Foster  Substance Abuse Treatment,

Substance Abuse Treatment, Prevention, and Policy (2023) 18:67

https://doi.org/10.1186/s13011-023-00571-w Prevention, and Policy

REVIEW Open Access

Consideration of vaping products

as an alternative to adult smoking: a narrative
review
Jane A. Foster1*

Abstract
Tobacco harm reduction is a public health approach to reduce the impact of cigarette smoking on individuals.
Non-combustible alternatives to cigarettes, such as electronic cigarettes (e-cigarettes), deliver nicotine to the user
in the absence of combustion. The absence of combustion in e-cigarettes reduces the level of harmful or potentially
harmful chemicals in the aerosol generated. This narrative review examines the published literature that studied
the chemistry of e-cigarette aerosols, the related toxicology in cell culture and animal models, as well as clinical stud-
ies that investigated short- and long-term changes in biomarkers of smoke exposure after switching to e-cigarettes.
In the context of the literature reviewed, the evidence supports the harm reduction potential for adult smokers who
switch to e-cigarettes.
Keywords Vaping, Non-combustible alternatives, Harm reduction, Electronic cigarette, Smoking

Background tobacco to generate a tobacco vapor that delivers nico-

While smoking rates have decreased steadily over the tine to the user (for review, [3]). Oral nicotine products
past 20 years, approximately 22% (just less than 1 bil- deliver nicotine mainly by absorption through the user’s
lion) of people aged 15 + worldwide smoke cigarettes, oral mucosa and include forms with and without tobacco
and smoking-related diseases accounted for 8.7 million (e.g., Snus and nicotine pouches, respectively) [4]. The
deaths worldwide in 2019 [1]. Tobacco harm reduction is non-combustible category of e-vapor products or elec-
a public health approach to reduce the harm associated tronic cigarettes (e-cigarettes) do not contain tobacco;
with smoking cigarettes. This approach provides smokers they deliver nicotine to the user when a liquid is heated
who do not quit with less harmful nicotine delivery prod- to form an aerosol (vapor) [4]. This literature review
ucts [2]. Non-combustible alternatives include heated focused on this last type of non-combustible category:
tobacco products, nicotine-containing e-vapor prod- e-cigarettes and examined the scientific evidence that
ucts, and oral nicotine products can serve as options for investigates whether switching from combustible ciga-
adult smokers who switch to these alternatives and stop rettes to e-cigarettes has the potential to improve health
smoking. Heated tobacco products are non-combustible outcomes for adult smokers.
alternatives with electronic heating elements that heat In the past 5 years, attention to e-cigarettes has
increased with approximately 9300 peer-reviewed stud-
ies on the topic of vaping products (or e-cigarettes), as
*Correspondence: well as more than 650 review articles (Web of Science,
Jane A. Foster
[email protected] “e-cigarette,” May 2023). Within the broad scope of
1
Department of Psychiatry & Behavioural Neurosciences, St. Joseph’s research topics in the literature, the papers selected for
Healthcare, 50 Charlton Ave. E., Hamilton, ON L8N 4A6, Canada this review focused on e-cigarettes in the context of key

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Foster S ubstance Abuse Treatment, Prevention, and Policy (2023) 18:67 Page 2 of 10

