Keywords
Nicotine products, relative risk, risk assessment, tobacco, harm reduction, systematic review.
This article is included in the Health Services gateway.
Nicotine products, relative risk, risk assessment, tobacco, harm reduction, systematic review.
An update of this study was initiated in November 2021 with the aim of bringing the literature search up to date and incorporating feedback received during the presentation of this work to the scientific community. A point raised several times was the lack of representation of tobacco products in low and middle income countries in their own category and the inappropriateness of placing these products in the same category as those manufactured and marketed in the United States. This issue has been rectified by limiting the dipping and chewing tobacco categories to products marketed in the United States and creating additional categories for smokeless tobacco from the rest of the world (except snus which already has its’ own category) and bidi cigarettes. We have also made efforts to improve the presentation of the study based on feedback regarding the lack of study characteristics tables and other pieces of data required for complete comprehension and reproduction of this work. In addition, the grant information and competing interests statements have been updated. Full details can be found in the main paper and in the extended information. We continue to encourage and welcome all constructive feedback from the scientific community and appreciate the comments of all those who take the time to read, consider, critique and debate its methods and findings.
See the authors' detailed response to the review by Mohamadi Sarkar, Chastain Anderson, Thaddeus Hannel and Brendan Noggle
See the authors' detailed response to the review by David Nutt
Tobacco smoking is known to cause over 8 million premature deaths every year worldwide1. Since the discovery of its severe toxicity in the 1960s, bringing an end to tobacco smoking has been a major priority for public health authorities2–4. The toxicity is attributed to tobacco combustion, which generates at least 250 known toxins and 69 known carcinogens1,2. Combustible tobacco consumption dates back thousands of years, and in that time several products have been developed including factory-made and roll-your-own cigarettes, bidis, cigarillos, cigars, western pipe tobacco and water pipe tobacco5. Consumers of these products are exposed to toxins with each inhalation, increasing their risk of potentially fatal health outcomes, such as lung cancer, oral cancer or cardiovascular disease6.
Beyond combustion, tobacco can also be consumed by placing small amounts in the oral or nasal cavities7. The tobacco mixes with saliva and releases chemicals which are ingested and can be associated with increased risk of oral and gastrointestinal cancers7. Different varieties of smokeless tobacco contain widely varying levels of toxins, with further divergence depending on how they are manufactured and stored8. Types of smokeless tobacco include United States (U.S.) varieties of chewing and dipping tobacco, Swedish snus, and Asian varieties, such as naswar, mishri or gutka7. Asian varieties of smokeless tobacco are often associated with higher levels of toxicity than modern U.S. and Swedish varieties, which have shown steadily decreasing levels of toxins as manufacturing and storage processes are optimized for reduced toxicity7.
Most users consume tobacco for the pleasurable effects associated with nicotine, which often makes cessation challenging9. To minimize the harms caused by traditional tobacco products and help people to quit, new methods of nicotine delivery have been developed that eliminate most of the known toxins associated with tobacco smoking and smokeless tobacco use10. Nicotine replacement therapies, electronic cigarettes, heated tobacco products, non-tobacco nicotine pouches and low tobacco-specific nitrosamines (TSNA)-varieties of smokeless tobacco have been introduced to the market, giving consumers the choice of several alternatives to higher risk tobacco products. The development of these alternative products has paved the way for tobacco harm reduction, which focuses on reducing the harms associated with smoking by encouraging users to switch to nicotine products with reduced toxicity e.g., nicotine replacement therapy (NRT), snus or e-cigarettes11. Success has been reported for harm reduction strategies in other areas of public health, such as alcohol abuse, where measures such as low-alcohol beverages have been introduced to reduce the harms associated with alcohol consumption while allowing the consumer to continue enjoying the product12. For many smokers, having access to products that deliver nicotine without the high toxicity of traditional tobacco products can mean the difference between successfully quitting smoking or continuing indefinitely. Indeed, there is a large body of high-quality evidence in the scientific literature supporting the efficacy of nicotine replacement for helping smokers to successfully stop smoking, increasing the rate of cessation by 50 – 60% compared with no intervention13.
While there is universal consensus regarding the significant harms of combustible tobacco products, and despite the observed efficacy of nicotine replacement therapies, the subject of tobacco harm reduction remains contentious. Harm reduction proponents argue in favor of the reduced risk profiles of non-combustible nicotine products and their potential benefits for public health if they were widely adopted instead of combustible tobacco products11,14. While tobacco harm reduction antagonists argue that not enough is known about the newer nicotine products, that they could even be just as harmful as combustible tobacco, and that they may be gateways to smoking for people who do not currently consume any nicotine products at all4,15.
The objective of this relative risk assessment of nicotine products is to systematically gather and appraise the best available evidence from the scientific literature regarding the risks of cancer and non-cancer tobacco-related diseases in healthy current users of a single nicotine product, compared with never and non-users of any nicotine product, at average consumption levels. In the first iteration of this study published in 2020, a systematic review, literature appraisal and analysis protocol were developed, which generates a combined risk score for each nicotine product based on the lifetime cancer risk (LCR), modelled from toxin emissions/content data, and epidemiological evidence of disease risk in exposed groups16. In the 2020 study, the combined risk score was calculated for 13 categories of nicotine products: combustible cigarettes, cut tobacco, cigarillos, western pipe tobacco, water pipe tobacco, cigars, dipping tobacco, chewing tobacco, heat-not-burn devices, snus, electronic cigarettes, non-tobacco pouches and NRT. This relative risk assessment builds on previous studies in the scientific literature including Nutt et al., 2014, which used a multi-criteria decision analysis model to assess the relative harms of 12 nicotine products, Abrams et al., 2018, which categorized the Nutt et al. spectrum into “extreme toxicity” and “much less harm” categories, and Stephens, 2018, which compared the lifetime cancer risk associated with vaporized nicotine products compared with tobacco smoke10,17,18. In this update, the systematic review and analysis developed in 2020 have been repeated, adding newly published data to fill some of the gaps and replace lower quality evidence with higher quality studies, where possible. We have also added minor methodological refinements where facilitated by new data. In addition, we have created two new product categories in the hierarchy, expanding the inclusion criteria of this study to incorporate smokeless tobacco from the rest of the world and bidis, a type of small hand-rolled cigarette/mini cigar originating from India.
This update follows the review and analysis protocol that were published previously, with a few minor amendments. Firstly, the systematic review was conducted according to the preferred reporting items for systematic review and meta-analysis (PRISMA) 2020 checklist (rather than the 2009 version)19. Secondly, the original methodology covered 13 categories of nicotine products (chewing tobacco, combustible cigarettes, cigarillos, cigars, cut tobacco, dipping tobacco, electronic cigarettes, heat-not-burn devices, NRT, non-tobacco pouches, snus, water pipe tobacco and western pipe tobacco). This review adds two categories for bidis and smokeless products from the rest of the world, thereby expanding the selection criteria compared with the 2020 iteration, as well as focusing the dipping and chewing tobacco categories on U.S. varieties only. The full Population-Intervention-Comparison-Outcomes-Study type (PICOS) question addressed in this review is outlined in Table 1.
Systematic searches were conducted using specific search terms pertaining to the health risks of nicotine products on May 9th 2022 in the MEDLINE (Pubmed) and NIH clinical trials (ClinicalTrials.gov) databases (see extended data). Due to the broad scope of the searches, the most relevant literature was targeted by searching at the title and abstract levels. The publication lists returned by the searches were exported and screened at the title, abstract and full-text levels according to pre-defined inclusion and exclusion criteria (Table 2). The screening steps were completed by one researcher and confirmed by a second. During each screening step, the reason for exclusion of each individual publication was recorded and the level of evidence assessed for the final shortlisted publications using the Oxford evidence-based medicine level of evidence scale20.
