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New study links vaping to increased respiratory symptoms in young adults

Young people who use electronic cigarettes or vape report increased respiratory symptoms, including wheezing and shortness of breath, compared to those who don’t use e-cigarettes, according to a new study.      The use of electronic cigarettes has increased in recent years among adolescents and young adults. Use of these products produces aerosols that contain volatile chemicals, including flavorings and oxidant metals with known lung toxicity. Detailed studies of the association of e-cigarette use with respiratory symptoms have been limited.     

In the study, researchers evaluated the associations of e-cigarette use with self-reported respiratory symptoms in a group of over 2,000 U.S. teens during a series of annual surveys across a 4-year time span. The participants were part of the Southern California Children’s Health Study between 2014 and 2018.      The odds of wheezing among the participants were 81% more likely among those who used e-cigarettes in the past 30 days than among those who never vaped.  Similarly, the odds of bronchitis-like symptoms were twice as likely in users, while those of shortness of breath were 78% more likely after adjusting for age, sex, race, and other factors. The findings remained statistically significant even after further adjustment for concurrent use of cigarettes and cannabis and secondhand exposure to e-cigarettes, cigarettes, and/or cannabis.   

Published in journal Thorax , the study was funded in part by the NHLBI.    

Media Coverage

• E-Cigarette Use Tied to Respiratory Symptoms in Young Adults
• Study links lung conditions to young people who vape
• Vaping Doubles Risk of Lung Problems in Teens: Study
• Vaping can take a toll on respiratory health of teens
• Vaping linked to bronchitic symptoms, shortness of breath in young people

• Open access
• Published: 18 May 2021

An updated overview of e-cigarette impact on human health

• Patrice Marques   ORCID: orcid.org/0000-0003-0465-1727 1 , 2 ,
• Laura Piqueras   ORCID: orcid.org/0000-0001-8010-5168 1 , 2 , 3 &
• Maria-Jesus Sanz   ORCID: orcid.org/0000-0002-8885-294X 1 , 2 , 3  

Respiratory Research volume  22 , Article number:  151 ( 2021 ) Cite this article

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The electronic cigarette ( e-cigarette ), for many considered as a safe alternative to conventional cigarettes, has revolutionised the tobacco industry in the last decades. In e-cigarettes , tobacco combustion is replaced by e-liquid heating, leading some manufacturers to propose that e-cigarettes have less harmful respiratory effects than tobacco consumption. Other innovative features such as the adjustment of nicotine content and the choice of pleasant flavours have won over many users. Nevertheless, the safety of e-cigarette consumption and its potential as a smoking cessation method remain controversial due to limited evidence. Moreover, it has been reported that the heating process itself can lead to the formation of new decomposition compounds of questionable toxicity. Numerous in vivo and in vitro studies have been performed to better understand the impact of these new inhalable compounds on human health. Results of toxicological analyses suggest that e-cigarettes can be safer than conventional cigarettes, although harmful effects from short-term e-cigarette use have been described. Worryingly, the potential long-term effects of e-cigarette consumption have been scarcely investigated. In this review, we take stock of the main findings in this field and their consequences for human health including coronavirus disease 2019 (COVID-19).

Electronic nicotine dispensing systems (ENDS), commonly known as electronic cigarettes or e-cigarettes , have been popularly considered a less harmful alternative to conventional cigarette smoking since they first appeared on the market more than a decade ago. E-cigarettes are electronic devices, essentially consisting of a cartridge, filled with an e-liquid, a heating element/atomiser necessary to heat the e-liquid to create a vapour that can be inhaled through a mouthpiece, and a rechargeable battery (Fig.  1 ) [ 1 , 2 ]. Both the electronic devices and the different e-liquids are easily available in shops or online stores.

Effect of the heating process on aerosol composition. Main harmful effects documented. Several compounds detected in e-cigarette aerosols are not present in e-liquid s and the device material also seems to contribute to the presence of metal and silicate particles in the aerosols. The heating conditions especially on humectants, flavourings and the low-quality material used have been identified as the generator of the new compounds in aerosols. Some compounds generated from humectants (propylene glycol and glycerol) and flavourings, have been associated with clear airways impact, inflammation, impairment of cardiovascular function and toxicity. In addition, some of them are carcinogens or potential carcinogens

The e-liquid typically contains humectants and flavourings, with or without nicotine; once vapourised by the atomiser, the aerosol (vapour) provides a sensation similar to tobacco smoking, but purportedly without harmful effects [ 3 ]. However, it has been reported that the heating process can lead to the generation of new decomposition compounds that may be hazardous [ 4 , 5 ]. The levels of nicotine, which is the key addictive component of tobacco, can also vary between the commercially available e-liquids, and even nicotine-free options are available. For this particular reason, e-cigarettes are often viewed as a smoking cessation tool, given that those with nicotine can prevent smoking craving, yet this idea has not been fully demonstrated [ 2 , 6 , 7 ].

Because e-cigarettes are combustion-free, and because most of the damaging and well-known effects of tobacco are derived from this reaction, there is a common and widely spread assumption that e-cigarette consumption or “vaping” is safer than conventional cigarette smoking. However, are they risk-free? Is there sufficient toxicological data on all the components employed in e-liquids ? Do we really know the composition of the inhaled vapour during the heating process and its impact on health? Can e-cigarettes be used to curb tobacco use? Do their consumption impact on coronavirus disease 2019 (COVID-19)? In the present review, we have attempted to clarify these questions based on the existing scientific literature, and we have compiled new insights related with the toxicity derived from the use of these devices.

Effect of e-cigarette vapour versus conventional cigarette exposure: in vivo and in vitro effects

Numerous studies have been performed to evaluate the safety/toxicity of e-cigarette use both in vivo and in in vitro cell culture.

One of the first studies in humans involved the analysis of 9 volunteers that consumed e-cigarettes , with or without nicotine, in a ventilated room for 2 h [ 8 ]. Pollutants in indoor air, exhaled nitric oxide (NO) and urinary metabolite profiles were analysed. The results of this acute experiment revealed that e-cigarettes are not emission-free, and ultrafine particles formed from propylene glycol (PG) could be detected in the lungs. The study also suggested that the presence of nicotine in e-cigarettes increased the levels of NO exhaled from consumers and provoked marked airway inflammation; however, no differences were found in the levels of exhaled carbon monoxide (CO), an oxidative stress marker, before and after e-cigarette consumption [ 8 ]. A more recent human study detected significantly higher levels of metabolites of hazardous compounds including benzene, ethylene oxide, acrylonitrile, acrolein and acrylamide in the urine of adolescent dual users ( e-cigarettes and conventional tobacco consumers) than in adolescent e-cigarette -only users (Table 1 ) [ 9 ]. Moreover, the urine levels of metabolites of acrylonitrile, acrolein, propylene oxide, acrylamide and crotonaldehyde, all of which are detrimental for human health, were significantly higher in e-cigarette -only users than in non-smoker controls, reaching up to twice the registered values of those from non-smoker subjects (Table 1 ) [ 9 ]. In line with these observations, dysregulation of lung homeostasis has been documented in non-smokers subjected to acute inhalation of e-cigarette aerosols [ 10 ].

Little is known about the effect of vaping on the immune system. Interestingly, both traditional and e-cigarette consumption by non-smokers was found to provoke short-term effects on platelet function, increasing platelet activation (levels of soluble CD40 ligand and the adhesion molecule P-selectin) and platelet aggregation, although to a lesser extent with e-cigarettes [ 11 ]. As found with platelets, the exposure of neutrophils to e-cigarette aerosol resulted in increased CD11b and CD66b expression being both markers of neutrophil activation [ 12 ]. Additionally, increased oxidative stress, vascular endothelial damage, impaired endothelial function, and changes in vascular tone have all been reported in different human studies on vaping [ 13 , 14 , 15 , 16 , 17 ]. In this context, it is widely accepted that platelet and leukocyte activation as well as endothelial dysfunction are associated with atherogenesis and cardiovascular morbidity [ 18 , 19 ]. In line with these observations the potential association of daily e-cigarettes consumption and the increased risk of myocardial infarction remains controversial but benefits may occur when switching from tobacco to chronic e-cigarette use in blood pressure regulation, endothelial function and vascular stiffness (reviewed in [ 20 ]). Nevertheless, whether or not e-cigarette vaping has cardiovascular consequences requires further investigation.

More recently, in August 2019, the US Centers for Disease Control and Prevention (CDC) declared an outbreak of the e-cigarette or vaping product use-associated lung injury (EVALI) which caused several deaths in young population (reviewed in [ 20 ]). Indeed, computed tomography (CT scan) revealed local inflammation that impaired gas exchange caused by aerosolised oils from e-cigarettes [ 21 ]. However, most of the reported cases of lung injury were associated with use of e-cigarettes for tetrahydrocannabinol (THC) consumption as well as vitamin E additives [ 20 ] and not necessarily attributable to other e-cigarette components.

On the other hand, in a comparative study of mice subjected to either lab air, e-cigarette aerosol or cigarette smoke (CS) for 3 days (6 h-exposure per day), those exposed to e-cigarette aerosols showed significant increases in interleukin (IL)-6 but normal lung parenchyma with no evidence of apoptotic activity or elevations in IL-1β or tumour necrosis factor-α (TNFα) [ 22 ]. By contrast, animals exposed to CS showed lung inflammatory cell infiltration and elevations in inflammatory marker expression such as IL-6, IL-1β and TNFα [ 22 ]. Beyond airway disease, exposure to aerosols from e-liquids with or without nicotine has also been also associated with neurotoxicity in an early-life murine model [ 23 ].

Results from in vitro studies are in general agreement with the limited number of in vivo studies. For example, in an analysis using primary human umbilical vein endothelial cells (HUVEC) exposed to 11 commercially-available vapours, 5 were found to be acutely cytotoxic, and only 3 of those contained nicotine [ 24 ]. In addition, 5 of the 11 vapours tested (including 4 that were cytotoxic) reduced HUVEC proliferation and one of them increased the production of intracellular reactive oxygen species (ROS) [ 24 ]. Three of the most cytotoxic vapours—with effects similar to those of conventional high-nicotine CS extracts—also caused comparable morphological changes [ 24 ]. Endothelial cell migration is an important mechanism of vascular repair than can be disrupted in smokers due to endothelial dysfunction [ 25 , 26 ]. In a comparative study of CS and e-cigarette aerosols, Taylor et al . found that exposure of HUVEC to e-cigarette aqueous extracts for 20 h did not affect migration in a scratch wound assay [ 27 ], whereas equivalent cells exposed to CS extract showed a significant inhibition in migration that was concentration dependent [ 27 ].

In cultured human airway epithelial cells, both e-cigarette aerosol and CS extract induced IL-8/CXCL8 (neutrophil chemoattractant) release [ 28 ]. In contrast, while CS extract reduced epithelial barrier integrity (determined by the translocation of dextran from the apical to the basolateral side of the cell layer), e-cigarette aerosol did not, suggesting that only CS extract negatively affected host defence [ 28 ]. Moreover, Higham et al . also found that e-cigarette aerosol caused IL-8/CXCL8 and matrix metallopeptidase 9 (MMP-9) release together with enhanced activity of elastase from neutrophils [ 12 ] which might facilitate neutrophil migration to the site of inflammation [ 12 ].

In a comparative study, repeated exposure of human gingival fibroblasts to CS condensate or to nicotine-rich or nicotine-free e-vapour condensates led to alterations in morphology, suppression of proliferation and induction of apoptosis, with changes in all three parameters greater in cells exposed to CS condensate [ 29 ]. Likewise, both e-cigarette aerosol and CS extract increased cell death in adenocarcinomic human alveolar basal epithelial cells (A549 cells), and again the effect was more damaging with CS extract than with e-cigarette aerosol (detrimental effects found at 2 mg/mL of CS extract vs. 64 mg/mL of e-cigarette extract) [ 22 ], which is in agreement with another study examining battery output voltage and cytotoxicity [ 30 ].

All this evidence would suggest that e-cigarettes are potentially less harmful than conventional cigarettes (Fig.  2 ) [ 11 , 14 , 22 , 24 , 27 , 28 , 29 ]. Importantly, however, most of these studies have investigated only short-term effects [ 10 , 14 , 15 , 22 , 27 , 28 , 29 , 31 , 32 ], and the long-term effects of e-cigarette consumption on human health are still unclear and require further study.

Comparison of the degree of harmful effects documented from e-cigarette and conventional cigarette consumption. Human studies, in vivo mice exposure and in vitro studies. All of these effects from e-cigarettes were documented to be lower than those exerted by conventional cigarettes, which may suggest that e-cigarette consumption could be a safer option than conventional tobacco smoking but not a clear safe choice

Consequences of nicotine content

Beyond flavour, one of the major issues in the e-liquid market is the range of nicotine content available. Depending on the manufacturer, the concentration of this alkaloid can be presented as low , medium or high , or expressed as mg/mL or as a percentage (% v/v). The concentrations range from 0 (0%, nicotine-free option) to 20 mg/mL (2.0%)—the maximum nicotine threshold according to directive 2014/40/EU of the European Parliament and the European Union Council [ 33 , 34 ]. Despite this normative, however, some commercial e-liquids have nicotine concentrations close to 54 mg/mL [ 35 ], much higher than the limits established by the European Union.

The mislabelling of nicotine content in e-liquids has been previously addressed [ 8 , 34 ]. For instance, gas chromatography with a flame ionisation detector (GC-FID) revealed inconsistencies in the nicotine content with respect to the manufacturer´s declaration (average of 22 ± 0.8 mg/mL vs. 18 mg/mL) [ 8 ], which equates to a content ~ 22% higher than that indicated in the product label. Of note, several studies have detected nicotine in those e-liquids labelled as nicotine-free [ 5 , 35 , 36 ]. One study detected the presence of nicotine (0.11–6.90 mg/mL) in 5 of 23 nicotine-free labelled e-liquids by nuclear magnetic resonance spectroscopy [ 35 ], and another study found nicotine (average 8.9 mg/mL) in 13.6% (17/125) of the nicotine-free e-liquids as analysed by high performance liquid chromatography (HPLC) [ 36 ]. Among the 17 samples tested in this latter study 14 were identified to be counterfeit or suspected counterfeit. A third study detected nicotine in 7 of 10 nicotine-free refills, although the concentrations were lower than those identified in the previous analyses (0.1–15 µg/mL) [ 5 ]. Not only is there evidence of mislabelling of nicotine content among refills labelled as nicotine-free, but there also seems to be a history of poor labelling accuracy in nicotine-containing e-liquids [ 37 , 38 ].

A comparison of the serum levels of nicotine from e-cigarette or conventional cigarette consumption has been recently reported [ 39 ]. Participants took one vape from an e-cigarette , with at least 12 mg/mL of nicotine, or inhaled a conventional cigarette, every 20 s for 10 min. Blood samples were collected 1, 2, 4, 6, 8, 10, 12 and 15 min after the first puff, and nicotine serum levels were measured by liquid chromatography-mass spectrometry (LC–MS). The results revealed higher serum levels of nicotine in the conventional CS group than in the e-cigarette group (25.9 ± 16.7 ng/mL vs. 11.5 ± 9.8 ng/mL). However, e-cigarettes containing 20 mg/mL of nicotine are more equivalent to normal cigarettes, based on the delivery of approximately 1 mg of nicotine every 5 min [ 40 ].

In this line, a study compared the acute impact of CS vs. e-cigarette vaping with equivalent nicotine content in healthy smokers and non-smokers. Both increased markers of oxidative stress and decreased NO bioavailability, flow-mediated dilation, and vitamin E levels showing no significant differences between tobacco and e-cigarette exposure (reviewed in [ 20 ]). Inasmuch, short-term e-cigarette use in healthy smokers resulted in marked impairment of endothelial function and an increase in arterial stiffness (reviewed in [ 20 ]). Similar effects on endothelial dysfunction and arterial stiffness were found in animals when they were exposed to e-cigarette vapor either for several days or chronically (reviewed in [ 20 ]). In contrast, other studies found acute microvascular endothelial dysfunction, increased oxidative stress and arterial stiffness in smokers after exposure to e-cigarettes with nicotine, but not after e-cigarettes without nicotine (reviewed in [ 20 ]). In women smokers, a study found a significant difference in stiffness after smoking just one tobacco cigarette, but not after use of e-cigarettes (reviewed in [ 20 ]).

It is well known that nicotine is extremely addictive and has a multitude of harmful effects. Nicotine has significant biologic activity and adversely affects several physiological systems including the cardiovascular, respiratory, immunological and reproductive systems, and can also compromise lung and kidney function [ 41 ]. Recently, a sub-chronic whole-body exposure of e-liquid (2 h/day, 5 days/week, 30 days) containing PG alone or PG with nicotine (25 mg/mL) to wild type (WT) animals or knockout (KO) mice in α7 nicotinic acetylcholine receptor (nAChRα7-KO) revealed a partly nAChRα7-dependent lung inflammation [ 42 ]. While sub-chronic exposure to PG/nicotine promote nAChRα7-dependent increased levels of different cytokines and chemokines in the bronchoalveolar lavage fluid (BALF) such as IL-1α, IL-2, IL-9, interferon γ (IFNγ), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1/CCL2) and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), the enhanced levels of IL-1β, IL-5 and TNFα were nAChRα7 independent. In general, most of the cytokines detected in BALF were significantly increased in WT mice exposed to PG with nicotine compared to PG alone or air control [ 42 ]. Some of these effects were found to be through nicotine activation of NF-κB signalling albeit in females but not in males. In addition, PG with nicotine caused increased macrophage and CD4 + /CD8 + T-lymphocytes cell counts in BALF compared to air control, but these effects were ameliorated when animals were sub-chronically exposed to PG alone [ 42 ].

Of note, another study indicated that although RANTES/CCL5 and CCR1 mRNA were upregulated in flavour/nicotine-containing e-cigarette users, vaping flavour and nicotine-less e-cigarettes did not significantly dysregulate cytokine and inflammasome activation [ 43 ].

In addition to its toxicological effects on foetus development, nicotine can disrupt brain development in adolescents and young adults [ 44 , 45 , 46 ]. Several studies have also suggested that nicotine is potentially carcinogenic (reviewed in [ 41 ]), but more work is needed to prove its carcinogenicity independently of the combustion products of tobacco [ 47 ]. In this latter regard, no differences were encountered in the frequency of tumour appearance in rats subjected to long-term (2 years) inhalation of nicotine when compared with control rats [ 48 ]. Despite the lack of carcinogenicity evidence, it has been reported that nicotine promotes tumour cell survival by decreasing apoptosis and increasing proliferation [ 49 ], indicating that it may work as a “tumour enhancer”. In a very recent study, chronic administration of nicotine to mice (1 mg/kg every 3 days for a 60-day period) enhanced brain metastasis by skewing the polarity of M2 microglia, which increases metastatic tumour growth [ 50 ]. Assuming that a conventional cigarette contains 0.172–1.702 mg of nicotine [ 51 ], the daily nicotine dose administered to these animals corresponds to 40–400 cigarettes for a 70 kg-adult, which is a dose of an extremely heavy smoker. We would argue that further studies with chronic administration of low doses of nicotine are required to clearly evaluate its impact on carcinogenicity.

In the aforementioned study exposing human gingival fibroblasts to CS condensate or to nicotine-rich or nicotine-free e-vapour condensates [ 29 ], the detrimental effects were greater in cells exposed to nicotine-rich condensate than to nicotine-free condensate, suggesting that the possible injurious effects of nicotine should be considered when purchasing e-refills . It is also noteworthy that among the 3 most cytotoxic vapours for HUVEC evaluated in the Putzhammer et al . study, 2 were nicotine-free, which suggests that nicotine is not the only hazardous component in e-cigarettes [ 24 ] .

The lethal dose of nicotine for an adult is estimated at 30–60 mg [ 52 ]. Given that nicotine easily diffuses from the dermis to the bloodstream, acute nicotine exposure by e-liquid spilling (5 mL of a 20 mg/mL nicotine-containing refill is equivalent to 100 mg of nicotine) can easily be toxic or even deadly [ 8 ]. Thus, devices with rechargeable refills are another issue of concern with e-cigarettes , especially when e-liquids are not sold in child-safe containers, increasing the risk of spilling, swallowing or breathing.

These data overall indicate that the harmful effects of nicotine should not be underestimated. Despite the established regulations, some inaccuracies in nicotine content labelling remain in different brands of e-liquids . Consequently, stricter regulation and a higher quality control in the e-liquid industry are required.

Effect of humectants and their heating-related products

In this particular aspect, again the composition of the e-liquid varies significantly among different commercial brands [ 4 , 35 ]. The most common and major components of e-liquids are PG or 1,2-propanediol, and glycerol or glycerine (propane-1,2,3-triol). Both types of compounds are used as humectants to prevent the e-liquid from drying out [ 2 , 53 ] and are classified by the Food and Drug Administration (FDA) as “Generally Recognised as Safe” [ 54 ]. In fact, they are widely used as alimentary and pharmaceutical products [ 2 ]. In an analysis of 54 commercially available e-liquids , PG and glycerol were detected in almost all samples at concentrations ranging from 0.4% to 98% (average 57%) and from 0.3% to 95% (average 37%), respectively [ 35 ].

