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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

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