Inclusion criteria | Exclusion criteria |
---|---|
Studies that report on the health risks to primary consumers of nicotine products | Studies that report only on the efficacy of nicotine products for smoking cessation |
Studies that report on specific health risk metrics or information related to the use of a nicotine product | Studies that focus on ethical, environmental or sociological factors associated with the use of nicotine products |
Studies reporting on epidemiological data of nicotine product health risks | Non-human studies |
Studies reporting on toxin emissions and content of nicotine products* | Non-English studies |
In vitro studies | |
Removed inclusion/exclusion criteria | |
Only U.S./western smokeless tobacco products | Asian smokeless tobacco products |
Risks related to secondhand and thirdhand consumption |
The shortlisted studies were analyzed in detail to extract health risk data and relevant meta-data, including the nicotine product, brand, disease/symptom, methodology used, measurement and unit, error in measurement, significance of measurement, geographic location, sample size and conflict of interest.
For the toxin emissions/content studies, only data points for Group 1 International Agency for Research on Cancer (IARC) carcinogens were extracted. Data were sought for NNN and NNK, formaldehyde, 2-amino-naphthalene, 4-aminobiphenyl, benzo(a)pyrene, 1,3-butadiene, benzene, vinyl chloride, ethylene oxide, arsenic, chromium-IV and cadmium for inhalable products, and NNN and NNK, benzo(a)pyrene, arsenic, chromium-IV and cadmium for ingestible products. In addition, studies that reported sample collection conducted before 1st January 1990 were excluded due to lack of relevance to the current market.
For the epidemiological studies, only adjusted odds ratios pertaining to tobacco-related diseases were extracted and only data points that adjusted for smoking were included. Data were sought for myocardial infarction, stroke, cardiovascular disease, coronary heart disease, atrial fibrillation, heart disease, asthma, asthma attack, bronchitis, wheeze, COPD, CHD mortality, cardiovascular disease mortality, chronic lower respiratory disease, cerebrovascular disease mortality and chronic obstructive pulmonary disease mortality for the non-cancer outcomes. Data were sought for oral cancer, oropharyngeal cancer, mouth cancer, lip cancer, tongue cancer, cancers of the upper aero-digestive tract, head and neck cancer, larynx cancer, esophageal cancer, hypopharyngeal cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, rectal cancer, gastrointestinal cancer, colorectal cancer, anal cancer, liver cancer, cardia cancer, kidney cancer, cervical cancer, non-Hodgkin’s lymphoma, acute lymphoblastic lymphoma, acute myeloid lymphoma, chronic myeloid lymphoma multiple myeloma and cancer mortality for the cancer outcomes. Where stratification was available, data points for current users were prioritized over former/ever users, data points for both sexes were prioritized over single sex datasets (within the same study), and non- or never users of any other nicotine product were prioritized over dual users. If stratification was provided by consumption level, moderate consumption matching as closely as possible to the assumptions used in the LCR analysis were selected. In applying these additional selection criteria to the data, we aim to adjust for confounders, reduce the risk of bias and focus on risk associated with the same consumption levels across all analyses. No automation tools were used for data extraction and all data points were verified by a second reviewer. The information extracted included the nicotine product, brand, disease/symptom, methodology used, measurement and unit, error in measurement, significance of measurement, geographic location, sample size and conflict of interest.
The extracted and harmonized dataset was analyzed in two main segments: lifetime cancer risk and epidemiological data.
Lifetime cancer risk. The lifetime cancer risk (LCR) of each nicotine product was calculated separately for inhalable and smokeless products. The inhalable products LCR calculation was based on the methodology outlined by Stephens9, whereas the LCR of the smokeless products was determined using the methodology outlined by the FDA10.
The LCR of each inhalable nicotine product was calculated from the toxin emissions data by adjusting the OEHHA unit risk values12. A total of 12 toxins are included in the inhalable nicotine product analysis. The toxins selected are all International Agency for Research on Cancer (IARC) Group 1 carcinogens (“known carcinogens”) for which OEHHA unit risk values and emissions data were available13. The protocol used in this study deviates slightly from that of Stephens. Firstly, whereas in Stephen’s protocol Group 1 and Group 2B carcinogens are included, only Group 1 carcinogens were included here18. The Group 1 carcinogens were selected because this grouping applies to toxins for which “sufficient evidence” of cancer in humans has been observed, whereas in the Group 2B category only “limited” or “inadequate” evidence of cancer in humans is available, meaning that the classification in this group is primarily based on evidence from experimental animals or mechanistic studies21. In this review, we exclude evidence from animal or in vitro studies, therefore Group 2B carcinogens (as well as Group 2A and 3) were also excluded from this toxin emissions analysis. Secondly, we convert the unit risk values to risk per µg or ng per breath in order to match the units of the converted toxin concentrations, which are reported per puff. This is contrary to the methodology outlined by Stephens, which takes unit risk values in their original form of risk per µg per m3 and adjusts the smoke/vapour toxicants to match these units.
For each carcinogen, the OEHHA unit risk values were sourced and converted from risk per μg per m3 to risk per μg per breath by assuming the average breath volume of a healthy human is 500 mL14. The toxin emissions of the nicotine products were reported in varying units. For instance, combustible cigarette studies reported toxin emissions as μg or ng per stick, whereas electronic cigarette studies reported toxin emissions as μg or ng per 150 puffs. Therefore, the toxin emissions data for each product were converted to per puff values. In order to make this conversion, the average number of puffs per product per session was extracted from puff topography studies in the scientific literature (see extended data11). The cancer potency of each nicotine product was calculated by adjusting the unit risk values with the observed masses of toxins in the emissions from each inhaled nicotine product using Equation 1:
Equation 1: Cancer potency of the nicotine product
Where Pi is the cancer potency of the ith nicotine product, Ci,j is the mass of the jth toxin in the ith nicotine product and Uj is the unit risk for the jth toxin. The cancer potency (Pi) represents the excess cancer risk associated with continuous lifetime use of each nicotine product. To put the cancer potency values into real-world context, the lifetime cancer risk was calculated by adjusting the cancer potency values for average consumption patterns of each product, using Equation 2:
Equation 2: Lifetime cancer risk of inhalable nicotine products
Where LCRi is the lifetime cancer risk of the ith nicotine product, Pi is the cancer potency of the ith nicotine product, Di is the average daily number of puffs taken by users of each nicotine product and B is the average number of breath taken in one day (40,000 breaths, equivalent of 20 m3 breathed per day). The lifetime cancer risk (LCRi) represents the excess cancer risk associated with average daily use of each nicotine product over the course of a person’s lifetime.
For the non-inhaled (smokeless) products, the estimated lifetime cancer risk (ELCR) equation as defined by the FDA was used10. This equation calculates the lifetime cancer risk based on adjustment of the cancer slope factor for each carcinogen with the observed amounts of toxins measured in smokeless tobacco products and average consumption of the products:
Equation 3: Estimated lifetime cancer risk of smokeless nicotine products
Where ELCRi is the estimated lifetime cancer risk of the ith product, Ci,j is the concentration of the jth toxin in the ith product, IRi,j is the intake rate of the jth toxin in the ith product, ABi,j is the absorption rate of the jth toxin in the ith product, EFi,j is the exposure frequency of the jth toxin in the ith product, EDi,j is the exposure duration of the jth toxin in the ith product, BW is the body weight of the average user, AT is the averaging time of use and CSFj is the cancer slope factor of the jth toxin.