With regards to toxicity, little is known about the effects of humectants when they are heated and chronically inhaled. Studies have indicated that PG can induce respiratory irritation and increase the probability of asthma development [ 55 , 56 ], and both PG and glycerol from e-cigarettes might reach concentrations sufficiently high to potentially cause irritation of the airways [ 57 ]. Indeed, the latter study established that one e-cigarette puff results in a PG exposure of 430–603 mg/m 3 , which is higher than the levels reported to cause airway irritation (average 309 mg/m 3 ) based on a human study [ 55 ]. The same study established that one e-cigarette puff results in a glycerol exposure of 348–495 mg/m 3 [ 57 ], which is close to the levels reported to cause airway irritation in rats (662 mg/m 3 ) [ 58 ].

Airway epithelial injury induced by acute vaping of PG and glycerol aerosols (50:50 vol/vol), with or without nicotine, has been reported in two randomised clinical trials in young tobacco smokers [ 32 ]. In vitro, aerosols from glycerol only-containing refills showed cytotoxicity in A549 and human embryonic stem cells, even at a low battery output voltage [ 59 ]. PG was also found to affect early neurodevelopment in a zebrafish model [ 60 ]. Another important issue is that, under heating conditions PG can produce acetaldehyde or formaldehyde (119.2 or 143.7 ng/puff at 20 W, respectively, on average), while glycerol can also generate acrolein (53.0, 1000.0 or 5.9 ng/puff at 20 W, respectively, on average), all carbonyls with a well-documented toxicity [ 61 ]. Although, assuming 15 puffs per e-cigarette unit, carbonyls produced by PG or glycerol heating would be below the maximum levels found in a conventional cigarette combustion (Table 2 ) [ 51 , 62 ]. Nevertheless, further studies are required to properly test the deleterious effects of all these compounds at physiological doses resembling those to which individuals are chronically exposed.

Although PG and glycerol are the major components of e-liquids other components have been detected. When the aerosols of 4 commercially available e-liquids chosen from a top 10 list of “ Best E-Cigarettes of 2014” , were analysed by gas chromatography-mass spectrometry (GC–MS) after heating, numerous compounds were detected, with nearly half of them not previously identified [ 4 ], thus suggesting that the heating process per se generates new compounds of unknown consequence. Of note, the analysis identified formaldehyde, acetaldehyde and acrolein [ 4 ], 3 carbonyl compounds with known high toxicity [ 63 , 64 , 65 , 66 , 67 ]. While no information was given regarding formaldehyde and acetaldehyde concentrations, the authors calculated that one puff could result in an acrolein exposure of 0.003–0.015 μg/mL [ 4 ]. Assuming 40 mL per puff and 15 puffs per e-cigarette unit (according to several manufacturers) [ 4 ], each e-cigarette unit would generate approximately 1.8–9 μg of acrolein, which is less than the levels of acrolein emitted by a conventional tobacco cigarette (18.3–98.2 μg) [ 51 ]. However, given that e-cigarette units of vaping are not well established, users may puff intermittently throughout the whole day. Thus, assuming 400 to 500 puffs per cartridge, users could be exposed to up to 300 μg of acrolein.

In a similar study, acrolein was found in 11 of 12 aerosols tested, with a similar content range (approximately 0.07–4.19 μg per e-cigarette unit) [ 68 ]. In the same study, both formaldehyde and acetaldehyde were detected in all of the aerosols tested, with contents of 0.2–5.61 μg and 0.11–1.36 μg, respectively, per e-cigarette unit [ 68 ]. It is important to point out that the levels of these toxic products in e-cigarette aerosols are significantly lower than those found in CS: 9 times lower for formaldehyde, 450 times lower for acetaldehyde and 15 times lower for acrolein (Table 2 ) [ 62 , 68 ].

Other compounds that have been detected in aerosols include acetamide, a potential human carcinogen [ 5 ], and some aldehydes [ 69 ], although their levels were minimal. Interestingly, the existence of harmful concentrations of diethylene glycol, a known cytotoxic agent, in e-liquid aerosols is contentious with some studies detecting its presence [ 4 , 68 , 70 , 71 , 72 ], and others finding low subtoxic concentrations [ 73 , 74 ]. Similar observations were reported for the content ethylene glycol. In this regard, either it was detected at concentrations that did not exceed the authorised limit [ 73 ], or it was absent from the aerosols produced [ 4 , 71 , 72 ]. Only one study revealed its presence at high concentration in a very low number of samples [ 5 ]. Nevertheless, its presence above 1 mg/g is not allowed by the FDA [ 73 ]. Figure  1 lists the main compounds detected in aerosols derived from humectant heating and their potential damaging effects. It would seem that future studies should analyse the possible toxic effects of humectants and related products at concentrations similar to those that e-cigarette vapers are exposed to reach conclusive results.

Impact of flavouring compounds

The range of e-liquid flavours available to consumers is extensive and is used to attract both current smokers and new e-cigarette users, which is a growing public health concern [ 6 ]. In fact, over 5 million middle- and high-school students were current users of e-cigarettes in 2019 [ 75 ], and appealing flavours have been identified as the primary reason for e-cigarette consumption in 81% of young users [ 76 ]. Since 2016, the FDA regulates the flavours used in the e-cigarette market and has recently published an enforcement policy on unauthorised flavours, including fruit and mint flavours, which are more appealing to young users [ 77 ]. However, the long-term effects of all flavour chemicals used by this industry (which are more than 15,000) remain unknown and they are not usually included in the product label [ 78 ]. Furthermore, there is no safety guarantee since they may harbour potential toxic or irritating properties [ 5 ].

With regards to the multitude of available flavours, some have demonstrated cytotoxicity [ 59 , 79 ]. Bahl et al. evaluated the toxicity of 36 different e-liquids and 29 different flavours on human embryonic stem cells, mouse neural stem cells and human pulmonary fibroblasts using a metabolic activity assay. In general, those e-liquids that were bubblegum-, butterscotch- and caramel-flavoured did not show any overt cytotoxicity even at the highest dose tested. By contrast, those e-liquids with Freedom Smoke Menthol Arctic and Global Smoke Caramel flavours had marked cytotoxic effects on pulmonary fibroblasts and those with Cinnamon Ceylon flavour were the most cytotoxic in all cell lines [ 79 ]. A further study from the same group [ 80 ] revealed that high cytotoxicity is a recurrent feature of cinnamon-flavoured e-liquids. In this line, results from GC–MS and HPLC analyses indicated that cinnamaldehyde (CAD) and 2-methoxycinnamaldehyde, but not dipropylene glycol or vanillin, were mainly responsible for the high cytotoxicity of cinnamon-flavoured e-liquids [ 80 ]. Other flavouring-related compounds that are associated with respiratory complications [ 81 , 82 , 83 ], such as diacetyl, 2,3-pentanedione or acetoin, were found in 47 out of 51 aerosols of flavoured e-liquids tested [ 84 ] . Allen et al . calculated an average of 239 μg of diacetyl per cartridge [ 84 ]. Assuming again 400 puffs per cartridge and 40 mL per puff, is it is possible to estimate an average of 0.015 ppm of diacetyl per puff, which could compromise normal lung function in the long-term [ 85 ].

The cytotoxic and pro-inflammatory effects of different e-cigarette flavouring chemicals were also tested on two human monocytic cell lines—mono mac 6 (MM6) and U937 [ 86 ]. Among the flavouring chemicals tested, CAD was found to be the most toxic and O-vanillin and pentanedione also showed significant cytotoxicity; by contrast, acetoin, diacetyl, maltol, and coumarin did not show any toxicity at the concentrations assayed (10–1000 µM). Of interest, a higher toxicity was evident when combinations of different flavours or mixed equal proportions of e-liquids from 10 differently flavoured e-liquids were tested, suggesting that vaping a single flavour is less toxic than inhaling mixed flavours [ 86 ]. Also, all the tested flavours produced significant levels of ROS in a cell-free ROS production assay. Finally, diacetyl, pentanedione, O-vanillin, maltol, coumarin, and CAD induced significant IL-8 secretion from MM6 and U937 monocytes [ 86 ]. It should be borne in mind, however, that the concentrations assayed were in the supra-physiological range and it is likely that, once inhaled, these concentrations are not reached in the airway space. Indeed, one of the limitations of the study was that human cells are not exposed to e-liquids per se, but rather to the aerosols where the concentrations are lower [ 86 ]. In this line, the maximum concentration tested (1000 µM) would correspond to approximately 80 to 150 ppm, which is far higher than the levels found in aerosols of some of these compounds [ 84 ]. Moreover, on a day-to-day basis, lungs of e-cigarette users are not constantly exposed to these chemicals for 24 h at these concentrations. Similar limitations were found when five of seven flavourings were found to cause cytotoxicity in human bronchial epithelial cells [ 87 ].

Recently, a commonly commercialized crème brûlée -flavoured aerosol was found to contain high concentrations of benzoic acid (86.9 μg/puff), a well-established respiratory irritant [ 88 ]. When human lung epithelial cells (BEAS-2B and H292) were exposed to this aerosol for 1 h, a marked cytotoxicity was observed in BEAS-2B but not in H292 cells, 24 h later. However, increased ROS production was registered in H292 cells [ 88 ].

Therefore, to fully understand the effects of these compounds, it is relevant the cell cultures selected for performing these assays, as well as the use of in vivo models that mimic the real-life situation of chronic e-cigarette vapers to clarify their impact on human health.

The e-cigarette device

While the bulk of studies related to the impact of e-cigarette use on human health has focused on the e-liquid components and the resulting aerosols produced after heating, a few studies have addressed the material of the electronic device and its potential consequences—specifically, the potential presence of metals such as copper, nickel or silver particles in e-liquids and aerosols originating from the filaments and wires and the atomiser [ 89 , 90 , 91 ].

Other important components in the aerosols include silicate particles from the fiberglass wicks or silicone [ 89 , 90 , 91 ]. Many of these products are known to cause abnormalities in respiratory function and respiratory diseases [ 89 , 90 , 91 ], but more in-depth studies are required. Interestingly, the battery output voltage also seems to have an impact on the cytotoxicity of the aerosol vapours, with e-liquids from a higher battery output voltage showing more toxicity to A549 cells [ 30 ].

A recent study compared the acute effects of e-cigarette vapor (with PG/vegetable glycerine plus tobacco flavouring but without nicotine) generated from stainless‐steel atomizer (SS) heating element or from a nickel‐chromium alloy (NC) [ 92 ]. Some rats received a single e-cigarette exposure for 2 h from a NC heating element (60 or 70 W); other rats received a similar exposure of e-cigarette vapor using a SS heating element for the same period of time (60 or 70 W) and, a final group of animals were exposed for 2 h to air. Neither the air‐exposed rats nor those exposed to e-cigarette vapor using SS heating elements developed respiratory distress. In contrast, 80% of the rats exposed to e-cigarette vapor using NC heating units developed clinical acute respiratory distress when a 70‐W power setting was employed. Thus, suggesting that operating units at higher than recommended settings can cause adverse effects. Nevertheless, there is no doubt that the deleterious effects of battery output voltage are not comparable to those exerted by CS extracts [ 30 ] (Figs.  1 and 2 ).

E-cigarettes as a smoking cessation tool

CS contains a large number of substances—about 7000 different constituents in total, with sizes ranging from atoms to particulate matter, and with many hundreds likely responsible for the harmful effects of this habit [ 93 ]. Given that tobacco is being substituted in great part by e-cigarettes with different chemical compositions, manufacturers claim that e -cigarette will not cause lung diseases such as lung cancer, chronic obstructive pulmonary disease, or cardiovascular disorders often associated with conventional cigarette consumption [ 3 , 94 ]. However, the World Health Organisation suggests that e-cigarettes cannot be considered as a viable method to quit smoking, due to a lack of evidence [ 7 , 95 ]. Indeed, the results of studies addressing the use of e-cigarettes as a smoking cessation tool remain controversial [ 96 , 97 , 98 , 99 , 100 ]. Moreover, both FDA and CDC are actively investigating the incidence of severe respiratory symptoms associated with the use of vaping products [ 77 ]. Because many e-liquids contain nicotine, which is well known for its powerful addictive properties [ 41 ], e-cigarette users can easily switch to conventional cigarette smoking, avoiding smoking cessation. Nevertheless, the possibility of vaping nicotine-free e-cigarettes has led to the branding of these devices as smoking cessation tools [ 2 , 6 , 7 ].

In a recently published randomised trial of 886 subjects who were willing to quit smoking [ 100 ], the abstinence rate was found to be twice as high in the e-cigarette group than in the nicotine-replacement group (18.0% vs. 9.9%) after 1 year. Of note, the abstinence rate found in the nicotine-replacement group was lower than what is usually expected with this therapy. Nevertheless, the incidence of throat and mouth irritation was higher in the e-cigarette group than in the nicotine-replacement group (65.3% vs. 51.2%, respectively). Also, the participant adherence to the treatment after 1-year abstinence was significantly higher in the e-cigarette group (80%) than in nicotine-replacement products group (9%) [ 100 ].

On the other hand, it is estimated that COPD could become the third leading cause of death in 2030 [ 101 ]. Given that COPD is generally associated with smoking habits (approximately 15 to 20% of smokers develop COPD) [ 101 ], smoking cessation is imperative among COPD smokers. Published data revealed a clear reduction of conventional cigarette consumption in COPD smokers that switched to e-cigarettes [ 101 ]. Indeed, a significant reduction in exacerbations was observed and, consequently, the ability to perform physical activities was improved when data was compared with those non-vapers COPD smokers. Nevertheless, a longer follow-up of these COPD patients is required to find out whether they have quitted conventional smoking or even vaping, since the final goal under these circumstances is to quit both habits.

Based on the current literature, it seems that several factors have led to the success of e-cigarette use as a smoking cessation tool. First, some e-cigarette flavours positively affect smoking cessation outcomes among smokers [ 102 ]. Second, e-cigarettes have been described to improve smoking cessation rate only among highly-dependent smokers and not among conventional smokers, suggesting that the individual degree of nicotine dependence plays an important role in this process [ 97 ]. Third, the general belief of their relative harmfulness to consumers' health compared with conventional combustible tobacco [ 103 ]. And finally, the exposure to point-of-sale marketing of e-cigarette has also been identified to affect the smoking cessation success [ 96 ].

Implication of e-cigarette consumption in COVID-19 time

Different reports have pointed out that smokers and vapers are more vulnerable to SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infections or more prone to adverse outcomes if they suffer COVID-19 [ 104 ]. However, while a systematic review indicated that cigarette smoking is probably associated with enhanced damage from COVID-19, a meta-analysis did not, yet the latter had several limitations due to the small sample sizes [ 105 ].

Interestingly, most of these reports linking COVID-19 harmful effects with smoking or vaping, are based on their capability of increasing the expression of angiotensin-converting enzyme 2 (ACE2) in the lung. It is well known that ACE2 is the gate for SARS-CoV-2 entrance to the airways [ 106 ] and it is mainly expressed in type 2 alveolar epithelial cells and alveolar macrophages [ 107 ]. To date, most of the studies in this field indicate that current smokers have higher expression of ACE2 in the airways (reviewed by [ 108 ]) than healthy non-smokers [ 109 , 110 ]. However, while a recent report indicated that e-cigarette vaping also caused nicotine-dependent ACE2 up-regulation [ 42 ], others have revealed that neither acute inhalation of e-cigarette vapour nor e-cigarette users had increased lung ACE2 expression regardless nicotine presence in the e-liquid [ 43 , 110 ].

In regard to these contentions, current knowledge suggests that increased ACE2 expression is not necessarily linked to enhanced susceptibility to SARS-CoV-2 infection and adverse outcome. Indeed, elderly population express lower levels of ACE2 than young people and SARS-CoV-2/ACE2 interaction further decreases ACE2 expression. In fact, most of the deaths provoked by COVID-19 took place in people over 60 years old of age [ 111 ]. Therefore, it is plausible that the increased susceptibility to disease progression and the subsequent fatal outcome in this population is related to poor angiotensin 1-7 (Ang-1-7) generation, the main peptide generated by ACE2, and probably to their inaccessibility to its anti-inflammatory effects. Furthermore, it seems that all the efforts towards increasing ACE2 expression may result in a better resolution of the pneumonic process associated to this pandemic disease.

Nevertheless, additional complications associated to COVID-19 are increased thrombotic events and cytokine storm. In the lungs, e-cigarette consumption has been correlated to toxicity, oxidative stress, and inflammatory response [ 32 , 112 ]. More recently, a study revealed that while the use of nicotine/flavour-containing e-cigarettes led to significant cytokine dysregulation and potential inflammasome activation, none of these effects were detected in non-flavoured and non-nicotine-containing e-cigarettes [ 43 ]. Therefore, taken together these observations, e-cigarette use may still be a potent risk factor for severe COVID-19 development depending on the flavour and nicotine content.

In summary, it seems that either smoking or nicotine vaping may adversely impact on COVID-19 outcome. However, additional follow up studies are required in COVID-19 pandemic to clarify the effect of e-cigarette use on lung and cardiovascular complications derived from SARS-CoV-2 infection.

Conclusions

The harmful effects of CS and their deleterious consequences are both well recognised and widely investigated. However, and based on the studies carried out so far, it seems that e-cigarette consumption is less toxic than tobacco smoking. This does not necessarily mean, however, that e-cigarettes are free from hazardous effects. Indeed, studies investigating their long-term effects on human health are urgently required. In this regard, the main additional studies needed in this field are summarized in Table 3 .

The composition of e-liquids requires stricter regulation, as they can be easily bought online and many incidences of mislabelling have been detected, which can seriously affect consumers’ health. Beyond their unknown long-term effects on human health, the extended list of appealing flavours available seems to attract new “never-smokers”, which is especially worrying among young users. Additionally, there is still a lack of evidence of e-cigarette consumption as a smoking cessation method. Indeed, e-cigarettes containing nicotine may relieve the craving for smoking, but not the conventional cigarette smoking habit.

Interestingly, there is a strong difference of opinion on e-cigarettes between countries. Whereas countries such as Brazil, Uruguay and India have banned the sale of e-cigarettes , others such as the United Kingdom support this device to quit smoking. The increasing number of adolescent users and reported deaths in the United States prompted the government to ban the sale of flavoured e-cigarettes in 2020. The difference in opinion worldwide may be due to different restrictions imposed. For example, while no more than 20 ng/mL of nicotine is allowed in the EU, e-liquids with 59 mg/dL are currently available in the United States. Nevertheless, despite the national restrictions, users can easily access foreign or even counterfeit products online.

In regard to COVID-19 pandemic, the actual literature suggests that nicotine vaping may display adverse outcomes. Therefore, follow up studies are necessary to clarify the impact of e-cigarette consumption on human health in SARS-CoV-2 infection.

In conclusion, e-cigarettes could be a good alternative to conventional tobacco cigarettes, with less side effects; however, a stricter sale control, a proper regulation of the industry including flavour restriction, as well as further toxicological studies, including their chronic effects, are warranted.

Availability of data and materials

Not applicable.

Abbreviations

Angiotensin-converting enzyme 2

Angiotensin 1-7

Bronchoalveolar lavage fluid

Cinnamaldehyde

US Centers for Disease Control and Prevention

Carbon monoxide

Chronic obstructive pulmonary disease

Coronavirus disease 2019

Cigarette smoke

Electronic nicotine dispensing systems

e-cigarette or vaping product use-associated lung injury

Food and Drug Administration

Gas chromatography with a flame ionisation detector

Gas chromatography-mass spectrometry

Granulocyte–macrophage colony-stimulating factor

High performance liquid chromatography

Human umbilical vein endothelial cells

Interleukin

Interferon γ

Liquid chromatography-mass spectrometry

Monocyte chemoattractant protein-1

Matrix metallopeptidase 9

α7 Nicotinic acetylcholine receptor

Nickel‐chromium alloy

Nitric oxide

Propylene glycol

Regulated on activation, normal T cell expressed and secreted

Reactive oxygen species

Severe acute respiratory syndrome coronavirus 2

Stainless‐steel atomizer

Tetrahydrocannabinol

Tumour necrosis factor-α

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Acknowledgements

The authors gratefully acknowledge Dr. Cruz González, Pulmonologist at University Clinic Hospital of Valencia (Valencia, Spain) for her thoughtful suggestions and support.

This work was supported by the Spanish Ministry of Science and Innovation [Grant Number SAF2017-89714-R]; Carlos III Health Institute [Grant Numbers PIE15/00013, PI18/00209]; Generalitat Valenciana [Grant Number PROMETEO/2019/032, Gent T CDEI-04/20-A and AICO/2019/250], and the European Regional Development Fund.

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Marques, P., Piqueras, L. & Sanz, MJ. An updated overview of e-cigarette impact on human health. Respir Res 22 , 151 (2021). https://doi.org/10.1186/s12931-021-01737-5

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Wednesday, October 26, 2022

NIH-funded studies show damaging effects of vaping, smoking on blood vessels

Combining e-cigarettes with regular cigarettes may increase health risks.

Long-term use of electronic cigarettes, or vaping products, can significantly impair the function of the body’s blood vessels, increasing the risk for cardiovascular disease. Additionally, the use of both e-cigarettes and regular cigarettes may cause an even greater risk than the use of either of these products alone. These findings come from two new studies supported by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH).  

