Electronic cigarettes (e-cigarettes) are electronic devices that deliver nicotine by heating a nicotine-based solution to release aerosols that are then inhaled by the user (Kaisar et al., 2016). E-cigarettes are often referred to as smokeless cigarettes, cig-a-like, vaporette, technofogger, personal vaporizer, vaping device, vapor pen, or e-hookah. E-cigarettes mimic the smoking of classic tobacco cigarettes which instead burn nicotine through the combustion of tobacco, dispensing copious toxic substances and carcinogens during the process (Li et al., 2018).
Specifically, the Food and Drug Administration (FDA) has pinpointed 93 of the over 4000 chemicals in tobacco cigarettes to be harmful or potentially harmful constituents (HPHCs). E-cigarettes customarily comprise of a blend of nicotine, artificial flavoring, additives, water, and either propylene glycol and/or vegetable glycerin (i.e., glycerol) as a delivery system. This concoction is referred to as e-juice, e-liquid, juice, vapor juice, or smoke juice, and is electrically heated by a battery-powered vaporizer. Generally, e-cigarette vapors produce considerably fewer toxic compounds than tobacco smoke does; the concentrations of toxic compounds found in e-cigarette vapors are anywhere from 9 to 450 times less than those found in tobacco smoke (Goniewicz et al., 2014).
E-cigarettes were developed in 2003 by Chinese pharmacist Hon Lik, who himself wanted a safer substitute and cessation tool for tobacco cigarettes, and e-cigarettes became a product available in Europe and USA starting in 2006 (Hajek et al., 2014; Orellana-Barrios et al., 2015; Kaisar et al., 2016). E-cigarettes were marketed as a innocuous alternative to conventional cigarettes with no side effects, as well as a cessation tool for smoking, despite inadequate short-term or long-term research on either aspects (Li et al., 2018).
These beliefs and perceptions surrounding e-cigarettes, which are not fully supported by empirical research, have quickly become mainstream and have dangerous consequences. For instance, some pregnant women may have the false perception that vaping, as opposed to smoking, is safe for use during pregnancy (Li et al., 2018).
However, studies have demonstrated that nicotine is damaging for the maturing fetus (Holbrook, 2016), and that e-cigarette exposure during fetal development may have cognitive and neurological ramifications on the future child (Nguyen et al., 2018). Furthermore, young people who would otherwise not smoke tobacco but who believe e-cigarettes are harmless may be encouraged to vape (Barrington-Trimis et al., 2016). Unfortunately, vaping in adolescence has been linked to experimenting with tobacco cigarettes in adulthood, as a result of reliance on nicotine (Menakuru & Ali, 2018).
Regardless, e-cigarettes have become increasingly popular, such that 3.5 million e-cigarette gadgets were sold in 2012 (Li et al., 2018). Total e-cigarette sales in 2016 in the USA were $751.2 million (Cantrell et al., 2018), and there are currently over 460 unique e-cigarette brands on the market. Besides being perceived as safe, e-cigarettes have gained popularity due to other attributes which are also more favorable compared to traditional smoking (Peters et al., 2013).
For instance, because e-cigarettes are odorless and do not produce the strong aromas associated with traditional smoking, users are able to puff discreetly in public and around non-users or non-smokers without their discomfort. This aspect of e-cigarettes also facilitates children and high school students to puff discreetly without notice at home or at school.
The existence of a plentiful assortment of different flavors (i.e., fruit, candy, tobacco, mint) in e-liquids also make vaping highly popular among children, teenagers, and other young people (Ambrose et al., 2015; Villanti et al., 2017). Unsurprisingly, e-cigarettes have now become a widespread phenomenon, especially among the younger generation (Li et al., 2018), such that e-cigarettes are presently the number one tobacco product used in high school and middle school students in the USA (Jamal et al., 2017). One positive aspect to the rise of e-cigarette use is the decline in conventional tobacco cigarette use by youth in the USA (Li et al., 2018).
