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The safety of electronic cigarettes is uncertain.^[1]^[2]^[3] There is little data about their safety, and considerable variability among e-cigarettes and in their liquid ingredients^[4] and thus the contents of the aerosol delivered to the user.^[5] Reviews on the safety of e-cigarettes have reached significantly different conclusions.^[6] A 2014 World Health Organization (WHO) report cautioned about potential risks of using e-cigarettes.^[7] Regulated US Food and Drug Administration (FDA) products such as nicotine inhalers are likely safer than e-cigarettes,.^[8] A systematic review suggests that e-cigarettes are less harmful than smoking and since they contain no tobacco and do not involve combustion, users may avoid several harmful constituents usually found in tobacco smoke.^[9]^[10]^[11] However, e-cigarettes cannot be considered harmless.^[12]

E-cigarettes have been found to reduce lung and myocardial function, increase inflammation, and have toxic content including carcinogens, but to a much lower extent than combustible cigarettes in virtually all cases.^[3]^[13] The long-term effects of e-cigarette use are unknown.^[13]^[14]^[15] A 2015 study found serious adverse events related to e-cigarettes were hypotension, seizure, chest pain, rapid heartbeat, disorientation, and congestive heart failure but it was unclear to the degree they were the result of e-cigarettes.^[16] Less serious adverse effects may include abdominal pain, headache, blurry vision,^[16] throat and mouth irritation, vomiting, nausea, and coughing.^[5] A 2014 WHO report said, "ENDS [electronic nicotine delivery system] use poses serious threats to adolescents and fetuses."^[7] Aside from toxicity exposure in normal use, there are also risks from misuse or accidents^[9] such as nicotine poisoning (especially among infants and children),^[17] contact with liquid nicotine,^[18] fires caused by vaporizer malfunction,^[5] and explosions resulting from extended charging, unsuitable chargers, or design flaws.^[9] Battery explosions are caused by an increase in internal battery temperature and some have resulted in severe skin burns.^[1] There is a small risk of battery explosion in devices modified to increase battery power.^[19]

The cytotoxicity of e-liquids varies,^[20] and contamination with various chemicals have been detected in the liquid.^[21] Metal parts of e-cigarettes in contact with the e-liquid can contaminate it with metals.^[9] Many chemicals including carbonyl compounds such as formaldehyde can inadvertently be produced when the nichrome wire (heating element) that touches the e-liquid is heated and chemically reacted with the liquid.^[22] Normal usage of e-cigarettes,^[23] and reduced voltage (3.0 V^[24]) devices generate very low levels of formaldehyde.^[22] Later-generation e-cigarettes used with higher power may generate equal or higher levels of formaldehyde than compared to smoking.^[14]^{[Notes 1]} A 2015 review found that these levels were the result of overheating under test conditions that bear little resemblance to common usage.^[25] A 2015 Public Health England (PHE) report found that high levels of formaldehyde only occurred in overheated "dry-puffing".^[26] Users detect the "dry puff" or "dry hit" and avoid it, and they concluded that "There is no indication that EC users are exposed to dangerous levels of aldehydes."^[27] However, e-cigarette users may "learn" to overcome the unpleasant taste due to elevated aldehyde formation, when the nicotine craving is high enough.^[19] E-cigarette users who use devices that contain nicotine are exposed to its potentially harmful effects.^[24] Nicotine is associated with cardiovascular disease, potential birth defects, and poisoning.^[28] In vitro studies of nicotine have associated it with cancer, but carcinogenicity has not been demonstrated in vivo.^[28] There is inadequate research to demonstrate that nicotine is associated with cancer in humans.^[29] The risk is probably low from the inhalation of propylene glycol and glycerin.^[13] No information is available on the long-term effects of the inhalation of flavors.^[21]

E-cigarettes create an aerosol that consists of fine and ultrafine particles of particulate matter, with the majority of particles in the ultrafine range.^[5]^[30] The vapor have been found to contain flavors, propylene glycol, glycerin, nicotine, tiny amounts of toxicants, carcinogens, heavy metals, and metal nanoparticles, and other substances.^[5]^[13] Exactly what the vapor comprises varies in composition and concentration across and within manufacturers.^[24] E-cigarette vapor potentially contains harmful substances not found in tobacco smoke.^[31] The majority of toxic chemicals found in tobacco smoke are absent in e-cigarette vapor.^[9] E-cigarette vapor contains lower concentrations of potentially toxic chemicals than with cigarette smoke.^[32] Those which are present, are mostly below 1% the corresponding levels permissible by workplace safety standards.^[33] 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] Concern exists that some of the mainstream vapor exhaled by e-cigarette users may be inhaled by bystanders, particularly indoors.^[34] E-cigarette use by a parent might lead to inadvertent health risks to offspring.^[35] A 2014 review recommended that e-cigarettes should be regulated for consumer safety.^[36] There is limited information available on the environmental issues around production, use, and disposal of e-cigarettes that use cartridges.^[37]

Health effects

Concerns

Reviews on the safety of e-cigarettes, evaluating roughly the same studies, have reached significantly different conclusions.^[6] Due to various methodological issues, severe conflicts of interest, and inconsistent research, no definite conclusions can be determined regarding the safety of e-cigarettes.^[12] However, e-cigarettes cannot be regarded as harmless.^[12] 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 long-term use of e-cigarettes.^[36] 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.^[38] 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."^[17] 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]

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.^[39] A 2014 review recommended that e-cigarettes could be adequately regulated for consumer safety with existing regulations on the design of electronic products.^[36] Regulation of the production and promotion of e-cigarettes may help lower some adverse effects associated with tobacco use.^[34] 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.^[40] 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.^[40] The industry could also lead vapers to tobacco products, which would increase instead of decrease overall addiction.^[40]

Unknown

The health effects related to e-cigarette use is mostly unknown.^[41] The health effects on intensive e-cigarette users are unknown.^[14] 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."^[42] The English National Health Service has stated, "While e-cigarettes may be safer than conventional cigarettes, we don’t yet know the long-term effects of vaping on the body."^[43] The American Diabetes Association states "There is no evidence that e-cigarettes are a healthier alternative to smoking."^[44] In August 2014, the Forum of International Respiratory Societies stated that e-cigarettes have not been demonstrated to be safe.^[45] Health Canada has stated that, "their safety, quality, and efficacy remain unknown."^[46] 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."^[47]

Positives relative to cigarettes

A 2015 Public Health England (PHE) report stated that e-cigarettes are estimated to be 95% less harmful than smoking,^[49] although this estimate has been disputed.^[50] 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."^[51] A 2014 systematic review suggests that e-cigarettes are less harmful than smoking because there is no tobacco, no combustion, and users may avoid several harmful constituents usually found in tobacco smoke.^[9] 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.^[52] Scientific studies advocate caution before designating e-cigarettes as beneficial but vapers continue to believe they are beneficial.^[53]

Negatives

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."^[54] 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."^[55] Since 2009, the FDA has pointed out that e-cigarettes contain “detectable levels of known carcinogens and toxic chemicals to which users could be exposed.” For example, there are e-cigarette cartridges that are marketed as “tobacco-free,” however the FDA detected a toxic compound found in antifreeze, tobacco-specific compounds that have been shown to cause cancer in humans, and other toxic tobacco-specific impurities. 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.^[56] 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."^[57] No long-term studies have evaluated future tobacco use as a result of e-cigarette use.^[58] E-cigarette vapor potentially contains harmful substances not found in tobacco smoke.^[31]