The findings, which appear today in the journal  Arteriosclerosis, Thrombosis, and Vascular Biology , add to growing evidence that long-term use of e-cigarettes can harm a person’s health. Researchers have known for years that tobacco smoking can cause damage to blood vessels. However, the effects of e-cigarettes on cardiovascular health have been poorly understood. The two new studies – one on humans, the other on rats – aimed to change that.

“In our human study, we found that chronic e-cigarettes users had impaired blood vessel function, which may put them at increased risk for heart disease,” said Matthew L. Springer, Ph.D., a professor of medicine in the Division of Cardiology at the University of California in San Francisco, and leader of both studies. “It indicates that chronic users of e-cigarettes may experience a risk of vascular disease similar to that of chronic smokers.” 

In this first study, Springer and his colleagues collected blood samples from a group of 120 volunteers that included those with long-term e-cigarette use, long-term cigarette smoking, and those who didn't use. The researchers defined long-term e-cigarette use as more than five times/week for more than three months and defined long-term cigarette use as smoking more than five cigarettes per day.

They then exposed each of the blood samples to cultured human blood vessel (endothelial) cells in the laboratory and measured the release of nitric oxide, a chemical marker used to evaluate proper functioning of endothelial cells. They also tested cell permeability, the ability of molecules to pass through a layer of cells to the other side. Too much permeability makes vessels leaky, which impairs function and increases the risk for cardiovascular disease.

The researchers found that blood from participants who used e-cigarettes and those who smoked caused a significantly greater decrease in nitric oxide production by the blood vessel cells than the blood of nonusers. Notably, the researchers found that blood from those who used e-cigarettes also caused more permeability in the blood vessel cells than the blood from both those who smoked cigarettes and nonusers. Blood from those that used e-cigarettes also caused a greater release of hydrogen peroxide by the blood vessel cells than the blood of the nonusers. Each of these three factors can contribute to impairment of blood vessel function in people who use e-cigarettes, the researchers said.

In addition, Springer and his team discovered that e-cigarettes had harmful cardiovascular effects in ways that were different from those caused by tobacco smoke. Specifically, they found that blood from people who smoked cigarettes had higher levels of certain circulating biomarkers of cardiovascular risks, and the blood people who used e-cigarettes had elevated levels of other circulating biomarkers of cardiovascular risks.

“These findings suggest that using the two products together, as many people do, could increase their health risks compared to using them individually,” Springer said.  “We had not expected to see that.”

In the second study, the researchers tried to find out if there were specific components of cigarette smoke or e-cigarette vapor that were responsible for blood vessel damage. In studies using rats, they exposed the animals to various substances found in tobacco smoke or e-cigarettes. These included nicotine, menthol (a cigarette additive), the gases acrolein and acetaldehyde (two chemicals found in both tobacco smoke and e-cigarette vapors), and inert carbon nanoparticles to represent the particle-like nature of smoke and e-cigarette vapor.

Using special arterial flow measurements, the researchers demonstrated that blood vessel damage does not appear to be caused by a specific component of cigarette smoke or e-cigarette vapor. Instead, they said, it appears to be caused by airway irritation that triggers biological signals in the vagus nerve that somehow leads to blood vessel damage, possibly through an inflammatory process. The vagus is a long nerve extending from the brain that connects the airway to the rest of the nervous system and plays a key role in heart rate, breathing, and other functions. The researchers showed that detaching the nerve in rats prevented blood vessel damage caused by tobacco smoke, demonstrating its key role in this process. 

“We were surprised to find that there was not a single component that you could remove to stop the damaging effect of smoke or vapors on the blood vessels,” Springer said. “As long as there’s an irritant in the airway, blood vessel function may be impaired.”   

The finding has implications for efforts to regulate tobacco products and e-cigarettes, as it underscores how difficult it is to pinpoint any one ingredient in them that is responsible for blood vessel damage. “What I like to tell people is this: Just breathe clean air and avoid using these products,” Springer said.

Lisa Postow, Ph.D., an NHLBI program officer in NHLBI’s Division of Lung Diseases, agreed that the study results “provide further evidence that exposure to e-cigarettes could lead to harmful cardiovascular health effects.” She added that more data is needed to fully understand the health effects of e-cigarettes. The NIH and others are continuing to explore this area.

Research reported in the e-cigarette study was funded by NHLBI grants U54HL147127, P50HL120163, and R01HL120062 and the U.S. Food and Drug Administration Center for Tobacco Products (FDA CTP); and grant P50CA180890 from the National Cancer Institute at the NIH and FDA CTP. Research reported in the cigarette smoke/-vagal nerve study was supported by NHLBI grants R01HL120062 and U54HL147127 and FDA CTP and grant P50CA180890 from the National Cancer Institute at the NIH and FDA CTP. For additional funding details, please see the full journal articles.

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit www.nhlbi.nih.gov .   

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Chronic e-cigarette use impairs endothelial function on the physiological and cellular levels. Arteriosclerosis, Thrombosis, and Vascular Biology. DOI: 10.1161/ATVBAHA.121.317749

Impairment of Endothelial Function by Cigarette Smoke is not Caused by a Specific Smoke Constituent, but by Vagal Input from the Airway. Arteriosclerosis, Thrombosis, and Vascular Biology. DOI: 10.1161/ATVBAHA.122.318051

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Latest Cochrane Review finds high certainty evidence that nicotine e-cigarettes are more effective than traditional nicotine-replacement therapy (NRT) in helping people quit smoking

A Cochrane review  has found the strongest evidence yet that e-cigarettes, also known as ‘vapes’, help people to quit smoking better than traditional nicotine replacement therapies, such as patches and chewing gums.

New evidence published today in the Cochrane Library finds high certainty evidence that people are more likely to stop smoking for at least six months using nicotine e-cigarettes, or ‘vapes’, than using nicotine replacement therapies, such as patches and gums. Evidence also suggested that nicotine e-cigarettes led to higher quit rates than e-cigarettes without nicotine, or no stop smoking intervention, but less data contributed to these analyses. The updated Cochrane review includes 78 studies in over 22,000 participants – an addition of 22 studies since the last update in 2021.

Smoking is a significant global health problem. According to the World Health Organisation (WHO), in 2020, 22.3% of the global population used tobacco, despite it killing up to half of its users. Stopping smoking reduces the risk of lung cancer, heart attacks and many other diseases. Though most people who smoke want to quit, many find it difficult to do so permanently. Nicotine patches and gum are safe, effective and widely used methods to help individuals quit.

E-cigarettes heat liquids with nicotine and flavourings, allowing users to ‘vape’ nicotine instead of smoking. Data from the review showed that i f six in 100 people quit by using nicotine replacement therapy, eight to twelve would quit by using electronic cigarettes containing nicotine. This means an additional two to six people in 100 could potentially quit smoking with nicotine containing electronic cigarettes.

Dr Jamie Hartmann-Boyce, Associate Professor at the University of Oxford, Editor of the Cochrane Tobacco Addiction Group, and an author of the new publication, said:

“Electronic cigarettes have generated a lot of misunderstanding in both the public health community and the popular press since their introduction over a decade ago. These misunderstandings discourage some people from using e-cigarettes as a stop smoking tool. Fortunately, more and more evidence is emerging and provides further clarity. With support from Cancer Research UK, we search for new evidence every month as part of a living systematic review. We identify and combine the strongest evidence from the most reliable scientific studies currently available. For the first time, this has given us high-certainty evidence that e-cigarettes are even more effective at helping people to quit smoking than traditional nicotine replacement therapies, like patches or gums.”

In studies comparing nicotine e-cigarettes to nicotine replacement treatment, significant side effects were rare. In the short-to-medium term (up to two years), nicotine e-cigarettes most typically caused throat or mouth irritation, headache, cough, and feeling nauseous. However, these effects appeared to diminish over time.

Dr Nicola Lindson, University Research Lecturer at the University of Oxford, Cochrane Tobacco Addiction Group’s Managing Editor, and author of the publication said:

“ E-cigarettes do not burn tobacco; and as such they do not expose users to the same complex mix of chemicals that cause diseases in people smoking conventional cigarettes. E-cigarettes are not risk free, and shouldn’t be used by people who don’t smoke or aren’t at risk of smoking. However, evidence shows that nicotine e-cigarettes carry only a small fraction of the risk of smoking. In our review, we did not find evidence of substantial harms caused by nicotine containing electronic cigarettes when used to quit smoking. However, due to the small number of studies and lack of data on long-term nicotine-containing electronic cigarette usage – usage over more than two years – questions remain about long-term effects.”

The researchers conclude that more evidence, particularly about the effects of newer e-cigarettes with better nicotine delivery than earlier ones, is needed to assist more people quit smoking. Longer-term data is also needed.

Michelle Mitchell, chief executive at Cancer Research UK, said:

“We welcome this report which adds to a growing body of evidence showing that e-cigarettes are an effective smoking cessation tool. We strongly discourage those who have never smoked from using e-cigarettes, especially young people. This is because they are a relatively new product and we don’t yet know the long term health effects. While the long term effects of vaping are still unknown, the harmful effects of smoking are indisputable – smoking causes around 55,000 cancer deaths in the UK every year. Cancer Research UK supports balanced evidence-based regulation on e-cigarettes from UK governments which maximises their potential to help people stop smoking, whilst minimising the risk of uptake among others.”

• Read the full Cochrane review and plain language summary 
• Learn more about Cochrane Tobacco Addition Group
• Science Media Centre: Expert reaction to cochrane review on electronic cigarettes for smoking cessation

 Hartmann-Boyce J, Lindson N, Butler AR, McRobbie H, Bullen C, Begh R, Theodoulou A, Notley C, Rigotti NA, Turner T, Fanshawe TR, Hajek P. Electronic cigarettes for smoking cessation. Cochrane Database of Systematic Reviews 2022, Issue 11. Art. No.: CD010216. DOI: 10.1002/14651858.CD010216.pub7

This work was supported by Cancer Research UK [A ref. A29845]

To speak to a team member about this project please contact Dr. Hartmann-Boyce, [email protected] or Dr. Lindson, [email protected] .

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Studies show that about 9 percent of the population and nearly 28 percent of high school students are e-cigarette users.

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Restricted airways, scarred lung tissue found among vapers

MGH News and Public Affairs

Small study looks at chronic e-cigarette users, seeing partial improvement once they stop

Chronic use of e-cigarettes, commonly known as vaping, can result in small airway obstruction and asthma-like symptoms, according to researchers at Harvard-affiliated Massachusetts General Hospital.

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Chemical flavorings found in e-cigarettes linked to respiratory disease

In the first study to microscopically evaluate the pulmonary tissue of e-cigarette users for chronic disease, the team found in a small sample of patients fibrosis and damage in the small airways, similar to the chemical inhalation damage to the lungs typically seen in soldiers returning from overseas conflicts who had inhaled mustard or similar types of noxious gases. The study was published in  New England Journal of Medicine Evidence .

“All four individuals we studied had injury localized to the same anatomic location within the lung, manifesting as small airway-centered fibrosis with constrictive bronchiolitis, which was attributed to vaping after thorough clinical evaluations excluded other possible causes,” says lead author Lida Hariri, an associate professor of pathology at Harvard Medical School and a pathologist and physician investigator at MGH. “We also observed that when patients ceased vaping, they had a partial reversal of the condition over one to four years, though not complete due to residual scarring in the lung tissue.”

A huge increase in vaping, particularly among young adults and adolescents, has occurred in the United States, with studies showing about 9 percent of the population and nearly 28 percent of high school students are e-cigarette users. Unlike cigarette smoking, however, the long-term health risks of chronic vaping are largely unknown.

In order to determine the underlying pathophysiology of vaping-related symptoms, the MGH team examined a cohort of four patients, each with a three- to eight-year history of e-cigarette use and chronic lung disease. All patients underwent detailed clinical evaluation, including pulmonary function tests, high resolution chest imaging, and surgical lung biopsy. Constrictive bronchiolitis, or narrowing of the small airways due to fibrosis within the bronchiolar wall, was observed in each patient. So was significant overexpression of MUC5AC, a gel-forming protein in the mucus layer of the airway that has been seen in airway cell and sputum samples of individuals who vape. In addition, three of the four patients had evidence of mild emphysema consistent with their former combustible cigarette smoking history, though researchers concluded this was distinct from the findings of constrictive bronchiolitis seen in the patient cohort.

Because the same type of lung damage was observed in all patients, as well as partial improvement in symptoms after e-cigarette usage was stopped, researchers concluded that vaping was the most likely cause after thorough evaluation and exclusion of other possible causes. “Our investigation shows that chronic pathological abnormalities can occur in vaping exposure,” says senior author David Christiani, a professor of medicine at HMS and a physician investigator at Mass General Research Institute. “Physicians need to be informed by scientific evidence when advising patients about the potential harm of long-term vaping, and this work adds to a growing body of toxicological evidence that nicotine vaping exposures can harm the lung.”

A hopeful sign from the study was that three of the four patients showed improvements in their pulmonary function tests and high-resolution computed tomography (HRCT) chest imaging after they ceased vaping. “While there is growing evidence to show that vaping is a risky behavior with potential long-term health consequences for users,” says Hariri, “our research also suggests that quitting can be beneficial and help to reverse some of the disease.”

The study was funded by the National Institutes of Health.

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July 17, 2023

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Current evidence identifies health risks of e-cigarette use, long-term research needed

by American Heart Association

Research increasingly reveals health risks of e-cigarette use, and more studies are needed about the long-term impact e-cigarettes may have on the heart and lungs, according to a new scientific statement from the American Heart Association published in the journal Circulation .

The statement, "Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products," details the latest usage data and trends, identifies current health impacts, highlights existing basic and clinical scientific evidence surrounding e-cigarettes and recommends research priorities to further understand the short- and long-term health effects of e-cigarette use.

Vaping products, also known as e-cigarettes, are battery-operated systems that heat a liquid solution, or e-liquid, to create an aerosol that is inhaled into the lungs. Most e-liquid formulations deliver nicotine, which has been established as having negative health effects as well as strong addictive properties.

The products may also contain other substances, most commonly tetrahydrocannabinol (THC), the psychoactive element of cannabis, as well as methamphetamine, methadone or vitamins. The liquids also include humectants (hygroscopic carriers such as propylene glycol and vegetable glycerol) that act as solvents and create a water aerosol or vapor, flavoring agents, cooling agents such as menthol and sweeteners, in addition to metals from the heating coil and other chemicals.

"E-cigarettes deliver numerous substances into the body that are potentially harmful, including chemicals and other compounds that are likely not known to or understood by the user. There is research indicating that nicotine-containing e-cigarettes are associated with acute changes in several hemodynamic measures, including increases in blood pressure and heart rate ," said the volunteer chair of the scientific statement writing committee Jason J. Rose, M.D., M.B.A., an associate professor of medicine at the University of Maryland School of Medicine in Baltimore.

"There has also been research indicating that even when nicotine is not present, ingredients in e-cigarettes, particularly flavoring agents, independently carry risks associated with heart and lung diseases in animals. Negative effects of e-cigarettes have been shown through in vitro studies and in studies of individuals exposed to chemicals in commercially available products."

The writing committee points to the significance of the clinical diagnosis of "E-cigarette, or Vaping, product use Associated Lung Injury" (EVALI). EVALI was first recognized as a condition by the U.S. Centers for Disease Control and Prevention in 2019, when approximately 2,800 hospitalizations occurred among e-cigarette users in less than a year. This is cited in the statement as one example that emphasizes the lack of knowledge surrounding the risks of e-cigarettes and their ingredients.

In the case of the EVALI hospitalizations, vitamin E acetate has been implicated as the ingredient likely causing illness. This substance is used as a thickening agent in some e-cigarette liquids.

Studies gauging the specific impact e-cigarettes have on heart attacks and strokes are limited. Much research on e-cigarette use has been conducted in people who have also used or were currently using traditional cigarettes. Additionally, large survey studies have focused on younger adults who have a low occurrence of heart attacks and strokes. The writing committee says longer-term studies of e-cigarettes users of all ages are needed, including among people who already have cardiovascular disease.

One recent analysis of the adult Population Assessment of Tobacco and Health (PATH) study found a statistically significant association between former or current e-cigarette use at the time participants enrolled in the study and the development of incident respiratory disease (chronic obstructive pulmonary disease/COPD, chronic bronchitis, emphysema or asthma) within the next two years. The PATH Study, an ongoing study that started in 2013, is one of the first large tobacco research efforts undertaken by the National Institutes of Health and the U.S. Food and Drug Administration.

Additional studies cited in the statement indicate a rapid increase since 2010 in the number of people who had ever used e-cigarettes or were currently using the devices, and most of those users were current or former traditional cigarette smokers. In addition, by 2016, data from the Behavioral Risk Factor Surveillance System indicated about 1.2 million adults in the U.S. who had never smoked combustible cigarettes before were currently using e-cigarettes.

The writing committee noted that e-cigarettes are reported to be the most commonly used tobacco product among youth, particularly high school and middle school students. The statement cites data showing that almost three out of four young people using e-cigarettes exclusively report using flavored e-cigarette products. This high rate of use by youth makes it critical to assess the short- and long-term health effects of these products, according to the statement.

"Young people often become attracted to the flavors available in these products and can develop nicotine dependence from e-cigarette use. There is significant concern about young people assuming e-cigarettes are not harmful because they are widely available and marketed to an age group that includes many people who have never used any tobacco products," Rose said.

"The long-term risks of using e-cigarettes are unknown, but if the risks of chronic use are like combustible cigarettes, or even if the risks are reduced but still present, we may not observe them for decades. What is equally concerning is that studies show that some youth who use e-cigarettes go on to use other tobacco products, and there is also a correlation between e-cigarette use and substance use disorders."

Given the established, high health risks of smoking combustible cigarettes, e-cigarette products have been evaluated as smoking cessation tools. The writing committee examined the limited research in this area and concluded that any benefits e-cigarettes may offer to help people stop smoking or stop using tobacco products needs to be clearly balanced alongside the products' known and unknown potential health risks, including the known risk of long-term dependence on these products.

"E-cigarette companies have suggested that their products are a way to quit smoking traditional cigarettes. There is no strong evidence to support this beyond any short-term benefit. The lack of long-term scientific safety data on e-cigarette use, along with the potential for the addiction to e-cigarette products seen among youth, are among the reasons the American Heart Association does not recommend e-cigarette use for cessation efforts," said Rose Marie Robertson, M.D., FAHA, the Association's deputy chief science and medical officer and co-director of the Association's Tobacco Center of Regulatory Science.

"It's also important to note that e-cigarette products are not approved by the U.S. Food and Drug Administration (FDA) for tobacco cessation. The Association recommends a combination of multiple-episode cessation counseling accompanied by personalized nicotine replacement therapy with FDA-approved doses and formulations, as well as medications to help control cravings, to help people who smoke combustible cigarettes with cessation. And all of this needs to be undertaken with the understanding that quitting often takes many tries, and any failures should be seen as just episodes to learn from on the road to finally beating a powerful addiction for good."

The scientific statement writing committee emphasizes a critical need for additional knowledge and research, specifically:

• Future research should focus on gaining knowledge about serious and potentially long-term effects of e-cigarettes on the heart, blood vessels and lungs.
• Studies are needed that include patients with pre-existing cardiopulmonary disease, such as coronary artery disease or chronic obstructive pulmonary disease , to evaluate and compare outcomes among e-cigarette users in comparison to traditional smokers, and those who use e-cigarettes along with traditional cigarettes (referred to as dual users) and nonsmokers.
• More in-depth research is needed about the common chemical ingredients in e-cigarettes and the effects they independently have on pulmonary and cardiac health.
• Clinical studies are needed to study the risks and potential benefits of e-cigarettes as alternatives to traditional combustible cigarettes.
• Since the long-term health impact of e-cigarettes may take decades to emerge, more molecular and laboratory studies are needed in the interim to help determine the biological implications of e-cigarette use .

"Because e-cigarettes and other vaping systems have only been in the U.S. for about 15 years, we do not yet have enough information on their long-term health effects, so we must rely on shorter term studies, molecular experiments and research in animals to try to assess the true risk of using e-cigarettes," Jason Rose added. "It is necessary for us to expand this type of research since the adoption of e-cigarettes has grown exponentially, especially in young people, many of whom may have never used combustible cigarettes."

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Study Links E-Cigarette Use with Higher Risk of Heart Failure

Large study adds to growing body of evidence that vaping may harm the heart.

Apr 02, 2024

Contact: Nicole Napoli , [email protected], 202-669-1465

WASHINGTON (Apr 02, 2024) -

People who use e-cigarettes are significantly more likely to develop heart failure compared with those who have never used them, according to one of the largest prospective studies to date investigating possible links between vaping and heart failure. The findings are being presented at the American College of Cardiology’s Annual Scientific Session.

Heart failure is a condition affecting more than 6 million U.S. adults in which the heart becomes too stiff or too weak to pump blood as effectively as it should. It can often lead to debilitating symptoms and frequent hospitalizations as people age. Electronic nicotine products, which include e-cigarettes, vape pens, hookah pens, personal vaporizers and mods, e-cigars, e-pipes and e-hookahs, deliver nicotine in aerosol form without combustion. Since they were first introduced in the U.S. in the late 2000s, electronic nicotine products have often been portrayed as a safer alternative to smoking, but a growing body of research has led to increased concern about potential negative health effects.