topics related to tobacco harm reduction, including aero- are now available worldwide (https://​gsthr.​org). E-ciga-
sol chemistry studies, toxicological assessments of e-cig- rette use has increased in the past decade – there were
arette aerosols with in vitro and in vivo in comparison to approximately 58 million e-cigarette users worldwide in
cigarette smoke, and clinical investigations that examined 2020, representing 7.1% of the total population, and a
the short- and long-term benefits of switching to e-ciga- sizeable increase from 1.7% estimated in 2012 [48].
rettes for adult smokers (Table 1). By focusing on studies
that compare e-cigarettes to cigarettes, the objective of Toxicological assessment of e‑cigarette aerosol
this review is to provide the reader with the current evi- Cigarette smoke contains more than 6000 constituents
dence related to the potential health benefits for smok- [49], many of which are considered harmful or poten-
ers if they switch to e-cigarettes. Notably, it is important tially harmful chemicals (HPHCs). Different regulatory
to understand the research evidence on the effects of authorities including the World Health Organization,
switching from combustible cigarettes to e-cigarettes at Health Canada, and U.S. FDA have established lists of
several levels. HPHCs that contribute to smoking-related diseases and
should be considered in non-combustible alternative
E‑cigarettes/e‑vapor products evaluation [8]. It is well-established that combustion of
History tobacco generates high levels of HPHCs that increase
While e-cigarettes are common and most individuals health risks and contribute to smoking-related diseases
have some knowledge related to e-cigarettes, there are a [50]. A key feature of reduced risk products (RRPs), such
lot of misconceptions and the history of their develop- as e-cigarettes, is that these devices deliver nicotine to
ment is not well known. The first e-cigarette was sold the user in the absence of combustion and hence were
in China in 2004, but the history of its development designed to reduce exposure to HPHCs compared to cig-
goes back to 1927 with the U.S. patent of an “electrical arette smoke [51]. Investigations reviewed here assessed
vaporizer” by Joseph Robinson [46]. Other milestones in whether switching to e-cigarettes present less risk than
e-cigarette/e-vapor product development are depicted smoking: 1) compare the constituents of the aerosol from
in Fig. 1 and include the 1963 patent by Herbert Gilbert e-cigarettes to cigarette smoke, 2) examine the toxicity
for a “smokeless non-tobacco cigarette.” In 1979, Phil Ray of aerosols in vitro using tissue culture approaches and
and Norman Jacobson conducted a clinical trial to test in vivo using animal studies, 3) measure HPHC levels in
the feasibility of inhaling nicotine without smoke and blood and urine from individuals who switch to e-ciga-
coined the term “vaping” [46]. In 1985, Advance Tobacco rettes and compare them with values in adult smokers,
Products Inc. commercialized a version of Ray/Jacobson’s and 4) compare clinical biomarkers of exposure that are
device called “Favor,” but it was banned by the U.S. Food known risk factors for smoking-related diseases in indi-
and Drug Administration (FDA) in 1987 [46]. The mod- viduals who switch to e-cigarettes and those who con-
ern form emerged with the 2003 patent by Hon Lik for a tinue to smoke cigarettes.
nicotine delivery system that vaporized liquid to deliver Aerosol chemistry studies have shown reduced HPHC
nicotine to the user in an aerosol, leading to sales of the levels in some e-cigarette aerosols compared to cigarette
first e-cigarette in 2004 in China [46]. The technology of smoke [5–7, 9]. Notably, Ruyan, the company that mar-
this first device is different from current devices on the keted the first e-cigarette in China, reported reduced lev-
market, but all of them use heat to vaporize a liquid and els of several known HPHCs in their 2008 safety report
generate a nicotine-containing aerosol. [52]. It is important to note the standard lab methodolo-
gies for assessing e-cigarette aerosols have continued to
Types of e‑cigarettes be developed in the past decade, and many recent stud-
There are three types of e-cigarettes on the market today: ies use the standards published in the CORESTA E-cig-
disposable self-contained devices, refillable devices, and arette Task Force Technical Report [53]. Across several
pod-based devices (Fig. 2). Among these subcategories, studies, levels of carbonyls and tobacco-specific nitrosa-
there are numerous different devices and a wide range of mines were reduced by more than 90%. For example, the
e-liquid compositions, which makes generalization and level of the carcinogen N-nitrosonornicotine (NNN) was
comparison challenging. While the main components detected at 0.05 ng/puff for an e-cigarette compared to
are similar, it is important to note that some devices are 24.9 ng/puff for a reference cigarette [6]. A recent report
closed, whereas others have open systems that allow the measured a panel of carbonyl compounds, such as acet-
user to add their own e-liquids. The broad range of e-cig- aldehyde, acrolein, and formaldehyde, and polycyclic
arette devices and designs has resulted in regulatory chal- aromatic hydrocarbons classified as carcinogenic or
lenges. Following their initial sale in China, e-cigarettes possibly carcinogenic in the aerosols from three e-cig-
were distributed in Europe and the U.S. in 2006 [47] and arette products in comparison to cigarette smoke [9].
Foster Substance Abuse Treatment, Prevention, and Policy (2023) 18:67 Page 3 of 10

