An e-cigarette user will regularly inhale a mixture of chemicals into their lungs. This mixture contains very low concentrations of numerous chemicals that are known to cause cancer. A heavy user may inhale these chemicals multiple times a day, every day, for many years. It is currently unknown whether this extent of exposure is sufficient to cause cancer. However, there are signs of cellular damage and biomarkers of exposure to cancer-causing chemicals in e-cigarette users that have led to concern that e-cigarettes may cause cancer in some users.
Cancer is a condition that often arises 20 years or more after the initiation of tobacco use. Since e-cigarettes are a relatively new product, becoming popular after 2010 (see Section 18.1.1.2), the vast majority of users have not been exposed for this length of time. A comprehensive Australian review has found no prospective studies of sufficient quality on which to assess the risk of cancer for e-cigarette users.1,2
The current lack of epidemiological evidence for the causation of cancer by e-cigarettes cannot be taken to mean that e-cigarette use is not able to cause cancer. Assessing such risk will take a longer timeframe than is possible given the recent introduction of e-cigarettes to the market.
Studies of the long-term risk of cancer from e-cigarette use are hampered by a number of issues:
- The relatively short period of time that e-cigarettes have been used,
- Many e-cigarette users have a history of smoking,
- Rapid changes in the types of e-cigarette devices, their modes of use and e-liquid composition mean that previous studies may not reflect the risks of contemporary and future e-cigarette use.
A number of lines of evidence support the biological plausibility that long-term exposure to e-cigarette aerosols could increase the risk of cancer. There are chemicals present at low concentrations in e-cigarette aerosols are capable of causing DNA damage and mutagenesis.3 Some experiments using laboratory-grown cells show that e-cigarette chemicals can induce damage. Biological samples from e-cigarette users have been found to contain evidence of various toxic compounds at levels higher than in non-users. However it is unknown whether they are high enough to significantly increase risk of cancer.4 These studies elicit a cause for concern that e-cigarette use may lead to cancer in the long term.
18.6.4.1 Chemicals in e-cigarettes that may cause cancer
A number of carcinogens (chemicals that are known causes of cancer in humans and/or animals) have be found in e-liquids and/or the aerosols from e-cigarettes. Most of these chemicals are present at low levels in e-cigarette emissions, considerably lower than those found in tobacco smoke.5-7 See Section 18.5.5.4 for a discussion of the health concerns of the chemicals found in e-cigarettes.
It is currently unknown whether the doses of carcinogens in e-cigarettes are sufficient to cause cancer after long term inhalation exposure of users.
The carcinogens found in e-cigarettes include benzo[a]pyrene, acrolein, arsenic, benzene, cadmium, formaldehyde, styrene and toluene (see Table 18.5.1).8,9 Compared with tobacco smoke, e-cigarette emissions have much lower concentrations of most carcinogens.5-7 A study that detected carcinogenic aldehydes and polycyclic aromatic hydrocarbons (PAHs) in e-cigarette aerosols found that these chemicals were present at much lower concentrations compared to heated tobacco products and conventional cigarettes. For example, the highest powered of the three e-cigarettes in this study produced 64.5 ng of formaldehyde per puff compared to 156.9 ng from the heated tobacco product and 255.5 ng from the cigarette. Benzo[a]pyrene, a carcinogenic PAH, was detected at only 1.1 pg per puff compared to 25.6 pg from the heated tobacco product and 457 pg from the cigarette (noting that pg refers to picogram, which is 1/1000 th of a nanogram and one millionth of a microgram).
A number of studies and major reviews predict that the presence of toxic metals in e-cigarettes may be at a similar or even higher level than in conventional cigarettes, which may pose a risk for cancer.6,10-12
In terms of nicotine exposure, the US Surgeon General’s most recent report concluded that there is insufficient data to conclude that nicotine causes or contributes to cancer.13 However, the International Agency for Research on Cancer Advisory Group has recommended that nicotine’s potential as a carcinogen be reassessed as a matter of high priority, because of increased population exposure to nicotine from e-cigarettes, and recent mechanistic data that ‘suggest an association with DNA damage and other pathways of carcinogenesis.’14
18.6.4.2 Effects of e-cigarettes on cells grown in laboratories
Results from some experiments exposing cells grown in laboratories to e-cigarette chemicals are consistent with promotion of the type of damage that triggers cancer. But this evidence comes from artificial systems and its relevance to human exposure is uncertain.
One experiment has shown that exposure of lung lining cells to e-cigarette aerosols can induce pre-cancerous changes to the cells, indicating the possibility that these chemicals could contribute to the development of lung cancer.15 E-liquids also have detrimental effects on oral cells grown in the laboratory. Some types of flavoured e-liquids were able to cause cellular and DNA damage consistent with the types of damage that could trigger cancer.16
Other studies of lung cells grown in the laboratory have shown that exposure to e-cigarette chemicals can lead to oxidative stress17,18 (cellular damage that may lead to cancer) and genotoxicity17,19 (leading to mutations in the DNA sequence that increase the risk of cancer).
Treatment of lung cancer cells with e-cigarette chemicals has been shown to increase the rate of a phenomenon called epithelial-to-mesenchymal transition20 - considered a first step in the transition to metastasis (the spreading of cancer).