“More and more studies are linking e-cigarettes to harmful effects and finding that it might not be as safe as previously thought,” said Yakubu Bene-Alhasan, MD, a resident physician at MedStar Health in Baltimore and the study’s lead author. “The difference we saw was substantial. It’s worth considering the consequences to your health, especially with regard to heart health.”

For the study, researchers used data from surveys and electronic health records in All of Us, a large national study of U.S. adults run by the National Institutes of Health, to analyze associations between e-cigarette use and new diagnoses of heart failure in 175,667 study participants (an average age of 52 years and 60.5% female). Of this sample, 3,242 participants developed heart failure within a median follow-up time of 45 months.

The results showed that people who used e-cigarettes at any point were 19% more likely to develop heart failure compared with people who had never used e-cigarettes. In calculating this difference, researchers accounted for a variety of demographic and socioeconomic factors, other heart disease risk factors and participants’ past and current use of other substances, including alcohol and tobacco products. The researchers also found no evidence that participants’ age, sex or smoking status modified the relationship between e-cigarettes and heart failure.

Breaking the data down by type of heart failure, the increased risk associated with e-cigarette use was statistically significant for heart failure with preserved ejection fraction (HFpEF)—in which the heart muscle becomes stiff and does not properly fill with blood between contractions. However, this association was not significant for heart failure with reduced ejection fraction (HFrEF)—in which the heart muscle becomes weak and the left ventricle does not squeeze as hard as it should during contractions. Rates of HFpEF have risen in recent decades, which has led to an increased focus on determining risk factors and improving treatment options for this type of heart failure.

The findings align with previous studies conducted in animals, which signaled e-cigarette use can affect the heart in ways that are relevant to the heart changes involved in heart failure. Other studies in humans have also shown links between e-cigarette use and some risk factors associated with developing heart failure. However, previous studies attempting to assess the direct connection between e-cigarette use and heart failure have been inconclusive, which Bene-Alhasan said is due to the inherent limitations of the cross-sectional study designs, smaller sample sizes and the smaller number of heart failure events seen in previous research.

Researchers said the new study findings point to a need for additional investigations of the potential impacts of vaping on heart health, especially considering the prevalence of e-cigarette use among younger people. Surveys indicate that about 5% to 10% of U.S. teens and adults use e-cigarettes. In 2018, the U.S. Surgeon General called youth e-cigarette use an epidemic and warned about the health risks associated with nicotine addiction.

“I think this research is long overdue, especially considering how much e-cigarettes have gained traction,” Bene-Alhasan said. “We don’t want to wait too long to find out eventually that it might be harmful, and by that time a lot of harm might already have been done. With more research, we will get to uncover a lot more about the potential health consequences and improve the information out to the public.”

Bene-Alhasan also said e-cigarettes are not recommended as a tool to quit smoking, since many people may continue vaping long after they quit smoking. The U.S. Centers for Disease Control and Prevention recommends a combination of counseling and medications as the best strategy for quitting smoking.

Researchers said that the study’s prospective observational design allows them to infer, but not conclusively determine, a causal relationship between e-cigarette use and heart failure. However, with its large sample size and detailed data on substance use and health information, Bene-Alhasan said the study is one of the most comprehensive studies to assess this relationship to date.

For more information about the health effects of e-cigarettes, visit CardioSmart.org/StopSmoking .

Bene-Alhasan will present the study, “Electronic Nicotine Product Use Is Associated with Incident Heart Failure - The All of Us Research Program,” on Sunday, April 7, 2024, at 3:15 p.m. ET / 19:15 UTC in Hall B4-5.

ACC.24  will take place April 6-8, 2024, in Atlanta, bringing together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow  @ACCinTouch ,  @ACCMediaCenter  and  #ACC24  for the latest news from the meeting.

The American College of Cardiology  (ACC) is the global leader in transforming cardiovascular care and improving heart health for all. As the preeminent source of professional medical education for the entire cardiovascular care team since 1949, ACC credentials cardiovascular professionals in over 140 countries who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. Through its world-renowned family of  JACC  Journals, NCDR registries, ACC Accreditation Services, global network of Member Sections, CardioSmart patient resources and more, the College is committed to ensuring a world where science, knowledge and innovation optimize patient care and outcomes. Learn more at  ACC.org .

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• Impact of vaping on...

Impact of vaping on respiratory health

Linked editorial.

Protecting children from harms of vaping

• Related content
• Peer review
• Andrea Jonas , clinical assistant professor
• Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Stanford University, Stanford, CA, USA
• Correspondence to A Jonas andreajonas{at}stanford.edu

Widespread uptake of vaping has signaled a sea change in the future of nicotine consumption. Vaping has grown in popularity over the past decade, in part propelled by innovations in vape pen design and nicotine flavoring. Teens and young adults have seen the biggest uptake in use of vape pens, which have superseded conventional cigarettes as the preferred modality of nicotine consumption. Relatively little is known, however, about the potential effects of chronic vaping on the respiratory system. Further, the role of vaping as a tool of smoking cessation and tobacco harm reduction remains controversial. The 2019 E-cigarette or Vaping Use-Associated Lung Injury (EVALI) outbreak highlighted the potential harms of vaping, and the consequences of long term use remain unknown. Here, we review the growing body of literature investigating the impacts of vaping on respiratory health. We review the clinical manifestations of vaping related lung injury, including the EVALI outbreak, as well as the effects of chronic vaping on respiratory health and covid-19 outcomes. We conclude that vaping is not without risk, and that further investigation is required to establish clear public policy guidance and regulation.

Abbreviations

BAL bronchoalveolar lavage

CBD cannabidiol

CDC Centers for Disease Control and Prevention

DLCO diffusing capacity of the lung for carbon monoxide

EMR electronic medical record

END electronic nicotine delivery systems

EVALI E-cigarette or Vaping product Use-Associated Lung Injury

LLM lipid laden macrophages

THC tetrahydrocannabinol

V/Q ventilation perfusion

Introduction

The introduction of vape pens to international markets in the mid 2000s signaled a sea change in the future of nicotine consumption. Long the mainstay of nicotine use, conventional cigarette smoking was on the decline for decades in the US, 1 2 largely owing to generational shifts in attitudes toward smoking. 3 With the advent of vape pens, trends in nicotine use have reversed, and the past two decades have seen a steady uptake of vaping among young, never smokers. 4 5 6 Vaping is now the preferred modality of nicotine consumption among young people, 7 and 2020 surveys indicate that one in five US high school students currently vape. 8 These trends are reflected internationally, where the prevalence of vape products has grown in both China and the UK. 9 Relatively little is known, however, regarding the health consequences of chronic vape pen use. 10 11 Although vaping was initially heralded as a safer alternative to cigarette smoking, 12 13 the toxic substances found in vape aerosols have raised new questions about the long term safety of vaping. 14 15 16 17 The 2019 E-cigarette or Vaping product Use-Associated Lung Injury (EVALI) outbreak, ultimately linked to vitamin E acetate in THC vapes, raised further concerns about the health effects of vaping, 18 19 20 and has led to increased scientific interest in the health consequences of chronic vaping. This review summarizes the history and epidemiology of vaping, and the clinical manifestations and proposed pathophysiology of lung injury caused by vaping. The public health consequences of widespread vaping remain to be seen and are compounded by young users of vape pens later transitioning to combustible cigarettes. 4 21 22 Deepened scientific understanding and public awareness of the potential harms of vaping are imperative to confront the challenges posed by a new generation of nicotine users.

Sources and selection criteria

We searched PubMed and Ovid Medline databases for the terms “vape”, “vaping”, “e-cigarette”, “electronic cigarette”, “electronic nicotine delivery”, “electronic nicotine device”, “END”, “EVALI”, “lung injury, diagnosis, management, and treatment” to find articles published between January 2000 and December 2021. We also identified references from the Centers for Disease Control and Prevention (CDC) website, as well as relevant review articles and public policy resources. Prioritization was given to peer reviewed articles written in English in moderate-to-high impact journals, consensus statements, guidelines, and included randomized controlled trials, systematic reviews, meta-analyses, and case series. We excluded publications that had a qualitative research design, or for which a conflict of interest in funding could be identified, as defined by any funding source or consulting fee from nicotine manufacturers or distributors. Search terms were chosen to generate a broad selection of literature that reflected historic and current understanding of the effects of vaping on respiratory health.

The origins of vaping

Vaping achieved widespread popularity over the past decade, but its origins date back almost a century and are summarized in figure 1 . The first known patent for an “electric vaporizer” was granted in 1930, intended for aerosolizing medicinal compounds. 23 Subsequent patents and prototypes never made it to market, 24 and it wasn’t until 1979 that the first vape pen was commercialized. Dubbed the “Favor” cigarette, the device was heralded as a smokeless alternative to cigarettes and led to the term “vaping” being coined to differentiate the “new age” method of nicotine consumption from conventional, combustible cigarettes. 25 “Favor” cigarettes did not achieve widespread appeal, in part because of the bitter taste of the aerosolized freebase nicotine; however, the term vaping persisted and would go on to be used by the myriad products that have since been developed.

Timeline of vape pen invention to widespread use (1970s-2020)

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The forerunner of the modern vape pen was developed in Beijing in 2003 and later introduced to US markets around 2006. 26 27 Around this time, the future Juul Laboratories founders developed the precursor of the current Juul vape pen while they were students at the Stanford Byers-Center for Biodesign. 28 Their model included disposable cartridges of flavored nicotine solution (pods) that could be inserted into the vape pen, which itself resembled a USB flash drive. Key to their work was the chemical alteration of freebase nicotine to a benzoate nicotine salt. 29 The lower pH of the nicotine salt resulted in an aerosolized nicotine product that lacked a bitter taste, 30 and enabled manufacturers to expand the range of flavored vape products. 31 Juul Laboratories was founded a decade later and quickly rose to dominate the US market, 32 accounting for an estimated 13-59% of the vape products used among teens by 2020. 6 8 Part of the Juul vape pen’s appeal stems from its discreet design, as well as its ability to deliver nicotine with an efficiency matching that of conventional cigarettes. 33 34 Subsequent generations of vape pens have included innovations such as the tank system, which allowed users to select from the wide range of different vape solutions on the market, rather than the relatively limited selection available in traditional pod based systems. Further customizations include the ability to select different vape pen components such as atomizers, heating coils, and fluid wicks, allowing users to calibrate the way in which the vape aerosol is produced. Tobacco companies have taken note of the shifting demographics of nicotine users, as evidenced in 2018 by Altria’s $12.8bn investment in Juul Laboratories. 35

Vaping terminology

At present, vaping serves as an umbrella term that describes multiple modalities of aerosolized nicotine consumption. Vape pens are alternatively called e-cigarettes, electronic nicotine delivery systems (END), e-cigars, and e-hookahs. Additional vernacular terms have emerged to describe both the various vape pen devices (eg, tank, mod, dab pen), vape solution (eg, e-liquid, vape juice), as well as the act of vaping (eg, ripping, juuling, puffing, hitting). 36 A conventional vape pen is a battery operated handheld device that contains a storage chamber for the vape solution and an internal element for generating the characteristic vape aerosol. Multiple generations of vape pens have entered the market, including single use, disposable varieties, as well as reusable models that have either a refillable fluid reservoir or a disposable cartridge for the vape solution. Aerosol generation entails a heating coil that atomizes the vape solution, and it is increasingly popular for devices to include advanced settings that allow users to adjust features of the aerosolized nicotine delivery. 37 38 Various devices allow for coil temperatures ranging from 110 °C to over 1000 °C, creating a wide range of conditions for thermal degradation of the vape solution itself. 39 40

The sheer number of vape solutions on the market poses a challenge in understanding the impact of vaping on respiratory health. The spectrum of vape solutions available encompasses thousands of varieties of flavors, additives, and nicotine concentrations. 41 Most vape solutions contain an active ingredient, commonly nicotine 42 ; however, alternative agents include tetrahydrocannabinol (THC) or cannabidiol (CBD). Vape solutions are typically composed of a combination of a flavorant, nicotine, and a carrier, commonly propylene glycol or vegetable glycerin, that generates the characteristic smoke appearance of vape aerosols. Some 450 brands of vape now offer more than 8000 flavors, 41 a figure that nearly doubled over a three year period. 43 Such tremendous variety does not account for third party sellers who offer users the option to customize a vape solution blend. Addition of marijuana based products such as THC or CBD requires the use of an oil based vape solution carrier to allow for extraction of the psychoactive elements. Despite THC vaping use in nearly 9% of high schoolers, 44 THC vape solutions are subject to minimal market regulation. Finally, a related modality of THC consumption is termed dabbing, and describes the process of inhaling aerosolized THC wax concentrate.

Epidemiology of vaping

Since the early 2000s, vaping has grown in popularity in the US and elsewhere. 8 45 Most of the 68 million vape pen users are concentrated in China, the US, and Europe. 46 Uptake among young people has been particularly pronounced, and in the US vaping has overtaken cigarettes as the most common modality of nicotine consumption among adolescents and young adults. 47 Studies estimate that 20% of US high school students are regular vape pen users, 6 48 in contrast to the 5% of adults who use vape products. 2 Teen uptake of vaping has been driven in part by a perception of vaping as a safer alternative to cigarettes, 49 50 as well as marketing strategies that target adolescents. 33 Teen use of vape pens is further driven by the low financial cost of initiation, with “starter kits” costing less than $25, 51 as well as easy access through peer sales and inconsistent age verification at in-person and online retailers. 52 After sustained growth in use over the 2010s, recent survey data from 2020 suggest that the number of vape pen users has leveled off among teens, perhaps in part owing to increased perceived risk of vaping after the EVALI outbreak. 8 53 The public health implications of teen vaping are compounded by the prevalence of vaping among never smokers (defined as having smoked fewer than 100 lifetime cigarettes), 54 and subsequent uptake of cigarette smoking among vaping teens. 4 55 Similarly, half of adults who currently vape have never used cigarettes, 2 and concern remains that vaping serves as a gateway to conventional cigarette use, 56 57 although these results have been disputed. 58 59 Despite regulation limiting the sale of flavored vape products, 60 a 2020 survey found that high school students were still predominantly using fruit, mint, menthol, and dessert flavored vape solutions. 48 While most data available surround the use of nicotine-containing vape products, a recent meta-analysis showed growing prevalence of adolescents using cannabis-containing products as well. 61

Vaping as harm reduction

Despite facing ongoing questions about safety, vaping has emerged as a potential tool for harm reduction among cigarette smokers. 12 27 An NHS report determined that vaping nicotine is “around 95% less harmful than cigarettes,” 62 leading to the development of programs that promote vaping as a tool of risk reduction among current smokers. A 2020 Cochrane review found that vaping nicotine assisted with smoking cessation over placebo 63 and recent work found increased rates of cigarette abstinence (18% v 9.9%) among those switching to vaping compared with conventional nicotine replacement (eg, gum, patch, lozenge). 64 US CDC guidance suggests that vaping nicotine may benefit current adult smokers who are able to achieve complete cigarette cessation by switching to vaping. 65 66

The public health benefit of vaping for smoking cessation is counterbalanced by vaping uptake among never smokers, 2 54 and questions surrounding the safety of chronic vaping. 10 11 Controversy surrounding the NHS claim of vaping as 95% safer than cigarettes has emerged, 67 68 and multiple leading health organizations have concluded that vaping is harmful. 42 69 Studies have demonstrated airborne particulate matter in the proximity of active vapers, 70 and concern remains that secondhand exposure to vaped aerosols may cause adverse effects, complicating the notion of vaping as a net gain for public health. 71 72 Uncertainty about the potential chronic consequences of vaping combined with vaping uptake among never smokers has complicated attempts to generate clear policy guidance. 73 74 Further, many smokers may exhibit “dual use” of conventional cigarettes and vape pens simultaneously, further complicating efforts to understand the impact of vape exposure on respiratory health, and the role vape use may play in smoking cessation. 12 We are unable to know with certainty the extent of nicotine uptake among young people that would have been seen in the absence of vaping availability, and it remains possible that some young vape pen users may have started on conventional cigarettes regardless. That said, declining nicotine use over the past several decades would argue that many young vape pen users would have never had nicotine uptake had vape pens not been introduced. 1 2 It remains an open question whether public health measures encouraging vaping for nicotine cessation will benefit current smokers enough to offset the impact of vaping uptake among young, never smokers. 75

Vaping lung injury—clinical presentations

Vaping related lung injury: 2012-19.

The potential health effects of vape pen use are varied and centered on injury to the airways and lung parenchyma. Before the 2019 EVALI outbreak, the medical literature detailed case reports of sporadic vaping related acute lung injury. The first known case was reported in 2012, when a patient presented with cough, diffuse ground glass opacities, and lipid laden macrophages (LLM) on bronchoalveolar lavage (BAL) return in the context of vape pen use. 76 Over the following seven years, an additional 15 cases of vaping related acute lung injury were reported in the literature. These cases included a wide range of diffuse parenchymal lung disease without any clear unifying features, and included cases of eosinophilic pneumonia, 77 78 79 hypersensitivity pneumonitis, 80 organizing pneumonia, 81 82 diffuse alveolar hemorrhage, 83 84 and giant cell foreign body reaction. 85 Although parenchymal lung injury predominated the cases reported, additional cases detailed episodes of status asthmaticus 86 and pneumothoraces 87 attributed to vaping. Non-respiratory vape pen injury has also been described, including cases of nicotine toxicity from vape solution ingestion, 88 89 and injuries sustained owing to vape pen device explosions. 90

The 2019 EVALI outbreak

In the summer of 2019 the EVALI outbreak led to 2807 cases of idiopathic acute lung injury in predominantly young, healthy individuals, which resulted in 68 deaths. 19 91 Epidemiological work to uncover the cause of the outbreak identified an association with vaping, particularly the use of THC-containing products, among affected individuals. CDC criteria for EVALI ( box 1 ) included individuals presenting with respiratory symptoms who had pulmonary infiltrates on imaging in the context of having vaped or dabbed within 90 days of symptom onset, without an alternative identifiable cause. 92 93 After peaking in September 2019, EVALI case numbers steadily declined, 91 likely owing to identification of a link with vaping, and subsequent removal of offending agents from circulation. Regardless, sporadic cases continue to be reported, and a high index of suspicion is required to differentiate EVALI from covid-19 pneumonia. 94 95 A strong association emerged between EVALI cases and the presence of vitamin E acetate in the BAL return of affected individuals 96 ; however, no definitive causal link has been established. Interestingly, the EVALI outbreak was nearly entirely contained within the US with the exception of several dozen cases, at least one of which was caused by an imported US product. 97 98 99 The pattern of cases and lung injury is most suggestive of a vape solution contaminant that was introduced into the distribution pipeline in US markets, leading to a geographically contained pattern of lung injury among users. CDC case criteria for EVALI may have obscured a potential link between viral pneumonia and EVALI, and cases may have been under-recognized following the onset of the covid-19 pandemic.

CDC criteria for establishing EVALI diagnosis

Cdc lung injury surveillance, primary case definitions, confirmed case.

Vape use* in 90 days prior to symptom onset; and

Pulmonary infiltrate on chest radiograph or ground glass opacities on chest computed tomography (CT) scan; and

Absence of pulmonary infection on initial investigation†; and

Absence of alternative plausible diagnosis (eg, cardiac, rheumatological, or neoplastic process).

Probable case

Pulmonary infiltrate on chest radiograph or ground glass opacities on chest CT; and

Infection has been identified; however is not thought to represent the sole cause of lung injury OR minimum criteria** to exclude infection have not been performed but infection is not thought to be the sole cause of lung injury

*Use of e-cigarette, vape pen, or dabbing.

†Minimum criteria for absence of pulmonary infection: negative respiratory viral panel, negative influenza testing (if supported by local epidemiological data), and all other clinically indicated infectious respiratory disease testing is negative.

EVALI—clinical, radiographic, and pathologic features

In the right clinical context, diagnosis of EVALI includes identification of characteristic radiographic and pathologic features. EVALI patients largely fit a pattern of diffuse, acute lung injury in the context of vape pen exposure. A systematic review of 200 reported cases of EVALI showed that those affected were predominantly men in their teens to early 30s, and most (80%) had been using THC-containing products. 100 Presentations included predominantly respiratory (95%), constitutional (87%), and gastrointestinal symptoms (73%). Radiological studies mostly featured diffuse ground glass opacities bilaterally. Of 92 cases that underwent BAL, alveolar fluid samples were most commonly neutrophil predominant, and 81% were additionally positive for LLM on Oil Red O staining. Lung biopsy was not required to achieve the diagnosis; however, of 33 cases that underwent tissue biopsy, common features included organizing pneumonia, inflammation, foamy macrophages, and fibrinous exudates.