Table 1 Research studies ­citeda

Year Design Main Findings Reference

2014 Aerosol Chemistry Reduced levels of HPHCs in aerosol from e-cigarette compared to cigarette smoke [5]
2016 Aerosol Chemistry Reduced levels of HPHCs in aerosol from e-cigarette compared to cigarette smoke [6]
2020 Aerosol Chemistry Reduced levels of HPHCs in aerosol from e-cigarette compared to cigarette smoke [7]
2021 Aerosol Chemistry Reduced levels of HPHCs in aerosol from e-cigarette compared to cigarette smoke [8, 9]
In vitro toxicology No significant or low cytotoxicity of e-cigarette aerosol on human bronchial epithelial BEAS-2B [9]
cell line
2018 Aerosol Chemistry Low levels of aromatic amines, volatile organic compounds, polycycli aromatic hydrocarbon [10]
benzo[a]pyrene in e-liquid and aerosol
2020 Aerosol Chemistry Emission levels for most HPHCs were not detectable in 34 commercially available e-cigarettes. [11]
Carbonyls including formaldehyde were detected but variable across devices
2014 In vitro toxicology No cytotoxicity following exposure to e-cigarette aqueous extracts in human lung epithelial [12]
carcinma cells A549. No mutagenic effects in Ames test. No mutagenic effects in micronuclease
assay using chinese hamster ovary cells CHO-K1
2020 In vitro toxicology No mutagenic effect in Ames test and no genotoxicity in in vitro micronuclease assay follow- [13]
ing exposure to e-liquids and aerosols. Reduced cytotoxicity of e-cigarette aerosol compared
to tobacco smoke
2016 In vitro toxicology Reduced cytotoxicity in human lung epithelial cells following exposure to e-cigarette aerosol [14]
compared to tobacco smoke
2017 In vitro toxicology Compared several e-cigarettes for cytotoxicity and detected both cytotoxic and non-cytotoxic [15]
effects
2016 Cellular and Molecular Changes No impact of exposure to e-cigarette aerosol on endothelial cell migration compared to cigarette [16]
smoke
2017 Cellular and Molecular Changes No oxidative stress in human bronchial epithelial cells exposed to e-cigarette aersol extracts [17]
2016 Cellular and Molecular Changes No activation of oxidative stress pathways in human coronary artery endothelial cells in response [18]
to e-cigarette aerosol compared to cigarette smoke
2019 Cellular and Molecular Changes No tissue damage to buccal and small airway cultures, and no impact on cilia beat in small airway [19]
cultures following exposure to e-cigarette aerosol. Increased expression of inflammatory genes
in buccal cells exposed to e-cigarette aerosols
2019 Cellular and Molecular Changes Reduced levels of oxidative stress from exposure to e-cigarette aerosol compared to tobacco [20]
smoke on human bronchial epithelial cells. Increased expression of inflammatory mediators
2019 Cellular and Molecular Changes No effect of e-cigarette aerosol on airway epithelial morphology or barrier viability. No difference [21]
in immune activation between air exposure and e-cigarettee aerosol exposure
2021 Cellular and Molecular Changes Biological impact of exposure to e-cigarette reduced in comparison to cigarette smoke includ- [22]
ing histology, cytotoxicity, cellular function, and gene expression
2017 Cellular and Molecular Changes Reduced impact of exposure to e-cigarettes on gene expression compared to cigarette smoke [23]
2020 Cellular and Molecular Changes Similar effect of e-cigarette aerosol and cigarette smoke on barrier integrity of airway epithelial [24]
cells. No imact on cilia beat frequency in response to exposure to e-cigarette aerosol
2016 Cellular and Molecular Changes Differential changes in gene expression in response to exposure to e-cigarette aerosol compared [25]
to cigarette smoke. Alterations in glycerophospholipid biosynthesis noted in response to e-ciga-
rette aerosol exposure
2017 Cellular and Molecular Changes Reduced cellular and gene expression effects in human bronchial epithelial cells following expo- [26]
sure to e-cigarette aerosol compared to cigarette smoke
2020 Cellular and Molecular Changes Increased salivary inflammatory mediator levels in e-cigarette users compared to non-users [27]
2017 Cellular and Molecular Changes Reduced bronchial epithelial function in response to exposure to both cigarette smoke and e-cig- [28]
arette aerosols
2020 Cellular and Molecular Changes Impaired in vivo (rats) endothelial function in response to exposure to e-cigarette aerosol [29]
2016 Cellular and Molecular Changes Reduced toxic effects of acute e-cigarette aerosol exposure in C57Bl/6 J mice compared to ciga- [30]
rette smoke
2021 Cellular and Molecular Changes Increased levels of fibronectin as a measure of tissue injury in B6C3F1 following exposure [31]
to e-cigarette aerosol compared to cigarette smoke
2020 Cellular and Molecular Changes Exposure to e-cigarette aerosol did not change ceramide profiles or related enzymes in ApoE-/- [32]
mice
2020 Cellular and Molecular Changes Long term (6 month) exposure to e-cigarette aerosol did not compromise bone integrity in ApoE- [33]
/- mice
2021 Cellular and Molecular Changes Reduction effect of exposure to e-cigarette aerosol on lung function and gene expression [34]
in ApoE-/- mice compared to cigarette smoke
Foster S ubstance Abuse Treatment, Prevention, and Policy (2023) 18:67 Page 4 of 10