Objective of Paper
Although e-liquid constituents in e-cigarettes are ‘generally recognized as safe’ (GRAS) by the FDA when used in foods, these chemical compounds may change, transform, interact, and decompose into different by-products once superheated by the vaporizer, creating a unique aerosol composition that is inhaled into the lung (Kaisar et al., 2016; Shields et al., 2017). Thus, hazardous compounds may be inhaled unknowingly during vaping. Additionally, it remains unclear how e-cigarette aerosols impact the human body, both short-term and long-term. The purpose of this paper is to 1) summarize current knowledge of the toxicity (or potential toxicity) of the major components in e-liquids (i.e., vehicle base solution and artificial flavorings) and their produced aerosols, and 2) summarize recent findings on the short-term effects of e-cigarette use in humans.
Toxicity of Vehicle Base Solution
E-liquid is commonly composed of propylene glycol (PG) and/or vegetable glycerin (VG), which make up 80–97% of e-liquid weight (Han et al., 2016). PG and VG are humectants (i.e., water-absorbing) and are typically used as solvents, food additives, or in cosmetic products (Cotta, Stephen, and Mohammad, 2017). PG is a main component of US-manufactured tobacco cigarettes, and PG itself has low toxicity to humans whether through ingestion, skin absorption, or inhalation.
However, higher occupational exposures may cause dermal irritation or allergic manifestations. Existing research has demonstrated that PG can be transformed into propylene oxide during heating, the latter of which may potentially cause cancer in humans, as determined by the International Agency for Research on Cancer (IARC) (Shields et al., 2017).
In addition, when heated to high temperatures, PG and VG can oxidize into toxic aldehydes and other carbonyl compounds of lower molecular weight such as formaldehyde, acrolein, acetone, and acetaldehyde, which are also released in tobacco smoke (Kosmider et al., 2014; Goniewicz et al., 2014). Furthermore, the concentrations of these aldehydes in e-cigarette vapor may be above sanctioned safety levels. For instance, one study found median formaldehyde levels in e-cigarette aerosols to be double that of the limit denoted by the American Conference of Governmental Industrial Hygienists (ACGIH) (Klager et al., 2017).
Aldehydes (i.e., formaldehyde, acetaldehyde, and acrolein) are electrophilic carbonyl compounds that are known human irritants (Watson, Bates, & Kennedy, 1988). Formaldehyde is a group 1 human carcinogen identified by IARC that has been linked to death from myeloid leukemia (Hauptmann et al., 2009) and nasal-related cancer (Paolino et al., 2018). Acetaldehyde is an IARC group 2b possible human carcinogen that has been linked to nasopharyngeal and laryngeal carcinomas (Feron, Kruysse, Woutersen, 1982; Woutersen et al., 1986). Acrolein, although not identified as a human cancer-causing agent by IARC, has been implicated in cardiovascular disease, respiratory injury, and nasal irritation (DeJarnett et al., 2014; Snow et al., 2017).
Additionally, of these three aldehydes, acrolein is the most hazardous at lower levels (Watson, Bates, & Kennedy, 1988). Specifically, while formaldehyde, acetaldehyde, and acrolein all cause irritation in the eyes, olfactory system, and respiratory tract mucosa, acrolein causes harm at lower dose exposures relative to formaldehyde and acetaldehyde. Chronic and/or extremely high exposures to these aldehydes can lead to everlasting epithelial damage (Watson, Bates, & Kennedy, 1988).
The quantities of aldehydes and other carbonyl compounds produced by e-cigarette vapors depend on the e-liquid composition as well as the voltage of the battery (Kosmider et al., 2014). For instance, in one study, predominantly PG-based e-liquids formed the highest concentrations of carbonyl compounds, suggesting that temperature fosters decomposition in PG more strongly than in VG (Kosmider et al., 2014). Batteries with high voltage output, and thus, elevated heating temperatures and more solvent uptake per puff, were found to produce increased concentrations of formaldehyde, acetaldehyde, and acetone. Alarmingly, usage of high voltage e-cigarettes produced aerosol concentrations of formaldehyde that were comparable to the range of those recorded in conventional cigarette smoke (Kosmider et al., 2014).
