Estimating the Public Health Impact from Introducing Tobacco-Free Nicotine Pouches Into the US


 BackgroundFor smokers not intending to quit, switching to a reduced-risk nicotine product should be healthier than continuing smoking. We estimate the health impact, over the period 2000-2050, of introducing into the US the nicotine pouch ZYN. ZYN’s toxicant profile and method of use is like that for Swedish snus, a product with known health effects much less than smoking. MethodsOur modelling approach is similar to others developed for estimating potential effects of new tobacco products. It starts with a simulated cohort of 100,000 individuals in the year 2000 subdivided by age, sex, and smoking status (including years since quitting). They are followed annually accounting for births, net immigrations, deaths and product use changes, with follow-up carried out in the Base Case (ZYN not introduced) and Modified Case (ZYN introduced). Using informed assumptions about initiation, quitting and switching rates, distributions of the population over time are then constructed for each Case, which are used to estimate product-related mortality based on assumptions about the relative risk according to product use. ResultsWhereas in both Base and Modified Cases, the prevalence of any current product use is predicted to decline from about 22% to 10% during follow-up, in the Modified Case about 25% of current users use ZYN by 2050, about a quarter being dual users and the rest ZYN-only users. Over the 50 years, deaths at ages 35-84 from product use among the 100,000 are estimated as 249 less in the Modified than the Base Case, equivalent to about 700,000 less deaths in the whole US. Sensitivity analyses varying individual parameter values confirm the benefits of switching to ZYN, which increase as either the switching rate to ZYN increases or the initiation rate of ZYN relative to smoking increases. Even assuming the reduction in excess mortality risk using ZYN use is 20% of that from smoking rather than the 3.5% assumed in the main analyses, the reduction in product-related deaths would still be 213, or about 600,000 in the US. ConclusionsAlthough such model-based estimates are subject to uncertainties, the results suggest that introducing ZYN could substantially reduce smoking-attributable deaths.


Background
Smoking is a major cause of preventable disease, and responsible for many millions of deaths and years of life lost [1]. While the healthiest option for smokers is to quit smoking immediately and completely, many public health experts and institutions have embraced harm reduction as an alternative approach in tobacco control [2][3][4]. Tobacco harm reduction is aimed at adult smokers who would otherwise continue smoking and attempts to persuade them to switch to smoke-free alternatives such as snus, e-cigarettes or heat-not-burn products; all of which have been shown to substantially reduce toxicant levels as compared to cigarettes [5][6][7][8].
Evidence to support tobacco harm reduction comes from extensive epidemiological ndings over many years relating to Swedish smokers switching to snus. Studies clearly show that any increase in disease and death rates associated with the use of snus is much less than that associated with smoking [5,9]. In Sweden, where snus use is common, the prevalence of smoking and the incidence of mortality from smoking-associated diseases are the lowest in Europe [10].
Swedish Match recently introduced a new smoke-free product known as ZYN that is currently marketed in the US and Europe. ZYN is a non-heated, tobacco leaf-free and spit-free nicotine pouch for oral use with an appearance similar to Swedish snus products. Use of ZYN does not involve any inhalation of smoke or vapour. It is intended for adult tobacco and nicotine consumers, and comes in different avours and nicotine strengths. It is intended to be used under the upper lip for up to an hour and then discarded. Chemical characterization of nicotine pouches and snus suggests that users of nicotine pouches are exposed to lower levels of toxic compounds than are users of snus [11].
For products introduced more recently into the market various modelling approaches have been used to estimate their future population health impact. These techniques are based on various informed assumptions, including their rate of uptake, the effect their uptake has on the prevalence of cigarette smoking, and the relative toxicity of the product compared to cigarettes. A review of these approaches has recently been published [12]. Some approaches concern speci c new products, such as e-cigarettes or heat-not-burn cigarettes, while others are more general, using terms like modi ed risk tobacco product, new nicotine product, or new tobacco product [12].
Here we use a dynamic population microsimulation model to estimate the effect that the hypothetical introduction of ZYN in 2000 might have had in the US on overall mortality and on the combined distribution of smoking and ZYN use over the subsequent 50 years. The approach used has similarities to that of Vugrin et al. (2015) [13] and has also been used by Apelberg et al. (2018) [14] when studying the effects of reducing nicotine levels in cigarettes in the US.
These similarities include the methodology used to correct for changes in mortality over time, the assumption that tobacco-related death does not occur in those aged less than 35 years, and the data sources used to determine the initial cigarette smoking distribution, the distribution of time quit for former smokers, never smoker death rates above age 34 years, and the relative risk for smoking compared to never having smoked.