EVALI—outcomes

Most patients with EVALI recovered, and prognosis was generally favorable. A systematic review of identified cases found that most patients with confirmed disease required admission to hospital (94%), and a quarter were intubated. 100 Mortality among EVALI patients was low, with estimates around 2-3% across multiple studies. 101 102 103 Mortality was associated with age over 35 and underlying asthma, cardiac disease, or mental health conditions. 103 Notably, the cohorts studied only included patients who presented for medical care, and the samples are likely biased toward a more symptomatic population. It is likely that many individuals experiencing mild symptoms of EVALI did not present for medical care, and would have self-discontinued vaping following extensive media coverage of the outbreak at that time. Although most EVALI survivors recovered well, case series of some individuals show persistent radiographic abnormalities 101 and sustained reductions in DLCO. 104 105 Pulmonary function evaluation of EVALI survivors showed normalization in FEV 1 /FVC on spirometry in some, 106 while others had more variable outcomes. 105 107 108

Vaping induced lung injury—pathophysiology

The causes underlying vaping related acute lung injury remain interesting to clinicians, scientists, and public health officials; multiple mechanisms of injury have been proposed and are summarized in figure 2 . 31 109 110 Despite increased scientific interest in vaping related lung injury following the EVALI outbreak, the pool of data from which to draw meaningful conclusions is limited because of small scale human studies and ongoing conflicts due to tobacco industry funding. 111 Further, insufficient time has elapsed since widespread vaping uptake, and available studies reflect the effects of vaping on lung health over a maximum 10-15 year timespan. The longitudinal effects of vaping may take decades to fully manifest and ongoing prospective work is required to better understand the impacts of vaping on respiratory health.

Schematic illustrating pathophysiology of vaping lung injury

Pro-inflammatory vape aerosol effects

While multiple pathophysiological pathways have been proposed for vaping related lung injury, they all center on the vape aerosol itself as the conduit of lung inflammation. Vape aerosols have been found to harbor a number of toxic substances, including thermal degradation products of the various vape solution components. 112 Mass spectrometry analysis of vape aerosols has identified a variety of oxidative and pro-inflammatory substances including benzene, acrolein, volatile organic compounds, and propylene oxide. 16 17 Vaping additionally leads to airway deposition of ultrafine particles, 14 113 as well as the heavy metals manganese and zinc which are emitted from the vaping coils. 15 114 Fourth generation vape pens allow for high wattage aerosol generation, which can cause airway epithelial injury and tissue hypoxia, 115 116 as well as formaldehyde exposure similar to that of cigarette smoke. 117 Common carrier solutions such as propylene glycol have been associated with increased airway hyper-reactivity among vape pen users, 31 118 119 and have been associated with chronic respiratory conditions among theater workers exposed to aerosolized propylene glycol used in the generation of artificial fog. 120 Nicotine salts used in pod based vape pen solutions, including Juul, have been found to penetrate the cell membrane and have cytotoxic effects. 121

The myriad available vape pen flavors correlate with an expansive list of chemical compounds with potential adverse respiratory effects. Flavorants have come under increased scrutiny in recent years and have been found to contribute to the majority of aldehyde production during vape aerosol production. 122 Compounds such as cinnamaldehyde, 123 124 2,5-dimethylpyrazine (chocolate flavoring), 125 and 2,3-pentanedione 126 are common flavor additives and have been found to contribute to airway inflammation and altered immunological responses. The flavorant diacetyl garnered particular attention after it was identified on mass spectrometry in most vape solutions tested. 127 Diacetyl is most widely associated with an outbreak of diacetyl associated bronchiolitis obliterans (“popcorn lung”) among workers at a microwave popcorn plant in 2002. 128 Identification of diacetyl in vape solutions raises the possibility of development of a similar pattern of bronchiolitis obliterans among individuals who have chronic vape aerosol exposure to diacetyl-containing vape solutions. 129

Studies of vape aerosols have suggested multiple pro-inflammatory effects on the respiratory system. This includes increased airway resistance, 130 impaired response to infection, 131 and impaired mucociliary clearance. 132 Vape aerosols have further been found to induce oxidative stress in lung epithelial cells, 133 and to both induce DNA damage and impair DNA repair, consistent with a potential carcinogenic effect. 134 Mice chronically exposed to vape aerosols developed increased airway hyper-reactivity and parenchymal changes consistent with chronic obstructive pulmonary disease. 135 Human studies have been more limited, but reveal increased airway edema and friability among vape pen users, as well as altered gene transcription and decreased innate immunity. 136 137 138 Upregulation of neutrophil elastase and matrix metalloproteases among vape users suggests increased proteolysis, potentially putting those patients at risk of chronic respiratory conditions. 139

THC-containing products

Of particular interest during the 2019 EVALI outbreak was the high prevalence of THC use among EVALI cases, 19 raising questions about a novel mechanism of lung injury specific to THC-containing vape solutions. These solutions differ from conventional nicotine based products because of the need for a carrier capable of emulsifying the lipid based THC component. In this context, additional vape solution ingredients rose to attention as potential culprits—namely, THC itself, which has been found to degrade to methacrolein and benzene, 140 as well as vitamin E acetate which was found to be a common oil based diluent. 141

Vitamin E acetate has garnered increasing attention as a potential culprit in the pathophysiology of the EVALI outbreak. Vitamin E acetate was found in 94% of BAL samples collected from EVALI patients, compared with none identified in unaffected vape pen users. 96 Thermal degradation of vitamin E acetate under conditions similar to those in THC vape pens has shown production of ketene, alkene, and benzene, which may mediate epithelial lung injury when inhaled. 39 Previous work had found that vitamin E acetate impairs pulmonary surfactant function, 142 and subsequent studies have shown a dose dependent adverse effect on lung parenchyma by vitamin E acetate, including toxicity to type II pneumocytes, and increased inflammatory cytokines. 143 Mice exposed to aerosols containing vitamin E acetate developed LLM and increased alveolar protein content, suggesting epithelial injury. 140 143

The pathophysiological insult underlying vaping related lung injury may be multitudinous, including potentially compound effects from multiple ingredients comprising a vape aerosol. The heterogeneity of available vape solutions on the market further complicates efforts to pinpoint particular elements of the vape aerosol that may be pathogenic, as no two users are likely to be exposed to the same combination of vape solution products. Further, vape users may be exposed to vape solutions containing terpenes, medium chain triglycerides, or coconut oil, the effects of which on respiratory epithelium remain under investigation. 144

Lipid laden macrophages

Lipid laden alveolar macrophages have risen to prominence as potential markers of vaping related lung injury. Alveolar macrophages describe a scavenger white blood cell responsible for clearing alveolar spaces of particulate matter and modulating the inflammatory response in the lung parenchyma. 145 LLM describe alveolar macrophages that have phagocytosed fat containing deposits, as seen on Oil Red O staining, and have been described in a wide variety of pulmonary conditions, including aspiration, lipoid pneumonia, organizing pneumonia, and medication induced pneumonitis. 146 147 During the EVALI outbreak, LLM were identified in the alveolar spaces of affected patients, both in the BAL fluid and on both transbronchial and surgical lung biopsies. 148 149 Of 52 EVALI cases reported in the literature who underwent BAL, LLM were identified in over 80%. 19 100 101 148 149 150 151 152 153 Accordingly, attention turned to LLM as not only a potential marker of lung injury in EVALI, but as a possible contributor to lung inflammation itself. This concern was compounded by the frequent reported use of oil based THC vape products among EVALI patients, raising the possibility of lipid deposits in the alveolus resulting from inhalation of THC-containing vape aerosols. 154 The combination of LLM, acute lung injury, and inhalational exposure to an oil based substance raised the concern for exogenous lipoid pneumonia. 152 153 However, further evaluation of the radiographic and histopathologic findings failed to identify cardinal features that would support a diagnosis of exogenous lipoid pneumonia—namely, low attenuation areas on CT imaging and foreign body giant cells on histopathology. 155 156 However, differences in the particle size and distribution between vape aerosol exposure and traditional causes of lipoid pneumonia (ie, aspiration of a large volume of an oil-containing substance), could reasonably lead to differences in radiographic appearance, although this would not account for the lack of characteristic histopathologic features on biopsy that would support a diagnosis of lipoid pneumonia.

Recent work suggests that LLM reflect a non-specific marker of vaping, rather than a marker of lung injury. One study found that LLM were not unique to EVALI and could be identified in healthy vape pen users, as well as conventional cigarette smokers, but not in never smokers. 157 Interestingly, this work showed increased cytokines IL-4 and IL-10 among healthy vape users, suggesting that cigarette and vape pen use are associated with a pro-inflammatory state in the lung. 157 An alternative theory supports LLM presence reflecting macrophage clearance of intra-alveolar cell debris rather than exogenous lipid exposure. 149 150 Such a pattern would be in keeping with the role of alveolar macrophages as modulating the inflammatory response in the lung parenchyma. 158 Taken together, available data would support LLM serving as a non-specific marker of vape product use, rather than playing a direct role in vaping related lung injury pathogenesis. 102

Clinical aspects

A high index of suspicion is required in establishing a diagnosis of vaping related lung injury, and a general approach is summarized in figure 3 . Clinicians may consider the diagnosis when faced with a patient with new respiratory symptoms in the context of vape pen use, without an alternative cause to account for their symptoms. Suspicion should be especially high if respiratory complaints are coupled with constitutional and gastrointestinal symptoms. Patients may present with non-specific markers indicative of an ongoing inflammatory process: fevers, leukocytosis, elevated C reactive protein, or elevated erythrocyte sedimentation rate. 19

Flowchart outlining the procedure for diagnosing a vaping related lung injury

Vaping related lung injury is a diagnosis of exclusion. Chest imaging via radiograph or CT may identify a variety of patterns, although diffuse ground glass opacities remain the most common radiographic finding. Generally, patients with an abnormal chest radiograph should undergo a chest CT for further evaluation of possible vaping related lung injury.

Exclusion of infectious causes is recommended. Testing should include evaluation for bacterial and viral causes of pneumonia, as deemed appropriate by clinical judgment and epidemiological data. Exclusion of common viral causes of pneumonia is imperative, particularly influenza and SARS-CoV-2. Bronchoscopy with BAL should be considered on a case-by-case basis for those with more severe disease and may be helpful to identify patients with vaping mediated eosinophilic lung injury. Further, lung biopsy may be beneficial to exclude alternative causes of lung injury in severe cases. 92

No definitive therapy has been identified for the treatment of vaping related lung injury, and data are limited to case reports and public health guidance on the topic. Management includes supportive care and strong consideration for systemic corticosteroids for severe cases of vaping related lung injury. CDC guidance encourages consideration of systemic corticosteroids for patients requiring admission to hospital, or those with higher risk factors for adverse outcomes, including age over 50, immunosuppressed status, or underlying cardiopulmonary disease. 100 Further, given case reports of vaping mediated acute eosinophilic pneumonia, steroids should be implemented in those patients who have undergone a confirmatory BAL. 77 79

Additional therapeutic options include empiric antibiotics and/or antivirals, depending on the clinical scenario. For patients requiring admission to hospital, prompt subspecialty consultation with a pulmonologist can help guide management. Outpatient follow-up with chest imaging and spirometry is recommended, as well as referral to a pulmonologist. Counseling regarding vaping cessation is also a core component in the post-discharge care for this patient population. Interventions specific to vaping cessation remain under investigation; however, literature supports the use of behavioral counseling and/or pharmacotherapy to support nicotine cessation efforts. 66

Health outcomes among vape pen users

Health outcomes among chronic vape pen users remains an open question. To date, no large scale prospective cohort studies exist that can establish a causal link between vape use and adverse respiratory outcomes. One small scale prospective cohort study did not identify any spirometric or radiographic changes among vape pen users over a 3.5 year period. 159 Given that vaping remains a relatively novel phenomenon, many users will have a less than 10 “pack year” history of vape pen use, arguably too brief an exposure period to reflect the potential harmful nature of chronic vaping. Studies encompassing a longer period of observation of vape pen users have not yet taken place, although advances in electronic medical record (EMR) data collection on vaping habits make such work within reach.

Current understanding of the health effects of vaping is largely limited to case reports of acute lung injury, and health surveys drawing associations between vaping exposure and patient reported outcomes. Within these limitations, however, early work suggests a correlation between vape pen use and poorer cardiopulmonary outcomes. Survey studies of teens who regularly vape found increased frequencies of respiratory symptoms, including productive cough, that were independent of smoking status. 160 161 These findings were corroborated in a survey series identifying more severe asthma symptoms and more days of school missed owing to asthma among vape pen users, regardless of cigarette smoking status. 162 163 164 Studies among adults have shown a similar pattern, with increased prevalence of chronic respiratory conditions (ie, asthma or chronic obstructive pulmonary disease) among vape pen users, 165 166 and higher risk of myocardial infarction and stroke, but lower risk of diabetes. 167

The effects of vaping on lung function as determined by spirometric studies are more varied. Reported studies have assessed lung function after a brief exposure to vape aerosols, varying from 5-60 minutes in duration, and no longer term observational cohort studies exist. While some studies have shown increased airway resistance after vaping exposure, 130 168 169 others have shown no change in lung function. 137 170 171 The cumulative exposure of habitual vape pen users to vape aerosols is much longer than the period evaluated in these studies, and the impact of vaping on longer term respiratory heath remains to be seen. Recent work evaluating ventilation-perfusion matching among chronic vapers compared with healthy controls found increased ventilation-perfusion mismatch, despite normal spirometry in both groups. 172 Such work reinforces the notion that changes in spirometry are a feature of more advanced airways disease, and early studies, although inconsistent, may foreshadow future respiratory impairment in chronic vapers.

Covid-19 and vaping

The covid-19 pandemic brought renewed attention to the potential health impacts of vaping. Studies investigating the role of vaping in covid-19 prevalence and outcomes have been limited by the small size of the populations studied and results have been inconsistent. Early work noted a geographic association in the US between vaping prevalence and covid-19 cases, 173 and a subsequent survey study found that a covid-19 diagnosis was five times more likely among teens who had ever vaped. 174 In contrast, a UK survey study found no association between vaping status and covid-19 infection rates, although captured a much smaller population of vape pen users. 175 Reports of nicotine use upregulating the angiotensin converting enzyme 2 (ACE-2) receptor, 176 which serves as the binding site for SARS-CoV-2 entry, raised the possibility of increased susceptibility to covid-19 among chronic nicotine vape pen users. 177 178 Further, vape use associated with sharing devices and frequent touching of the mouth and face were posited as potential confounders contributing to increased prevalence of covid-19 in this population. 179

Covid-19 outcomes among chronic vape pen users remain an open question. While smoking has been associated with progression to more severe infections, 180 181 no investigation has been performed to date among vaping cohorts. The young average age of chronic vape pen users may prove a protective factor, as risk of severe covid-19 infection has been shown to increase with age. 182 Regardless, a prudent recommendation remains to abstain from vaping to mitigate risk of progression to severe covid-19 infection. 183

Increased awareness of respiratory health brought about by covid-19 and EVALI is galvanizing the changing patterns in vape pen use. 184 Survey studies have consistently shown trends toward decreasing use among adolescents and young adults. 174 185 186 In one study, up to two thirds of participants endorsed decreasing or quitting vaping owing to a combination of factors including difficulty purchasing vape products during the pandemic, concerns about vaping effects on lung health, and difficulty concealing vape use while living with family. 174 Such results are reflected in nationwide trends that show halting growth in vaping use among high school students. 8 These trends are encouraging in that public health interventions countering nicotine use among teens may be meeting some measure of success.

Clinical impact—collecting and recording a vaping history

Vaping history in electronic medical records.

Efforts to prevent, diagnose, and treat vaping related lung injury begin with the ability of our healthcare system to identify vape users. Since vaping related lung injury remains a diagnosis of exclusion, clinicians must have a high index of suspicion when confronted with idiopathic lung injury in a patient with vaping exposure. Unlike cigarette use, vape pen use is not built into most EMR systems, and is not included in meaningful use criteria for EMRs. 187 Retrospective analysis of outpatient visits showed that a vaping history was collected in less than 0.1% of patients in 2015, 188 although this number has been increasing. 189 190 In part augmented by EMR frameworks that prompt collection of data on vaping history, more recent estimates indicate that a vaping history is being collected in up to 6% of patients. 191 Compared with the widespread use of vaping, particularly among adolescent and young adult populations, this number remains low. Considering generational trends in nicotine use, vaping will likely eventually overcome cigarettes as the most common mode of nicotine use, raising the importance of collecting a vaping related history. Further, EMR integration of vaping history is imperative to allow for retrospective, large scale analyses of vape exposure on longitudinal health outcomes at a population level.

Practical considerations—gathering a vaping history

As vaping becomes more common, the clinician’s ability to accurately collect a vaping history and identify patients who may benefit from nicotine cessation programs becomes more important. Reassuringly, gathering a vaping history is not dissimilar to asking about smoking and use of other tobacco products, and is summarized in box 2 . Collecting a vaping history is of particular importance for providers caring for adolescents and young adults who are among the highest risk demographics for vape pen use. Adolescents and young adults may be reluctant to share their vaping history, particularly if they are using THC-containing or CBD-containing vape solutions. Familiarity with vernacular terms to describe vaping, assuming a non-judgmental approach, and asking parents or guardians to step away during history taking will help to break down these barriers. 192

Practical guide to collecting a vaping history

Ask with empathy.

Young adults may be reluctant to share history of vaping use. Familiarity with vaping terminology, asking in a non-judgmental manner, and asking in a confidential space may help.

Ask what they are vaping

Vape products— vape pens commonly contain nicotine or an alternative active ingredient, such as THC or CBD. Providers may also inquire about flavorants, or other vape solution additives, that their patient is consuming, particularly if vaping related lung injury is suspected.

Source— ask where they source their product from. Sources may include commercially available products, third party distributors, or friends or local contacts.

Ask how they are vaping

Device— What style of device are they using?

Frequency— How many times a day do they use their vape pen (with frequent use considered >5 times a day)? Alternatively, providers may inquire how long it takes to deplete a vape solution cartridge (with use of one or more pods a day considered heavy use).

Nicotine concentration— For individuals consuming nicotine-containing products, clinicians may inquire about concentration and frequency of use, as this may allow for development of a nicotine replacement therapy plan.

Ask about other inhaled products

Clinicians should ask patients who vape about use of other inhaled products, particularly cigarettes. Further, clinicians may ask about use of water pipes, heat-not-burn devices, THC-containing products, or dabbing.

The following provides a practical guide on considerations when collecting a vaping history. Of note, collecting a partial history is preferable to no history at all, and simply recording whether a patient is vaping or not adds valuable information to the medical record.

Vape use— age at time of vaping onset and frequency of vape pen use. Vape pen use >5 times a day would be considered frequent. Alternatively, clinicians may inquire how long it takes to deplete a vape solution pod (use of one or more pods a day would be considered heavy use), or how frequently users are refilling their vape pens for refillable models.

Vape products— given significant variation in vape solutions available on the market, and variable risk profiles of the multitude of additives, inquiring as to which products a patient is using may add useful information. Further, clinicians may inquire about use of nicotine versus THC-containing vape solutions, and whether said products are commercially available or are customized by third party sellers.

Concurrent smoking— simultaneous use of multiple inhaled products is common among vape users, including concurrent use of conventional cigarettes, water pipes, heat-not-burn devices, and THC-containing or CBD-containing products. Among those using marijuana products, gathering a history regarding the type of product use, the device, and the modality of aerosol generation may be warranted. Gathering such detailed information may be challenging in the face of rapidly evolving product availability and changing popular terminology. Lastly, clinicians may wish to inquire about “dabbing”—the practice of inhaling heated butane hash oil, a concentrated THC wax—which may also be associated with lung injury. 193

Future directions

Our understanding of the effects of vaping on respiratory health is in its early stages and multiple trials are under way. Future work requires enhanced understanding of the effects of vape aerosols on lung biology, such as ongoing investigations into biomarkers of oxidative stress and inflammation among vape users (clinicaltrials.gov NCT03823885 ). Additional studies seek to elucidate the relation between vape aerosol exposure and cardiopulmonary outcomes among vape pen users ( NCT03863509 , NCT05199480 ), while an ongoing prospective cohort study will allow for longitudinal assessment of airway reactivity and spirometric changes among chronic vape pen users ( NCT04395274 ).

Public health and policy interventions are vital in supporting both our understanding of vaping on respiratory health and curbing the vaping epidemic among teens. Ongoing, large scale randomized controlled studies seek to assess the impact of the FDA’s “The Real Cost” advertisement campaign for vaping prevention ( NCT04836455 ) and another trial is assessing the impact of a vaping prevention curriculum among adolescents ( NCT04843501 ). Current trials are seeking to understand the potential for various therapies as tools for vaping cessation, including nicotine patches ( NCT04974580 ), varenicline ( NCT04602494 ), and text message intervention ( NCT04919590 ).

Finally, evaluation of vaping as a potential tool for harm reduction among current cigarette smokers is undergoing further evaluation ( NCT03235505 ), which will add to the body of work and eventually lead to clear policy guidance.

Several guidelines on the management of vaping related lung injury have been published and are summarized in table 1 . 194 195 196 Given the relatively small number of cases, the fact that vaping related lung injury remains a newer clinical entity, and the lack of clinical trials on the topic, guideline recommendations reflect best practices and expert opinion. Further, published guidelines focus on the diagnosis and management of EVALI, and no guidelines exist to date for the management of vaping related lung injury more generally.

Summary of clinical guidelines

• View inline

Conclusions

Vaping has grown in popularity internationally over the past decade, in part propelled by innovations in vape pen design and nicotine flavoring. Teens and young adults have seen the biggest uptake in use of vape pens, which have superseded conventional cigarettes as the preferred modality of nicotine consumption. Despite their widespread popularity, relatively little is known about the potential effects of chronic vaping on the respiratory system, and a growing body of literature supports the notion that vaping is not without risk. The 2019 EVALI outbreak highlighted the potential harms of vaping, and the consequences of long term use remain unknown.

