in e-cigarette designs, which has an impact on the amounts of ingredients being exposed to non-users.[128] Heavy advertising and promotion included the assertion that vaping would present little risk to bystanders.[269] E-cigarettes are marketed as "free of primary and second-hand smoke risk" due to no carbon monoxide or tar is expected to be generated during use.[221] However, there is a concern for the health impact of nicotine and other ingredients.[221] Exposure to second-hand vapor may be common.[167] Concerns exist that the increased rates of e-cigarette users who have never smoked could cause harms to public health from the increased nicotine addiction.[140] The growing experimentation with vaping among people under that age of 18 is especially concerning in respect to public health.[144] Ethical concerns arise from possibly vulnerable bystanders being exposed to the not yet known health effects of second-hand vapor.[140] Especially compared to the adverse effects of traditional cigarettes, the overall safety of e-cigarettes is not likely to justify significant public health concerns.[140] Overall, there is a possibility they may greatly harm the public's health.[61] Vaping in areas where smoking is banned indoors could be a move in the wrong direction for public health when considering air quality in addition to being unfavorable for an individual who may have quit nicotine use if they did not vape.[83] Some of the few studies examining the effects on health shown that being exposed to e-cigarette vapor may produce biological effects.[5] Their indiscriminate use is a threat to public health.[141]

Some non-users have reported adverse effects from the second-hand vapor.[135] Second-hand vapor exhaled into the air by e-cigarette users can expose others to potentially harmful chemicals.[266] Vaping exposes non-users to particulate matter with a diameter of 2.5 μm, which poses health risks to non-users.[128] E-cigarettes produce propylene glycol aerosols at levels known to cause eye and respiratory irritation to non-users.[57] A 2014 study demonstrated that non-smokers living with vaping device users were exposed to nicotine.[228] A 2015 study concluded that, for indirect exposure, two chemicals—nicotine and propylene glycol—exceeded California Environmental Protection Agency exposure level standards for noncarcinogenic health effects.[57] Between January 2012 and December 2014, the FDA noted 35 adverse effect reports regarding second-hand vaping exposure.[270] A 2016 survey found a sizable percentage of middle and high school students were exposed to second-hand e-cigarette vapors.[128] It is recommended that adolescents stay away from being exposed to second-hand e-cigarette vapor.[180] A 2016 study showed that most participated coughed right away and briefly following a single exposure to e-cigarette vapor, while after 15 minutes it induced a diminished cough reflex sensitivity in healthy never-smokers.[271] Nicotine-free e-cigarette vapor did not have this effect.[271] The health effects of passive exposure to e-cigarettes with no nicotine, as well as the extent of exposure to these products, have just begun to be studied.[57] E-cigarettes that do not contain nicotine generate hazardous vapors[272] and could still present a risk to non-users.[273] Research has not evaluated whether non-users can have allergic reactions from nut potential allergens in e-cigarette aerosol.[57]

Since e-cigarettes do not burn tobacco, no side-stream smoke or any cigarette smoke is produced.[5] Only what is exhaled by e-cigarettes users enters the surrounding air.[23] It is not clear how much of inhaled e-cigarette aerosol is exhaled into the environment where non-users can be exposed.[57] Exhaled vapor consists of nicotine and some other particles, primarily consisting of propylene glycol, glycerin, flavors, and aroma transporters.[23] Bystanders are exposed to these particles from exhaled e-cigarette vapor.[5] Clean air is safer than e-cigarette vapor.[274] A mixture of harmful substances, particularly nicotine, ultrafine particles, and VOCs can be exhaled into the air.[82] The liquid particles condenses into a viewable fog.[28] The e-cigarette vapor is in the air for a short time, with a half-life of about 10 seconds; traditional cigarette smoke is in the air 100 times longer.[28] This is because of fast revaporization at room temperature.[28]