Adverse effects

As of 2015^[update], the short-term and long-term effects from using e-cigarettes remain unclear.^[14] Adverse effects are mostly associated with short-term use and the reported adverse effects decreased over time.^[60] Long-term studies regarding the effects of constant use of e-cigarettes are unavailable.^[60] The adverse effects of e-cigarettes on people with cancer is unknown.^[17] A 2014 Cochrane review found no serious adverse effects reported in trials,^[61] but serious events have been reported in case studies.^[13]

The evidence suggests they produce less harmful effects than combusted tobacco.^[11] 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.^[53] Many health benefits are associated with switching from tobacco to e-cigarettes including decreased weight gain after smoking cessation and improved exercise tolerance.^[62] 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.^[63] Many people use e-cigarettes to quit smoking, but few succeed.^[64] They frequently use both, which increases their health risks by using both products.^[64] Quitting smoking entirely would probably have much greater beneficial effects to overall health than vaping to decrease the number of cigarettes smoked.^[5]

More serious adverse effects frequently related with smoking cessation including depression, insomnia, and anxiety are uncommon with e-cigarette use.^[16] A 2015 study found serious adverse events related to e-cigarettes were hypotension, seizure, chest pain, rapid heartbeat, disorientation, and congestive heart failure but it was unclear to the degree they were the result of e-cigarettes.^[16] Less serious adverse effects include abdominal pain, headache, blurry vision,^[16] throat and mouth irritation, vomiting, nausea, and coughing.^[5] Short-term adverse effects reported most often were mouth and throat irritation, dry cough, and nausea.^[60] The majority of adverse effects reported were nausea, vomiting, dizziness and oral irritation.^[9] Some case reports found harms to health brought about by e-cigarettes in many countries, such as the US and in Europe; the most common effect was dryness of the mouth and throat.^[22] Some e-cigarettes users experience adverse effects like throat irritation which could be the result of exposure to nicotine, nicotine solvents, or toxicants in the aerosol.^[17]

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.^[13] 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.^[41] The man from the UK reportedly died from severe lipoid pneumonia in 2011.^[41] Reports to the Food and Drug Administration (FDA) for minor adverse effects identified with using e-cigarettes include headache, chest pain, nausea, and cough.^[1] Major adverse effects reported to the FDA included hospitalizations for pneumonia, congestive heart failure, seizure, rapid heart rate, and burns.^[1] However no direct relationship has been proven between these effects and e-cigarette use, and some of them may be due to existing health problems.^[1] Many of the observed negative effects from e-cigarette use concerning the nervous system and the sensory system are probably related to nicotine overdose or withdrawal.^[65] 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.^[66] E-cigarettes were associated with fewer adverse effects than nicotine patches.^[67]

Poisoning

Nicotine poisoning related to e-cigarettes include ingestion, inhalation, or absorption via the skin or eyes.^[17] Accidental poisoning can result from using undiluted concentrated nicotine when mistakenly used as prepared e-liquids.^[69] E-cigarettes involve accidental nicotine exposure in children.^[18] Accidental exposures in pediatric patients include ingesting of e-liquids and inhaling of e-cigarette vapors.^[18] Choking on e-cigarette components is a potential risk.^[18] It is recommended that youth access to e-cigarettes be prohibited.^[70]

Four adults died in the US and Europe, after intentionally ingesting liquid.^[41] Two children, one in the US in 2014 and another in Israel in 2013, died after ingesting liquid nicotine.^[71] Death from accidental nicotine poisoning is very uncommon.^[72]

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.^[73] Minor, moderate, and serious adverse effects involved adults and young children.^[74] Minor effects correlated with e-cigarette liquid poisoning were tachycardia, tremor, chest pain and hypertension.^[75] More serious effects were bradycardia, hypotension, nausea, respiratory paralysis, atrial fibrillation and dyspnea.^[75] The exact correlation is not fully known between these effects and e-cigarettes.^[75] 58% of e-cigarette calls to US poison control centers were related to children 5 years old or less.^[74] 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.^[74] Most of the e-cigarette and traditional cigarette calls were a minor effect.^[74] Severe outcomes were more than 2.5 times more frequent in children exposed to e-cigarettes and nicotine e-liquid than with traditional cigarettes.^[76] E-cigarette sales were roughly equivalent to just 3.5% of traditional cigarette sales, but of the total number of e-cigarette and traditional cigarette calls to US poison control centers in December 2014, the reported e-cigarettes calls were 44%.^[74]

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;^[74] inhalation/nasal exposure resulted in nausea, vomiting, dizziness, agitated, or headache;^[74] ocular exposure resulted in eye irritation or pain, red eye or conjunctivitis, blurred vision, headache, or corneal abrasion;^[74] multiple routes of exposure resulted in eye irritation or pain, vomiting, red eye or conjunctivitis, nausea, or cough;^[74] and dermal exposure that resulted in nausea, dizziness, vomiting, headache, or tachycardia.^[74] 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%).^[74] In nine reported calls, exposed individuals stated the device leaked.^[74] In five reported calls, individuals used e-liquid for their eyes rather than use eye drops.^[74] In one reported call, an infant was given the e-liquid by an adult who thought it was the infant's medication.^[74] There were also reports of choking on e-cigarette components.^[18]

From January 1, 2016 and April 30, 2016, the American Association of Poison Control Centers (AAPCC) reported 623 exposures related to e-cigarettes.^[64] The AAPCC reported 3,067 exposures relating to e-cigarettes and liquid nicotine in 2015, and 3,783 in 2014.^[78] From September 1, 2010 to December 31, 2014, there were at least 5,970 e-cigarette calls to US poison control centers.^[74] 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%.^[67] 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.^[75] E-cigarette calls was 401 for the month of April 2014.^[74] 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.^[9]

Risks related to e-liquid

Fruit flavored e-liquids.

There is a possibility that inhalation, ingestion, or skin contact can expose people to high levels of nicotine.^[34] Concerns with exposure to the e-liquids include leaks or spills and contact with contaminants in the e-liquid.^[79] This may be especially risky to children, pregnant women, and nursing mothers.^[34] The liquid quickly absorbs into the skin.^[80] The nicotine in e-liquid can be hazardous to infants.^[81] Even a portion of e-liquid may be lethal to a little child.^[82] An excessive amount of nicotine for a child that is capable of being fatal is 0.1–0.2 mg/kg of body weight.^[34] Less than a 1 tablespoon of contact or ingestion of e-liquid can cause nausea, vomiting, cardiac arrest, seizures, or coma.^[83] An accidental ingestion of only 6 mg may be lethal to children.^[38]^[84]

Children are susceptible to ingestion due to their curiosity and desire for oral exploration.^[76] E-cigarettes are packed in colorful containers^[74] and children may be attracted to the flavored liquids.^[58] More youth-oriented flavors include "My Birthday Cake" or "Tutti Frutti Gumballs".^[71] Many nicotine cartridges and bottles of liquid are not child-resistant to stop contact or accidental ingestion of nicotine by children.^[11] "Open" e-cigarette devices, with a refillable tank for e-liquids, are believed to be the biggest risk to young children.^[83] It is recommended that e-cigarettes be kept in a safe place, where children and pets do not have access to them.^[85]