18.6.4.3 Effects of e-cigarettes on experimental animals
Some experimental studies in rodent models of disease indicate the potential of e-cigarette exposure to trigger lung tumour growth, consistent with a risk for cancer in humans.
Mice exposed to e-cigarette aerosols for 12 weeks sustained DNA damage in lungs, heart, and bladder cells and diminished DNA repair (a situation that can promote the development of cancer) in the lungs.21 After 54 weeks of exposure, nine out of 40 mice developed lung cancer tumours (adenocarcinoma) and 23 developed a precancerous bladder condition (bladder urothelial hyperplasia).22
In another study, rats exposed to the chemicals from e-cigarettes over four weeks showed signs of toxicological damage. These effects included oxidative damage and genotoxic damage, which may increase the risk of cancer developing. However, tumour growth in these animals was not reported.23 Another study has demonstrated that e-cigarette exposure resulted in oxidative stress in the lungs and liver in mice.17 Genotoxic effects, however, were not seen in these mice, even after six months of exposure.17
18.6.4.4 Biomarkers of damage and cancer risk in e-cigarette users
A biomarker, in the case of e-cigarette use, is a substance in the body that can be measured to indicate exposure to specific chemicals from e-cigarettes. Biomarkers of exposure might be detected in people’s breath, saliva, urine, blood and other samples. Biomarkers may also indicate damage—or the potential for damage—to human systems, and may predict the risk of disease. Biomarkers of e-cigarette exposure and damage are described in more detail in Section 18.5.6.
While biological samples from e-cigarette users can contain biomarkers for various carcinogens and toxic compounds at levels higher than non-users, it is unknown whether they are high enough to significantly increase risk of cancer.4 Furthermore, these chemicals may have entered the body from other sources of pollution, aside from e-cigarettes.
Biomarkers of carcinogens that are associated with bladder cancer have been found in the urine of e-cigarette.24 E-cigarette users, compared to non-users, had elevated levels of acrolein-DNA adducts in their mouths. These adducts consist of acrolein bound to DNA, which indicates a risk of DNA damage from this carcinogen.25
Biomarkers of exposure to toxic chemicals, including carcinogens, were detected in samples from wave 1 (2013-2014), of the Population Assessment of Tobacco and Health (PATH) Study.26 This is a nationally representative, prospective study from the US. People who exclusively used e-cigarettes had higher levels of biomarkers for the carcinogens NNK (4-(Methylnitros-amino)-1-(3-pyridyl)-1-butanone), lead, cadmium and acrylonitrile than never-users. But e-cigarette-only users had lower levels of the carcinogens NNK, cadmium, acrylonitrile and acrolein than tobacco users.26 A drawback from this study is that the types of e-cigarettes used in 2013-2014 may not be similar to contemporary e-cigarettes. See Section 18.5.6 for more detail about carcinogen biomarkers in e-cigarette users.
18.6.4.5 Risk of cancer for e-cigarette users
Given the relatively short time frame in which e-cigarette use has been popular, there is insufficient time for the type of studies that are required to provide high-quality estimates of the cancer risks of e-cigarette use. A major Australian review has found that no long-term prospective studies of the kind necessary for predicting the long-term risks of cancer had at that point (2021) been completed anywhere in the world. This authors of this review concluded that therefore there was no available evidence one way or the other on the relationship of e-cigarette use to the long-term risk of invasive cancer risk or precancer/subclinical cancer outcomes.1,2
One short-term prospective study has measured self-reported health outcomes for 343 people who used e-cigarettes only, 693 who used tobacco and 319 dual users. There was no significant difference in the rates of cancer diagnosis after two years of follow-up in the study that will run for five years.27 However, the limited time-frame and sample size means this study may not be informative about long-term cancer risk.27
18.6.4.6 Attempts to predict the risk of cancer from e-cigarette use
Some studies have used toxicological data to predict the risk of cancer from e-cigarette use and to compare this to risks associated with other tobacco products. These studies commonly predict lesser risks of cancer from e-cigarettes than conventional cigarettes, but greater than ambient air. As e-cigarette device types are rapidly evolving, the accuracy of past studies to predict the risks from contemporary and future e-cigarette types is uncertain.
A study from 2020 estimated the risk of cancer from metal contamination in e-cigarette aerosols.11 The authors estimated cancer risk by multiplying the cancer slope factor (an estimate of the risk of cancer) for specific metals by the estimated daily dose of exposure. Their results estimated that chromium and nickel were the leading contributors to cancer risk, with minor contributions from cadmium, lead, and arsenic. They concluded that some e-cigarettes may be significant sources of metal exposures, capable of increasing the risk of cancer.11
A similar study from 2017 compared estimated cancer risks of e-cigarettes to conventional cigarettes, heated tobacco products and nicotine inhalers (used for cessation), taking into account the exposure to 15 different carcinogens.6 The estimated mean lifetime risk of cancer from first and second generation (see Section 18.1.1) e-cigarette use was less than 1% of that estimated for conventional cigarettes, but 10-fold more than that for nicotine inhalation devices used for cessation. However, newer devices with variable power settings were much more varied, with some ranging more closely to the risk from conventional cigarettes. The higher risks were likely associated with the higher levels of carbonyl reaction products such as carcinogenic aldehydes that are generated at higher power levels.
Relevant news and research
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References
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