A 2017 review found that the "rapid production of new products has made it hard for the concerned stakeholders such as researchers in the public health field and policy makers to ensure that the products introduced to the public are safe for the users and non-users who are involuntarily exposed to e-cigarette vapors."[228] Little research exists on the exhaled particles, nicotine, and cancer-promoting chemicals into indoor air.[134] Concern exists that some of the mainstream vapor exhaled by e-cigarette users may be inhaled by bystanders, particularly indoors.[41] People living with e‐cigarette users had increased salivary concentrations of cotinine.[128] A small number of e-cigarette studies exist on the effect of indoor air quality done on human test subjects in natural settings.[228] Though, the available studies presented conflicting scientific evidence on the exact exposure from the e-cigarette vapor contents which may be a result of the contrasting methodology used during the research process.[228] Vaping can expose non-users to aldehydes and it reduced indoor air quality due to their released aldehydes.[128] Since e-cigarettes involve an aerosolization process, it is suggested that no meaningful amounts of carbon monoxide are emitted.[45] Thus, cardiocirculatory effects caused by carbon monoxide are not likely.[45] However, in an experimental study, e-cigarettes increased levels of carcinogenic polycyclic aromatic hydrocarbons in the surrounding air.[45] Passive inhalation of vapor might have significant adverse effects.[41] Though, e-cigarettes exposes non-users to nicotine but not to tobacco-related combustion toxicants.[41] Exposure to e-cigarette vapor can reduce lung function.[275]

E-cigarettes do pollute the air in the form of exhaled mainstream aerosol from people using e-cigarettes.[71] Nicotine, ultrafine particles, and products of heating propylene glycol and glycerin are increased in the air where e-cigarettes are being used, although, as expected, at lower levels than produced by smoking the same number of traditional cigarettes.[71] As with traditional cigarettes, however, when several people are using e-cigarettes indoors at the same time, the air can become polluted.[71] For example, levels of fine particulate matter (PM_2.5) in a large hotel event room (4,023m³) increased from 2–3 μg/m³ to as high as 819 μg/m³ (interquartile range: 761–975 μg/m³) when 59–86 people were using e-cigarettes.[71] This level is comparable to a very (conventional tobacco) smoky bar or casino and dramatically exceeds the US Environmental Protection Agency annual time-weighted standard for PM_2.5 of 12 μg/m³.[71]

Evidence has also shown that bystanders absorb nicotine when people around them use e-cigarettes at levels comparable with exposure to traditional cigarette second-hand smoke.[71] In a study of non-smokers living with nicotine e-cigarette users, those living with traditional cigarette smokers, or those living in homes where no one used either product, cotinine (a metabolite of nicotine) levels in bystanders' urine were significantly elevated in both the people exposed to second-hand e-cigarette aerosol and those exposed to second-hand tobacco smoke compared with people living in aerosol- and smoker-free homes.[71] Interestingly, the levels of elevated urinary cotinine in the two exposed groups were not significantly different (although the passive smokers had higher point estimates), despite the fact that the increase in air pollution in the smokers' homes was much higher than in the e-cigarette users' homes (geometric mean air nicotine concentrations of 0.13 μg/m³ in e-cigarette users' homes, 0.74 μg/m³ in smokers' homes, and 0.02 μg/m³ in the control homes).[71]

On the basis of emerging evidence, in 2014 the American Industrial Hygiene Association concluded that "e-cigarettes are not emission-free and that their pollutants could be of health concern for users and those who are exposed secondhand....[T]heir use in the indoor environment should be restricted, consistent with current smoking bans, until and unless research documents that they will not significantly increase the risk of adverse health effects to room occupants."[71] Similarly, in 2016 the American Society of Heating, Refrigeration and Air-Conditioning Engineers (ASHRAE) updated its standard for "Ventilation for Acceptable Indoor Air Quality" to incorporate emissions from e-cigarettes into the definition of "environmental tobacco smoke," which is incompatible with acceptable indoor air quality.[71] As of April 2017, 12 US states and 615 localities had prohibited the use of e-cigarettes in venues in which traditional cigarette smoking was prohibited.[71]

There are benefits to banning vaping indoors in public and working areas, since there is a potential harm of renormalizing tobacco use in smoke-free areas, in addition to, vaping may result in spread of nicotine and other chemicals indoors.[276] E-cigarettes used in indoor environments can put at risk non-smokers to elevated levels of nicotine and aerosol emissions.[8] Non-smokers exposed to e-cigarette aerosol produced by a machine and pumped into a room were found to have detectable levels of the nicotine metabolite cotinine in their blood.[5] The same study stated that 80% of nicotine is normally absorbed by the user, so these results may be higher than in actual second-hand exposure.[5] A 2015 PHE report concluded that e-cigarettes "release negligible levels of nicotine into ambient air with no identified health risks to bystanders".[277] The e-cigarette vapor creates personal exposures that would warrant supervision.[11]

A no smoking or vaping sign from the US.