Nicotine toxicity is of concern when e-cigarette solutions are swallowed intentionally by adults as a suicidal overdose.^[40] Six people attempted suicide by injecting e-liquid.^[41] One adolescent attempted suicide by swallowing the e-liquid.^[18] Three deaths were reported to have resulted from swallowing or injecting e-liquid containing nicotine.^[41] An excessive amount of nicotine for an adult that is capable of being fatal is 0.5–1 mg/kg of body weight.^[34] An oral lethal dose for adults is about 30–60 mg.^[53] 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.^[86] Reports of serious adverse effects associated with acute nicotine toxicity that resulting in hospitalization were very uncommon.^[87] Death from intentional nicotine poisoning is very uncommon.^[72] Clear labeling of devices and e-liquid could reduce unintentional exposures.^[74] Child-proof packaging and directions for safe handling of e-liquids could minimize some of the risks.^[81] In January 2016, the Child Nicotine Poisoning Prevention Act of 2015 was passed into law in the US,^[88] which requires child-proof packaging.^[89]

There was inconsistent labeling of the actual nicotine content on e-liquid cartridges from some brands,^[5] and some nicotine has been found in ‘no nicotine' liquids.^[21] A 2015 PHE report noted overall the labelling accuracy has improved.^[90] Most inaccurately-labelled examples contained less nicotine than stated.^[90] Due to nicotine content inconstancy, it is recommended that e-cigarette companies develop quality standards with respect to nicotine content.^[24]

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.^[81] 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.^[38] This includes leaking cartridges, accidental contact with nicotine when changing cartridges, and potential of unintended overdose.^[38] 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."^[91]

Cannabinoid-containing e-liquids need lengthy, complex processing, some being available online without any toxicological and clinical evaluation.^[92] It is thought that cannabinoids vaped at reduced temperatures is safer because it creates smaller amounts of toxicants than the burning of a hot cannabis cigarette.^[92] The health effects of vaping cannabis formulations is mostly unknown.^[92]

Fires, explosions, and other battery-related malfunctions

Most e-cigarettes use lithium batteries, the improper use of which may result in accidents.^[9] It has been recommended that manufacturing quality standards be imposed in order to prevent such accidents.^[9] Better product design and standards could probably reduce some of the risks.^[79] Concern exists from risks associated with e-cigarette explosions for children and adults.^[18]

Some batteries are not well designed, are made with poor quality components, or have defects.^[1] Major injuries have occurred from battery explosions and fires.^[5] A man endured a unilateral corneoscleral laceration with prolapsed iris tissue and hyphemato to the eye area when an e-cigarette exploded in his mouth.^[93] A young man endured bilateral corneal burns to the eye area when an e-cigarette exploded near his chest.^[93] E-cigarette explosions have resulted in burns, lost teeth, neck fractures, and battery acid contact to the face, mouth, and eyes.^[93] A man died when charging an e-cigarette blown up and caught on fire next to oxygen equipment.^[93] House and car fires and skin burns have resulted from some of the explosions.^[1] The explosions were the result of extended charging, use of unsuitable chargers, or design flaws.^[9] There is a possible risk to bystanders from e-cigarette explosions.^[93] There is also a risk of property damage as a result of flammable materials catching on fire from an e-cigarette explosion.^[93] The United States Fire Administration said that 25 fires and explosions were caused by e-cigarettes between 2009 and August 2014.^[94] In the UK fire service call-outs had risen, from 43 in 2013 to 62 in 2014.^[95] A 2015 PHE report concluded that the risks of fire from e-cigarettes "appear to be comparable to similar electrical goods".^[96] Since e-cigarettes are not subjected to product safety testing, they may not have safety designs to avoid overheating, thermal runaway, and battery failure including fire and explosions.^[93] There is inadequate product labeling to inform users of the possible serious harms.^[93] The risk from serious adverse effects is low, but the aftermath may be disastrous in respect to an e-cigarette blast.^[93] Victims have filed lawsuits to make restitution from the e-cigarette blasts.^[41] Adverse effects may be under-reported because reports to the FDA is voluntary.^[93]

In January 2015 the US Federal Aviation Administration issued a safety alert to air carriers that e-cigarettes should not be allowed in checked baggage after a review of fire safety issues, including two fires caused by e-cigarettes in checked baggage.^[94]^[97] The International Civil Aviation Organization, a United Nations agency, also recommends prohibiting e-cigarettes in checked luggage.^[94] A spokesman for the Tobacco Vapor Electronic Cigarette Association said that e-cigarettes do not pose a problem if they are packed correctly in static-free packaging, but that irresponsible people may sometimes pack them carelessly or tamper with them.^[94] In-flight use of e-cigarettes is prohibited in the US.^[97]

Users may alter many of the devices, such as using them to administer other drugs like cannabis.^[5] E-liquid mixing is another way users tamper with e-cigarettes.^[98] Mixing liquid in an unclean area runs the risk of contamination.^[16] Users may add various flavorings and diluents.^[98] Vodka or other forms of alcohol may also be added.^[98] The addition of alcohol or nicotine could expose the user to more toxicants, especially when added in combinations.^[98] Some ingredients in e-liquids could be flammable; this risk is more of concern for users who are inexperienced or do not use protective gear.^[98] Users can adjust the voltage of some e-cigarettes.^[98] The amount of vapor produced is controlled by the power of the battery, which has led some users to adjust their e-cigarettes to increase battery power to obtain a stronger nicotine "hit", but there is a small risk of battery explosion.^[19] Some users add more or larger batteries to nonadjustable e-cigarettes, which may lead to battery leakage or explosion.^[98] The extent to which teens are altering e-cigarettes, such as dripping the liquids onto the atomizer to get more nicotine intake, is not known.^[18]

Toxicology

The long-term health impacts of e-cigarette use are unknown.^[13] The long-term health impacts of the main chemicals nicotine and propylene glycol in the aerosol are not fully understood.^[99] There is limited peer-reviewed data about the toxicity of e-cigarettes for a complete toxicological evaluation,^[100] and their cytotoxicity is unknown.^[15] The chemicals and toxicants included in e-cigarettes have not been completely disclosed and their safety is not guaranteed.^[34] They are similar in toxicity to other nicotine replacement products,^[101] but e-cigarettes manufacturing standards are variable standards, and many as a result are probably more toxic than nicotine replacement products.^[102] The UK National Health Service noted that the toxic chemicals found by the FDA were at levels one-thousandth that of cigarette smoke, and that while there is no certainty that these small traces are harmless, initial test results are reassuring.^[103] While there is variability in the ingredients and concentrations of ingredients in e-cigarette liquids, tobacco smoke contains thousands of chemicals, most of which are not understood and many of which are known to be harmful.^[36]

Carcinogenicity

Concerns about the carcinogenicity of e-cigarettes arise from both nicotine^[28] and from other chemicals that may be in the vapor.^[24] 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.^[28] 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".^[29] 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".^[29] Nicotine in the form of nicotine replacement products is less of a risk than compared to smoking,^[29] and they have not been shown to be associated with cancer in the real world.^[28]

There is no long-term research concerning the cancer risk related to the potentially small level of exposure to the identified carcinogens in the vapor.^[8] 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."^[99] The e-cigarette vapors triggered DNA strand breaks and lowered cell survival in vitro.^[41] 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] 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."^[104]

Since nicotine-containing e-liquids are made from tobacco they may contain impurities like cotinine, anabasine, anatabine, myosmine and beta-nicotyrine.^[13] The majority of e-cigarettes evaluated included carcinogenic tobacco-specific nitrosamines (TSNAs); heavy metals such as cadmium, nickel, and lead; and the carcinogen toluene.^[34] However, in comparison to traditional cigarette smoke, the toxic substance levels identified in e-cigarette vapor were 9- to 450-fold less.^[34] E-liquid with tin was cytotoxic.^[12] E-cigarettes cannot be considered absolutely safe because there is no safe level for carcinogens.^[106]