Discussions regarding the potential harms of vaping are reminiscent of scientific debates about the health effects of cigarette use in the 1940s. Interesting parallels persist, including the fact that only a minority of conventional cigarette users develop acute lung injury, yet the health impact of sustained, longitudinal cigarette use is unquestioned. The true impact of vaping on respiratory health will manifest over the coming decades, but in the interval a prudent and time tested recommendation remains to abstain from consumption of inhaled nicotine and other products.

Questions for future research

How does chronic vape aerosol exposure affect respiratory health?

Does use of vape pens affect respiratory physiology (airway resistance, V/Q matching, etc) in those with underlying lung disease?

What is the role for vape pen use in promoting smoking cessation?

What is the significance of pulmonary alveolar macrophages in the pathophysiology of vaping related lung injury?

Are particular populations more susceptible to vaping related lung injury (ie, by sex, demographic, underlying comorbidity, or age)?

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: AJ conceived of, researched, and wrote the piece. She is the guarantor.

Competing interests: I have read and understood the BMJ policy on declaration of interests and declare the following interests: AJ receives consulting fees from DawnLight, Inc for work unrelated to this piece.

Patient involvement: No patients were directly involved in the creation of this article.

Provenance and peer review: Commissioned; externally peer reviewed.

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RESOURCES INFORMATION LIBRARY

Research, data & articles.

This resource is collection of the best and latest research on vaping and other reduced-harm products, medical journal articles, as well as journalistic pieces organized by topic that contain valuable data, information, and perspectives on tobacco harm reduction, vaping, and safer nicotine products.

Our intention is update this resource with additional sources as they become available, so please check back often.

Jump to Topic…

Science // Smoking Cessation Science // Harm Reduction Science // Health Effects Science // Flavors Science // Youth Usage Science // Smokeless Tobacco Science // Regulatory Effects News // Smoking Cessation News // Harm Reduction News // COVID-19 News // EVALI News // Youth Usage News // Social Justice News // Taxes News // Tobacco Control

Highlighted Resources

These resources are some of the highest rated, latest research on vaping.

Balancing Consideration of the Risks and Benefits of E-Cigarettes

Nicotine without smoke: tobacco harm reduction, electronic cigarettes for smoking cessation, a randomized trial of e-cigarettes versus nicotine-replacement therapy, educational videos, recommended videos, what vaping did.

Vaping: what people are getting wrong | The Economist

Vaping: a more balanced message | Michigan Public Health

Why bans of low-risk nicotine alternatives to smoking in lmic's will do more harm than good, vaping demystified.

The E-Cigarette Summit 2019, London | Ethan Nadelman Presentation

Why Health Groups Lie About Vaping

Vaporized: U.K. Government Promotes Vaping As Smoking Cessation Tool | CNBC Prime

Marc Slis, Vape Shop Owner - Michigan Testimony

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Stop Smoking Start Vaping

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Velvet Glove, Iron Fist

Christopher Snowden

The Rediscovery of Tobacco

Jacob Grier

The Cigarette Century

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The Cigarette

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Cigarette Wars

Cassandra Tate

Sander L. Gilman & Zhou Xun

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For Smokers Only

Ashes to Ashes

Richard Kluger

Say Why To Drugs

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Scientific Research / Articles

Smoking cessation, harm reduction, health effects, youth usage, smokeless tobacco, regulatory effects, news media / blog articles, social justice, tobacco control.

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• Help & Support

Where There’s Smoke: New Research Publication Lights Fire about Dangers of Vaping

by Stacey Sturner | January 12, 2023

• E-Cigarettes

The American Journal of Preventive Medicine recently published a new paper, titled “ Cigarette-E-cigarette Transitions and Respiratory Symptom Development ,” which assessed the respiratory health effects of 16 tobacco product transitions, including from non-use to e-cigarette use.

Funded in part by the American Lung Association, the study suggests e-cigarette initiation among nonusers and subsequent cigarette smoking may cause significant lung health impacts. These results reinforce the urgency for robust e-cigarette regulations, as well as demonstrate that additional research is needed to better determine the specific harms of e-cigarettes.

“The topline finding that e-cigarette initiation among nonusers is associated with increased respiratory morbidity is an important point to emphasize given continued high rates of e-cigarette usage among youth and young adult never smokers in the U.S.,” stated Andrew Stokes, PhD , assistant professor of global health at the Boston University School of Public Health and senior author of the paper. “It adds to our body of scientific evidence urgently calling for the public health intervention in support of more stringent regulatory e-cigarette standards.”

Dr. Stokes was a 2020-2022 recipient of the Lung Association’s Public Policy Research Award, which aims to empower scientists who are impacting lung health. In February 2022, he likewise served as senior author of a paper published in the  American Journal of Respiratory and Critical Care Medicine , revealing young adults who use e-cigarettes are more likely to develop respiratory issues within one year of vaping.

The latest study, like the one published in February, used data from the Food and Drug Administration’s (FDA) Population Assessment of Tobacco and Health (PATH) cohort, a longitudinal study tracking changes in tobacco use over time among participants. Among 33,231 observations from 13,528 unique participants, the study authors found that nonusers who started e-cigarette use had 62% greater rate of wheezing.

Albert Rizzo, MD, Chief Medical Officer of the Lung Association, added, “Anything that can be done to help curb the e-cigarette epidemic is an important step forward. This research further amplifies our organization’s warning against e-cigarette use due to the resulting health ramifications. It’s a mission-critical public policy initiative, now and always.”

“What is exceedingly clear is that e-cigarette initiation among nonusers is associated with increased respiratory morbidity,” continued Dr. Stokes. “We’re just starting to scratch the surface in our systematic identification of behavioral patterns most closely tied to respiratory events.”

The Lung Association has called on the FDA to end the sale of all flavored tobacco products, including flavored e-cigarettes. Flavors attract youth and the high levels of nicotine found in many e-cigarettes quickly hook kids. States including California and Massachusetts, as well as Washington, D.C. and multiple other cities have passed legislation to end the sale of flavored tobacco products in their states.

In addition, the Lung Association has called on federal officials to do more to ensure youth who are addicted to vaping and other tobacco products have resources to help them end their addiction.

To learn more about e-cigarette risks or a list of proven-effective cessation programs available to help youth and adults quit all tobacco products for good, please visit: Lung.org/quit-smoking .

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Blog last updated: August 25, 2023

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Study Raises Questions About Anti-Vaping Bias at FDA

Related articles.

A new study sheds light on a worrying trend at the Food and Drug Administration: the agency appears to be funding low-grade vaping research and using it to justify strict e-cigarette regulation.

"The health care costs attributable to vaping are already substantial and likely to increase." So concluded the authors of a study just published in the journal Tobacco Control. They based this conclusion on the results of a model that compared the self-reported vaping habits and health care consumption of a few thousand participants from the National Health Interview Survey (NHIS). Exclusive use of e-cigarettes generated $1.3 billion worth of health care expenditures in 2018 alone, they found.

The study had several critical flaws, as my colleague Dr. Chuck Dinerstein noted , the most serious being “the assumption that e-cigarette use would negatively impact an individual’s health and that this negative impact would increase utilization and cost.” The authors assumed what they should have demonstrated.

That's especially troublesome because existing evidence suggests that vaping is far less harmful than smoking. Instead of boosting healthcare expenditures, e-cigarette use probably reduces the amount of money spent to treat sick smokers. In sum, the Tobacco Control paper is terrible—“ a baffling piece of work ,” as Peter Hajek, Director of the Tobacco Dependence Research Unit at Queen Mary University of London, put it.

While the research itself is scientifically suspect, two other troubling details have come to light in recent days. First, the Food and Drug Administration (FDA) paid for this low-quality study—then publicly denied any involvement until the paper was published. Second, the agency's actions appear to reflect a broader effort to shape the peer-reviewed vaping literature, then use it to justify excessive e-cigarette regulations.

“ Completely false and inaccurate”

Last Friday, a vaping-industry trade group called the American Vapor Manufacturers (AVM) reported on Twitter that it had “received a first-hand tip that the federal government was involved in an embargoed announcement set for this evening.” [1] All AVM knew was that “the announcement was connected to federal vaping policy.” Michael Felberbaum, assistant commissioner for media affairs at the FDA, was quick to dispute AVM's report :

“ This is completely false and inaccurate. There is no FDA vaping-related policy announcement on Monday. There has been no information shared with anyone because there’s no announcement to share information regarding.”

AVM deleted its previous tweet following Felberbaum's repudiation, but the Tobacco Control paper, published on Monday, May 23, clearly contradicted both of his assertions. The authors acknowledged that “This study was funded by National Heart, Lung, and Blood Institute and the Food and Drug Administration (FDA) Center for Tobacco Products (Grant number: U54 HL147127.” In a sidebar titled “What this paper adds ( p 5 ),” the authors also explained how their work could “affect research, practice and/or policy”:

“ This first estimate of healthcare utilization and expenditures attributable to e-cigarette use will provide valuable information to Food and Drug Administration regulatory impact analyses of proposed regulations that affect e- cigarette use.”

An abstract of the grant published by Grantome (a database that tracks public research funding) tells the same story :

“ Healthcare costs play a central role in FDA regulatory impact analysis … The healthcare cost estimates from this project will be useful metrics for measuring the impact of tobacco use on public health, allowing a comparison of the relative magnitude of health effects of different tobacco products on specific populations.”

Anti-vaping bias at FDA?

Political influences sometimes bias the policy and messaging of federal agencies; it's neither surprising nor noteworthy that the FDA appears to have succumbed to such pressure in this one instance. What's striking, however, is the agency's overall adversarial approach to e-cigarette regulation.

At the same time it funds anti-vaping research, the FDA continues to restrict the number of e-cigarette products adult smokers can legally purchase; the few options that remain on the market are mostly sold by tobacco industry-owned brands. Documents just released via a freedom of information request (FOIA) indicate that the agency has made it a priority to review these products ahead of millions of others from smaller manufacturers.

What might explain the FDA's seemingly biased stance? A branch of economics called Public Choice Theory provides some helpful insight. Researchers this field have found that people working in government are primarily motivated by the same incentive that drives behavior in the marketplace—self-interest. According to Jane Shaw, senior associate at the Political Economy Research Center :

" Their incentives explain why many regulatory agencies appear to be 'captured' by special interests ... Capture occurs because bureaucrats do not have a profit goal to guide their behavior. Instead, they usually are in government because they have a goal or mission. They rely on Congress for their budgets, and often the people who will benefit from their mission can influence Congress to provide more funds. Thus interest groups—who may be as diverse as lobbyists for regulated industries or leaders of environmental groups—become important to them. Such interrelationships can lead to bureaucrats being captured by interest groups. "

We can't know for certain what motivates the FDA's behavior, but there are several reasons to suspect that this capture phenomenon is in play. The agency’s Center for Tobacco Products (CTP) is funded exclusively by “user fees” from tobacco manufacturers and importers, the vaping industry's primary competition. As if written with Shaw's analysis in mind, t he 2009 Family Smoking Prevention and Tobacco Control Act established the center,  legislation "crafted, in part, by the nation's leading cigarette company, Philip Morris," Boston University tobacco policy analyst Dr. Michael Siegel noted in June 2009.

The Tobacco Control Act stipulates that "the tobacco fees are only available pursuant to an annual appropriation from Congress, which provides FDA the authority to collect and spend fees." These user fees represent a staggering amount of money, the Government Accountability Office reported in 2014 :

As of March 31, 2014, the Food and Drug Administration (FDA) spent about $1.48 billion (79 percent) of the $1.88 billion in total tobacco user fees it collected since fiscal year 2009. FDA spent the majority of tobacco user fees on key activities led by the agency’s Center for Tobacco Products (CTP), which is funded solely by tobacco user fees.

To sum things up thus far, the FDA funds questionable vaping research, which it uses to inform heavy-handed e-cigarette restrictions. This effort is led by the CTP, which relies on tobacco-industry user fees, as the agency itself acknowledges . That arrangement is unique to the CTP; the Congressional Research Service reported in 2021 (p 4) that FDA's other centers “are generally funded by a combination of discretionary appropriations from the General Fund and user fees.”

Shaping research and media coverage

There is clear evidence that the FDA's stance on vaping has influenced much more than this single Tobacco Control paper. The kinds of studies many academic researchers can pursue as they investigate the health effects of e-cigarettes are heavily influenced by FDA regulation. The authors of a February 2022 analysis summarized it this way :

In the US, research of EC [electronic cigarettes] as a smoking cessation aid is not permitted because EC are regulated by the Food and Drug Administration (FDA) as consumer tobacco products and not as a medical device. As a result, only harm-reduction studies are currently permitted and not cessation studies. Additionally, due to misconceptions about safety and to avoid controversy by appealing to popular opinion, leadership at potential study sites has shown hesitancy in allowing EC intervention research to occur within their patient populations.

We also have reason to suspect that the FDA shapes how major media outlets cover vaping research. Documents acquired through another FOIA request seem to indicate that the agency has vetted entire stories published in the New York Times.

In one email chain from May 2014 (screenshot below), three FDA staffers appear to have discussed how much influence they wielded over the final text of a piece authored by Times reporter Sabrina Tavernise . “I'd so like to write them [the Times] back and tell them how much Sabrina relies on Us for her stories,” Steven Immergut , former FDA acting associate commissioner for external affairs,” wrote to his colleagues. “Quote approval?? Please..How about entire story vetting! That would be a story.”

Commentators routinely seek input from federal agencies on regulatory issues; ACSH contacted the FDA for comment on this story and received no reply. But as common sense should dictate, allowing the FDA (or any other stakeholder) to approve a story is unacceptable. For example, when it was discovered that a tobacco-industry PR firm had quietly paid for and vetted a pro-smoking story published in True Magazine in 1968, the public health establishment rightly went berserk. Yet strikingly similar behavior from a federal agency with a massive conflict of interest has engendered almost no criticism.

Research has shown that e-cigarettes are much less harmful than combustible tobacco and very effective as smoking-cessation tools. I haven't purchased a pack of Camels in nearly a decade thanks to vaping, and many other ex-smokers  tell similar stories. But none of this seems to matter to the FDA,  major medical journals ,  anti-smoking groups , or corporate news outlets , all of which seem committed to discouraging e-cigarette use.

So, here were are. Tobacco-related diseases continue to kill thousands of people every year. We finally have a viable intervention that could help save many of these lives, yet the institutions that should welcome this news seem to view vaping as a threat. We may never know with certainty what motivates this behavior. But if the FDA is really committed "to safeguarding the public health," it will quickly reverse course. 

[1] A Twitter user alerted us to AVM's comments about FDA support for the Tobacco Control study. We followed up with the trade group and verified the claims they made. ACSH has no financial ties to the vaping industry.

View the discussion thread.

By Cameron English

Director of Bioscience 

Cameron English is a writer, editor and co-host of the Science Facts and Fallacies Podcast. Before joining ACSH, he was managing editor at the Genetic Literacy Project.

Latest from Cameron English :

Environmental Health Sciences Center

E-cigarette & vaping research

The pinkerton laboratory breathes fresh air into vaping research at uc davis , uc davis environmental health sciences center co-director kent pinkerton is leading new research to investigate how electronic cigarette (e-cigarette) vapor affects respiratory health. graduate students morgan poindexter and navid singhrao explain what the pinkerton lab is up to..

By Morgan Poindexter and Navid Singhrao

Why study e-cigarettes and vaping right now?

Recent deaths and serious health complications in mostly young, healthy users of vaping products has awakened public consciousness surrounding the dangers of e-cigarettes. Legislators and concerned citizens are seeking information on the public health consequences of these devices, yet the scientific picture is murky at best. This is a new field of research, and while the US Centers for Disease Control says e-cigarettes are unsafe for most people , little is known about the long-term health impacts.

What’s clear is that vaping is a quickly growing problem for the majority of the population who don’t normally smoke. E-cigarettes first came onto the US market in 2007 and gained widespread popularity around 2013. Since then, sales have ballooned to $7 billion annually and are expected to continue to grow significantly.

The recent proliferation of vaping products has no doubt helped to spike its use among teens. For the first time in 2014, more teenagers used e-cigarettes or vaped nicotine than smoked cigarettes. In 2018, about 2 percent of middle school students and 8 percent of high school students said they smoked a cigarette in the past month, while an astounding 5 percent and 21 percent respectively said they vaped.

As with conventional cigarettes, there’s concern about secondhand smoke. Second-hand smoke exposure from vaping devices among adults in California has increased steadily three years in a row from about 20 percent to 33 percent. High-risk populations such as children, the elderly and kids of moms who vape while pregnant may be particularly vulnerable.

Why is so little known about vaping and health?

For one thing, researchers are struggling to keep pace with all the vaping products on the market. Studying the health effects is complicated by the hundreds (and perhaps thousands) of e-cigarette devices and e-liquids that are now available to consumers.

Compounding the proliferation of products, the Food and Drug Administration (FDA) largely has taken a hands-off approach and not vetted for safety most devices or flavored liquids . Initially, the FDA didn’t regulate e-cigarettes at all unless they were marketed for therapeutic purposes. New regulations took effect in 2016 , but the agency mysteriously deleted the section in them about flavored tobacco products.

New e-cigarettes, such as third generation devices or open-tank systems, allow consumers to customize how and what they vape, making it difficult for researchers to pin down the composition of chemicals users breathe. These newer devices allow any e-liquid to be added and offer variable power settings, which can increase the temperature, as well as the amount of vapor or aerosol and delivery of nicotine .

While third generation e-cigarette devices are becoming more popular, scientists don’t know how varying device settings and e-liquid formulations influence chemical exposure and respiratory health when compared with smoking conventional tobacco cigarettes.

Pods: Invasion of the body snatchers?

What does science say about vaping so far?

Although much of the concern about vaping has to do with the unknowns, what scientists have learned already is worrisome. For example, common e-cigarette devices or liquid configurations (e.g., temperature, e-liquid base formulation, flavoring chemicals) produce chemical byproducts like formaldehyde, acetaldehyde, acrolein, benzene and toluene at levels approaching and occasionally exceeding conventional cigarettes.

The temperature a user vapes, and the ratio of propylene glycol (PG) to vegetable glycerin (VG) in the e-liquid can change the amount of harmful byproducts a person may be exposed to. The potentially harmful chemical byproducts come from the main e-liquid components: PG, VG, nicotine or added flavorings. When these base chemicals heat up during vaping, changes occur through a process called thermal degradation, which leads to the formation of hundreds of new chemicals and compounds. Thermal degradation of PG and VG alone can produce toxic chemicals like formaldehyde, acetaldehyde and acrolein.

The amount of nicotine in the e-liquid also influences the chemical composition of the inhaled vapor. Nicotine breaks down chemically when heated and interacts with the other chemicals (PG, VG, flavors) to form many potentially harmful byproducts that can affect health. Some of the health problems known include:

• Cancer : Nicotine specific nitrosamines such as NNK and NNN in e-cigarette vapor are linked to cancer, as is formaldehyde, which t he International Agency for Research on Cancer classifies as a Human Carcinogen.  Scientists are still determining the overall health effects of these nicotine byproducts, but some evidence suggests that e-cigarette vapor can damage cell DNA. This type of DNA damage is one of the reasons that smoking regular cigarettes is linked to lung cancer.
• Lung disease : Nicotine and its byproducts are also associated with lung diseases such as chronic obstructive pulmonary disease (COPD).

How is the Pinkerton Lab contributing to e-cigarette research?

Using innovative research methods and a murine (mouse) model, Pinkerton’s team will focus on:

Combined expertise . A collaboration with Dr. Tran Nguyen in the Department of Environmental Toxicology couples detailed information about the chemical composition of e-cigarette vapor with biological data from mice. The Pinkerton Lab is also working with Dr. Elliot Spindle at Oregon’s Health and Sciences to understand what effects exposure to vape has on pregnant mice and their offspring.

New technology . To determine the impact on lungs, the Pinkerton Lab created its own exposure chamber to precisely monitor and alter variables at a per puff level. Most e-cigarettes can operate at a range of temperatures or wattages using a myriad of e-liquids that have varying amounts of nicotine and ratios of solvents like PG and VG. The Pinkerton Lab’s chamber allows exposure of mice or cell cultures to any combination of vaping to determine which conditions create the most harmful levels of chemicals. So far, the Pinkerton Lab has observed an increase in harmful carbonyl compounds such as formaldehyde and acetone in vapor when e-cigarette devices operate at higher temperatures (550°F), which suggests a greater risk to the lungs.

Pinpointing new mechanisms in disease . Focusing on how e-cigarette aerosol triggers mechanisms in the respiratory system, the Lab is analyzing levels of inflammation, structural damage and gene/protein expression in the lungs of mice after chronic exposure to e-cigarette vapor. If exposure to vapor increases inflammation in the lungs, this could lead to damage in the lung’s cells and disruption of normal lung function. Previous studies have suggested that e-cigarette vapor may disrupt the lung’s immune system, which makes fighting off infections from bacteria or viruses more difficult.