The available evidence demonstrates that the e-cigarette vapor emitted from e-cigarettes is not just "harmless water vapor" as is repeatedly stated in the advertising of e-cigarettes, and they can cause indoor air pollution.[5] A 2014 practice guideline by NPS MedicineWise states, "Although data on health effects of passive vapour are currently lacking, the risks are argued to be small, but claims that e-cigarettes emit only water vapour are nevertheless incorrect. Serum cotinine levels (a metabolite of nicotine) have been found to be similar in bystanders exposed to either e-cigarette vapour or cigarette smoke."[278] A 2015 California Department of Public Health has reported that "Mainstream and secondhand e-cigarette aerosol has been found to contain at least ten chemicals that are on California's Proposition 65 list of chemicals known to cause cancer, birth defects, or other reproductive harm."[279]

A white paper published in 2014 by the American Industrial Hygiene Association concluded e-cigarettes emit airborne contaminants that may be inhaled by the user and those nearby.[235] Due to this possible risk, they urged restriction of their use indoors, similar to smoking bans, until research has shown the aerosol does not significantly harm others in the area.[235] A 2014 review suggested that the levels of inhaled contaminants from the e-cigarette vapor are not of significant health concern for human exposures by the standards used in workplaces to ensure safety.[11] The compounds that are present, are mostly below 1% of the corresponding levels permissible by workplace safety standards.[11] But workplace safety standards do not recognize exposure to certain vulnerable groups such as people with medical ailments, children, and infants who may be exposed to second-hand vapor.[5] Some chemicals from e-cigarette exposures could surpass workplace safety standards.[53] E-cigarette convention studies indicate that second-hand e-cigarette vapor may be significant for workers in conventions where there are people using e-cigarettes, particularly those who encounter the vapor in more than one of these events.[280] Exposure studies suggest that e-cigarette use in indoor areas is higher than the smoke-free level put forth by the US Surgeon General and the WHO Framework Convention on Tobacco Control.[280] The use of e-cigarettes in a smoke-free area could expose non-users to toxicants.[281] The effect on users and bystanders is probably much less harmful than traditional cigarettes.[23]

Second-hand vapor exposes bystanders to numerous pollutants at amounts higher than background air.[273] A 2016 WHO report stated that "While some argue that exposure to SHA [second-hand aerosol] is unlikely to cause significant health risks, they concede that SHA can be deleterious to bystanders with some respiratory pre-conditions. It is nevertheless reasonable to assume that the increased concentration of toxicants from SHA over background [air] levels poses an increased risk for the health of all bystanders."[282] A 2014 WHO report stated passive exposure was as a concern, indicating that current evidence is insufficient to determine whether the levels of exhaled vapor are safe to involuntarily exposed bystanders.[7] The report stated that "it is unknown if the increased exposure to toxicants and particles in exhaled aerosol will lead to an increased risk of disease and death among bystanders."[7] The British Medical Association (BMA) reported in 2013 that there are "concerns that the use of e-cigarettes could threaten the norm of not smoking in public places and workplaces."[283] Several medical organizations advocate that vaping be banned in public places and workplaces.[83] A 2014 review found it is safe to infer that their effects on bystanders are minimal in comparison to traditional cigarettes.[13] E-cigarette vapor has notably fewer toxicants than cigarette smoke.[5]

Graphic from the 2016 US Surgeon General's report entitled Aerosol and Other Risks.[284]

E‐cigarettes can be unsafe to non-users via third-hand exposure, including children, pregnant women, casino employees, housekeeping employees, and vulnerable groups.[128] E-cigarette use by a parent might lead to inadvertent health risks to offspring.[42] E-cigarettes pose many safety concerns to children.[42] 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.[42] 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.[277] 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.[57]