A 2014 review found higher levels of carcinogens and toxicants than in an FDA-approved nicotine inhaler, suggesting that FDA-approved devices may deliver nicotine more safely.^[8] In 2014, The World Lung Foundation 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."^[107]

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."^[24] Few of the methods used to analyze the chemistry of e-cigarettes in the studies the review evaluated were validated.^[24]

Propylene glycol and other content

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.^[108] The long-term effects of inhaled propylene glycol has not been studied,^[58] and is unknown.^[109] The effects of inhaled glycerin are unknown.^[84] Being exposed to propylene glycol may cause irritation to the eyes and respiratory tract.^[5] The risk from the inhalation of propylene glycol and glycerin is probably low.^[13] Propylene glycol and glycerin have not been shown to be safe.^[84] Some research states that propylene glycol emissions may cause respiratory irritation and raise the likelihood to develop asthma.^[52] Long-term inhalation of propylene glycol indoors could increase risk to children to develop asthma.^[38] To lessen the risks, most e-cigarettes companies began to use water and glycerin as replacement for propylene glycol.^[52] The inhaled glycerin could cause lipoid pneumonia.^[16]

Some e-cigarette products had acrolein identified in the aerosol.^[13] It may be generated when glycerin is heated to higher temperatures.^[13] Acrolein may induce irritation to the upper respiratory tract.^[5] Acrolein levels were reduced by 60% in dual users and 80% for those that completely switched to e-cigarettes when compared to traditional cigarettes.^[13] E-cigarettes vapor have been found to create oxidants and reactive oxygen species (OX/ROS).^[19] OX/ROS could react with other substances in the vapor because they are highly reactive.^[19] 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.^[19]

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.^[100] 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.^[33] The short-term toxicity of e-cigarette use appears to be low, with the exception for some people with reactive airways.^[21]

Flavoring

The essential propylene glycol and/or glycerin mixture may consist of natural or artificial substances to provide it flavor.^[21] The cytotoxicity of e-liquids varies,^[20] and contamination with various chemicals have been detected in the liquid.^[21] Some liquids were very toxic and others had little or no cytotoxicity.^[20] The cytotoxicity is mostly due to the amount and number of flavors added.^[20] Since nicotine has a bitter taste, nicotine e-liquids contain chemicals to cover up the nicotine taste.^[19] 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,^[110] and their safety has not been determined by the Flavor and Extract Manufacturers Association.^[41] In some cases e-liquids contain very large amounts of flavorings, which may cause irritation and inflammation on respiratory and cardiovascular systems.^[69] Some flavors are regarded as toxic and a number of them resemble known carcinogens.^[21] Some artificial flavors are known to be cytotoxic.^[21] Unflavored vapor is less cytotoxic than flavored vapor.^[23] A 2012 study demonstrated that in embryonic and adult cellular models, some substances of the vapor such as flavoring not found in tobacco smoke were cytotoxic.^[111]

Cinnamaldehyde has been described as a highly cytotoxic material in vitro in cinnamon-flavored refill liquids.^[1] 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.^[9] Some e-liquids containing cinnamaldehyde stimulate TRPA1, which might induce effects on the lung.^[19] E-liquids contain possibly toxic aldehydes and reactive oxygen species (ROS).^[19] Many flavors are known aldehydes, such as anisaldehyde, cinnamaldehyde, and isovaleraldehyde.^[19] The effects of aldehyde-containing flavors on pulmonary surfaces are unknown.^[19] A 2012 study found butterscotch flavor was highly toxic with one liquid and two others had a low toxicity.^[40] 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.^[34] Some additives may be added to reduce the irritation on the pharynx.^[84] The long-term toxicity is subject to the additives and contaminants in the e-liquid.^[21]

Certain flavorings contain diacetyl and acetyl propionyl which give a buttery taste.^[31] Diacetyl and acetyl propionyl are associated with bronchiolitis obliterans.^[31] 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] Both diacetyl and acetyl-propionyl have been found in concentrations above those recommended by the US National Institute for Occupational Safety and Health.^[31] Diacetyl is normally found at lower levels in e-cigarettes than in traditional cigarettes.^[31] Concerns exist that the flavors and additives in e-cigarettes might lead to diseases, including the popcorn lung.^[112] The cardiovascular effects, including a vast range of flavorings and fragrances, is unknown.^[113] 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.^[62] The precise ingredients of e-cigarettes are not known.^[114]

Formaldehyde

The IARC has categorized formaldehyde as a human carcinogen, and acetaldehyde is categorized as a potential carcinogenic to humans.^[22] Aldehydes may cause harmful health effects; though, in the majority of cases, the amounts inhaled are less than with traditional cigarettes.^[22] 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,^[22] to high temperatures.^[34] These compounds are frequently identified in e-cigarette aerosols.^[22] The propylene glycol-containing liquids produced the most amounts of carbonyls in e-cigarette aerosols.^[22] The levels of toxic chemicals in the 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.^[34] Reports regarding the levels of toxic chemicals were inconsistent.^[34] This includes a study showing that the levels of toxicants in e-cigarettes may be higher than with cigarette smoke.^[34]

Battery output voltage influences the level of the carbonyl substances in the vapor.^[22] A few new e-cigarettes let users boost the amount of vapor and nicotine provided by modifying the battery output voltage.^[22] E-cigarettes with higher voltages (5.0 V^[20]) can emit carcinogens including formaldehyde at levels comparable to cigarette smoke,^[115] while reduced voltages (3.0 V^[24]) generate aerosol with levels of formaldehyde and acetaldehyde roughly 13 and 807-fold less than in cigarette smoke.^[22] "Dripping", where the liquid is dripped directly onto the atomizer, can create carbonyls including formaldehyde.^[116]

A 2015 PHE report found that normal e-cigarette use generates very low levels of aldehydes.^[26] Normal usage of e-cigarettes generates very low levels of formaldehyde,^[23] and at normal settings they generate very low levels of formaldehyde.^[26] Later-generation e-cigarettes used with higher power may generate equal or higher levels of formaldehyde than compared to smoking.^[14]^{[Notes 2]} A 2015 review found that these levels were the result of overheating under test conditions that bear little resemblance to common usage.^[25] 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.^[26] Users detect the "dry puff" and avoid it, and they concluded that "There is no indication that EC users are exposed to dangerous levels of aldehydes."^[27] However, e-cigarette users may "learn" to overcome the unpleasant taste due to elevated aldehyde formation, when the nicotine craving is high enough.^[19]

Nicotine

Pregnant women, breastfeeding mothers, and the elderly are more sensitive to nicotine than other individuals.^[110] There are safety issues with the nicotine exposure from e-cigarettes, which may cause addiction and other adverse effects.^[24] Nicotine is regarded as a potentially lethal poison.^[17] Concerns exist that vaping can be harmful by exposing users to toxic levels of nicotine.^[17] At low amounts, it has a mild analgesic effect.^[110] At high enough doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradyarrhythmia, and possibly seizures and hypoventilation.^[35] 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.^[17] The health effects of nicotine in infants and children are unclear.^[35]

E-cigarettes provide nicotine to the blood quicker than nicotine inhalers.^[53] The levels were above that of nicotine replacement product users.^[17] E-cigarettes seem to have a pharmacokinetic nicotine profile closer to nicotine replacement products than with traditional cigarettes.^[119] How efficiently different e-cigarettes give nicotine is unclear.^[17] Serum cotinine levels are comparable to that of traditional cigarettes,^[120] 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.^[121]