Table 1 (continued)
Year Design Main Findings Reference

2020 Cellular and Molecular Changes Reduced biological response to exposure to e-cigarette aerosol in ApoE-/- mice compared to ciga- [35]
rette smoke
2020 Cellular and Molecular Changes Similar effect of e-cigarette aerosol and cigarette smoke on oxidative stress and inflammation [36]
related to fibrosis
2020 Cellular and Molecular Changes Comparable changes in gene expression in Balb/C mice following exposure to e-cigarette aerosol [37]
or cigarette smoke
2021 Cellular and Molecular Changes Activation of nicotine-related gene expression in brains of mice exposed to e-cigarette aerosol [38]
2015 Biomarkers of Exposure Reduced levels of carbon monoxide, nicotine, and acrolein in urine from individuals after switch- [39]
ing to e-cigarettes from combustible cigarettes
2017 Biomarkers of Exposure Reduced levels of biomarkers of exposure in urine samples from individuals after switching [40]
to e-cigarettes from combustible cigarettes
2018 Biomarkers of Exposure Nicotine-related in saliva were comparable between e-cigarette users and cigarette users. Urine [41]
levels of nicotine were not detectable in e-cigarette users
2021 Biomarkers of Exposure No metal detected in the hair samples of e-cigarette users [42]
2021 Biomarkers of Exposure Significant reduction in levels of biomarkers of exposure in cigarette users who switched [43]
to e-cigarettes. Also reduced in dual users
2017 Biomarkers of Exposure Reduced blood and urine levels of toxicants in individuals that switch from combustible cigarettes [44]
to e-cigarettes
2021 Biomarkers of Exposure Reduced urine levels of NNAL in individuals who switched from combustible cigarettes to e-ciga- [45]
rettes. Also reduced in dual users
HPHC harmful or potentially harmful chemicals, ApoE apolipoprotein E-deficient
a
reviews cited are not included in this table