Epidemiological data analysis. Risk ratios, odds ratios and hazard ratios were extracted from the epidemiological studies and a set of meta-analyses were performed to determine the relative risk of cardiovascular disease, respiratory disease, cancer and mortality in users of each nicotine product compared to non-users of any nicotine products. The epidemiological data extracted from the systematic literature searches was screened to include only relative risk values that compared current users of a single nicotine product to non-users of any nicotine product. Relative risk values were excluded if they were unadjusted for tobacco smoking. Where more than one study was available for a specific disease, the best available evidence was selected according to the Oxford Center for Evidence-based Medicine Level of Evidence Scale20. For instance, if a meta-analysis of prospective cohort studies and a single case-control study were available, the former would be included and the latter would be excluded.
The remaining data after screening were grouped by disease type into cardiovascular disease, respiratory disease, cancer and mortality. The cancer category was further broken out into oral, other head and neck, lung, gastrointestinal and other. Meta-analyses of the relative risk data for each disease category were conducted using a random-effects model in the Comprehensive Meta-analysis (CMA) software Version 3.3, with a statistical significance threshold of α = 0.05. The meta-analysis could also be conducted in the open-access alternative, the metaphor package of R. A final meta-analysis was conducted to obtain overall relative risk ratios of cancer and non-cancer diseases for each nicotine product.
In the LCR analysis, several of the combustible products lacked data points for multiple toxins. As the LCR was calculated for each toxin and then summed for each product, missing data points significantly skewed the result towards lower risk. In order to compensate for this, the missing data points for combustibles were filled with values from combustible cigarettes, for which all data points were available. The assumption being that the mechanism of combustion is likely to produce a similar profile of toxins. This assumption was applied to 92% of the data points for bidis, 58% for cut tobacco, 50% of the data points for cigars, 50% for cigarillos and 33% for water pipe tobacco. The room for error due to this assumption should be noted, particularly for bidis where almost all of the data points are assumed from combustible cigarettes.
In the epidemiological data analysis, no data were available for the cut tobacco category and very few studies differentiated between factory-made and roll-your-own cigarette smokers. Therefore, it was assumed that the studies investigating cigarette smokers most likely included a mix of factory-made and roll-your-own, with both identifying as combustible cigarette smokers. Based on this assumption, as well as the assumption that the two products would carry comparable risk, we used the same data for the combustible cigarettes and cut tobacco categories. No other assumptions were made in the epidemiological analysis and missing data was simply recorded using the data completeness score.
For each product, a data completeness score was derived which shows to what extent data points were available for each product and category of data. It serves to give an indication of the risk of error due to missing data for each product. The data completeness is calculated as a percentage, where all the possible data points for each product represent 100% and any missing data is calculated as a fraction of this total as follows.
Equation 1: Data completeness for each nicotine product
Where DCi is data completeness for the ith nicotine product, na,i is the number of data points available for the ith nicotine product and nt,i is the total number of possible data points for the ith nicotine product. The higher the data completeness percentage, the lower the risk of bias due to missing data.
The RRH combines the results of the lifetime cancer risk and epidemiological analysis, with a weighting system that accounts for the completeness of the dataset. In order to integrate these two analyses into a combined risk score for each nicotine product, an arbitrary scale from 0 to 100 was defined, with 0 representing non-users of nicotine products and 100 representing users of combustible cigarettes. Combustible cigarettes were selected as the top of the scale because they were the highest risk product in both of the analyses. Non-user groups were the control or baseline in both analyses, therefore no correction was required to the lower end of the scale. After converting both analyses onto a 100-point scale, a weighting of 68 was applied to the lifetime cancer risk analysis and 54 to the epidemiological analysis, according to the data completeness scores for each component.
The sensitivity of the RRH to each analysis was determined by simulating several weightings of the lifetime cancer risk and epidemiological data and assessing their outcomes on the risk hierarchy (see extended data). The analyses were weighted 68:54, 1:1 and 54:68, producing three simulations of the RRH.
Data was extracted from the scientific literature into a Microsoft Excel Version 16.41 spreadsheet. Microsoft Excel was used to conduct the lifetime cancer risk calculations. Comprehensive Meta-analysis (CMA) software Version 3.3 was used to conduct statistical meta-analyses in the epidemiological data-analysis. Calculation of the combined risk scores that were incorporated into the RRH was completed in Microsoft Excel.
A PRISMA flow diagram of the updated literature searches is shown in Figure 1. In this update, a total of 23,781 studies were identified in the literature searches. Of these, 5,981 were excluded as duplicates. At the title screening step, 14,876 studies were excluded, primarily due to lack of relevance to the PICOS question. This left 2,907 publications that were assessed in greater detail at the abstract level, where 2,027 studies were excluded. This left 880 studies to be examined at the full-text review, where 810 studies were excluded and 70 were included from the latest round of searches. This made a total of 123 unique studies included in the analysis.
The 70 new studies consist of 40 new toxin emissions studies and 30 new epidemiological studies. The new epidemiological studies consist of 12 meta-analyses, 10 single cohort studies, five case-control studies, two cross-sectional studies and one randomized controlled trial (Table 3). The sample sizes for cohort and cross-sectional studies are over 1,000, over 100 for case-control studies (combined case and controls) and they range from 33 to 75 for different groups in the randomized controlled trial. In total, 14 studies include only male participants, the rest are mixed with only one study limited to an exclusively female population. The confounder adjustment varies across the studies mostly because the risk for different diseases, populations and products are affected by different confounders. All included odds ratios are adjusted for smoking and the majority are also adjusted for other common risk factors, such as age, sex and socio-economic factors. Only two studies on NRT and snus have a declared conflict of interest. For the former, one of the three study authors is an employee of a consulting company that has provided services to GlaxoSmithKline consumer healthcare (a marketer of NRT products) and the other study is jointly funded by Philip Morris Products, Swedish Match and the European Smokeless Tobacco Council.