First-generation devices

When compared to traditional cigarettes older devices usually delivered low amounts of nicotine.^[17] 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.^[122] This is due to the minute nicotine particles in the vapor, which permit quick delivery into the bloodstream.^[122] The nicotine delivered from e-cigarettes enters the body slower than traditional cigarettes.^[123] Studies suggest that inexperienced users obtain moderate amounts of nicotine from e-cigarettes.^[124] Concerns were raised over inconsistent amounts of nicotine delivered when drawing on the device.^[125]

Later-generation devices

Later-generation e-cigarettes gives 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.^[17] E-cigarettes with stronger batteries heat solutions to higher temperatures, which may raise blood nicotine levels to those of traditional cigarettes.^[40] Research suggests that experienced e-cigarettes users are able to get as much nicotine from e-cigarettes as traditional cigarettes.^[17] Later-generation e-cigarettes containing sufficient nicotine elevates heart rate comparable to traditional cigarettes.^[113]

Concerns

The health effects of long-term nicotine use is unknown.^[109] It may be decades before the long-term health effects of nicotine vapor inhalation is known.^[126] It is not recommended for non-smokers.^[9] Nicotine affects practically every cell in the body.^[110] Nicotine can cause high blood pressure and abnormal heart rhythms.^[107] Vapers that get a higher amount of blood nicotine are probably correlated with increased heart rates.^[87] Nicotine may have adverse effects on lipids,^[127] cause insulin resistance.^[40] and can lower coronary blood flow.^[113] Nicotine lowers estrogen levels and has been associated with early menopause in women.^[107] Nicotine could have cancer-promoting properties, therefore long-term use may not be harmless.^[98] Nicotine may result in neuroplasticity variations in the brain.^[80] Nicotine could make cancer therapies less effective.^[16]

Youth

Children are more sensitive to nicotine than adults.^[110] In youth, nicotine may affect capabilities connected with higher cognitive function processes,^[35] later achievement, as well as the chance of nicotine addiction for life.^[107] The adolescents developing brain is especially sensitive to the harmful effects of nicotine.^[82] A short period of regular or occasional nicotine exposure in adolescence exerts long-term neurobehavioral damage.^[82] In August 2014, the American Heart Association noted that "e-cigarettes could fuel and promote nicotine addiction, especially in children."^[40] A 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."^[128]

Metals

There is limited evidence on the long-term exposure of metals.^[9] Exposure to the levels and kinds of metals found in the aerosol relies upon the material and other manufacturing designs of the heating element.^[40] 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.^[9] The device itself could contribute to the toxicity from the tiny amounts of silicate and heavy metals found in the liquid and vapor,^[116] because they have metal parts that come in contact with the e-liquid.^[9] Low levels of possibly harmful chromium, lead, and nickel metals have been found in the emissions.^[40] Chromium and nickel nanoparticles have also been found.^[5]

Metals may adversely affect the nervous system.^[70] A 2013 review found metallic and nanoparticles are associated with respiratory distress and disease.^[129] 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.^[34] A 2013 study found metal particles in the aerosol were at levels 10-50 times less than permitted in inhalation medicines.^[13] A 2014 review suggested that there is no evidence of contamination of the aerosol with metals that justifies a health concern.^[33]

Comparison of levels of toxicants in e-cigarette aerosol

Amounts of toxicants in e-cigarette aerosol compared with nicotine inhaler and cigarette smoke^[20]
Toxicant	Range of content in nicotine inhaler mist (15 puffs∗)	Content in aerosol from 12 e-cigarettes (15 puffs∗)	Content in traditional cigarette micrograms (μg) in smoke from one cigarette
Formaldehyde (μg)	0.2	0.2-5.61	1.6-52
Acetaldehyde (μg)	0.11	0.11-1.36	52-140
Acrolein (μg)	ND	0.07-4.19	2.4-62
o-Methylbenzaldehyde (μg)	0.07	0.13-0.71	—
Toluene (μg)	ND	ND-0.63	8.3-70
p- and m-Xylene (μg)	ND	ND-0.2	—
NNN (ng)	ND	ND-0.00043	0.0005-0.19
Cadmium (ng)	0.003	ND-0.022	—
Nickel (ng)	0.019	0.011-0.029	—
Lead (ng)	0.004	0.003-0.057	—

Abbreviations: μg, microgram; ng, nanogram; ND, not detected.^[20]
∗Fifteen puffs were chosen to estimate the nicotine delivery of one traditional cigarette.^[20]

Effects on breathing and lung function

The risks to the lungs are not fully understood,^[19] and concern exists regarding the negative effects on lung function.^[130] There is limited evidence on the long-term health effects to the lungs.^[14] Many ingredients used in e-liquids have not been examined in the lung.^[19] The effects of e-cigarette use in respect to asthma and other respiratory diseases are unknown.^[13] A 2015 review found e-cigarettes may induce acute lung disease.^[14] A 2015 study found that e-cigarette vapors can induce oxidative stress in lung endothelial cells.^[69] Constant lung inflammation as a result of the vapor could result in lung pathogenesis and induce serious diseases, including chronic obstructive pulmonary disease and fibrosis.^[41] The limited evidence suggests that e-cigarettes produce less short-term effects on lung function than traditional cigarettes.^[8] A 2014 case report observed the correlation between sub-acute bronchiolitis and vaping.^[14] After quitting vaping the symptoms improved.^[14]

The long-term effects regarding respiratory flow resistance are unknown.^[60] E-cigarettes could harm the respiratory system.^[21] The immediate effects of e-cigarettes after 5 minutes of use on pulmonary function resulted in considerable increases in resistance to lung airflow.^[1] A 2013 review found an instant increase in airway resistance after using a single e-cigarette.^[21] Any reported harmful effects to cardiovascular and respiratory functions after short-term use of e-cigarettes were appreciably milder in comparison to cigarette smoke.^[9] When used in the short-term, an e-cigarette resulted in a rise of respiratory resistance comparatively to traditional cigarettes.^[60] E-cigarette use could result in respiratory diseases among youth.^[131]

There is no data available on the long-term cardiovascular effects.^[8] There is no published research available on vaping and thrombosis, platelet reactivity, atherosclerosis, or blood vessel function.^[14] The minute nicotine particles in the vapor could increase the risk of cardiac arrhythmias and hypertension which may put some users, particularly those with atherosclerosis or other cardiovascular risk factors, at significant risk of acute coronary syndrome.^[122] Some case reports documented the possible cardiovascular adverse effects from using e-cigarettes, the majority associated was with improper use.^[122] Even though e-cigarettes are anticipated to produce fewer harmful substances than traditional cigarettes, limited evidence supports they comparatively have a lessened raised cardiovascular risk.^[122] E-cigarette use leads to sympathomimetic effects because of nicotine intake.^[132] It is argued that there could be a risk for harmful effects, including tachycardia-induced cardiomyopathy.^[132] E-cigarettes containing nicotine may have a lower cardiovascular effect than traditional cigarettes containing nicotine.^[113] Short-term physiological effects include increases in blood pressure and heart rate.^[14] A 2012 case report found a correlation between paroxysmal atrial fibrillation and vaping.^[14]

Comparable to a traditional cigarette, e-cigarette particles are tiny enough to enter the alveoli, enabling nicotine absorption.^[1] These particles are also tiny enough to go deep in the lungs and enter into the systemic circulation.^[5] Local pulmonary toxicity may occur because metal nanoparticles can deposit in the lung's alveolar sacs.^[5] E-cigarettes companies assert that the particulates produced by an e-cigarette are too tiny to be deposited in the alveoli.^[53] Different devices generate different particle sizes and cause different depositions in the respiratory tract, even from the same nicotine liquid.^[115] The aerosol production of e-cigarettes during vaping decreases, which requires a more forceful suction to create a similar volume of aerosol.^[66] A more forceful suction could affect the deposition of substances into the lungs.^[66] Reports in the literature have shown respiratory and cardiovascular effects by these smaller size particles, suggesting a possible health concern.^[133]