In this study, all of the carbonyl compounds measured attention. E-liquids contain a mixture of propylene gly-
were at very low levels in the e-cigarette aerosols; show- col, vegetable glycerin, nicotine, flavors, and other con-
ing a 99% reduction in total carbonyl content compared stituents. A recent study examined 34 commercially
to cigarette smoke [9]. Similarly, there was a 92–99% available e-cigarette devices and demonstrated that lev-
reduction in total polycyclic aromatic hydrocarbons in els of carbonyls, but particularly formaldehyde, varied
e-cigarette aerosols compared to cigarette smoke [9]. In across devices, whereas other HPHCs and selected met-
a separate study, a comprehensive analysis of combus- als were undetectable or very low in the e-cigarette aero-
tion-related HPHCs, including aromatic amines, volatile sols [11]. The presence of carbonyl compounds, such as
organic compounds, and polycyclic aromatic hydrocar- formaldehyde, in e-cigarette aerosols results from the
bon benzo[a]pyrene, in e-liquids and their aerosols from heated degradation of e-liquid components (e.g., propyl-
commercially available e-cigarettes in the U.S. demon- ene glycol and glycerin) and depends on device features
strated that most of these HPHCs were at very low or (e.g., closed vs open systems) and device settings (e.g.,
below detectable levels in e-liquids or e-cigarette aero- heating temperature and voltage) and result in higher
sols [10]. Part of the difficulty for the consumer and the HPHC levels in e-cigarette aerosols from some devices
non-expert scientist stems from the fact that there are [11, 56–59].
so many different devices on the market, not all research Understanding the toxicology of HPHCs in biologi-
study results apply to every device that is available. The cal systems is an essential component of assessing their
above-noted reports provided evidence of reduced levels risks and benefits. To this end, several investigations have
of HPHCs in e-cigarette aerosols compared to cigarette examined the toxicity of e-cigarette aerosols in tissue
smoke, others have raised concerns about the levels of cultures and animal models. The results of these stud-
carbonyl compounds such as acetaldehyde, acrolein, and ies fall into three categories for discussion: 1) no toxicity
formaldehyde in aerosols generated by heating e-liquids, observed, 2) less toxicity compared to cigarette smoke,
as well as metals that may be released from the device and 3) alternative or negative findings.
components [8, 54, 55]. These factors are important to
consider and may represent risks associated with e-cig- In vitro studies
arette use more generally. Moreover, potential risks of Several studies using tissue culture approaches
excipients in e-liquids and additional potentially harmful reported no toxicity following exposure to e-cigarette
chemicals generated from e-liquid heating have garnered aerosol, in comparison to the toxic effects observed
Foster Substance Abuse Treatment, Prevention, and Policy (2023) 18:67 Page 5 of 10

Fig. 1 The history of the e-cigarette. Innovation and invention over the past century leading to the development of e-cigarettes, which were first
sold in China in 2004. The timeline highlights some landmark events that contributed to the development of modern e-cigarettes (based on [46])

in the same systems following exposure to cigarette buccal and airway epithelial cultures exposed to e-cig-
smoke. Using an in vitro smoke/aerosol exposure sys- arette aerosol compared to alterations observed fol-
tem, exposure to e-cigarette aerosol from two com- lowing exposure to cigarette smoke [9, 19–22]. The
mercial e-cigarettes had no mutagenic (Ames assay) or above-noted studies showed no detrimental impact of
genotoxic effects (micronucleus assay) [12, 13]. Another e-cigarette aerosol exposure on the cultures. Additional
group performed scratch wound assays and reported studies have demonstrated lower toxicity of e-cigarette
no impact of e-cigarette aerosol on endothelial cell aerosol compared to cigarette smoke. Significantly
migration, compared to concentration-dependent inhi- reduced (94–99%) cytotoxicity in human bronchial
bition following exposure to cigarette smoke [16]. The epithelial cells, measured using the neutral red uptake
same group measured intracellular glutathione ratios, assay, was observed following exposure to e-cigarette
oxidant species generation, and activation of nuclear aerosols compared to cigarette smoke [13, 14]. Ciga-
factor erythroid-related factor 2 (Nrf2)-controlled anti- rette smoke negatively impacts airway epithelial cell
oxidant response elements and did not detect oxidative function in vitro [23]. Exposure to e-cigarette aerosol
stress in human bronchial epithelial cells exposed to did not impact cilia beat frequency in airway epithelial
e-cigarette aerosol extracts, whereas significant oxida- cells, but it did affect barrier integrity measured with
tive stress was found in cultures exposed to cigarette trans-epithelial electric resistance (TEER), albeit to a
smoke [17]. Similarly, activation of the oxidative-stress lower degree than cigarette smoke [22, 23]. A separate
related transcription factor Nrf2 and cytochrome p450 study showed a significant impact of e-cigarette aero-
family member genes was observed in human coro- sol on TEER following 10 days of exposure (compared
nary artery endothelial cells in response to cigarette to 24–48 h in the Haswell study) that was similar to
smoke but not e-cigarette aerosol [18]. Several reports cigarette smoke, suggesting that longer-term exposure
described no tissue damage or molecular changes in to e-cigarette aerosol may have an impact on epithelial
Foster S ubstance Abuse Treatment, Prevention, and Policy (2023) 18:67 Page 6 of 10