Disease | Reference | Location | Design | Sample size | Gender | Odds ratio (95% CI) | Confounders adjusted | Conflict of interest |
---|---|---|---|---|---|---|---|---|
COMBUSTIBLE CIGARETTES | ||||||||
Hypopharyngeal cancer | Jayalekshmi et al., 201322 | India | Prospective cohort study | 27,835 | Men | 1.6 (0.9 – 2.8) | Age, family income | None declared |
Liver cancer | Hassan et al., 200823 | USA | Case-control study | 206 (488) | Men and women | 1.5 (1.1 – 2.2) | Age, sex, race, education, marital status, state of residency, HCV, HBV, diabetes, heavy alcohol consumption and family history of cancer. | None declared |
Cardia cancer | Ye et al., 199924 | Sweden | Case-control study | 13 (64) | Men and women | 2.2 (1 – 4.8) | Age, residence area, BMI, socio-economic status, use of smokeless tobacco, and use of beer, wine and liquor | None declared |
Acute lymphoblastic leukemia | Fernberg et al., 200725 | Sweden | Prospective cohort study | 98,183 | Men | 1.94 (0.89 – 4.21) | Age, BMI, non-users of snuff | None declared |
Acute myeloid lymphoma | 1.29 (0.89 – 1.86) | |||||||
U.S. CHEWING TOBACCO | ||||||||
Stroke | Gupta et al., 202026 | USA | Meta-analysis (cohort & case- control studies) | 7 studies | Men and women | 1.21 (0.9 – 1.51) | Smoking | None declared |
Coronary heart disease | Gupta et al., 201927 | USA | Meta-analysis (cohort studies) | 2 studies | Men and women | 1.04 (0.83 – 1.24) | Never users of other tobacco products | None declared |
Liver cancer | Hassan et al., 200823 | USA | Case-control study | 103 (540) | Men and women | 0.3 (0.02 – 3.9) | Smoking, age, sex, race, education, marital status, state of residency, HCV, HBV, diabetes, heavy alcohol consumption, and family history of cancer. | None declared |
Cancer mortality | Henley et al., 200528 | USA | Prospective cohort study | 114,809 | Men | 1.23 (1.02 – 1.49) | Never users of other tobacco products, Race, education, current alcohol consumption, exercise, aspirin use, body mass index, quartiles of vegetable and fruit consumption, dietary fat consumption and type of occupation | None declared |
U.S. DIPPING TOBACCO | ||||||||
Coronary heart disease | Gupta et al., 201927 | USA | Meta-analysis (cohort & case- control studies) | 7 studies | Men and women | 0.96 (0.86 – 1.06) | Non-smokers only | None declared |
Liver cancer | Hassan et al., 200823 | USA | Case-control study | 102 (517) | Men and women | 0.4 (0.03 – 5.1) | Cigarette smoking, age, sex, race, education, marital status, state of residency, HCV, HBV, diabetes, heavy alcohol consumption and family history of cancer. | None declared |
Cancer mortality | Henley et al., 200528 | USA | Prospective cohort study | 114,809 | Men | 1.23 (1.02 – 1.49) | Never users of other tobacco products, race, education, current alcohol consumption, exercise, aspirin use, body mass index, quartiles of vegetable and fruit consumption, dietary fat consumption and type of occupation | |
All-cause mortality | 1.17 (1.11 – 1.23) | |||||||
CHD mortality | 1.12 (1.03 – 1.21) | None declared | ||||||
CVD mortality | 1.18 (1.11 – 1.26) | |||||||
ELECTRONIC CIGARETTES | ||||||||
Bronchitis | Braymiller et al., 202029 | USA | Cross-sectional | 2,196 | Men and women | 0.96 (0.63 – 1.46) | *Nicotine vapers only Cannabis vaping, sex, age, race/ethnicity, personal financial status, BMI, frequency of combustible cigarette use and frequency of combustible cannabis use | None declared |
Wheeze | 0.85 (0.54 – 1.35) | |||||||
SNUS | ||||||||
Coronary heart disease | Hansson et al., 200930 | Sweden | Prospective cohort study | 16,642 | Men | 0.85 (0.51 – 1.41) | Never smokers only, age, BP, diabetes, cholesterol | None declared |
Atrial fibrillation | Hergens et al., 201431 | Sweden | Meta-analysis (cohort) | 7 studies | Men | 0.97 (0.71 – 1.33) | Never smokers only, age, BMI, education | None declared |
Heart disease | Lee, 201132 | Sweden | Meta-analysis (cohort and case-control studies) | 9 studies | Men and women | 0.99 (0.85 – 1.14) | Never-smokers only (all), age, area of residence | Study funded by Philip Morris Products, Swedish Match and the European Smokeless Tobacco Council |
Oropharyngeal cancer/pharyngeal | 7 studies | Men and women | 1.01 (0.71 – 1.45) | Never smokers only, age, alcohol intake | ||||
Lung cancer | 2 studies | Men and women | 0.82 (0.52 – 1.28) | Never-smokers only, age | ||||
Stomach cancer | 5 studies | Men and women | 0.90 (0.35 – 2.30) | Never-smokers only, age | ||||
Oral cancer | Araghi et al., 202133 | Sweden | Meta-analysis (cohort) | 9 studies | Men | 0.79 (0.63 – 1.00) | Smoking, attained age and BMI | None declared |
Bladder cancer | Boffetta et al., 200534 | Norway | Prospective cohort study | 10,136 | Men | 0.72 (0.52 – 1.06) | Smoking of cigarettes, cigars and pipe, age | None declared |
Kidney cancer | 0.47 (0.23 – 0.94) | |||||||
Pancreatic cancer | Araghi et al., 201735 | Sweden | Meta-analysis (cohort) | 9 studies | Men | 0.96 (0.83 – 1.11) | Smoking, attained age and BMI | None declared |
Rectal cancer | Nordenvall et al., 201136 | Sweden | Retrospective cohort study | 336,381 | Men | 1.05 (0.85 – 1.31) | Non-smokers only, age, “other risk factors” | None declared |
Anal cancer | 0.61 (0.07 – 5.07) | |||||||
Cardia cancer | Ye et al., 199924 | Sweden | Case-control study | 9 (118) | Men and women | 0.5 (0.2 – 1.1) | Age, residence area, BMI, socio-economic status, use of smokeless tobacco, and use of beer, wine and liquor | None declared |
Acute lymphoblastic leukemia | Fernberg et al., 200725 | Sweden | Prospective cohort study | 40,932 | Men | 1.24 (0.39 – 4.01) | Non-smokers, age, BMI | None declared |
Acute myeloid lymphoma | 0.81 (0.41 – 1.6) | |||||||
Chronic myeloid leukemia | 1.17 (0.6 – 2.28) | |||||||
Multiple myeloma | 0.92 (0.61 – 1.4) | |||||||
All-cause mortality | Byhamre et al., 202137 | Sweden | Meta-analysis (cohort) | 169,103 | Men | 1.28 (1.20 – 1.35 | Never-smokers, attained age, BMI | None declared |
Cardiovascular disease mortality | 1.27 (1.15 – 1.41) | |||||||
Cancer mortality | 1.12 (1.00 – 1.26) | |||||||
WESTERN PIPE TOBACCO | ||||||||
All-cancer | Malhotra et al., 201738 | Global | Meta-analysis (cohort) | 21,930 | Men and women | 1.19 (0.82 – 1.73) | *Ever users Age, gender, BMI, race/ethnicity, socioeconomic status, alcohol intake, family history of cancer | None declared |
Acute lymphoblastic leukemia | Fernberg et al., 200725 | Sweden | Prospective cohort study | 16,988 | Men | 0.84 (0.18 – 3.92) | “Pure pipe smoker”, Age, BMI | None declared |
Acute myeloid lymphoma | 1.38 (0.85 – 2.24) | |||||||
WATER PIPE TOBACCO | ||||||||
Heart disease | Islami et al., 201339 | Global | Meta-analysis (cohort) | 21,930 | Men and women | 1.83 (1.1 – 3.07) | *Ever users Age, gender, BMI, race/ethnicity, socioeconomic status, alcohol intake, family history of cancer | None declared |
SMOKELESS (REST OF WORLD) | ||||||||
Myocardial infarction (paan) | Alexander, 2013 | Pakistan | Case-control study | 578 (757) | Men and women | 1.53 (1.14 – 2.05) | Non-smokers, age, sex, ethnicity, LDL-C, waist- to-hip ratio, history of diabetes or hypertension and family history of MI | None declared |
Stroke (Nass) | Etemadi et al., 201740 | Northeastern Iran | Meta-analysis (cohort & case- control studies) | 1,393 | Men and women | 0.98 (0.65 – 1.47) | Smoking | None declared |
Heart Disease (Mishri) | Gupta et al., 200541 | India | Cohort | 97,244 | Men | 0.89 (0.75 – 1.05) | Smoking, age education | None declared |
Bronchitis | Yusuf et al., 200842 | South Africa | Cross-sectional | 4,425 | Women | 1.18 (0.69 – 2.03) | Smoking, Age, Socioeconomic status, tuberculosis, cooking fuel, occupational exposure to irritants | None declared |
Oral cancer (Paan/ Betel quid with tobacco) | Asthana et al., 201943 | India | Meta-analysis (cohort & case- control studies) | 4 studies | Men and women | 7.43 (6.54 – 8.43) | Smoking | None declared |