Other effects

Concern exists regarding the immunological effects of e-liquid, and analysis on animals demonstrate that e-liquid vapor, appear to have adverse effects on the immune system.^[87] There were reports of e-cigarettes causing an immune system reaction involving inflammation of the gastrointestinal system.^[41] Long-term use could increase the risk of tuberculosis.^[12] It is possible that e-cigarettes could harm the periodontium because of the effects of nicotine on gum tissues and the immune system.^[134] Some health effects associated with e-cigarette use can include recurring ulcerative colitis, lipoid pneumonia, acute eosinophilic pneumonitis, sub-acute bronchial toxicity, reversible cerebral vasoconstriction syndrome, and reversal of chronic idiopathic neutrophilia.^[87]

Aerosol and e-liquid

The aerosol of e-cigarettes is generated when the e-liquid reaches a temperature of roughly 100-250 °C within a chamber.^[19] The user inhales the aerosol, commonly called vapor, rather than cigarette smoke.^[24] 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.^[24] The aerosol is made-up of liquid sub-micron particles of condensed vapor,^[135] which mostly consist of propylene glycol, glycerol, water, flavorings, nicotine, and other chemicals.^[9] After a puff, inhalation of the aerosol travels from the device into the mouth and lungs.^[24] The particle size distribution and sum of particles emitted by e-cigarettes are like traditional cigarettes, with the majority of particles in the ultrafine range.^[5]

After the aerosol is inhaled, it is exhaled.^[24] Emissions from electronic cigarettes are not comparable to environmental pollution or cigarette smoke as their nature and chemical composition are completely different^[9] The particles are larger, with the mean size being 600 nm in inhaled aerosol and 300 nm in exhaled vapor.^[21] Bystanders are exposed to these particles from exhaled e-cigarette vapor.^[5] There is a concern that some of the mainstream vapor exhaled by e-cigarette users can be inhaled by bystanders, particularly indoors, and have significant adverse effects.^[34]^[129] Since e-cigarettes involve an aerosolization process, it is suggested that no meaningful amounts of carbon monoxide are emitted.^[123] Thus, cardiocirculatory effects caused by carbon monoxide are not likely.^[123] E-cigarette use by a parent might lead to inadvertent health risks to offspring.^[35] E-cigarettes pose many safety concerns to children.^[35] 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.^[35]

E-liquid is the mixture used in vapor products such as electronic cigarettes.^[52] The main ingredients in the e-liquid usually are propylene glycol, glycerin, nicotine, and flavorings.^[101] However, there are e-liquids sold without propylene glycol, nicotine, or flavors.^[17]^[52]^[61] The liquid typically contains 95% propylene glycol and glycerin.^[84] The flavorings may be natural or artificial.^[21] About 8,000 flavors exist as of 2014.^[136] There are many e-liquids manufacturers in the USA and worldwide.^[137] While there are currently no US Food and Drug Administration (FDA) manufacturing standards for e-liquid, the FDA has proposed regulations that are expected to be finalized in late 2015.^[138] Industry standards have been created and published by the American E-liquid Manufacturing Standards Association (AEMSA).^[139]

Effects during pregnancy

Concerns exists regarding pregnant women exposure to e-cigarette vapor through direct use or via exhaled vapor.^[5] No evidence have shown that e-cigarettes are safe to use for pregnant women.^[140] No amount of nicotine is safe for pregnant women.^[140] As of 2014^[update], there are no conclusions on the possible hazards of pregnant women using e-cigarettes, and there is a developing research on the negative effects of nicotine on prenatal brain development.^[8] E-cigarette are assumed to be dangerous to the fetus during pregnancy if e-cigarettes are used by the mother.^[141] Nicotine is harmful to the growing fetus.^[142] Nicotine accumulates in the fetus because it goes through the placenta.^[38]

As of 2015^[update], the long-term issues of e-cigarettes on both mother and unborn baby are unknown.^[143] Prenatal nicotine exposure is associated with adverse effects on the growing fetus, including effects to normal growth of the endocrine, reproductive, respiratory, cardiovascular, and neurologic systems.^[140] Prenatal nicotine exposure is associated with lower birth weights than other babies,^[140] stillbirth,^[82] sudden infant death syndrome, and alterations to normal brain development.^[140] Prenatal nicotine exposure is associated with asthma and wheezing which may continue into adulthood.^[140] Gestational age nicotine exposure is associated with many neurological deficits.^[140] Prenatal exposure has been associated with obesity, diabetes, high cholesterol and high blood pressure in minors.^[107] Prenatal nicotine exposure in females may lead toward early menarche.^[140] An infant was born with necrotizing enterocolitis due to e-cigarette use during pregnancy.^[41]

In what way the e-liquid ingredients could affect a fetus is unknown.^[2] The toxicity of e-liquid flavorings was higher in embryonic stem cells compared to differentiated adult pulmonary fibroblasts, leading to concerns about pregnant women being exposed to the second-hand vapor.^[109] There are concerns about the health impacts of pediatric exposure to second-hand and third-hand e-cigarette vapor.^[18] The Surgeon General's 2014 report found "that nicotine adversely affects maternal and fetal health during pregnancy, and that exposure to nicotine during fetal development has lasting adverse consequences for brain development."^[17] The belief that e-cigarettes are safer than traditional cigarettes could increase their use in pregnant women.^[1] The toxic effects identified with e-cigarette refill liquids on stem cells may be interpreted as embryonic death or birth defects.^[1] Since e-cigarettes are not validated as cessation tools, may contain nicotine at inconsistent levels and added ingredients that are possibly harmful, allowing e-cigarettes to be used among pregnant women to decrease smoking puts this group at considerable risk.^[35] There is concern for breastfeeding women using e-cigarettes, due to the lack of data on propylene glycol transferring to breastmilk.^[21]

Environmental impact

There is limited information available on any environmental issues connected to the production, usage, and disposal of e-cigarette models that use cartridges.^[37] As of 2014^[update], no formal studies have been done to evaluate the environmental effects of making or disposing of any part of e-cigarettes including the batteries or nicotine production.^[37] As of 2014^[update], it is uncertain if the nicotine in e-liquid is United States Pharmacopeia-grade nicotine, a tobacco extract, or synthetic nicotine when questioning the environmental impact of how it is made.^[37] It is not clear which manufacturing methods are used to make the nicotine used in e-cigarettes.^[37] The emissions from making nicotine could be considerable from manufacturing if not appropriately controlled.^[37] Some e-cigarette brands that use cartridges state their products are ‘eco-friendly’ or ‘green’, despite the absence of any supporting studies.^[37] Some writers contend that such marketing may raise sales and increase e-cigarette interest, particularly among minors.^[37]

It is unclear how many traditional cigarettes are comparable to using one e-cigarette that uses a cartridge for the average user.^[37] Information is limited on energy and materials used for production of e-cigarettes versus traditional cigarettes, for comparable use.^[37] E-cigarettes can be made manually put together in small factories, or they can be made in automated lines on a much bigger scale.^[37] Larger plants will produce greater emissions to the surrounding environment, and thus will have a greater environmental impact.^[37] Although some brands have begun recycling services for their e-cigarette cartridges and batteries, the prevalence of recycling is unknown, as is the prevalence of information provided by manufacturers on how to recycle disposable parts.^[37] A 2014 review found "disposable e-cigarettes might cause an electrical waste problem."^[123] Since the majority of e-cigarettes are reusable they are possibly more environmentally friendly than using single-use devices.^[144] Compared to traditional cigarettes, e-cigarettes do not create litter in the form of discarded cigarette butts.^[144] Traditional cigarette tend to end up in the ocean where they cause pollution.^[144]

