A double-edged sword: e-cigarettes, and other electronic nicotine delivery systems (ENDS): reply

Disagreement in a scientific debate is healthy. Although we commend the intent of Lal et al. [1] to further elaborate on the impact of e-cigarettes and other electronic nicotine delivery systems (ENDS) on human health, we disagree on some of these authors’ assessment of the literature. And we certainly disagree with their statement that e-cigarettes are “becoming a nuisance for the society” when it is evident that these tar-free-emitting technologies are displacing cigarette smoking globally. While several studies have found that e-cigarette use at baseline predicts smoking at a later period, there is convincing evidence that there is a bidirectional association, with smoking at baseline predicting follow-up e-cigarette use too (Table 1). In fact, it is more plausible for these findings to be explained by the common liability model, rather than the gateway model [2]. Further indications for the absence of gateway to smoking effects for e-cigarettes come from examining the smoking rates among US youth over time. Reductions of > 60% and 50% in middle school and high school students’ rates of past 30 days smoking have been reported from 2011 to 2018, the period when e-cigarettes became very popular (Table 1). US youth now have the lowest smoking rates that have historically been recorded, with an accelerated rate of decline compared to previous years. Combined with the minimal rates of frequent e-cigarette use among never-smoking youth, it is likely that e-cigarettes have distracted US youth from smoking rather than recruiting more smokers (Table 1). While flavors could appeal to youth, they are particularly important for adult former smokers who are using e-cigarettes as smoking substitutes, and could possibly contribute to successfully quitting and preventing relapse (Table 1). Of course, it is not desirable for youth (as well as neversmoking adults) to initiate e-cigarette use, and continuous monitoring of use according to smoking status is warranted. In any case, it is important to consider both potential benefits and harms of any regulatory restrictions in different population subgroups, and estimate the overall public health impact before being implemented. The authors are also downplaying the much reduced malignancy risk of tar-free technologies compared to combustible cigarettes by citing in vitro studies that have been largely dismissed because of abnormal exposure protocols that do not replicate normal condition of use and lack of appropriate experimental controls [3]. While not risk free, there is no doubt that ECs are by far less harmful than smoking with lower toxin emissions and lower toxin exposure as evaluated by measuring biomarkers (Table 1). As noted in our recent Editorial [4], direct evidence for the reduction in lung cancer risk by suppressing tar exposure is not possible due to the substantial latency period of this disease. However, estimation of lifetime cancer risks—by modeling the cancer potencies of e-cigarette and ENDS emission aerosols using published chemical analyses of emissions and their associated inhalation unit risks—showed that the * Riccardo Polosa polosa@unict.it

Dear Editor, Disagreement in a scientific debate is healthy.
Although we commend the intent of Lal et al. [1] to further elaborate on the impact of e-cigarettes and other electronic nicotine delivery systems (ENDS) on human health, we disagree on some of these authors' assessment of the literature. And we certainly disagree with their statement that e-cigarettes are "becoming a nuisance for the society" when it is evident that these tar-free-emitting technologies are displacing cigarette smoking globally.
While several studies have found that e-cigarette use at baseline predicts smoking at a later period, there is convincing evidence that there is a bidirectional association, with smoking at baseline predicting follow-up e-cigarette use too (Table 1). In fact, it is more plausible for these findings to be explained by the common liability model, rather than the gateway model [2]. Further indications for the absence of gateway to smoking effects for e-cigarettes come from examining the smoking rates among US youth over time.
Reductions of > 60% and 50% in middle school and high school students' rates of past 30 days smoking have been reported from 2011 to 2018, the period when e-cigarettes became very popular (Table 1). US youth now have the lowest smoking rates that have historically been recorded, with an accelerated rate of decline compared to previous years. Combined with the minimal rates of frequent e-cigarette use among never-smoking youth, it is likely that e-cigarettes have distracted US youth from smoking rather than recruiting more smokers (Table 1).
While flavors could appeal to youth, they are particularly important for adult former smokers who are using e-cigarettes as smoking substitutes, and could possibly contribute to successfully quitting and preventing relapse (Table 1). Of course, it is not desirable for youth (as well as neversmoking adults) to initiate e-cigarette use, and continuous monitoring of use according to smoking status is warranted. In any case, it is important to consider both potential benefits and harms of any regulatory restrictions in different population subgroups, and estimate the overall public health impact before being implemented.
The authors are also downplaying the much reduced malignancy risk of tar-free technologies compared to combustible cigarettes by citing in vitro studies that have been largely dismissed because of abnormal exposure protocols that do not replicate normal condition of use and lack of appropriate experimental controls [3]. While not risk free, there is no doubt that ECs are by far less harmful than smoking with lower toxin emissions and lower toxin exposure as evaluated by measuring biomarkers ( Table 1). As noted in our recent Editorial [4], direct evidence for the reduction in lung cancer risk by suppressing tar exposure is not possible due to the substantial latency period of this disease. However, estimation of lifetime cancer risks-by modeling the cancer potencies of e-cigarette and ENDS emission aerosols using published chemical analyses of emissions and their associated inhalation unit risks-showed that the 1 3 cancer risk for vapers is several orders of magnitude lower compared to smoking (Table 1), a clear indication of the tremendous harm reduction potential of e-cigarettes. The same logic applies to other smoking-related and smokingexacerbated diseases such as COPD and asthma, in which regular long-term EC use has been shown to improve (not to worsen) subjective as well as objective respiratory outcomes (Table 1). Of note, in a 3.5-year follow-up of a small cohort of never-smoking daily EC users, no deterioration in spirometric indices, development of respiratory symptoms, changes in markers of lung inflammation nor signs of early lung damage on HRCT were noted [5]. Moreover, the recent outbreak of severe acute respiratory illnesses among several hundred US young adults and teens is NOT linked to commercial nicotine vaping products. Both the FDA (Food and Drug Administration) and the CDC (US Centers for Disease Control and Prevention) now acknowledge that the outbreak is caused by the consumption of some illegal, black market cannabis liquids containing dangerous adulterants [6,7].
We certainly do not disagree with Lal et al. [1] that improved regulation of these new technologies is needed. In particular, enhanced monitoring of e-cigarette refills should be in place, to prevent reckless alteration and to promote quality/safety control mechanisms. We have long supported and endorsed standards through the work of Technical Committee of the European Standardization body for e-cigarettes and e-liquids (CEN TC437) to ensure that manufacturers have quality control systems in place to prevent these problems and to safeguard consumers' health from marketing of non-approved vaping products. Nonetheless, regulation should be sensible, balanced, pragmatic, risk proportionate and evidence based. Overrestricting use of tobacco harm reduction products not only protects none but it also deprives smokers from the chance to improve their health. It also forces any youth who may unfortunately want to initiate an inhalational habit to have one option: combustible tobacco cigarettes.
We should not lose sight of the potential benefits of ECs compared to cigarettes as a lot of people still smoke conventional cigarettes and this will be a public health issue for a number of years to come. Table 1 Debunking key concerns about e-cigarettes

Concern
Key debunking references