A deeper understanding of inherited risks . Research shows that smoking cigarettes during pregnancy alters lung development in utero, can lead to lifelong decreases in lung function and increases the risk of respiratory disease in children. To understand the impact vaping has on lung development and function and whether or not it impacts health generationally, the Pinkerton Lab is examining the mechanisms underlying respiratory health. It’s likely the ways cells communicate and can block or switch on and off certain genes ( epigenetics ) are the drivers of any negative health outcomes.

Morgan Poindexter is an Immunology PhD candidate in Dr. Pinkerton’s lab. Morgan researches the effects vaping has on the lung's immune system and whether it damages the ability to fight off viruses like the flu. She has a BS in Molecular Biology and an MS in Biology, both from Arizona State University.

Navid Singhrao is a Pharmacology and Toxicology PhD student in Dr. Pinkerton’s lab. Navid studies the presence of metals in e-cigarette aerosols and how they impact lung function. He has a degree in Biochemistry from San Francisco State University, and worked in the biotech industry for several years before deciding to return to school.

US Centers for Disease Control Interim Guidance on Vaping

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Environmental Factor

Your online source for niehs news, vaping’s respiratory effects traced by leading basic researcher.

I spoke with NIEHS grantee Irfan Rahman, Ph.D., about how e-cigarettes can affect lung health and increase susceptibility to disease.

By Rick Woychik

At the 2023 meeting of the Society of Toxicology (SOT), held last month in Nashville, Tennessee, I listened to a variety of exciting talks by NIEHS scientists and grant recipients. Topics ranged from how artificial intelligence and machine learning can advance research into the health effects of chemicals to how environmental factors can influence neurological diseases.

I was thrilled to see many institute-funded scientists recognized for their outstanding toxicological research, including Irfan Rahman, Ph.D. , who took home the 2023 SOT Leading Edge in Basic Science Award. He was recognized for his groundbreaking work examining the biological mechanisms involved in e-cigarette and tobacco toxicity.

Rahman is a professor at the University of Rochester Medical Center, where he directs the Center for Inhalation and Flavoring Toxicological Research, among his many other duties. Since the 1980s, he has conducted pioneering research into the negative biological changes caused by cigarettes, secondhand smoke, and, more recently, e-cigarettes.

Last month, I sat down with Dr. Rahman to learn more about his research program, what inspired him to pursue a scientific career, and why he thinks vaping and e-cigarettes represent a major public health threat. I was deeply impressed by not only Dr. Rahman’s deep scientific knowledge in this area but also his passion for protecting human health.

Rick Woychik : You have worked to advance inhalation toxicology since the late 1980s. What inspired you to conduct such research?

Irfan Rahman : I was born in the city of Bhopal, India, and in my late teens, there was a major disaster at a pesticide plant there that caused hundreds of thousands of residents to be exposed to methyl isocyanate, which is a dangerous gas. The event had a profound effect on my personal life and prompted me to understand how inhaled toxicants can affect human health.

A significant amount of the gas ended up being emitted through our railway station, and our family lived about 3-5 miles away from that area. When the gas leaked in the early morning hours, people started panicking — thousands of people died immediately, and a lot of animals were dying, too. The gas caused asphyxia, making it hard for people to inhale oxygen.

Other motivators for me to pursue a career in inhalation toxicology were air pollution — I lived in a small village, and pollution levels were very high growing up — and the fact that there was a lot of cigarette smoke on planes that I experienced when flying in the 1980s. I remember planes being filled with smoke, and even if you requested a nonsmoking section, the secondhand environmental smoke still made its way to you.

More recently, I’ve been inspired to study vaping and e-cigarettes. I remember when the first e-cigarette devices made their way to stores in the early to mid-2000s. I knew at the time that, contrary to what many people assumed, these were not harmless devices that only caused inhalation of water vapor. There were dangerous chemicals in them, and I wanted to find out how they affect health.

RW : Thank you for sharing that story. The Bhopal Disaster is considered the worst industrial accident in history, but your experience is inspiring because out of that tragedy, you found your scientific calling.

You mentioned your early interest in studying the health effects of e-cigarettes. Your outstanding work in that area is a major reason you won the 2023 SOT Leading Edge in Basic Science Award. Can you expand on your research into vaping and e-cigarette flavoring?

IR : Vaping delivers nicotine to the lungs in ways that are seemingly safe but actually quite dangerous to lung health. During vaping, e-cigarette vapors, which include toxic chemicals, are inhaled into the lungs. Beyond nicotine, vaping can deliver substances such as vegetable glycerin, propylene glycol, volatile organic chemicals, anti-freezing agents, metals, and many other compounds. There are also many flavorants [flavoring chemicals] used in various e-cigarettes . All of these substances get into users’ air sacs, where oxygen transfer occurs. The chemicals replace oxygen, and they can cause irritability in the lung as well as breathing difficulties.

Among our other projects, my team has sought to understand how flavoring agents and other e-cigarette substances can affect circadian biology . When scientists began to investigate the molecular circuitry that dictates our circadian clocks, they originally worked out the details in certain sections of the brain. However, more recently, it was discovered that these same circuits and molecules play a role in establishing a circadian rhythm in the metabolism of cells in other parts of the body, including the lung. So, we want to study how flavoring agents may disrupt circadian biology and pave the way for lung injury, lung fibrosis, or susceptibility to respiratory disease.

RW : Speaking of susceptibility to respiratory disease, I understand that you conducted important research during the COVID-19 pandemic. Can you expand on that?

IR : In 2019, the first cases of E-Cigarette or Vaping Use-Associated Lung Injury, also called EVALI, began to crop up in the U.S. EVALI is a severe and potentially lethal lung disease, and some of the same disease mechanisms are involved in COVID-19. When we went into the pandemic, we determined that exposure to nicotine through e-cigarettes and vaping can actually increase the concentration of the ACE2 receptor for the SARS-CoV-2 virus, thereby making people more susceptible to the disease.

Also, vaping can interfere with mitochondria, which play an important role in healthy lung function. Mitochondria are the building blocks of cellular energy, and vaping chemicals can reduce that energy, causing lung cells to have less power to do their jobs. Eventually, such mitochondrial disruption produces inflammatory responses that can increase lung aging, so that a 45-year-old who vapes might actually have the lung function of a 60-year-old, for example. And that kind of accelerated lung aging, or lung cellular senescence, can also make individuals more vulnerable to diseases like COVID-19.

RW : Any final thoughts for Environmental Factor readers?

IR : Vaping is a major public health problem, in my view. It is a form of self-inflicted damage, in part because many are not aware of its health effects, or perhaps because they’ve been told it is harmless. Many young people in our country are getting addicted to e-cigarettes, and companies are producing a variety of vaping products with shiny packaging and nice-sounding flavors that make them even more enticing. But work by my team and others has provided important insights into vaping, and I try to spread the word about its negative effects whenever possible.

I am proud that through NIEHS funding, my team has been able to characterize some of the major effects of vaping, and I look forward to continuing this important research in the future. There are many unanswered questions about all of the negative biological consequences of e-cigarettes, and through further research, we will be able to answer them.

(Rick Woychik, Ph.D., directs NIEHS and the National Toxicology Program.)

Mentors shape career

Rick Woychik : Can you talk about some of the mentors who inspired you early in your career?

Irfan Rahman : Sure. Dr. N. Nath, my Ph.D. mentor at Nagpur University in India, was a wonderful person. He helped me start understanding the free-radical chemistry of tobacco smoke, and I learned a lot from him during those years.

Next, I completed postdoctoral training at the University of Miami and Georgetown University. During that time, my mentor was Dr. Donald Massaro. He was a top-notch lung physiologist and considered the king of lung disease. It was an honor to work with him.

Before joining the University of Rochester Medical Center faculty, I worked at the University of Edinburgh in Scotland. I collaborated closely with Drs. William MacNee and Kenneth Donaldson. They helped me advance my research and provided strong professional encouragement in air pollution and tobacco smoke research.

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New Australian vaping research finds 'suite of chemicals' in liquids used in vapes, some at 'dangerously high' levels

They are flavoured, colourful and popular with teenagers, but new Australian research is discovering mounting evidence that vapes are also unsafe to use.

Key points:

• Researchers found pesticides, cleaning agents and potentially dangerous chemicals in vaping products
• They also found trace elements of nicotine in products that claim to be nicotine-free
• An independent researcher backed the findings as evidence of the need for greater regulation 

Curtin University respiratory physiologist Alexander Larcombe studied 65 common liquids used in vapes from local suppliers   that are available in Australia.

Dr Larcombe said the results showed that many vapes contained carcinogenic and other harmful ingredients.

"There is a suite of chemicals in there, many are known to have negative impacts on your lung health," he said.

The study is the extension of a 2019 study published by the same researchers that looked at 10 vape ingredients. It is the most comprehensive study of products available in Australia to date.

It is estimated that more than 200,000 Australians use vapes, however, those using them with nicotine must have a prescription from a doctor.

Until recently, nicotine-free flavours were far more easily available online and from tobacconists.

The Therapeutic Goods Administration has recently cracked down on imports but can only regulate those with nicotine and imports of officially banned flavours, and there are far fewer regulations around the manufacture and supply of flavours alone within Australia.

In the latest study, the researchers looked at the "nicotine-free" products when they were fresh and after they had been repeatedly heated and cooled in a vape.

Dr Larcombe said his research, published in the Medical Journal of Australia on Monday, should counter common beliefs among vapers.

"We often get told, 'Well, it's much safer than smoking', but everything is safer than smoking," he said.

"A lot of the people who are using these things aren't trying to quit, they're teenagers who are trying them out at school."

'A dirty manufacturing process'

Researchers found evidence of a group of chemicals called polycyclic aromatic hydrocarbons (PAHs), which has been linked to lung, bladder and gastrointestinal cancers.

Dr Larcombe said the researchers found PAHs at a range of levels.

"There's not really any safe level of exposure to PAH that's accepted," he said.

The researchers also found "dangerously high levels" of lung irritant benzaldehyde, which is added to vapes to give them an almond flavour, in 61 of the 65 samples.

"It changes how some of the cells in your lungs work," Dr Larcombe said. "It impairs your lungs that are normally responsible for cleaning up pathogens."

The study also found high levels of a cinnamon flavouring known as trans-cinnamaldehyde in up to 48 of the liquids.

Its potential health effects are so concerning the substance has been added by the TGA   to an Australian list of banned flavours.

Six of the flavoured vapes promoted as nicotine-free still had traces of nicotine.

Dr Larcombe said that was against Australian law.

"It's indicative of a dirty manufacturing process or Australian companies getting [the liquids] from overseas," he said.

Pesticides, hospital cleaning agents found

Researchers also detected a chemical called 2-chlorophenol in up to 30 samples, which is commonly used in disinfectants and pesticides.

Dr Larcombe said the researchers suspected it was residue from pesticides sprayed on the crops used to generate glycerol, one of the main ingredients in the liquids.

"Somehow that pesticide has gone through the whole manufacturing process and is present in the [liquids]," he said.

"It was surprising and concerning that such a harmful chemical could be in there and people are breathing it in."

One of the main flavour enhancers in many vapes is benzyl alcohol. It was found in 42 of the liquids and, in some cases, at very high levels.

"What it does to the respiratory tract or what it does to your lungs from heating and breathing [it in] is unknown at this stage," Dr Larcombe said.

This was also a trace of a vanilla flavour called ethyl vanillin, which was in up to 59 of the liquids at reasonably high levels. 

Vapes also have a metal heating coil that heats the liquid, which degrades over time with use.

Dr Larcombe said it was made up of chromium, nickel and iron and that researchers had found "low levels" of those heavy metals.

He said the plastic container that held the liquid also broke down over time.

"You're probably breathing in microplastics and other stuff as well," he said.

Dr Larcombe said   most Australians would not know there was a difference between eating a flavour and inhaling it.

That was because when a chemical was heated — like what happened in the vaping process — it changed its chemical structure.

"Lower temperature heating can be just as bad, if not worse, in generating nasty output," he said.

Calls for stricter manufacturing rules

The findings have prompted Andrew Forrest's Minderoo Foundation to call for sweeping reforms to production of the liquids in Australia.

Minderoo Foundation — a Perth-based philanthropic organisation — said it funded the research in the area as part of its Collaborate Against Cancer initiative.

"We now have the evidence to support consistent tobacco licensing in all states," Minderoo Foundation Collaborate Against Cancer initiative chief executive Steve Burnell said.

"[As well as] restrictions on non-nicotine vaping products, changes to the Tobacco Advertising Prohibition Act and much stricter monitoring and compliance — all are required to protect our young people from these toxic products."

University of Adelaide research scientist Dr Miranda Ween — who is considered a world leader in e-cigarette research —   backed the findings.

She said it highlighted the need to regulate flavoured vapes, not just those that contained nicotine.

"We don't really have any kind of regulations in Australia about how they're made," she said.

"These people don't necessarily need to have good manufacturing practice qualifications."

Dr Ween said some of the advice and information about vapes from suppliers was not accurate nor based on the latest research.

In a statement, a spokesperson for the regulator, the TGA, said it would be reviewing its standards for nicotine-based vapes next year, but did not indicate if it would include those that just contained flavours.

The spokesperson said it tested products intercepted at the border for nicotine and banned ingredients. 

"This testing is part of a broader compliance program to monitor and address unlawful importation, advertising and supply."

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• Winter 2024 | VOL. 36, NO. 1 CURRENT ISSUE pp.A5-81

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Vaping and the Brain: Effects of Electronic Cigarettes and E-Liquid Substances

• Wilfredo López-Ojeda , Ph.D., M.S. , and
• Robin A. Hurley , M.D., F.A.N.P.A.

Search for more papers by this author

E-cigarettes (ECs), also known as vape pens, e-cigars, vaping devices, e-hookahs, mods, vapes, tank systems, electronic nicotine delivery systems (ENDS), and puff bars (fourth-generation ECs), are battery-operated electronic devices used to inhale a heat-generated aerosol from an e-liquid source ( 2 , 5 , 11 ). E-liquids contain basic ingredients, including water, propylene glycol, glycerol, optional nicotine (available at various concentrations), and flavoring agents (e.g., chocolate, cotton candy, and green apple) ( 4 ). E-liquids in disposable puff bars contain over 120 different substances, including cytotoxic chemicals ( 2 ). Refill solutions, e-liquid cartridges, and emission vapors (i.e., aerosol mix of small particles in the air) contain many other substances and hazardous chemicals, including solvents, volatile organic compounds (e.g., benzene and formaldehyde), acrolein, acids, and synthetic coolants ( 2 , 4 , 8 , 11 – 14 ). ECs can also be used to deliver marijuana. Using ECs is commonly known as “vaping” ( 15 ) ( Figure 1 ).

FIGURE 1. Generations of electronic cigarette (EC) designs, e-liquids, and components. A. First-generation disposable ECs were intended for a single use and were not rechargeable or refillable. Second-generation ECs included prefilled or refillable cartridges with rechargeable batteries. Third-generation ECs (referred to as “tanks” or “mods”) are adjustable devices, permitting users to modify the e-liquids (e.g., adding nicotine or marijuana), and are designed to create more abundant vapor emissions, thus delivering a higher dose of the substance. Fourth-generation ECs (commonly called “pod mods”) are prefilled or refillable (pods or cartridges), operate with low-power batteries, may exhibit the same customizable attributes of mods ( 1 ), and can deliver higher nicotine doses to users ( 2 , 3 ). At present, puff bars are the most popular form of ECs ( 2 ). Many e-liquids contain the same basic ingredients ( 2 , 4 ). B. Despite the rapid evolution of EC products, they typically contain the same basic components (second-generation EC pictured here): a cartridge with a reservoir designed for the e-liquid, a manual power switch to prepare and initiate atomization (vapor generation) of the e-liquid, a vaporizing chamber and heating coil to increase the temperature of the e-liquid, an atomizer unit to produce vapors from the heated e-liquid, a voltage regulator and microprocessor to regulate the electricity of the coil and light, a rechargeable lithium battery to power the device, and the light-emitting diode (LED) indicator (red, green, blue) to indicate when the user inhales through the mouthpiece or when the battery is running low. The LED visually emulates a conventional cigarette, and the vapor emissions seem to emulate the appearance of smoke ( 2 , 5 , 6 ).

ECs have several components, including a cartridge or “pod,” where the liquid solution containing nicotine, flavoring substances, and other chemicals is vaporized upon activation of an electronic heating element in the device that is triggered by inhalation ( 5 ). The heating element is powered by a rechargeable lithium battery ( 15 ). The consumer can choose the nicotine concentration of the e-liquid that is loaded into the EC cartridge ( 5 ) ( Figure 1 ). The technology of pod mods allows manufacturers to combine acid mixtures and other dangerous chemicals with nicotine salts or crystals to elevate the nicotine concentrations of their products ( 2 , 3 ). This design allows delivery of higher drug doses via relatively inconspicuous devices with reduced electrical power that closely resemble electronic USB drives ( 2 , 3 , 16 , 17 ). Popular pods contain approximately 59.2–66.7 mg/mL of nicotine, which is comparable to one pack of 20 conventional cigarettes ( 3 , 15 , 18 ). Once the cartridge or pod is installed in the EC device, the user then inhales the vaporized products of the e-liquid into the lungs, and the residues are exhaled into the air ( 5 , 15 ).

It has been suggested, incorrectly, that ECs are less harmful than conventional cigarettes ( 19 ). ECs are promoted as containing fewer chemicals, having lower levels of carcinogens, and producing fewer toxic agents than conventional cigarettes ( 19 , 20 ). However, they are not emission-free devices, and their aerosol emissions are not harmless ( 5 , 6 , 11 , 20 ). Bystanders to exhaled vaping fumes can be exposed to toxic aerosols and carcinogenic agents (e.g., acrolein, benzene, diacetyl, and formaldehyde) through second-hand or third-hand exposure ( 6 , 11 , 21 ). Elements from second-hand EC vapor increase particulate matter in the air, which can be harmful and lead to preclinical forms of cardiovascular, pulmonary, and other diseases ( 6 , 7 , 11 , 22 , 23 ). Third-hand exposure (through residual chemicals left on surfaces, skin, hair, and clothing following vaping) plays a role in the overall exposure of children to nicotine and a variety of toxicants ( 24 , 25 ).

Vaping causes serious damage throughout the human body, including organs in the cardiovascular, central nervous, immunological, and respiratory systems. This damage is primarily due to the deleterious effects of toxic compounds that exacerbate oxidative stress responses and inflammatory reactions, causing endothelial dysfunction, cellular senescence, and subsequent disease sequelae ( 2 , 6 – 10 ) ( Figure 2 ). The nicotine and nonnicotinic agents in ECs, including hazardous neurotoxic elements (i.e., aluminum, arsenic, chromium, cadmium, copper, lead, manganese, nickel, tin, and zinc) and other by-products, pose serious threats to the brain ( 8 , 13 , 26 , 27 ). To date, only a few studies have investigated the effects of these compounds on neurological function, mostly in animal models ( 8 , 28 ).

FIGURE 2. Vaping causes serious systemic disturbances throughout the body, including damage to organs of the cardiovascular, nervous, immunological, and respiratory systems. Damage is primarily due to the deleterious effects of toxic compounds contained in the e-liquid, which exacerbate oxidative stress responses and inflammatory reactions, resulting in endothelial dysfunction, cellular senescence, and subsequent disease sequelae ( 2 , 6 – 10 ).

COVER . Artistic depiction of the effects of vaping electronic cigarettes in the brain. The gray and smoky outline of the brain represents widespread effects, and the colored arrows represent neural pathways responsible for the psychiatric, neurological, and cognitive effects of nicotine, the e-liquid substances, and their by-products.

All images were created with Canva and BioRender.com , for which the Mid-Atlantic (VISN 6) MIRECC holds renewable registrations.

According to the Centers for Disease Control and Prevention, ECs “have the potential to benefit adults who smoke and who are not pregnant if used as a complete substitute for regular cigarettes and other smoked tobacco products” ( 29 ). However, use of ECs may increase the risk of future cigarette smoking among adolescents and young adults ( 30 ). The use of any form of tobacco product (smoked, smokeless, or electronic) by youths is considered unsafe ( 15 ). The U.S. Surgeon General has concluded that exposure to nicotine during adolescence can cause addiction and impair the developing adolescent brain ( 11 ).

The use of ECs has skyrocketed among U.S. adolescents and young adults since 2014 ( 31 , 32 ). In 2018, usage increased 77.8% over the previous year, the largest surge of youth tobacco consumption ever recorded by the Centers for Disease Control and Prevention ( 33 ). Most adolescents and young adult users do not know that ECs may contain higher concentrations of nicotine than conventional cigarettes ( 15 , 34 ). Similar trends have been reported among youth in countries outside the United States ( 35 – 38 ). However, the United States dominates the global vaping market. By 2022, over 2.6 million young Americans reported current use of ECs ( 39 ). Global market research reports indicated that ECs generated $22.45 billion in U.S. dollars in 2022 and a compounded annual growth of 30.6% was projected from 2023 to 2030 ( 40 ).