Toxicity of Artificial Flavorings
Over 7,000 different flavorings exist in the market for e-cigarettes, often in a sweet fruit or candy flavor (preferred by young people) or a tobacco flavor (preferred by tobacco smokers) (Li et al., 2018; Zare, Nemati, & Zheng, 2018). While the Flavors and Extracts Manufacturers’ Association (FEMA) approves most of these flavorings for e-cigarettes based on ingestion tests for safety, these flavors have not been tested for safety when inhaled (FEMA, 2014). Thus, the GRAS status for e-cigarette flavorings may be misleading, especially given that e-cigarette flavors can consist of many different chemicals such as diacetyl, glycidol, acetol, acetone, aromatic hydrocarbons, tobacco-specific nitrosamines (TSNAs), and volatile organic compounds (VOC), many of which may cause pulmonary inflammation or damage (Allen et al., 2016; Tierney et al., 2016).
Sweet flavorings often are composed of diacetyl (2,3-butanedione) or acetyl propionyl (2,3-pentanedione) (Farsalinos et al., 2015; Allen et al., 2016). Although exposure levels of diacetyl and acetyl propionyl from e-cigarette vapors are lower than those from tobacco cigarettes (by one to two degrees of magnitude), there remains toxicological concern. Diacetyl, a chemical that provides a buttery flavor in food products, has recently caused widespread alarm as the agent responsible for the incurable bronchiolitis obliterans, known as ‘popcorn lung disease’ (Kreiss et al., 2002; Kanwal et al., 2006). Workers in popcorn factories were exposed to diacetyl, which despite being safe for ingestion, is toxic in inhalation. In laboratory studies, diacetyl has been found to provoke epithelial injury and necrosis in the nasal passageways and pulmonary airways of rats (Hubbs et al., 2002; 2008) and mice (Morgan et al., 2008).
Another agent in artificial butter flavoring is acetyl propionyl, which is structurally similar to diacetyl (Day et al., 2011). Acetyl propionyl became a popular substitute for diacetyl after the rampant backlash from ‘popcorn lung disease’, despite little toxicological knowledge surrounding the effects of acetyl propionyl inhalation at the time. However, acetyl propionyl has more recently been implicated in respiratory and olfactory cytotoxicity in rats and mice (Hubbs et al., 2012; Morgan et al., 2012).
Specifically, rat studies have demonstrated that diacetyl is more toxic than acetyl propionyl in the upper respiratory tract (i.e., nose, larynx, and trachea), while the reverse is true in the lung, specifically regarding the development of bronchial and alveolar fibrosis (Morgan et al., 2016). A recent study identified both diacetyl and acetyl propionyl to be present in 74% of 159 diverse samples tested; 47% of samples containing diacetyl and 42% of samples containing acetyl propionyl produced aerosols that surpassed the safety limits set forth by National Institute for Occupational Safety and Health (NIOSH) for occupational exposure (Farsalinos et al., 2015).
Although PG and VG are thought to be the primary producers of toxic aldehydes during thermal decomposition, it has been demonstrated that e-cigarette flavorings not only generate aldehydes during vaporization, but may actually lead in and serve as the main contributor of aldehyde production, releasing concentrations that surpass safety limits (Khlystov & Samburova, 2016). In particular, Khlystov & Samburova (2016) found that, given otherwise identical e-liquid compositions, those that were unflavored generated considerably lower levels of aldehydes in vapors compared to those that were flavored. This suggests that flavoring compounds, which do not initially contain those aldehydes, must undergo thermal decomposition during vaporization.
Furthermore, an increase in flavoring concentration was followed by an exponential increase in aldehyde concentration, which further corroborates the role of e-cigarette flavors in aldehyde production (Khlystov & Samburova, 2016). Just a single puff from a flavored e-cigarette released aldehyde concentrations (i.e., formaldehyde, acrolein) that surpassed the threshold limit values (TLVs) denoted by the American Conference of Governmental Industrial Hygienists (ACGIH) (Khlystov & Samburova, 2016). In another study, benzaldehyde was detected in the aerosols of e-cigarettes, with highest concentrations in cherry-flavored e-cigarettes (Kosmider et al., 2016); in particular, 30 e-cigarette puffs released more benzaldehyde than that would be inhaled from a traditional cigarette.