Fig. 2 E-cigarette types. Schematics showing the design of disposable, refillable, and pod-based e-cigarettes. (Reproduced with permission
from Elsevier [4])

barrier function [24]. Differential gene expression anal- physiological systems [28, 29]. However, in the con-
yses in donor-derived differentiated airway epithelial text of tobacco harm reduction, the collective evidence
cells exposed to air, 3R4F smoke, or e-cigarette aerosol from numerous assays supports the hypothesis that
revealed that smoke induced significant upregulation of e-cigarette aerosols are less toxic than cigarette smoke.
873 RNAs associated with fibrosis, DNA damage sign-
aling, oxidative stress response, and lung cancer [23]. In vivo studies
In contrast, 113 differentially expressed RNAs were Animal studies provide important results regarding the
identified as responsive to the highest concentration of biological impact of HPHCs on host systems. Investiga-
e-cigarette aerosol, but only 3 exceeded a fold change tors have examined the effects of e-cigarette aerosols on
of 2 [23]. Similar findings were observed using RNA- key indicators in animal models known to be affected
sequencing in differentiated human bronchial epithelial following exposure to cigarette smoke, including tis-
cells and a human bronchial epithelial cell line [20, 25, sue histology, gene expression, cardiovascular function,
26]. Notably, a negative impact of e-cigarette aerosol on oxidative stress, and inflammation [30–38, 60]. Mice
inflammatory processes in the cell lines was observed exposed to e-cigarette aerosols showed a reduced level
in one of these studies [20]. The potential for e-cigarette of lung inflammation and a lower impact on cell prolif-
use to impact inflammation was recently demonstrated; eration compared to the cigarette smoke-exposed group
e-cigarette users (including those who also used mari- [30]. In contrast, Sun and colleagues reported a compara-
juana) had higher salivary inflammatory mediator levels ble or greater number of histological lung lesions in mice
compared to non-users [27]. Another group reported exposed to e-cigarette aerosols versus cigarette smoke; an
that exposure to e-cigarette aerosol was associated effect that was suggested to be associated with the acute
with cytotoxicity in human pulmonary fibroblasts, lung increase in oxidative stress [31]. Atherosclerosis-prone
epithelial cells, and stem cells, but the authors did not apolipoprotein E-deficient (Apoe-/-) mice are used as an
include a cigarette smoke group for comparison [15]. animal model of atherosclerosis and more generally for
In vitro studies reported impaired endothelial function understanding the pathophysiology of cardiovascular dis-
and reduced epithelial function following exposure to eases [60]. A recent series of studies in this model system
both e-cigarette aerosol and cigarette smoke compared demonstrated reduced cardiovascular effects from expo-
to air, underscoring that e-cigarette aerosol can impact sure to e-cigarette aerosol compared to cigarette smoke,
Foster Substance Abuse Treatment, Prevention, and Policy (2023) 18:67 Page 7 of 10