The increased popularity and use of ECs seems to be linked (in part) to novelty and the alluring flavors of various e-liquid options ( 41 ). The flavoring chemicals and additives of ECs are largely unregulated ( 8 , 14 , 21 ). In 2020, the Food and Drug Administration enacted a ban on flavored EC pods in an effort to reduce accelerated use among young consumers ( 42 ). A technicality in the ban, which did not include “disposable products” (i.e., puffs ECs), has allowed young consumers and suppliers to keep these devices in high demand ( 2 , 43 , 44 ). At present, several thousand flavoring options and hundreds of brands are available ( 14 , 26 ). However, the explosion in EC use also suggests that users may be experiencing dependency to both smoking and vaping ( 12 , 45 ).

Studies in Animal Models and Humans

Subchronic exposure to e-liquid (without nicotine) hindered growth and development of nematodes, caused abnormal general neuromotor behavior, and impaired advanced learning and memory ( 46 ). A study in mice indicated that chronic exposure (2 months) to vaporized elements from ECs resulted in toxic metal aggregation in the central nervous system, potentially leading to endogenous dysregulation, including metal dyshomeostasis and neurotoxicity ( 47 ). Another study in mice compared the neurological effects of short-term exposure to EC vapor and smoke from conventional cigarettes over 14 days. The EC-vapor-exposed group showed neurotoxicity leading to neuroinflammatory responses (confirmed via tumor necrosis factor alpha expression in brain tissue), and comparable cognitive and memory impairments were observed in both groups. In addition, the EC group showed longer latencies to find food rewards, with a lack of improvement in spatial memory learning ( 48 ). Taken together, these results link EC-induced neuroinflammation to deleterious alterations in cognitive and memory function ( 46 – 48 ).

It is well established that nicotine exposure during adolescence alters the structure and function of the developing brain, impairing several cognitive processes and increasing rates of mood disorders and addiction ( 11 ). Deterioration in cognitive functions (e.g., attention, impulse control, memory, and reasoning) is linked to smoking conventional cigarettes during adolescence and early adulthood, increasing the risk of long-lasting mental health concerns ( 49 , 50 ). A recent cross-sectional study reported that EC use was associated with subjective cognitive deficits in U.S. adults ( 51 ).

The toxicity of several commercially available EC refills across a range of concentrations (0.001%–1%) was analyzed with in vitro experiments using stem cells from mice and humans. Some samples had no cytotoxic effects, and others displayed high levels of cytotoxicity. Interestingly, cytotoxicity was not linked to nicotine concentrations but was linked to the amount and concentration of flavoring toxicants ( 52 ). Popular flavors, such as caramel and butterscotch, potentiated levels of cytotoxic effects; thus, commonly known flavoring chemicals should not be assumed to be harmless ( 52 ). Similar results have been reported in other studies ( 16 , 53 ).

Flavoring Additives and Other Toxicants

Menthol was introduced to conventional cigarettes in the 1950s and is also widely found in ECs ( 8 , 54 ). This popular flavoring agent increases nicotine bioavailability ( 54 ), enhances nicotine reward-related behavior, and potentiates nicotine actions in midbrain dopaminergic neurons ( 55 ). Menthol also promotes smoking initiation among youths ( 56 ). Conventional menthol cigarette smokers are twice as likely to become lifelong smokers compared with conventional nonmenthol cigarette smokers ( 57 ). The evidence suggests that menthol is a highly reinforcing sensory cue when paired with nicotine and promotes addiction.

Farnesol, a sesquiterpene alcohol found in many foods, such as peaches and vegetables, is commonly added to ECs as a flavor enhancer (e.g., green apple) ( 8 , 58 ). This additive promotes reward-related behavior (via nicotinic acetylcholine receptors), amplifying the effects of nicotine on dopaminergic neurons in the ventral tegmental area and altering the function of dopamine and GABA neurons in the midbrain ( 58 , 59 ). Many EC constituents and flavoring agents chemically decompose during vaporization, which transforms them into different toxicants, and variations in heating temperature contribute to this process. Effects of these substances are unknown ( 4 , 8 , 60 ).

A recent study investigated the long-term impact of maternal exposure to EC vapor on blood-brain barrier integrity and behavioral outcomes in postnatal mice. Vapor exposure led to cellular and molecular alterations, which are potentially associated with long-term neurotoxicity and cerebrovascular diseases ( 61 ). These changes resulted in postnatal blood-brain barrier disruptions and neurodevelopmental and behavioral impairments ( 61 ). The investigators concluded that maternal exposure to EC vapors was related to motor disabilities and learning and memory dysfunction among the offspring that persist into adolescence and adulthood ( 61 ). These findings are relevant because the use of ECs among pregnant women (both smokers and nonsmokers) has increased since the introduction of ECs to the U.S. market ( 62 – 64 ).

Another in vivo study in mice demonstrated that nonnicotinic toxicants (e.g., volatile organic compounds, acetaldehyde, acrolein, and formaldehyde) of EC emissions appeared to abruptly alter the biological and molecular integrity of the blood-brain barrier by reducing gene expression of occludin, a protein essential for stabilizing the blood-brain barrier. Changes were observed within tight junctions of blood vessels in the frontal cortex, and paracellular permeability was increased in thalamic nuclei ( 27 ). These alterations contributed to neurovascular dysfunction that promoted neuroinflammation, resulting in cognitive deficits ( 27 , 60 ).

Endothelial cell-derived microvesicles are both biomarkers and mediators of vascular health and pathogenesis in humans ( 65 ). Activation of endothelial cell-derived microvesicles in EC users decreased activation of nitric oxide synthase in microvascular endothelial cells and production of nitric oxide in the brain ( 9 ). These changes caused further biomolecular and cellular alterations in the blood-brain barrier, resulting in vascular dysregulation in the brain and increased risk of cerebrovascular diseases ( 9 , 66 ).

Conclusions

ECs do not seem to be a safer alternative to conventional cigarettes during smoking-cessation therapy. They appear to share similar chemical profiles (nicotine, nonnicotinic toxicants, and other emitted substances). Therefore, users may experience equal or possibly higher pathophysiological alterations, resulting in many health issues and higher risks for certain chronic diseases (e.g., asthma and cancer), as well as neurological conditions (e.g., addiction, stroke, cognitive dysfunction, and neurodevelopmental disorders). Bystanders exposed to second-hand or third-hand EC vapors also appear to be at higher risk for these diseases.

Furthermore, the nonnicotinic constituents in ECs potentiate epigenetic alterations, cellular dysfunction, neuroinflammation, oxidative stress, neurotransmitter dysregulation, and other abnormalities. ECs without nicotine also appear to have substantial detrimental effects on vital central nervous system regulatory components, such as the blood-brain barrier. The added flavorings, solvents, acids, synthetic coolants, volatile organic compounds, and other toxicants, including aerosolized by-products and metabolites of e-liquids, warrant attention, because flavorings seem to have increased the popularity of ECs among adolescents and young adults. Popularity of ECs has also increased among pregnant women, nonsmokers, and former conventional cigarette smokers.

Additional studies are needed to fully understand effects of the chemical constituents (especially nonnicotinic compounds) in e-liquids and their vaporized by-products, which are physiologically and pharmacokinetically uncharacterized. Flavoring substances are largely unregulated based on their clearance for ingestion. However, they are not intended for inhalation, and the exposure of respiratory and nervous tissue to these substances has not been properly studied. The popularity and increasing usage of e-liquids raise major concerns for public health.

This research was supported by the Department of Veterans Affairs Veterans Integrated Service Network 6 MIRECC.

The authors report no financial relationships with commercial interests.

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• Clinical Trials on the Effects of Vaping

Home / Resources / Clinical Trials on the Effects of Vaping

What is Vaping?

Vaping refers to inhaling and exhaling aerosolized particles from an e-cigarette. An e-cigarette is an electronic device filled with a nicotine-based liquid that is vaporized when the device is used.

Vaping was initially hailed as an important innovation. It was believed smokers could use e-cigarettes as an alternative to tobacco. This would reduce exposure to nicotine, tar, and other hazardous substances.

What’s more, many smokers considered vaping soothing, giving them “something to do with their hands” and a way to react in stressful situations where they would usually smoke. Some people succeeded in using vaping as a stepping stone to quit smoking.

With that said, the long term effects of vaping have not been fully studied. While many individuals view vaping as a step in the right direction to eliminate smoking, more research needs to be compiled on the effects it can have on individuals and society as a whole.

What Conditions is Vaping Associated With?

The unique condition associated with vaping is referred by the new medical acronym EVALI.

It stands for E-Cigarette or Vaping Associated Lung Injury.

As of October 22, 2019, 34 known deaths were associated with EVALI. The median age of victims was 45 and 59% of them were men.

In total, nearly 2,300 cases of EVALI were reported to the CDC by November 20, 2019. All 50 states have been affected except Alaska.

Samples of lung tissue taken from victims have tested positive for high amounts of vitamin E acetate, a toxin in some vaping products. Vitamin E acetate is believed to be safe when used in nutritional supplements or skincare products, but not when ingested.

Lung damage caused by EVALI can cause symptoms similar to pneumonia. Damage to the lungs makes it difficult for the body to take in oxygen and distribute it throughout the body.

EVALI is distinct from, but related to, bronchiolitis obliterans – also known as popcorn lung. This is an inflammatory condition that affects the tiniest airways within the lungs. Inflammation can lead to scarring that blocks airways, causing coughing and shortness of breath.

What Research Currently Exists Around Vaping?

The association between vaping and EVALI is already an established scientific fact. However, it is not yet clear exactly what risk factors contribute to the development of EVALI.

Current research focuses on finding a definitive answer for what chemicals or other factors may be responsible for EVALI. This will help the medical community understand why some e-cigarette enthusiasts are affected and others are not, paving the way for effective treatment.

Why Are Further Vaping Clinical Trials Important?

Vaping clinical trials will be essential to the long-term health and quality of life of those affected by EVALI or popcorn lung. Evidence of disease has been found in teens as well as elderly adults.

Unfortunately, there is no treatment capable of reversing the lung damage caused by EVALI. As with other pervasive lung disorders, such as COPD, therapies are likely to focus on preserving healthy lung function.

Current Vaping Clinical Trials

This is the current list of active vaping clinical trials on record with  ClinicalTrials.gov .

Patients are advised to watch this space carefully, since new clinical resources for vaping health are being developed rapidly.

Conditions: Coronary Artery Disease Interventions: Behavioral: Smoking cessation; Behavioral: Switching to E-cigarette Sponsors: Samsung Medical Center Recruiting

Conditions: Vaping; Adolescent Behavior; Communication Research Interventions: Other: Tailored Sponsors: Abramson Cancer Center at Penn Medicine; University of Florida Recruiting

Conditions: Vaping; Pregnancy Related; Pediatric Respiratory Diseases Sponsors: University College Dublin; Royal College of Surgeons, Ireland Recruiting

Conditions: Vaping; Electronic Cigarette Use Interventions: Other: Vaping Sponsors: Laval University; Ministere de la Sante et des Services Sociaux Recruiting

Conditions: E Cigarette Use Interventions: Behavioral: adapted vaping cessation intervention Sponsors: Veterans Medical Research Foundation; University of California Recruiting

Conditions: E-cigarette Use Interventions: Drug: Local heating + L-NAME (NG-nitro-L-arginine methyl ester; nitric oxide synthase inhibitor); Other: Chronic estrogen exposure Sponsors: Anna Stanhewicz, PhD Recruiting

Conditions: Electronic Cigarette Use Interventions: Behavioral: Social Media Use Reduction Sponsors: University of Oklahoma; Stanford University; University of Southern California; University of Wisconsin, Madison; National Institute on Drug Abuse (NIDA) Recruiting

Conditions: Obesity; Smoking Cessation Interventions: Other: ENDS; Other: CI; Other: No ENDS; Other: NI Sponsors: Brown University; National Institute of General Medical Sciences (NIGMS) Recruiting

Conditions: E-cigarette Use; Withdrawal Interventions: Drug: Transdermal Nicotine Patch; Drug: Placebo Nicotine Patch Sponsors: Johns Hopkins University; National Institute on Drug Abuse (NIDA) Recruiting

Conditions: Nicotine Vaping; Nicotine Dependence Interventions: Drug: Nicotine; Other: Placebo Sponsors: University of Southern California Recruiting

Conditions: Cigarette Smoking; E-Cigarette Use; Smoking Cessation Interventions: Drug: Varenicline; Behavioral: Counseling; Behavioral: Guided Self-Change Booklets Sponsors: Yale University; National Cancer Institute (NCI) Recruiting

Conditions: Cigarette Smoking; Nicotine Vaping Interventions: Behavioral: Promotion factors; Behavioral: Mitigation strategies Sponsors: Virginia Polytechnic Institute and State University; Medical University of South Carolina Recruiting

It is not yet known whether EVALI represents a widespread health risk that could affect millions of users or is isolated to certain products or practices. Whatever the case, thousands of people face severe health effects right now.

Today’s vaping clinical trials will be essential to the health of former and future e-cigarette users. Being aware of the potential risks of vaping – and making family and friends aware of those risks – is advisable as more information becomes available.

• https://www.centeronaddiction.org/e-cigarettes/recreational-vaping/what-vaping
• https://www.drugabuse.gov/publications/drugfacts/vaping-devices-electronic-cigarettes
• https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html
• https://www.cdc.gov/media/releases/2019/p1028-first-analysis-lung-injury-deaths.html
• https://rarediseases.info.nih.gov/diseases/9551/bronchiolitis-obliterans
• https://www.cdc.gov/mmwr/volumes/68/wr/mm6841e3.htm?s_cid=mm6841e3_w

Other Resources

• Guide to Clinical Trials for Alcohol
• Guide to Clinical Trials for Asbestos
• Clinical Trial Guide for Seniors and the Elderly
• Guide to Clinical Trials for Minorities
• Clinical Trial Guide for Parents and Children
• Guide to Clinical Trials for Pets
• Guide To Keeping Your Health Records Secure
• Clinical Trials on the Effects of Bullying
• Clinical Trials on the Positive Effects of Gardening and Experiencing Nature
• Clinical Trials on the Disaster Mental Health
• A Guide to Sleep and Clinical Trials
• A Guide to Clinical Trial Recruitment
• What is Clinical Research?
• Research Studies for Money

Secondhand e-cigarette vapor may pose risk to children: study

Researchers found that children in the study who were regularly around vaping had higher levels of metabolites, or substances, linked to chemicals found in e-cigarettes in their bodies.

We all know that secondhand cigarette smoke is a bad thing − the dangers of tobacco smoke exposure to children specifically have long been known to cause ailments from asthma attacks and infections to Sudden Infant Death Syndrome.

What we know less about, however, are the effects of prolonged exposure to electronic cigarette vapor. One set of researchers recently took to paving the way in hopes of eventually finding more answers.

A recent pilot study presented this month at the conference of the National Association of Pediatric Nurse Practitioners found that secondhand "smoke," or vapor from vaping and e-cigarettes may, in fact, impact the children in your life.

How researchers studied the effects of secondhand e-cigarette exposure

The study , conducted by researchers at Emory University’s Nell Hodgson Woodruff School of Nursing and Rollins School of Public Health, evaluated secondhand electronic cigarette exposure through multiple means in children aged 4 through 12.

The test group included 48 parent/child pairs, 22 of which included parents who vaped daily and 26 of which included parents who did not vape or smoke. Thirteen of the parents in the exposure group used both traditional and electric cigarettes.

Traditionally, blood tests are considered the standard for evaluating secondhand smoke impacts, but the team also used less invasive saliva testing and exhaled breath tests to determine what the children of vaping adults were exposed to. They then compared this to a control group of kids who were not regularly exposed to e-cigarette vapor.

Researchers found that children in the study who were regularly around vaping had higher levels of metabolites linked to chemicals found in e-cigarettes in their bodies. These can disrupt dopamine levels in the body, cause inflammation, and lead to cellular damage due to oxidative stress . This cellular damage is linked to numerous diseases like diabetes, heart disease and cancer.

"We identified several metabolites or substances that were significantly different between exposed and unexposed children," Jeannie Rodriguez, associate professor at Emory’s School of Nursing and lead author of the study, told USA TODAY. "Some of these substances are likely associated with the chemicals found in the e-liquid that the parent heats, inhales, and then exhales. Others that we found are associated with the creation and breakdown of dopamine, cell-damaging processes, and inflammation."

She said the study was exploratory and a preliminary setup for further research, meaning data was not collected on the actual occurrence or likelihood of any such conditions. However, its findings do set up a pathway for future studies that may explore and address these risks more specifically.

Menthol cigarette ban: Where does menthol cigarette ban stand? Inside the high-stakes battle at Biden's door.

Not a harmless cigarette alternative

With laws and regulations around traditional tobacco products becoming stricter, electronic cigarettes became more popular in the 2000s. Manufacturers have been criticized for marketing toward a younger audience, leading to legislation that bans flavors considered attractive to kids, and to people who are trying to quit smoking or looking for a "less harmful" way to consume tobacco.

E-cigarettes as we know them now were widely introduced to the U.S. in 2007 . By 2008, the World Health Organization (WHO) proclaimed that it did not consider electronic cigarettes a legitimate smoking cessation aid and demanded that manufacturers remove these claims from marketing materials at the time. By 2011, the U.S. Food and Drug Administration (FDA) announced it would regulate e-cigarettes like traditional cigarettes and tobacco products under the Food Drug and Cosmetics Act. Controversy and changing legislature around these topics have persisted.

“Many people who smoke have switched to using e-cigarettes, thinking it’s safer for them and others nearby,” Rodriguez said in a statement published by the college . “However, there are chemicals in the liquids used in a vape that are hazardous for you and those that you care about who are exposed to the vapors you exhale.”

Teens using THC: Teen delta-8 use rising, now equates to 1-2 students in average class size, study shows

Parents largely unaware that vaping causes secondhand exposure

After the study, a focus group of parents was informed of the findings. Many seemed surprised to hear just how harmful vaping around their children could be, according to researchers.

Of the parents who were vape users, more than half (11 of 19) shared that they thought vaping around their kids was a "minor health hazard or not a health hazard at all." Additionally, 12 of 22 parents who used these products said they did not know if exposure to electronic cigarette vapors was harmful to children, according to the research presentation.

Multiple parents shared that they had turned to vaping as a tool to lessen or stop the use of cigarettes, and more expressed a belief that vaping was overall healthier and safer than traditional tobacco use.

“The appeal for vaping is that, at least in my mind and I say this all the time to people that ask me, I say, vaping for me is probably about 95% better than smoking cigarettes," said one parent quoted in the findings. “For me, it seems it portrays itself as the healthier version," said another.

Others said that they believed their bodies felt better while vaping, leading them to think it was better overall, while others said that the simple power of addiction was what kept them turning to e-cigarettes.

There is not yet a consensus on secondhand electronic cigarette vapor exposure and its effects, as research in the area remains limited. In the meantime, however, Rodriguez said it's still worth exercising caution when vaping around your kids.

"With the increase in vaping, it is important for us to understand any health effects secondhand exposure may have, particularly on children," she said. "If parents are concerned about any potential health effects from secondhand vape exposure for their children, they should consult with their child’s pediatric health care provider and consider limiting the exposure until more is known."

Clarification: This story was updated to remove references to misconceptions about e-cigarettes that were not referenced in the study .

The town named the vape shop capital of the UK

Blackburn has more vape shops per person than anywhere else in Britain, according to new research.

The town ranks as the country’s vaping capital as it has the highest concentration of vape shops, according to Go Smoke Free, an online vape shop which conducted the research.

There are a total of 27 registered vape retailers serving its population of 119,707 residents, averaging 22.56 stores per 100,000 people.

Bolton came in second with 41 stores for 202,369 people, averaging 20.26 retailers per 100,000 residents.

Manchester ranks third with 110 shops in total, but the city’s larger population of 554,400 means this works out to 19.84 stores per 100,000 residents.

London came in 38th with 292 vape shops serving 8.9 million residents, averaging 3.28 retailers per 100,000 people.

Meanwhile, Oxford, with its population of 163,967 was at the bottom of the rankings with just one vape shop, equalling 0.61 stores per 100,000 people.

The research analysed Companies House records for active “vape” stores which were listed as “retail sale of tobacco products in specialised stores”.

A Go Smoke Free spokesman said: “Disposable vapes have gained popularity in recent years.

“The new disposable vape ban should help to discourage children from taking up vaping, while encouraging adults to shift to more sustainable alternatives, such as refillable vapes.”

It added: “This study highlights which areas of the UK are most likely to be affected by the upcoming disposable vape ban. 

“These cities could see a significant shift in their vaping culture, with the ban impacting consumer behaviour, and existing vape retailers adapting their offerings to cater to the new legislation.”

Disposable vapes are to be banned and other e-cigarettes will be placed behind shop counters as part of the Government’s efforts to stop children becoming addicted .

The ban on disposable vapes could come into force as soon as this year or early next year at the latest.

Single-use e-cigarettes are available for as little as £3 each, sparking fears that children have been lured into the habit by “pocket money” prices.

Ministers are seeking to draw up measures which will stop children from taking up the habit, while ensuring that they do not deter the use of e-cigarettes as a route to quit smoking .

The plans will also involve a crackdown on the marketing and flavours of vapes and could see increased taxes placed on them.

A Cancer Research UK study found that between January 2021 to August 2023, the prevalence of disposable e-cigarette use grew from 0.1 per cent to 4.9 per cent of the adult population.

The proportion of those aged 18 to 24 using disposable vapes was significantly higher at 14.4 per cent, including 7.1 per cent who did not have a history of smoking tobacco.

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