Outline of the approach
The approach involves three stages.
The rst stage de nes the population in the baseline year, 2000. A hypothetical population of 100,000 US individuals is subdivided by sex and age, and also into never, current and former cigarette smokers, with former smokers subdivided by years quit. The new product, ZYN, is assumed not to have been available before 2000.
In the second stage, the population is followed up annually until 2050. Every year the population is updated to take into account births, net immigrations, deaths and changes in nicotine product use, with the distribution of sex, age and cigarette smoking in the immigrant population assumed to be equal to that used for the initial population.
Follow-up is carried out in two scenarios: the "Base Case" where the new product, ZYN, is never introduced; and the "Modi ed Case" where it is introduced immediately after baseline. Note that the use of nicotine-containing products other than cigarettes or ZYN is not considered in either scenario. Table 1 details the nicotine use groups considered. In the Base Case, which concerns only groups 1 (never smokers), 2 (current cigarette smokers) and 3 (former cigarette smokers), our application of the model allows individuals to initiate smoking (change from group 1 to 2) or to quit smoking (change from group 2 to 3), but not to re-initiate smoking (change from group 3 to 2). Transitions to never smokers (group 1) are not possible, while transitioning from never to former smokers (change from group 1 to 3) is assumed not to occur in a single period. In the Modi ed Case nine groups are involved: 1-3: never ZYN by never, current and former cigarettes; 4-6: current ZYN by never, current and former cigarettes and 7-9: former ZYN by never, current and former cigarettes.
Twelve transitions between the groups are considered. Three relate to initiation (changes from group 1 to each of groups 2, 4 and 5), three to quitting (changes from group 2 to 8, 4 to 6 and 5 to 9) and six to switching (changes from group 2 to 5, 2 to 6, 4 to 5, 4 to 8, 5 to 6 and 5 to 8). Other possible transitions are not considered, for comparability with the Base Case.
Based on the initial population distribution, the transition probabilities between groups, and changes in the simulated population due to births, net immigrations and deaths, data are available at each year from 2000 to 2050 on the distribution of the population by age, sex and nicotine use for both the populations in the Base Case and the Modi ed Case.
Finally, in the third stage, the data on the distributions by age, sex and nicotine use are processed to estimate mortality associated with nicotine use from all causes, the difference between the two measuring the population health impact of introducing ZYN.
Additional details of the methods and data used are described below.
Population at baseline at year 2000 The initial cigarette smoking distribution by sex and age group is as used by Vugrin et al. [13], based on data from the National Health Interview Survey (NHIS), and is given in Additional File 1

Net migration and births
At every year during follow-up, the population is scaled up to allow for the inclusion of immigrants and new births.
The sex distribution in newborns and the sex, age and cigarette use distributions for the immigrants are both assumed to be the same as at baseline. The estimates of net migrations and births used were the US Census Bureau 2008 National Population Projections, and are shown in Additional File 2 Tables A2.1 (migrations) and A2.2 (births).
Estimation of histories of cigarette smoking for the Base Case Additional File 3 Table A3.1 gives the smoking initiation and cessation rates by sex and age used in the Base Case.
Using methodology similar to that of Vugrin et al. (2015) [13], these rates were derived from smoking histories for birth cohorts reconstructed from NHIS data. Initiation rates for ages 0-19 were derived from the 1980-1984 cohorts, for ages 20-24 from the 1975-1979 cohorts and so on. Initiation rates for individuals above age 30 are set to zero, as nearly all initiation occurs at younger ages [17]. Derivation of cessation rates was similar, with rates for ages 0-18 from the 1980-84 cohorts, for ages 19-24 from the 1975-79 cohorts, and so on. CISNET rates were available up to age 84, older individuals being assigned the rate for age 84. As cessation rates in the CISNET data represent successful smoking cessation rates for at least two years, re-initiation rates are set to zero. Both the initiation and cessation rates are assumed to be time independent.

