Tobacco-specific nitrosamines (TSNAs) are a group of carcinogenic compounds formed primarily during the curing and processing of tobacco. Among these, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN) are the most biologically significant as they are both classified by the International Agency for Research on Cancer (IARC) as Group 1 carcinogens (1). They are also listed as Harmful and Potentially Harmful Constituents (HPHCs) in tobacco products and tobacco smoke by the FDA (2). Their carcinogenicity is mediated through cytochrome P450-driven α-hydroxylation, leading to DNA adduct formation and subsequent mutations in oncogenes and tumor suppressor genes (3). Substantial evidence from animal models and human epidemiological studies links NNK to lung adenocarcinoma (4, 5) and NNN to esophageal squamous cell carcinoma (6). Collectively, exposure to TSNAs represents a well-established biological pathway to carcinogenesis, rendering their quantification a benchmark for assessing the carcinogenic risk of tobacco and nicotine products.

Over the past decade, electronic cigarettes (e-cigarettes) have emerged as a crucial nicotine delivery system within the field of harm reduction. Their rapid popularity and widespread adoption are largely driven by the ability to deliver nicotine without combustion coupled with a perception of reduced harm compared to conventional cigarettes (7, 8). Consequently, e-cigarettes are increasingly used for both smoking cessation and recreational purposes (9). A Cochrane systematic review led by Lindson (10) demonstrated that nicotine-containing e-cigarettes are associated with increased quit rates compared to conventional nicotine replacement therapies (NRT) or e-cigarettes without nicotine. Evidence from 90 completed studies, including 49 randomized controlled trials, suggests that nicotine e-cigarettes are more effective than nicotine replacement therapy for smoking cessation, with quit rates about 1.6 times higher (RR 1.59, 95% CI 1.30–1.93) (10). Overall, adverse events were generally mild and comparable across groups, while serious adverse events were rare and too infrequent to establish clear differences (10). While these findings support the potential of e-cigarettes as a cessation aid, concerns persist regarding their long-term safety, particularly with regard to user exposure to potentially toxic substances present in their emissions (9, 10). These concerns are further complicated by the heterogeneity of e-cigarette devices, evolving formulations, and their dual use with combustible cigarettes (11).

Despite the absence of combustion, the extent of TSNA exposure from e-cigarette use remains a topic of ongoing investigation and debate. Several studies demonstrate that e-cigarettes produce notably lower levels of toxicants than combustible cigarettes; however, evidence specific to TSNA emissions from e-cigarettes is inconsistent. Some studies reported undetectable levels of TSNAs in e-cigarette aerosols, while others identified measurable levels. Regardless of the detected or undetected levels of TSNAs in e-cigarette emissions, evidence consistently shows that cigarette smoke produces higher TSNA levels than e-cigarette aerosols. Additionally, some investigations, conducted without direct cigarette comparators, suggested the presence of TSNAs across different e-cigarette products, with concentrations influenced by device design, heating mechanisms, and formulation characteristics.

Despite the absence of combustion, the degree to which e-cigarette use contributes to TSNA exposure remains uncertain and contested. While several studies suggest that e-cigarettes emit substantially lower levels of toxicants than combustible cigarettes, the evidence specific to TSNAs is heterogeneous. Some analyses have reported TSNAs to be undetectable in e-cigarette aerosols (12, 13), whereas others have detected measurable and at times variable concentrations (14). Moreover, although comparative data generally show cigarette smoke yielding higher TSNA levels than e-cigarette emissions, methodological differences in aerosol collection, analytical sensitivity, and device selection complicate interpretation across studies (15). Additional investigations conducted without direct cigarette comparators have further highlighted product-dependent variability, with TSNA concentrations appearing to differ according to device type, heating parameters, and liquid composition (14, 16). Taken together, these inconsistencies underscore the need for a systematic evaluation of the available evidence to clarify the extent and determinants of TSNA exposure from e-cigarette use.

Fragmented and conflicting data have perpetuated uncertainty, and patients increasingly seek guidance on whether e-cigarettes reduce cancer risk compared with traditional smoking, emphasizing the need for clear, evidence-based communication. The purpose of this analysis was to address this gap by systematically comparing TSNA levels reported in e-cigarette emissions and combustible cigarette smoke. By synthesizing the available data, the goal was to provide a definitive and practical understanding of relative TSNA exposure, ensuring that cancer risk communication is grounded in toxicological evidence.