Mouth cancer (Pan- tobacco) | Sankaranarayanan et al., 198944 | India | Case-control study | 87 (181) | Men | 4.06 (1.95 – 8.4) | Smoking, alcohol and snuff use | None declared |
Larynx cancer (Khaini, Zarda, Mawa, Pan, Gutkha) | Sapkota et al., 200745 | India | Meta-analysis (case-control studies) | 5 studies | Men and women | 1.112 (0.651 – 1.898) | Never smokers only, center, age, sex, SES, alcohol consumption, tobacco snuffing, tobacco pack years | None declared |
Hypopharyngeal cancer (Khaini, Zarda, Mawa, Pan, Gutkha) | 3.102 (2.03 – 4.741) | |||||||
BIDIS | ||||||||
Myocardial infarction | Teo et al., 200646 | Global | Case-control study | 12,461 (14,637) | Men and women | 2.89 (2.11 – 3.96) | Smoking bidis only, age, gender | None declared |
Cardiovascular disease | Duong et al., 201747 | India & Pakistan | Prospective cohort study | 9,479 | Men | 1.55 (1.17 – 2.06) | *Sample contains users of both cigarettes and bidis (26%), as well as exclusive bidi smokers (74%) Socioeconomic status, age, BMI, asset index, education, cooking fuel, INTERHEART risk score, diabetes, hypertension and center | None declared |
COPD, chronic bronchitis, emphysema or asthma | 1.73 (1.23 – 2.45) | |||||||
Oral cancer | Jayalekshmi et al., 201048 | India | Prospective cohort study | 66,277 | Men and women | 1.1 (0.7 – 1.5) | Tobacco use, attained age, calendar time, income, education, alcohol drinking | None declared |
Mouth cancer | Sankaranarayanan et al., 198944 | India | Case-control study | 49 (140) | Men | 2.12 (1.19 – 27.88) | Smoking, alcohol and snuff use | None declared |
Larynx cancer | Jayalekshmi et al., 201322 | India | Prospective cohort study | 25,403 | Men | 4.4 (1.8 – 10.8) | Never smokers, attained age, family income | None declared |
Hypopharyngeal cancer | 3.1 (1.0 – 9.4) | |||||||
Lung cancer | Jayalekshmy et al., 200849 | India | Prospective cohort study | 7,562 | Men | 4.9 (2.4 – 10) | Never smokers, attained age, religion, education, family income, occupation | None declared |
Stomach cancer | Jayalekshmi et al., 201550 | India | Prospective cohort study | 25,403 | Men | 1.9 (1.1 – 3.4) | Tobacco use, alcohol use, calendar year, attained age, occupation, education | None declared |
NICOTINE REPLACEMENT THERAPY | ||||||||
Lung cancer | Murray et al., 200951 | USA | Randomized controlled trial | 75 | Men and women | 1.04 (0.97 – 1.12) | Cigarettes per day, lifetime pack-years of smoking, age, and sex | Third author is employed by Pinney Associates, which provides services to GSK consumer healthcare |
Gastrointestinal cancer | 33 | 0.97 (0.82 – 1.14) | ||||||
All-cancer | 203 | 1.01 (0.97 – 1.06) |
There are 40 new toxin emissions studies included in this update (Table 4). The new data covers combustible cigarettes, cigars, U.S. dipping tobacco, e-cigarettes, heated tobacco products, snus, cut tobacco, smokeless (rest of world), non-tobacco nicotine pouches and NRT. The protocols used to determine toxin emissions are mostly well described and the majority comply with a published standard (e.g., international standards organization or Health Canada Intense). Most studies use the HCI condition with a puff volume of 55 mL, puff duration of 2 or 3 seconds and puff interval of 30 seconds. For cigars and cut tobacco, a puff volume of 35 mL is used. The EN ISO 17294-2:2016/EN 13805:2014 was used for non-tobacco pouches, NRT and one of the snus studies. The remaining studies used in-house methods or protocols referenced elsewhere in the scientific literature. Of the 41 studies, 10 were funded by and/or conducted by researchers at tobacco companies and five studies had another declared conflict of interest.
Toxin | Reference | Product | Concentration | Protocol | Parameters | Conflict of interest |
---|---|---|---|---|---|---|
COMBUSTIBLE CIGARETTES | ||||||
NNN and NNK | Murphy et al., 201852 | 3R4F | 49.91 ng/puff | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at British American Tobacco |
Formaldehyde | Tayyarah and Long, 201453 | Marlboro Gold, L&B | 7.12 – 10.4 μg/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company |
1,3-butadiene | Murphy et al., 201852 | 3R4F | 9.91 μg/puff | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at British American Tobacco |
Benzene | Tayyarah and Long, 201453 | Marlboro Gold, L&B | 9.63 – 10.3 μg/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company |
Benzo(a)pyrene | Murphy et al., 201852 | 3R4F | 1.18 ng/puff | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at British American Tobacco |
Tayyarah and Long, 201453 | Marlboro Gold, L&B | 1.33 – 2.07 ng/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company | |
Cadmium | Tayyarah and Long, 201453 | Marlboro Gold, L&B | 8.25 – 13 μg/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company |
CIGARS | ||||||
Benzene | Appel et al., 199054 | Cigar (brand not disclosed) | 228 – 1025 μg/stick | FTC standard | Puff volume 35 mL, puff duration 2 s, puff interval 30 s | None declared |
Benzo(a)pyrene | Appel et al., 199054 | Cigar (brand not disclosed) | 96 – 292 ng/stick | FTC standard | Puff volume 35 mL, puff duration 2 s, puff interval 30 s | None declared |
U.S. DIPPING TOBACCO | ||||||
NNN and NNK | Song et al., 201655 | Husky Straight Long-cut, Grizzly Fine Cut Wintergreen Fine cut, Timber Wolf Fine Cut Natural Fine cut, Copenhagen Mid-Cut Black Bourbon Flavored, Copenhagen Pouches, Copenhagen Snuff, Skoal Bandits Mint | 6.02 μg/g DWB | Not stated (chemical analysis performed externally) | N/A | None declared |
Richter et al., 200856 | 40 brands of top-selling moist snuff in United States in 2004 | 8.694 ng/g | Richter and Spierto, 2003 method | N/A | None declared | |
Stepanov et al., 200657 | Ariva Hard snuff | 56 ng/g WWB | Modified version of previously published method Adams et al., 1983 method | N/A | None declared | |
Benzo(a)pyrene | Song et al., 201655 | Husky Straight Long-cut, Grizzly Fine Cut Wintergreen Fine cut, Timber Wolf Fine Cut Natural Fine cut, Copenhagen Mid-Cut Black Bourbon Flavored, Copenhagen Pouches, Copenhagen Snuff, Skoal Bandits Mint | 77.75 ng/g DWB | Not stated (chemical analysis performed externally) | N/A | None declared |
ELECTRONIC CIGARETTES | ||||||
NNN and NNK | Murphy et al., 201852 | Vype ePen and eCaps | 0.006 ng/puff | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Margham et al., 201658 | Vype ePen | < 1.245 (LOD) – 3.28 ng/15 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco | |
Tayyarah and Long, 201453 | SKYCIG and blue eCig | < 0.06 ng/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company | |
Belushkin et al., 202059 | 34 e-cigarette devices | < 0.083 – 0.173 ng/puff | CORESTA CRM No. 81 | Puff volume 55/80 mL, puff duration 3/4 s, puff interval 30 s | Study by researchers at PMI R&D | |
Laugesen, 200860 | Ruyan (16 mg cartridge) | 5.33 ng/cartridge | “Labstat method TWT-333” | Puff volume 60 mL, puff duration NS, puff interval NS | Study funded by Ruyan® e-cigarettes | |
Formaldehyde | Li et al., 202161 | 3rd generation Evolv DNA 75 Color modular vaping device | 0.15 μg/puff | CORESTA protocol | Puff volume 55 mL, puff duration 3 s, puff interval NS | One author has received consulting fees from ENDS manufacturers |
Farsalinos et al., 201762 | CE4 top coil atomizer, Innokin iTaste VV V3.0 variable voltage battery device and Halo Café Mocha liquid with 6 mg/mL nicotine concentration | 71.82 μg/puff | Not stated | Puff volume 60 mL, puff duration 4 s, puff interval 30 s | One author has received consulting fees from ENDS manufacturers | |
Salamanca et al., 201863 | CE4 top coil atomizer with Innokin iTaste VV V3.0 variable voltage battery | 13.5 μg/puff (at 7.3 V) | Not stated | Puff volume 60 mL, puff duration 4 s, puff interval 30 s | None declared | |
Murphy et al., 201852 | Vype ePen and eCaps | 0.398 μg/puff | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco | |
Nicol et al., 202064 | “Conventional e-cigarette” | 5.48–5.5 μg/100 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco | |
Tayyarah and Long, 201453 | SKYCIG and blue eCig | < 0.35 μg/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company | |
Geiss et al., 201565 | Second generation refillable e-cigarettes | 19–23.5 ng/puff | ISO 3308 | Puff volume 35 mL, puff duration 4 s, puff interval 30 s | None declared | |
Son et al., 202066 | Cig-a-like, Top-coil, mod’, JUUL | 0.04 – 1.35 ng/puff | Not stated | Puff volume 25 mL, puff duration 3 s, puff interval 30 s | None declared | |
Chen et al., 202167 | Vapros Spinner II vape pen | 126 – 22,717 ng/puff | Not stated | Puff volume NS, puff duration 4 s, puff interval 25 s | None declared | |
Belushkin et al., 202059 | 34 e-cigarette devices | 484 – 31,400 ng/puff | CORESTA CRM No. 81 | Puff volume 55/80 mL, puff duration 3/4 s, puff interval 30 s | Study by researchers at PMI R&D | |
Landmesser et al., 202168 | Not described | 22.6 – 39.1 ng/puff | CORESTA CRM No. 81 | Puff volume 55 mL, puff duration 4 s, puff interval 25 s | Two authors employed by Altria Client Services, LLC | |
Nyakutsikwa et al., 202169 | Not described | 0.16 μg/L | Not stated | Puff volume NS, puff duration NS, puff interval NS | One author is a member of WHO and ISO working groups | |
Farsalinos et al., 201870 | Nautilus mini atomizer and Evic VTC Mini variable wattage battery | 0.5 – 1 μg/12 puffs | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | One author received funding from AEMSA and Tennessee Smoke-Free Assocation | |
1,3-butadiene | Murphy et al., 201852 | Vype ePen and eCaps | 0.001 μg/puff | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Tayyarah and Long, 201453 | SKYCIG and blue eCig | < 0.0005 μg/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company | |
Benzene | Murphy et al., 201852 | Vype ePen and eCaps | 0.001 μg/puff | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Tayyarah and Long, 201453 | SKYCIG and blue eCig | < 0.0005 μg/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company | |
Lee et al., 201771 | Cigalike | 0.5 – 6.6 ppb | Not stated | Puff volume NS, puff duration NS, puff interval 30 s | None declared | |
Benzo[a]pyrene | Tayyarah and Long, 201453 | SKYCIG and blue eCig | < 0.02 ng/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company |
Murphy et al., 201852 | Vype ePen and eCaps | 0.006 ng/puff | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco | |
4-aminobiphenyl | Margham et al., 201658 | Vype ePen | < 0.05 μLOQ) ng/15 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Nicol et al., 202064 | “Conventional e-cigarette” | < 0.014 μg/100 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco | |
Tayyarah and Long, 201453 | SKYCIG and blue eCig | < 0.01 ng/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company | |
2-naphthylamine | Margham et al., 201658 | Vype ePen | < 0.12 (LOQ) ng/15 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Vinyl chloride | Margham et al., 201658 | Vype ePen | < 6.57 (LOD) ng/15 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Ethylene oxide | Margham et al., 201658 | Vype ePen | < 0.36 (LOD) μg/15 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Cadmium | Margham et al., 201658 | Vype ePen | < 16.4 (LOD) – 22 ng/15 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Tayyarah and Long, 201453 | blue eCig | < 4 ng/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company | |
Belushkin et al., 202059 | 34 e-cigarette devices | < 0.06 ng/puff | CORESTA CRM No. 81 | Puff volume 55/80 mL, puff duration 3/4 s, puff interval 30 s | Study by researchers at PMI R&D | |
Arsenic | Tayyarah and Long, 201453 | blue eCig | < 4 ng/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company |
Belushkin et al., 202059 | 34 e-cigarette devices | < 0.12 – 1.33 ng/puff | CORESTA CRM No. 81 | Puff volume 55/80 mL, puff duration 3/4 s, puff interval 30 s | Study by researchers at PMI R&D | |
Nyakutsikwa et al., 202169 | Not described | 0.004 μg/L | Not stated | Puff volume NS, puff duration NS, puff interval NS | One author is a member of WHO and ISO working groups | |
Chromium | Margham et al., 201658 | Vype ePen | 10.5 ng/15 puffs | HCI Condition | Puff volume 55 mL, puff duration 3 s, puff interval 30 s | Study by researchers at British American Tobacco |
Tayyarah and Long, 201453 | SKYCIG and blue eCig | 0.01 – 0.09 ng/puff | CAN method | Puff volume 55 mL, puff duration NS, puff interval 30 s | Study by researchers at Lorillard Tobacco Company | |
Nyakutsikwa et al., 202169 | Not described | 0.007 μg/L | Not stated | Puff volume NS, puff duration NS, puff interval NS | One author is a member of WHO and ISO working groups | |
Belushkin et al., 202059 | 34 e-cigarette devices | < 0.09 – 1.8 ng/puff | CORESTA CRM No. 81 | Puff volume 55/80 mL, puff duration 3/4 s, puff interval 30 s | Study by researchers at PMI R&D | |
HEATED TOBACCO PRODUCTS | ||||||
NNN and NNK | Murphy et al., 201852 | THP1.0, THS2.2 and H-THP | 0.006 – 3.975 ng/puff | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at British American Tobacco |
Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | 19.6 - 23.9 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI | |
Li et al., 201973 | THS 2.2 | 17.8 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | None declared | |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 0.029 μg/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
Formaldehyde | Murphy et al., 201852 | THP1.0, THS2.2 and H-THP | 0.04 – 0.494 μg/puff | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at British American Tobacco |
Mallock et al., 201875 | 2 tobacco heating devices (brands not named) | 4.7 – 5.3 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | None declared | |
Salman et al., 201976 | IQOS | 0.85 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | One author is a paid consultant in litigation against tobacco industry | |
Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | 4.55 – 5.53 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI | |
Li et al., 201973 | THS 2.2 | 21.87 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | None declared | |
Farsalinos et al., 201870 | IQOS | 5 – 6.4 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | One author received funding from AEMSA and Tennessee Smoke-Free Association | |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 3.29 – 3.51 μg/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
Kim et al., 202077 | Three brands of HTP | 0.539 – 0.64 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | None declared | |
1,3-butadiene | Murphy et al., 201852 | THP1.0, THS2.2 and H-THP | 0.001 – 0.019 μg/puff | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at British American Tobacco |
Mallock et al., 201875 | 2 tobacco heating devices | 0.2 – 0.22 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | None declared | |
Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | 0.265 – 0.294 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI | |
Li et al., 201973 | THS 2.2 | 0.45 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | None declared | |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 0.029 μg/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
Benzene | Murphy et al., 201852 | THP1.0, THS2.2 and H-THP | 0.001 – 0.038 μg/puff | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at British American Tobacco |
Mallock et al., 201875 | 2 tobacco heating devices | 0.54 – 0.63 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | None declared | |
Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | 0.640 – 0.649 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI | |
Li et al., 201973 | THS 2.2 | 0.61 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | None declared | |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 0.056 μg/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
Benzo(a)pyrene | Murphy et al., 201852 | THP1.0, THS2.2 and H-THP | 0.003 – 0.049 ng/puff | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at British American Tobacco |
Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | < 1 – 1.29 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI | |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 0.354 – 0.356 ng/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
4-aminobiphenyl | Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | < 0.051 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 0.005 ng/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
2- aminonaphthalene | Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | < 0.035 – 0.046 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 0.004 – 0.012 ng/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
Arsenic | Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | < 1.13 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 0.576 ng/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
Cadmium | Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | < 0.35 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | < 0.162 ng/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
Chromium | Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | < 0.55 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI |
Forster et al., 201874 | THP1.0(T) and THP1.0(M) | 4.06 – 4.34 ng/consumable | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at BAT | |
Ethylene oxide | Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | 0.201 – 0.202 μg/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI |
Vinyl chloride | Schaller et al., 201672 | THS2.2 FR1 and THS2.2 FR1 M | < 3.54 ng/stick | HCI Condition | Puff volume 55 mL, puff duration 2 s, puff interval 30 s | Study by researchers at PMI |
SNUS | ||||||
NNN and NNK | Song et al., 201655 | Camel Frost Snus, Camel Spice Snus, Camel Original Snus, Marlboro Mild Snus, Marlboro Mint Snus, Marlboro Rich Snus, and Marlboro Spice Snus, Ettan Lossnus, General Mini Portion, and Skruf Stark Portion, Taxi Super Snuff Gwayi and Peter Stuyvesant Coffee Snus | 1.44 μg/g DWB | Not stated (chemical analysis performed externally) | N/A | None declared |
Stepanov et al., 201557 | Swedish snus | 0.393 – 0.441 μg/g WWB | In-house method | N/A | None declared | |
Arsenic | Song et al., 201655 | Camel Frost Snus, Camel Spice Snus, Camel Original Snus, Marlboro Mild Snus, Marlboro Mint Snus, Marlboro Rich Snus, and Marlboro Spice Snus, Ettan Lossnus, General Mini Portion, and Skruf Stark Portion, Taxi Super Snuff Gwayi and Peter Stuyvesant Coffee Snus | 0.73 μg/g DWB | Not stated (chemical analysis performed externally) | N/A | None declared |
Chromium | Azzopardi et al., 202178 | Granit Ice Blue White, Skruf Slim Fresh XStrong Mint, G3 Slim White XStrong Blue Mint | 815 – 1,700 ng/g DWB | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
CUT TOBACCO | ||||||
Benzo(a)pyrene | Appel et al., 199054 | Cut tobacco (brand not disclosed) | 37 – 43 ng/stick | FTC standard | Puff volume 35 mL, puff duration 2 s, puff interval 30 s | None declared |
BIDIS | ||||||
NNN and NNK | Wu et al., 200479 | 14 bidi cigarette brands | 10.69 – 88.2 ng/stick | FTC standard | Puff volume 35 mL, puff duration 2 s, puff interval 30 s | None declared |
SMOKELESS (REST OF WORLD) | ||||||
NNN and NNK | Stepanov et al., 200657 | Indian smokeless tobacco | 0.13 – 105.3 μg/g | In-house method | N/A | None declared |
Idris et al., 199180 | Toombak | 1.12 – 10.95 mg/g | In-house method | N/A | None declared | |
Stepanov et al., 201581 | Chaini khiani | 25.5 μg/g | In-house method | N/A | None declared | |
Nasrin et al., 202082 | 34 brands of zarda, gul and sada pata | 1.2 – 67 μg/g | CORESTA (modified) | N/A | None declared | |
Al-Mukhaini et al., 201683 | Afzal | 2.22 μg/g | Lawler et al., 2013 method (modified) | N/A | None declared | |
Stepanov et al., 201784 | Pandharpuri Sandeep, Om Special Pandharpuri, Tambakhu Gai Chhap, Miraj Tobacco, Chaini Khaini, Mawa ‘120-300’, Mawa ‘Bhola’, Betel Quid/Banarasi Paan | 0.078 - 41.51 μg/g | In-house method | N/A | None declared | |
Benzo(a)pyrene | Orisakwe et al., 201585 | 30 samples of Nigerian smokeless tobacco | 9.88 μg/kg | Not stated | N/A | None declared |
Arsenic | Al-Rmalli et al., 201186 | Betel quid | 4.56 mg/kg | In-house method | N/A | None declared |
Brima, 201687 | 33 samples of shamma | 0.7 – 1 μg/g | In-house method | N/A | None declared | |
Zakiullah et al., 201288 | 30 Pakistani brands of naswar | 0.15 – 14.04 mg/kg | In-house method | N/A | None declared | |
Cadmium | Hossain et al., 201889 | Zarda, gul | 1.05 – 3.53 μg/g | In-house method | N/A | None declared |
Orisakwe et al., 201490 | 30 Nigerian smokeless tobacco types | 0.01 – 0.17 μg/g | In-house method | N/A | None declared | |
Prabhakar et al., 201391 | DS Madras snuff, Shambhu, Minar, Madhu, Cool Lip, Hans, Parag 9000, Chaini Khaini, Bombay, Rajanigandha | 1.43 μg/g | In-house method | N/A | None declared | |
Brima, 201687 | 33 samples of shamma | 0 - 0.03 μg/g | In-house method | N/A | None declared | |
Guezguez et al., 202192 | Neffa | 1.3 – 2.8 μg/g | In-house method | N/A | None declared | |
Zakiullah et al., 201288 | 30 Pakistani brands of naswar | BDL - 9.2 mg/kg | In-house method | N/A | None declared | |
Chromium | Hossain et al., 201889 | Zarda, gul | 1.23 – 7.29 μg/g | In-house method | N/A | None declared |
Orisakwe et al., 201490 | 30 Nigerian smokeless tobacco types | 2.77 – 11.40 μg/g | In-house method | N/A | None declared | |
Brima, 201687 | 33 samples of shamma | 2.1 – 5.4 μg/g | In-house method | N/A | None declared | |
Zakiullah et al., 201288 | 30 Pakistani brands of naswar | 0.8 – 54.05 mg/kg | In-house method | N/A | None declared | |
NON-TOBACCO NICOTINE POUCHES | ||||||
NNN and NNK | Azzopardi et al., 202178 | Lyft freeze, lyft lime strong, lyft berry frost, lyft mint | < 20 ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
Benzo(a)pyrene | Azzopardi et al., 202178 | Lyft freeze, lyft lime strong, lyft berry frost, lyft mint | < 1 ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
Arsenic | Azzopardi et al., 202178 | Lyft freeze, lyft lime strong, lyft berry frost, lyft mint | < 50 – 80 ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
Chromium | Azzopardi et al., 202178 | Lyft freeze, lyft lime strong, lyft berry frost, lyft mint | < 50 ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
NICOTINE REPLACEMENT THERAPY | ||||||
NNN and NNK | Azzopardi et al., 202178 | NRT lozenge, 4 mg | < 20 ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
NRT gum, 4 mg | < 20 ng/g | |||||
Benzo(a)pyrene | Azzopardi et al., 202178 | NRT lozenge, 4 mg | < 1 ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
NRT gum, 4 mg | < 1 ng/g | |||||
Arsenic | Azzopardi et al., 202178 | NRT lozenge, 4 mg | < 50ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
NRT gum, 4 mg | < 50 ng/g | |||||
Cadmium | Azzopardi et al., 202178 | NRT lozenge, 4 mg | < 10 ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
NRT gum, 4 mg | 29 ng/g | |||||
Chromium | Azzopardi et al., 202178 | NRT lozenge, 4 mg | < 50 – 52 ng/g | EN ISO 17294- 2:2016/EN 13805:2014 | N/A | Study by researchers at British American Tobacco |
NRT gum, 4 mg | 743 ng/g DWB |
Toxin emissions/content data were available for all the product categories excluding western pipe tobacco, which was therefore excluded from the LCR analysis. The calculated cancer potency, assumed consumption, LCR, and number of excess cancer cases per 100,000 are presented in Table 5, as well as the data completeness score. The data completeness, including the combustible product assumption, is 100% for all products except the nicotine inhalator, which only has 25% of the data points. For bidis, over 90% of the data is assumed from combustible cigarettes meaning that the actual LCR may be prone to shift if more data becomes available. This is also true to a lesser extent for cut tobacco, cigarillos, cigars and water pipe tobacco.