Estimation of histories of product use for the Modi ed Case
In the pre-approval market setting, transition probabilities in the Modi ed Case are necessarily based on assumptions that cannot be validated. The transition probabilities in the Modi ed Case were derived from those in the Base Case as follows: Initiation. Overall initiation rates were set equal to that for initiating smoking in the Base Case, but split in the proportion 70:25:5 for initiation to exclusive cigarette smoking, exclusive ZYN use, and dual use.
Quitting. Each of the three quitting rates, from exclusive use of either product or of dual use were set equal to that for quitting smoking in the Base Case.
Re-initiation. All re-initiation rates were set to be zero.
Other switching rates. These were taken as 0.48% for age 10+. In the absence of other information, these switching rates were as used in a previous publication [18].
Estimating mortality attributable to cigarette smoking in the Base Case US death rates for never smokers aged 0-34 in 2000, given in Additional File 4 Table A4.1, were extracted from the Human Mortality Database [15]. As tobacco-attributable mortality is considered minimal before age 35 [19], the risk of death for current smokers was assumed to be equal to that for never smokers, an assumption also made by Vugrin et al. (2015) [13].
Death rates for never and current smokers for ages 35 and above are taken from Vugrin et al. (2015) [13], the never smoker death rates being estimated from NHIS Linked Mortality Files. Similarly to Vugrin et al. (2015) [13], the never smoker death rates are adjusted for changes over the period 2000-2050 using mortality scaling factors estimated using the Lee-Carter method [20], and are available in Additional File Table A4.2 (males) and Table A4.3 (females). Individuals aged 85 years or older were assumed to face the same risk of death, regardless of age, given the same sex and smoking history. Individuals were tracked until age 101, being then counted as dead. The never smoker death rates for ages 35 and above were then converted into annual probabilities of death by sex and age groups using standard demographic methods [13], and are shown in Additional File 4 Table A4.4.
Current smoker death rates were calculated by multiplying the never smoker death rates by the estimates of relative risk by age and sex given by Vugrin et al. (2015) [13], which were derived from NHIS Linked Mortality Files, and are shown in Additional File 4 Table A4.5.
Former smoker probabilities were estimated, following Hill and Camacho (2017) [21], by assuming that the decline in excess risk (compared to never smokers) follows a negative exponential function, with a half-life of 9.08 years. Thus a current smoker with an excess risk of E at the time of quitting, would have an excess risk of E/2 at 9.08 years after quitting, and of E/4 at 18.16 years after.
Estimating mortality attributable to cigarette smoking and ZYN use in the Modi ed Case The risk of death for those who have never used cigarettes or ZYN was taken to be that of never smokers in the Base Case. The excess risk of exclusive current ZYN users was taken to be 3.5% of that of exclusive current smokers of the same sex and age, while the excess risk of current dual users was taken to be that of current smokers. The estimate of 3.5% was based on the average of estimates made of 5% for snus use and 2% for nicotine replacement products made by a panel of experts at the Independent Scienti c Committee on Drugs [22]. For current ZYN users who were former smokers, the excess risk was taken to be the maximum of that for current ZYN use and former smoking. For former ZYN users who were current smokers, the excess risk was taken to be that of current smokers. For former ZYN users who had never smoked, the excess risk for current ZYN users was scaled down using the same half-life as used for former smokers. For former users of both products, the excess risk was taken to be the maximum of that for former ZYN use and former smoking.
Note that, in the following text, the term "product-related deaths" is used generally to describe either deaths attributable to cigarette smoking in the Base Case or deaths attributable to both cigarettes and ZYN in the Modi ed Case.