Benzaldehyde and vanillin have also been detected as flavor chemicals in e-cigarettes (Tierney et al., 2016). These findings are disturbing, given that nearly all e-cigarettes come with a flavoring and that most e-cigarette products do not provide information on the chemical concentrations of the flavorings (Tierney et al., 2016).
Short-term Effects of E-cigarette Use in Humans
Most studies focusing on the effects of e-cigarette aerosols on humans have been short-term studies, given the newness of e-cigarettes. However, many of these short-term studies have identified significant physiological changes or other unfavorable outcomes from e-cigarette use. For instance, within just 5 minutes of e-cigarette use, heart rate as well as systolic and diastolic blood pressure increase, although less so compared to conventional cigarette use (Vansickel & Eissenberg, 2013; Yan & D’Ruiz, 2015).
Additionally, using e-cigarettes for 5 minutes has been found to have adverse pulmonary effects, such as decreased fraction of exhaled nitric oxide (FENO) and increased total respiratory impedance and flow respiratory resistance (Vardavas et al., 2012). E-cigarettes have also been associated with decreased vitamin E levels, nitric oxide bioavailability, and flow-mediated dilation (FMD), which are indicators for endothelial dysfunction (Carnevale et al., 2016). Lastly, passive exposure to e-cigarette vapors have been associated with respiratory issues, such as asthma aggravations, coughing, bronchitis, trouble breathing, and pneumonia in bystanders (Durmowicz, Rudy, & Chen, 2016).
However, some research provides evidence that the changes in lung function brought on by e-cigarette use may be minimal and not clinically relevant, especially when compared to the more appreciable alterations brought on by traditional smoking. For instance, some researchers determined that active e-cigarette vaping led to a 3% reduction in forced expiratory volume in 1 second (FEV1), which was not substantial enough to impair lung function (Flouris et al., 2013).
At a molecular level, e-cigarette use has been associated with enhanced levels of proteins associated with oxidative stress, a feature also seen in tobacco cigarette smokers, but not in non-smokers (Reidel et al., 2018). Furthermore, within respiratory tract secretions, levels of innate defense proteins were found to be increased in e-cigarette users, a feature associated with chronic obstructive pulmonary disease (COPD) (Reidel et al., 2018). There is additional evidence that e-cigarette use (specifically acute inhalation of the vapors) alters lung biology and homeostasis (Staudt et al., 2018).
Specifically, healthy individuals with no history of smoking (neither e-cigarettes nor tobacco cigarettes) who were exposed to e-cigarette aerosols had transformations in the transcriptomes of their small airway epithelium (SAE) and alveolar macrophages (AM) (Staudt et al., 2018). These transcriptome alterations in the SAE are particularly meaningful, as the SAE is the first place where tobacco cigarette smokers experience aberrancies in the lung. Lastly, e-cigarette vapor also hindered DNA repair and caused DNA damage in murine lung, bladder, and hearts (and in human lung and bladder cells), and consequently may be implicated in human lung, bladder, or heart disease and cancer (Lee et al., 2018).
In addition to the e-liquid constituents discussed in this paper, various other chemical compounds have been identified in e-liquids, such as heavy metals (e.g., cadmium, lead, nickel, copper) (Cheng, 2014). The complexities of e-liquid constituents and their by-products produced during vaporization, along with the intricacies of e-cigarette design (i.e., battery, microprocessor) warrant continued investigation on the consequences of vaping.
Ultimately, current findings on e-cigarette toxicity suggest that, despite being advocated as a safer alternative to tobacco cigarettes, e-cigarettes are by no means a wholly safe device without potential health consequences. E-cigarettes do not merely release water vapor, but instead may expose users to toxic levels of harmful chemical compounds, the long-term health effects of which are still relatively unknown.