Public perceptions

Marketing and advertisement affects the public’s perception of e-cigarettes.^[109] Some tobacco users think vaping is safer than tobacco or other smoking cessation aids.^[145] It is generally considered by users that e-cigarettes are safer than tobacco.^[114] Many users think that e-cigarettes are healthier than traditional cigarettes for personal use or for other people.^[58] Usually, only a small proportion of users are concerned about the possible adverse health effects or toxicity of e-cigarettes.^[58] A 2014 worldwide survey found that 88% of respondents stated that vaping were less harmful than cigarette smoke and 11% believed that vaping were absolutely harmless.^[146] A 2013 four-country survey found higher than 75% of current and former smokers think e-cigarettes are safer than traditional cigarettes.^[1] The UK Action on Smoking and Health (ASH) found that in 2015, compared to the year before, "there has been a growing false belief that electronic cigarettes could be as harmful as smoking".^[147] Among smokers who had heard of e-cigarettes but never tried them, this "perception of harm has nearly doubled from 12% in 2014 to 22% in 2015."^[147] The UK ASH expressed concern that "The growth of this false perception risks discouraging many smokers from using electronic cigarettes to quit and keep them smoking instead which would be bad for their health and the health of those around them."^[147]

A 2015 PHE report noted that in the US belief among respondents to a survey that vaping was safer than smoking cigarettes fell from 82% in 2010 to 51% in 2014.^[148] The report blamed "misinterpreted research findings", attracting negative media coverage, for the growth in the "inaccurate" belief that e-cigarettes were as harmful as smoking,and concluded that "There is a need to publicise the current best estimate that using EC is around 95% safer than smoking".^{[duplication?]}^[149]

Bibliography

McNeill, A; Brose, LS; Calder, R; Hitchman, SC; Hajek, P; McRobbie, H (August 2015). "E-cigarettes: an evidence update A report commissioned by Public Health England" (PDF). UK: Public Health England.
Wilder, Natalie; Daley, Claire; Sugarman, Jane; Partridge, James (April 2016). "Nicotine without smoke: Tobacco harm reduction". UK: Royal College of Physicians.

Notes

^ citing "Carbonyl compounds in electronic cigarette vapors-effects of nicotine solvent and battery output voltage" by Kosmider.
^ citing "Carbonyl compounds in electronic cigarette vapors-effects of nicotine solvent and battery output voltage" by Kosmider.

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External links

Media related to Electronic cigarettes at Wikimedia Commons

[25] ting "Carbonyl compounds in electronic cigarette vapors-effects of nicotine solvent and battery output voltage" by Kosmider.

[118] ting "Carbonyl compounds in electronic cigarette vapors-effects of nicotine solvent and battery output voltage" by Kosmider.