Sensitivity analyses
Sensitivity analyses investigated the effect of varying the assumed values of each of a number of different parameters: Excess risk factor for exclusive ZYN use. Instead of 3.5%, alternatives of 0%, 7% and 20% were tested.
Excess risk factor for dual use. Instead of taking the maximum of the individual excess risks from smoking and from ZYN use, alternatives of the mean and the sum were tested.
Excess risks for current smoking. Instead of using the excess risks implied by the relative risk values shown in Additional File 4 Table A4.5, the excess risks were multiplied either by 0.8 or by 1.2.
Half-life of the negative exponential function. Instead of using 9.08 years, values of 4.54 or 18.16 years were used, Transition probabilities. For each of the quitting rates and the switching rates, alternatives of half or double the rate used in the Modi ed Case were used. For initiation, the Modi ed Case rates were constrained to add to the initiation rate used in the Base Case. One set of sensitivity analyses for initiation retained this constraint, so that if one of the rates were halved or doubled, the three rates were then multiplied by a scaling factor so that their sum remained the same. The other set of sensitivity analyses, which varied only the initiation rates for exclusive ZYN use and for dual use, did not keep this constraint, but kept the initiation rate to cigarettes unchanged, so allowing study of the possibility that use of ZYN might affect overall initiation rates.
Note that most of the sensitivity analyses only affect the Modi ed Case. However, the sensitivity analyses which vary the excess risks for current smoking, the half-life of the negative exponential function, or the quitting rate for cigarette smoking, affect both the Base and the Modi ed Case.
Each of the sensitivity analyses described above varies only one parameter at a time. A further analysis was carried out based on a Pessimistic Scenario in which 12 assumptions relating to the introduction of ZYN were varied simultaneously, each of which were found to reduce the advantage to ZYN when considered individually. Thus the excess risk for exclusive ZYN was taken to be 20% of that from smoking, and the excess risk for dual use was taken to be the sum of those for smoking and ZYN individually. Also the transition probabilities were halved for initiation rate for ZYN, quitting rates for ZYN and for dual use, and switching rates from smoking to ZYN use, from smoking to dual use, and from dual use to ZYN, while the transition probabilities were doubled for initiation rate for dual use, and switching rates from ZYN to smoking, from dual use to smoking, and from dual use to ZYN. The changes to the initiation rates described were made while keeping the overall initiation rate xed. Table 2 shows the predicted prevalences of tobacco use in the Base Case and the Modi ed Case by 10 year period over the 50 year follow-up period. For the sexes combined, the prevalences of never and former cigarette smokers are very similar in the Base and Modi ed Cases, never smokers rising steadily from almost 50% at baseline to over 63% after 50 years, and former smokers rising slightly from about 28% at baseline to about 30% at 2020, then falling to about 27% at 2050. For the Base Case the prevalences of current cigarette smokers falls steadily from about 22% at baseline to about 10% after 50 years, while for the Modi ed Case the prevalence of current cigarette-only smokers declines more to about 7%, but the prevalence of ZYN users (alone or with cigarettes) increases from zero at baseline to 2.5% after 50 years. At baseline, females compared to males have a smaller prevalence of former and current cigarette smokers, but by the end of follow-up these differences decline, in both the Base Case and the Modi ed Case. By the end of the followup the prevalences of current smoking (cigarettes, ZYN only, or dual) are quite similar in males and females.

Results
Despite the relatively low predicted uptake of ZYN in the Modi ed Case, reductions in overall deaths and deaths due to the products are clearly evident in the Modi ed Case, as seen in Table 3, which presents cumulative results for ages 35 to 84 years based on the population considered (100,000 initiating in 2000). Overall, there is an estimated reduction of 113 total deaths and 249 product-related deaths, the smaller difference for total deaths re ecting the fact that some of those who do not die of smoking-related diseases due to the introduction of ZYN will instead die later, but still before age 85 years, of other diseases not related to smoking. Given that the US population in 2000 was about 282 million, one would have to multiply the estimated reductions by about 2,820 to make them relevant to the whole population. When scaled up in this manner the reduction in numbers due to introduction of ZYN is about 320,000 total deaths and about 700,000 product-related deaths.  Given the uptake of ZYN is assumed to be quite low in our Modi ed Case (see Table 2) it is possible that initiation rates of ZYN might be even higher than this, with a consequently larger reduction in smoking-related deaths. There is also a reasonably large difference of 90.5 (311 vs 220.5) in relation to whether rates of switching from smoking to ZYN are doubled or halved.
It is also clear from Table 4 Table 4, the increase in life-years is about 5 to 7 times the reduction in product-related deaths, the exception being for analysis 19, where the ZYN initiation rate is doubled, and the ratio of the increase in life-years to the reduction in product-related deaths is much higher.
In the Pessimistic Scenario, which simultaneously made each of the changes described in analyses 4, 6, 13, 16, 23, 25, 27, 30, 31, 34, 36 and 37, an advantage was still seen resulting from the introduction of ZYN. Here there was an estimated reduction in product-related deaths of 20 and increase in life-years of 237 as compared to the Base Case. These compare with the estimates of 249 and 1419 in our main analysis, the modi ed Case.