as well as smaller effects on biomarkers of exposure no metals were detected in hair samples of e-cigarette
[32–35]. Long-term exposure up to 6 months yielded users [42].
the expected negative effects of cigarette smoke on lung Clinical studies have also been undertaken to measure
histology and function, as well as molecular or inflamma- biomarkers of exposure that are known risk factors for
tory changes. Conversely, no differences in lung function smoking-related diseases in individuals who switch to
or histopathological changes were observed following e-cigarettes compared to those who continue to smoke
exposure to e-cigarette aerosol, and less lung inflamma- cigarettes. Biomarkers of exposure provide quantifi-
tion was observed in Apoe-/- mice [34, 35]. In contrast, able measures of biological changes in individuals who
Ponzoni and colleagues reported similar alterations in smoke. Assessing changes in these biomarkers in indi-
gene expression in mice exposed to e-cigarette aerosol viduals who switch to RRPs is central to demonstrat-
or cigarette smoke [37]. Another group reported greater ing the potential for harm reduction for the individual.
negative cardiac effects in rats exposed to e-cigarette Blood carboxyhemoglobin—a biomarker for the HPHC
aerosols compared to cigarette smoke [36]. One recent carbon monoxide—was reduced by 70–97% as soon as
study found a significant impact of long-term exposure to 5 days after switching to e-cigarettes [43, 44]. Notably,
e-cigarette aerosol on nicotine levels and nicotine-related 14 of the 23 biomarkers of exposure were significantly
gene expression in the mouse brain compared to air (no reduced in adults who switched to e-cigarettes com-
comparison to smoke), highlighting the importance of pared to their baseline levels measured when they were
determining the potential risks associated with contin- smoking cigarettes [43, 44]. Another study demonstrated
ued use of nicotine over time [38]. Certainly, longitudinal reduced urinary levels of 4-(methylnitrosamino)-1-(3-
studies are needed to clarify the acute effects of e-ciga- pyridyl)-1-butanol (NNAL) in smokers who switched
rette aerosols. to e-cigarettes exclusively, as well as in dual users who
reduced the number of combustible cigarettes over the
Clinical studies
24-week study [45]. The results of clinical studies show-
Beyond cell culture and animal studies, it is critical to ing reduced levels of HPHCs and biomarkers of expo-
measure HPHC levels in human biospecimens such as sure in adult smokers who switch to e-cigarettes provide
saliva, blood, and urine to provide critical evidence of a base of evidence of the role these products can play in
the potential for reduced risk for adult smokers who tobacco harm reduction.
completely switch to e-cigarettes. Using a within-sub- User surveys suggested that the benefits of using of
ject study design, biomarkers of exposure, including e-cigarettes by smokers included less cigarette con-
carbon monoxide, nicotine, and acrolein, were meas- sumption, help with smoking cessation, and reduced
ured in urine from smokers before and after switch- craving and withdrawal symptoms [61, 62]. A recent
ing to e-cigarettes. The results showed reduced levels study examined the safety profile of e-cigarette use over
of all biomarkers at 4 weeks after switching, as well as a 2-year period and demonstrated reduced exposure to
reduced levels in dual users who did not completely HPHCs, and use was not associated with any clinical
switch to exclusive e-cigarette use [39]. In a similar health concerns including lung function and nicotine
study, an examination of 7 nicotine metabolites and 17 withdrawal effects [63]. However, other clinical studies
HPHCs in urine of smokers before and 2 weeks after investigating short-term effects on cardiovascular and
switching to e-cigarettes revealed that nicotine and lung function in e-cigarette users highlighted poten-
some polycyclic aromatic metabolites remained the tial risks associated with e-cigarette use. One study
same after 2 weeks; however, levels of most HPHCs examined vascular function, which is associated with
were significantly decreased [40]. In a cross-sectional cardiovascular disease, was similar between cigarette
study that focused on HPHCs in salivary and urine smokers and sole e-cigarette users [64]. Another study
samples, detected salivary levels of N1-nitrosonornico- showed similar increased levels of heart rate variability
tine (NNN) in e-cigarette users overlapped with those in cigarette and e-cigarette users, but acute blood pres-
measured in cigarette smokers, but urine levels of NNN sure increases observed in cigarette smokers were not
were very low or not detectable in e-cigarette users found in e-cigarette users [65]. In contrast, Barna and
[41]. As noted above, concern about exposure to met- colleagues demonstrated that e-cigarette use had no
als from the metallic heating device in e-cigarettes war- effect on respiratory function measured as persistent
rants attention. A study that detected metals in e-liquid alveolitis, which was evident in cigarette smokers [66].
and aerosols from e-cigarettes reported increased levels Importantly, individual differences in smoking behavior
of copper, chromium, tin, and lead in urine of e-ciga- and other lifestyle factors need to be considered when
rette and dual users compared to non-users; however, assessing the risks and benefits of e-cigarette use.
Foster S ubstance Abuse Treatment, Prevention, and Policy (2023) 18:67 Page 8 of 10

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NNAL 4-Methylnitrosamino)-1-(3-pyridyl)-1 butanol
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NNN  N1-Nitrosonornicotine
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Nrf2 Nuclear factor erythroid factor 2
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