This synthesis was undertaken as an analysis of comparative studies from the search results of a systematic review of e-cigarette emissions, with a focus on TSNAs. The primary research question was:

What are the levels of NNK and NNN detected in e-cigarette aerosols compared with combustible cigarette smoke under consumer-relevant laboratory conditions?

This analysis sought to clarify the extent of user exposure to TSNAs, particularly NNK and NNN, in e-cigarette emissions compared to combustible cigarette smoke. Across the 13 studies reviewed, validated analytical methods demonstrated that levels of TSNAs in e-cigarette aerosols were consistently several orders of magnitude lower than those measured in conventional cigarette smoke. Collectively, these findings delineate a clear toxicological gradient, with combustible cigarettes producing the highest exposures, e-cigarettes producing substantially lower exposures that fall below detection or near background air levels in most modern devices, and only a minority of older products yielding trace but measurable amounts.

The mechanistic evidence helps explain this pattern. Unlike in combustible cigarettes, where curing and pyrolysis generate elevated levels of TSNAs, e-cigarettes do not produce these compounds during use. Instead, their presence reflects impurities introduced during nicotine extraction or the nitrosation of minor alkaloids in the presence of nitrite. Jin and colleagues (16) demonstrated that in early cig-a-like products, the appearance of NNK and NNN was entirely attributable to nitrite contamination. Adding nitrite to nicotine solutions generated measurable TSNAs over time, which increased further with heat; nitrite-free formulations yielded either undetectable or background-level values in both liquid and aerosol phases. Independent investigations reinforce this interpretation. Farsalinos and colleagues (12) systematically compared TSNA concentrations in e-liquids and the aerosols generated from them. They found that aerosol levels never exceeded those already present in the e-liquid, and in several cases no TSNAs were detected in the aerosol at all despite trace levels in the e-liquid. This indicates that the process of vaporization does not create additional nitrosamines; rather, what appears in the aerosol reflects direct transfer of pre-existing contaminants from the liquid. Thus, when TSNAs are detected in e-cigarette emissions, their source is almost certainly the quality of the liquid ingredients, not the act of vaping itself. Converging evidence comes from product-surveillance studies conducted without cigarette comparators. In a multi-brand evaluation performed under CORESTA-consistent conditions, TSNAs in e-liquids were generally below quantification limits and remained below quantification in the corresponding aerosols; the investigators also emphasized the necessity of air blanks to prevent attributing background contamination to the device signal (34). A separate analytical validation program reported TSNAs in e-cigarette aerosols at levels observed in pharmaceutical-grade nicotine and provided transparent limits of quantitation and detection for NNK and NNN, enabling clearer interpretation of non-detects (13).

The clinical evidence aligns with these chemical findings. Biomarker studies consistently show that when smokers switch completely to e-cigarettes, exposure to TSNAs is markedly reduced. Shahab and colleagues (35) reported that urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) concentrations in long-term exclusive e-cigarette users were almost indistinguishable from those in users of licensed nicotine-replacement therapy, and far below the levels observed in smokers. Goniewicz and colleagues (36) observed similar patterns in large US cohorts, demonstrating that reductions in nitrosamine biomarkers are substantial when cigarette use is replaced entirely by vaping.

The evidence presented in this secondary analysis comparing e-cigarettes and cigarettes indicates that TSNA exposure from e-cigarettes is not an inherent property of vaping but largely reflects the quality of the e-liquid. Meaningful reductions in internal exposure to carcinogens are seen when combustible tobacco is replaced entirely with e-cigarettes. Communicating this nuance, that risk is lower but not absent and that benefit depends on both reputable products and full switching, provides a balanced and evidence-based framework for guiding decisions about use.

One possible reason the perception of TSNA exposure from e-cigarettes continues to circulate is the reliance on observational cohort studies. These analyses are valuable but have important limitations. Most e-cigarette users in such cohorts are former smokers, biomarker half-lives vary widely, and patterns of use are often self-reported in ways that make it difficult to distinguish exclusive from dual use. Under these conditions, residual effects of past smoking or concurrent cigarette use may be misattributed to e-cigarettes, creating the impression that vaping itself is a significant source of nitrosamines.