Discussion
Based on modelling of the effects of introducing ZYN into a sample of 100,000 of the US population in 2000, with subsequent follow-up until the year 2050, our main analysis estimates that smoking-related deaths would reduce by 249 as compared to the Base Case where ZYN is not introduced. This is equivalent to about 700,000 deaths in the whole US population. These estimates are based on product transition rates which suggest that by the year 2050 about a quarter of the 9.9% current total users of cigarettes or ZYN will be using ZYN. Sensitivity analyses suggest that a substantial reduction of smoking-related deaths following the introduction of ZYN would still be evident unless the assumed initiation rate of ZYN was considerably increased, with no concomitant reduction in the assumed initiation rate of cigarette smoking.
Various modelling approaches have been used to estimate the population health impact of introducing modi ed risk tobacco products [12]. The one used here is similar to that used by Vugrin et al. (2015) [13] who have discussed its strengths and weaknesses. The strengths include the use of population and mortality projections which closely correspond to Census projections, and the use of smoking initiation and cessation rates from recent cohorts so that smoking prevalence projections t in with observed US estimates based on NHIS data. Limitations mentioned by Vugrin et al. (2015) [13] include the restriction to all-cause mortality, while some other modelling approaches consider the major smoking-related causes of death individually [18], using a modelling approach which does not take into account daily cigarette consumption approach or years smoked, and assuming that smoking initiation and cessation rates remain constant over time. It should also be noted that the modeling fails to take into account pipe and cigar smoking, use of other reduced risk products and environmental tobacco smoke, factors considered unlikely to have a material effect on the results in other modelling approaches [18].
Our modelling approach assumes that there is no re-initiation of smoking by those who have quit, since the derived cessation rates represent successful cessation rates for at least two years. While this follows Vugrin et al. (2015) [13], one should note that our estimates may be optimistic if those who have quit smoking try ZYN, and because of this are led to revert to smoking. But the evidence from Sweden suggests that the great majority of tobacco users decide whether they smoke or use snus, and tend to stay using the chosen product [5].
Our estimates ignore the possibility that changes over time may occur that have nothing to do with tobacco use. These may include, for example, effects of medical advances, new infections, wars and global warming. But such factors are typically not considered in modelling, even in approaches which consider deaths occurring up to the year 2100, e.g. [14,23].
As with all such modelling approaches, the scenarios examined are hypothetical, and the results depend on the assumptions made. To illustrate the effect of uncertainties relating to the different assumptions, we include the results of various sensitivity tests. Thus, while our Modi ed Case assumes that the excess mortality risk of ZYN is only 3.5% of that from cigarettes, consistent with extensive evidence from epidemiological studies on snus [5,9], we also report the results of analyses in which this percentage can rise to 20%. Similarly we test for variations in the assumed values of the excess risk factor for dual use, the relative risk for current smoking and the quitting half-life, as well as variations in the assumed initiation, quitting and switching rates. Generally the results from these sensitivity analyses con rm that the introduction of ZYN into the US population would cause a substantial reduction in product-related deaths.

Conclusions
Had ZYN been introduced into a sample of 100,000 of the US population in the year 2000, we estimate that deaths from smoking-related diseases at ages 35-84 occurring by the year 2050 would reduce by 249, equivalent to almost 700,000 in the whole US population. These estimates assume that the prevalence of current ZYN use in 2050 would be about a quarter of the total current use of cigarettes and ZYN. Sensitivity analyses varying the parameter values assumed in the main analyses con rm that the introduction of ZYN is likely to substantially decrease smokingrelated deaths even under our least optimistic assumptions. For those smokers not intending to quit smoking, switching to ZYN can substantially reduce the risk of smoking-related diseases.

Availability of data and materials
All data used in this study are included in this published article and its supplementary information les, and the publicly available databases from which they came are referenced in the paper. The program used to carry out the analyses, written in R, is available from the authors on request.

Conformity to relevant guidelines
This paper conforms to relevant guidelines such as those by the ICMJE.

Competing interests
TL is an employee of Swedish Match. PNL and JSF are contracted consultants for the project and paid by Swedish Match.

Funding
The work described was wholly supported by Swedish Match.

Authors' contributions
The work was conceived and planned by PNL and TL. JSF carried out the analyses, which were checked by PNL. PNL drafted the paper, on which JSF and TL commented.