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[MMWR2014-74] Chatham-Stephens K, Law R, Taylor E, Melstrom P, Bunnell R, Wang B, Apelberg B, Schier JG (April 2014). "Notes from the field: calls to poison centers for exposures to electronic cigarettes--United States, September 2010-February 2014". MMWR Morb. Mortal. Wkly. Rep. 63 (13). Centers for Disease Control and Prevention (CDC): 292–3. PMID 24699766.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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@@ Line 4: / Line 4: @@
 E-cigarettes have been found to reduce lung and myocardial function, increase inflammation, and have toxic content including carcinogens, but to a much lower extent than combustible cigarettes in virtually all cases.<ref name=Harrell2014/><ref name=Hajek2014/> The long-term effects of e-cigarette use are unknown.<ref name=Hajek2014/><ref name=Orellana-Barrios2015>{{cite journal|last1=Orellana-Barrios|first1=Menfil A.|last2=Payne|first2=Drew|last3=Mulkey|first3=Zachary|last4=Nugent|first4=Kenneth|title=Electronic cigarettes-a narrative review for clinicians|journal=The American Journal of Medicine|year=2015|issn=0002-9343|doi=10.1016/j.amjmed.2015.01.033|pmid=25731134|volume=128|pages=674–81}}</ref><ref name=Rahman2014/> A 2015 study found serious adverse events related to e-cigarettes were hypotension, seizure, chest pain, rapid heartbeat, disorientation, and congestive heart failure but it was unclear to the degree they were the result of e-cigarettes.<ref name=BrelandSpindle2014/> Less serious adverse effects may include abdominal pain, headache, blurry vision,<ref name=BrelandSpindle2014/> throat and mouth irritation, vomiting, nausea, and coughing.<ref name=Grana2014/> A 2014 WHO report said, "ENDS [electronic nicotine delivery system] use poses serious threats to adolescents and fetuses."<ref name=WHOPosition2014/> Aside from [[toxicity]] exposure in normal use, there are also risks from misuse or accidents<ref name=FarsalinosPolosa2014/> such as [[nicotine poisoning]] (especially among infants and children),<ref name=Brandon2015/> contact with [[liquid nicotine]],<ref name=Durmowicz2014/> fires caused by vaporizer malfunction,<ref name=Grana2014/> and explosions resulting from extended charging, unsuitable chargers, or design flaws.<ref name=FarsalinosPolosa2014/> Battery explosions are caused by an increase in internal battery temperature and some have resulted in severe skin burns.<ref name=EbbertAgunwamba2015/> There is a small risk of battery explosion in devices modified to increase battery power.<ref name=Rowell2015/>
-The [[cytotoxicity]] of e-liquids varies,<ref name=Cooke2015/> and contamination with various chemicals have been detected in the liquid.<ref name=Bertholon2013/> Metal parts of e-cigarettes in contact with the e-liquid can contaminate it with metals.<ref name=FarsalinosPolosa2014/> Many chemicals including [[carbonyl compounds]] such as formaldehyde can inadvertently be produced when the [[nichrome wire]] ([[heating element]]) that touches the e-liquid is heated and chemically reacted with the liquid.<ref name=Bekki2014/> Normal usage of e-cigarettes,{{Sfn|Wilder|2016|p=82}} and reduced voltage (3.0&nbsp;V<ref name=Cheng2014/>) devices generate very low levels of [[formaldehyde]].<ref name=Bekki2014/> Later-generation e-cigarettes used with higher power may generate equal or higher levels of formaldehyde than compared to smoking.<ref name=Orellana-Barrios2015/>{{#tag:ref | citing "Carbonyl compounds in electronic cigarette vapors-effects of nicotine solvent and battery output voltage" by Kosmider.|group="Notes"}} A 2015 review found that these levels were the result of overheating under test conditions that bear little resemblance to common usage.<ref name=PolosaCampagna2015>{{cite journal|last1=Polosa|first1=R|last2=Campagna|first2=D|last3=Caponnetto|first3=P|title=What to advise to respiratory patients intending to use electronic cigarettes.|journal=Discovery medicine|date=September 2015|volume=20|issue=109|pages=155–61|pmid=26463097}}</ref> A 2015 [[Public Health England]] (PHE) report found that high levels of formaldehyde only occurred in overheated "dry-puffing".{{Sfn|McNeill|2015|p=77}} Users detect the "dry puff" {{failed verification span|text=or "dry hit"|date=December 2017}} and avoid it, and they concluded that "There is no indication that EC users are exposed to dangerous levels of aldehydes."{{Sfn|McNeill|2015|p=77-78}} However, e-cigarette users may "learn" to overcome the unpleasant taste due to elevated [[aldehyde]] formation, when the nicotine craving is high enough.<ref name=Rowell2015/> E-cigarette users who use devices that contain nicotine are exposed to its potentially harmful effects.<ref name=Cheng2014/> Nicotine is associated with cardiovascular disease, potential birth defects, and poisoning.<ref name=Jerry2015/> ''[[In vitro]]'' studies of nicotine have associated it with cancer, but carcinogenicity has not been demonstrated ''[[in vivo]]''.<ref name=Jerry2015/> There is inadequate research to demonstrate that nicotine is associated with cancer in humans.<ref name=SGUS2014/> The risk is probably low from the inhalation of propylene glycol and glycerin.<ref name=Hajek2014/> No information is available on the long-term effects of the inhalation of flavors.<ref name=Bertholon2013/>
+The [[cytotoxicity]] of e-liquids varies,<ref name=Cooke2015/> and contamination with various chemicals have been detected in the liquid.<ref name=Bertholon2013/> Metal parts of e-cigarettes in contact with the e-liquid can contaminate it with metals.<ref name=FarsalinosPolosa2014/> Many chemicals including [[carbonyl compounds]] such as formaldehyde can inadvertently be produced when the [[nichrome wire]] ([[heating element]]) that touches the e-liquid is heated and chemically reacted with the liquid.<ref name=Bekki2014/> Normal usage of e-cigarettes,{{Sfn|Wilder|2016|p=82}} and reduced voltage (3.0&nbsp;V<ref name=Cheng2014/>) devices generate very low levels of [[formaldehyde]].<ref name=Bekki2014/> Later-generation e-cigarettes used with higher power may generate equal or higher levels of formaldehyde than compared to smoking.<ref name=Orellana-Barrios2015/>{{#tag:ref | citing "Carbonyl compounds in electronic cigarette vapors-effects of nicotine solvent and battery output voltage" by Kosmider.|group="Notes"}} A 2015 review found that these levels were the result of overheating under test conditions that bear little resemblance to common usage.<ref name=PolosaCampagna2015>{{cite journal|last1=Polosa|first1=R|last2=Campagna|first2=D|last3=Caponnetto|first3=P|title=What to advise to respiratory patients intending to use electronic cigarettes.|journal=Discovery medicine|date=September 2015|volume=20|issue=109|pages=155–61|pmid=26463097}}</ref> A 2015 [[Public Health England]] (PHE) report found that high levels of formaldehyde only occurred in overheated "dry-puffing".{{Sfn|McNeill|2015|p=77}} Users detect the "dry puff" or "dry hit" and avoid it, and they concluded that "There is no indication that EC users are exposed to dangerous levels of aldehydes."{{Sfn|McNeill|2015|p=77-78}} However, e-cigarette users may "learn" to overcome the unpleasant taste due to elevated [[aldehyde]] formation, when the nicotine craving is high enough.<ref name=Rowell2015/> E-cigarette users who use devices that contain nicotine are exposed to its potentially harmful effects.<ref name=Cheng2014/> Nicotine is associated with cardiovascular disease, potential birth defects, and poisoning.<ref name=Jerry2015/> ''[[In vitro]]'' studies of nicotine have associated it with cancer, but carcinogenicity has not been demonstrated ''[[in vivo]]''.<ref name=Jerry2015/> There is inadequate research to demonstrate that nicotine is associated with cancer in humans.<ref name=SGUS2014/> The risk is probably low from the inhalation of propylene glycol and glycerin.<ref name=Hajek2014/> No information is available on the long-term effects of the inhalation of flavors.<ref name=Bertholon2013/>
 E-cigarettes create an aerosol that consists of fine and [[ultrafine particle]]s of [[particulate matter]], with the majority of particles in the ultrafine range.<ref name=Grana2014/><ref>{{cite journal|last1=Goniewicz|first1=ML|last2=Knysak|first2=J|last3=Gawron|first3=M|last4=Kosmider|first4=L|last5=Sobczak|first5=A|last6=Kurek|first6=J|last7=Prokopowicz|first7=A|last8=Jablonska-Czapla|first8=M|last9=Rosik-Dulewska|first9=C|last10=Havel|first10=C|last11=Jacob P|first11=3rd|last12=Benowitz|first12=N|title=Levels of selected carcinogens and toxicants in vapour from electronic cigarettes.|journal=Tobacco control|date=March 2014|volume=23|issue=2|pages=133–9|pmid=23467656|doi=10.1136/tobaccocontrol-2012-050859|pmc=4154473}}</ref> The vapor have been found to contain [[flavor#Flavorants or flavorings|flavors]], [[propylene glycol]], [[glycerin]], nicotine, tiny amounts of [[toxicant]]s, [[carcinogen]]s, [[heavy metals]], and metal [[nanoparticle]]s, and other substances.<ref name=Grana2014/><ref name=Hajek2014/> Exactly what [[electronic cigarette aerosol|the vapor comprises varies in composition and concentration]] across and within manufacturers.<ref name=Cheng2014/> E-cigarette vapor potentially contains harmful substances not found in tobacco smoke.<ref name=Hildick-SmithPesko2015/> The majority of toxic chemicals found in tobacco smoke are absent in e-cigarette vapor.<ref name=FarsalinosPolosa2014/> E-cigarette vapor contains lower concentrations of potentially toxic chemicals than with [[cigarette smoke]].<ref name="FernándezBallbè2015">{{cite journal|last1=Fernández|first1=Esteve|last2=Ballbè|first2=Montse|last3=Sureda|first3=Xisca|last4=Fu|first4=Marcela|last5=Saltó|first5=Esteve|last6=Martínez-Sánchez|first6=Jose M.|title=Particulate Matter from Electronic Cigarettes and Conventional Cigarettes: a Systematic Review and Observational Study|journal=Current Environmental Health Reports|volume=2 |pages=423–9|year=2015|issn=2196-5412|doi=10.1007/s40572-015-0072-x|pmid=26452675}}</ref> Those which are present, are mostly below 1% the corresponding levels permissible by [[Occupational safety and health|workplace safety standards]].<ref name=Burstyn2014/> But workplace safety standards do not recognize exposure to certain vulnerable groups such as people with [[medical conditions|medical ailments]], children, and infants who may be exposed to second-hand vapor.<ref name=Grana2014/> Concern exists that some of the mainstream vapor exhaled by e-cigarette users may be inhaled by bystanders, particularly indoors.<ref name=Rom2014/> E-cigarette use by a parent might lead to inadvertent health risks to offspring.<ref name=England2015/> A 2014 review recommended that e-cigarettes should be regulated for [[consumer safety]].<ref name=Saitta2014/> There is limited information available on the [[environmental issue]]s around production, use, and disposal of e-cigarettes that use cartridges.<ref name=Chang2014/>

Revision as of 17:09, 4 December 2017

Health effects

Concerns

Unknown

Positives relative to cigarettes

Negatives

Adverse effects

Poisoning

Risks related to e-liquid

Fires, explosions, and other battery-related malfunctions

Toxicology

Carcinogenicity

Propylene glycol and other content

Flavoring

Formaldehyde

Nicotine

First-generation devices

Later-generation devices

Concerns

Youth

Metals

Comparison of levels of toxicants in e-cigarette aerosol

Effects on breathing and lung function

Other effects

Aerosol and e-liquid

Effects during pregnancy

Environmental impact

Public perceptions

See also

Bibliography

Notes

References

External links