Our analysis helps explain why this interpretation may not be reliable. Across the studies we examined, TSNAs were largely absent from aerosols, with only trace amounts detected under limited conditions. Observational cohorts seldom capture information on the e-liquid or product being used, leaving out the factor that appears most decisive. This disconnect between what is measured in large population studies and what determines exposure helps to sustain the perception that e-cigarettes are substantial sources of TSNAs. When observational evidence is set alongside experimental and mechanistic findings, the picture becomes clearer. Nitrosamine exposure is driven by e-liquid and manufacturing quality and by the continued use of combustible cigarettes, not by vaping in isolation.

Most included studies were rated as strong in methodological quality, though several limitations warrant consideration. Most investigations were funded by the tobacco industry, which can be regarded as a source of concern. However, within this evidence base, methodological standards were generally high, with extensive use of validated analytical methods that reduce the likelihood of systematic bias. The two studies included in this analysis that were not industry funded both found e-cigarette emissions to contain only trace amount of NNK and NNN, which was substantially lower than cigarettes (14, 32). These results therefore concur with conclusions made by industry-funded studies. Nonetheless, independent replication remains important, but the overall rigor of the included studies lowers concern that funding source compromised the findings. Remaining limitations relate primarily to differences in reporting of device specifications, puffing regimens, and limits of detection, all of which hinder cross-study comparison. Although standardized methods such as CORESTA 81 (ISO 20768) were frequently applied, variation in puff volume, duration, and replicates complicates direct synthesis. The lack of uniform reporting of LOD and LOQ further complicates interpretation, particularly of “non-detect” findings. Greater transparency and standardization would strengthen the evidence base and allow for more reliable comparative analysis.

This study also carries both strengths and limitations. A key strength is the comprehensive identification of relevant studies, which was possible given the systematic approach used by the systematic review of e-cigarette emissions. By identifying and synthesizing data on NNK and NNN, this analysis addresses a gap in the cancer literature where direct comparisons with cigarettes have not previously been collated. The use of explicit eligibility criteria and structured quality assessment further enhances internal validity. At the same time, the analysis is constrained by the small number of eligible studies, by reliance on published data rather than raw laboratory outputs, and by heterogeneity in devices, e-liquids, and reporting formats including the reporting of LOD and LOQ levels. These constraints limited the ability to conduct a meta-analysis and necessitated a descriptive synthesis. Furthermore, given the rapidly evolving advances in e-cigarette devices, another analysis on this topic in the near future may reveal additional insights. Taken together, these limitations indicate that the results should be interpreted as indicative of consistent patterns across studies, rather than precise quantitative estimates of exposure.

While the short-term toxicological evidence is compelling, important gaps remain. Longitudinal epidemiological studies linking e-cigarette use to cancer outcomes will be essential, but these require extended follow-up with improved methods for reporting and measuring of respondent’s tobacco use histories, outcomes, and the exact device and e-liquid used. In the interim, progress can be made by standardizing TSNA measurement and reporting across laboratories, expanding emission studies to include a broader range of products and formulations, and investigating how product storage or aging may influence nitrosamine formation. Independent replication of existing findings will further build confidence and reduce reliance on industry-sponsored data.

Taken together, this analysis highlights that TSNA exposure from e-cigarettes is not an inevitable property of vaping but depends on the chemical quality of the e-liquid. Clearer reporting, more independent research, and sustained attention to methodological rigor will help move the field beyond the limitations of observational cohorts and toward a firmer understanding of the true cancer-related risks of e-cigarettes.

In conclusion, this analysis demonstrates that NNK and NNN levels in e-cigarette aerosols are consistently and substantially lower than those found in combustible cigarette smoke, with reductions typically exceeding 99%. In many modern devices, nitrosamines are undetectable, and where detected, they appear at trace levels likely reflecting nicotine purification and ingredient quality rather than inherent properties of vaping. For oncology practice, the evidence indicates that exclusive e-cigarette use confers a profound reduction in exposure to two of the most important tobacco-specific carcinogens.

Nevertheless, reductions are not synonymous with elimination. The variability introduced by dual use, unregulated products, and incomplete ingredient purification underscores the need for careful clinical guidance and regulatory oversight. The role of the oncology community is to articulate this evidence with clarity, precision, and balance, recognizing both the substantial benefits of reduced exposure and the residual uncertainties that only long-term studies will resolve.