The LCR data for each product is also plotted as a value relative to NRT in Figure 2. Combustible cigarettes have a relative LCR of 655.3, bidis of 652.2 cut tobacco of 645.5, cigarillos of 547.3, cigars of 330.1 and water pipe tobacco of 325.5, compared to NRT. There was not a significant amount of new data in the combustible categories so the associated LCRs have not shifted significantly compared with the 2020 iteration of this study. Bidis enter the scale just below combustible cigarettes, although it is important to note that the data available for bidis was very limited so this position may be subject to change. The smokeless (rest of world) category enters the scale at 223.3, with very large error bars representing the wide range of toxicity of products in this category. For example, the study by Zakiullah et al investigates the toxin content of 30 brands of Pakistani naswar and reports that the cadmium concentration ranges from below the detection limit (<0.01) to 9.2 mg/kg, whereas for other product categories the ranges were generally smaller, such as NRT with a cadmium concentration of 0.01 – 0.029 µg/g.
The heat-not-burn and electronic cigarette products have relative LCRs of 29.7 and 22.3, respectively. U.S. dipping tobacco, U.S. chewing tobacco and snus have values of 26.4, 14.9 and 6.4, respectively. The non-tobacco pouches have displaced NRT at the bottom of the scale with a relative score of 0.5. This is due to new data uncovered in this iteration reporting higher values of chromium and cadmium for nicotine gum, compared with non-tobacco nicotine pouches. However, it should be noted that most of the lower data points for both products (non-tobacco nicotine pouches and NRT) are below the limit of detection of the instruments. In these cases, we use the limit of detection as the lower limit, but this may be an overestimation and it is not possible to accurately quantitate these products relative to each other on the scale.
In total, 151 risk ratios across 12 categories of nicotine products were included in the epidemiological analysis, compared with 101 risk ratios across eight categories of nicotine products in the 2020 iteration. Heat-not-burn, non-tobacco pouches and cigarillos are not represented in the epidemiological analysis. In this update, new data has been added for NRT, electronic cigarettes, smokeless (rest of world), bidis, snus, U.S. chewing tobacco, U.S. dipping tobacco, water pipe tobacco and western pipe tobacco. Meta-analyses of cancer and non-cancer outcomes for each nicotine product were conducted and are presented in Table 6.
The completeness of the epidemiological data ranges from 33% for smokeless (rest of world), water pipe tobacco and electronic cigarettes to 100% for combustible cigarettes, cut tobacco, cigars and snus. More complete datasets are representative of the relative risk for a wider range of diseases, whereas less complete datasets generally represent a narrower range. While there is significant overlap in the diseases represented for most products, there remain significant gaps in the dataset for certain products.
For cancer outcomes, the products with the highest risk ratios are smokeless (rest of world) (RR 3.675, CI 95% 1.166 – 11.585), combustible cigarettes (RR 2.964, CI 95% 1.579 – 5.565) and cut tobacco (RR 2.964, CI 95% 1.579 – 5.565), followed by bidis (RR 2.884, CI 95% 1.75 – 4.752), water pipe tobacco (RR 2.639, CI 95% 1.635 – 4.258), western pipe tobacco (RR 1.924, CI 95% 1.345 – 2.751) and cigars (RR 1.672, CI 95% 1.218 – 2.295) (Figure 3). In all cases, users of these products have a statistically significant risk of cancer compared to non-users of nicotine products. The risk ratios associated with dipping tobacco (RR 1.31, CI 95% 0.685 – 2.503) and chewing tobacco (RR 1.205, CI 95% 0.906 – 1.601) are above one, but the lower limit of the 95% confidence interval is below one, meaning that these products are not associated with a significantly higher risk than non-use of nicotine products. The same is true for NRT (RR 1.017, CI 95% 0.977 – 1.058) and snus (RR 0.998, CI 95% 0.902 – 1.104). All four of these reduced risk products also have p-values > 0.05.
For non-cancer risk, the order is slightly different compared with cancer risk. Combustible cigarettes and cut tobacco (RR 1.941, CI 95% 1.676 – 2.248) occupy the highest position, followed by water pipe tobacco (RR 1.83, CI 95% 1.095 – 3.057), bidis (RR 1.708, CI 95% 1.542 – 1.891) and western pipe tobacco (RR 1.707, CI 95% 1.363 – 2.139). Further down the chart are snus (RR 1.242, CI 95% 1.007 – 1.533), U.S. chewing tobacco (RR 1.207, CI 95% 1.119 – 1.301), cigars (RR 1.202, CI 95% 1.077 – 1.341) and the smokeless (rest of world) category (RR 1.166, CI 95% 1.08 – 1.258). Finally, the lowest risk ratios are for U.S. dipping tobacco (RR 1.063, CI 95% 0.881 – 1.282) and electronic cigarettes (RR 0.908, CI 95% 0.666 – 1.238). The non-cancer risk for all products is statistically significant, except for the U.S. dipping tobacco and electronic cigarettes category.
The combined risk scores were derived by integrating the LCR and epidemiological analyses and plotting them on a scale from 0 to 100, with 0 representing non-users of any nicotine products and 100 representing users of combustible cigarettes (Figure 4).
Combustible products are associated with the highest risk scores ranging from 40 to 100, with combustible cigarettes at 100, cut tobacco at 99, bidis at 93, cigarillos at 84, water pipe tobacco at 66, western pipe tobacco at 61 and cigars at 40. This high toxicity part of the relative risk hierarchy also includes the smokeless (rest of world) category with a score of 51. All of the products in this higher part of the hierarchy, marked with red bars in Figure 4, have error bars that overlap with other high risk products, and carry a significantly higher risk compared with products in the lower part of the hierarchy (marked by green bars in Figure 4). With relative risk scores of less than 10, the lower part of the hierarchy includes U.S. chewing tobacco at 9, U.S. dipping tobacco at 8, snus at 6, heat-not-burn devices at 5, electronic cigarettes at 3, NRT at 0.4 and non-tobacco nicotine pouches at 0.1.
The data completeness has increased compared to the 2020 iteration, with combustible cigarettes, smokeless (rest of world), cigars, U.S. dipping tobacco, U.S. chewing tobacco and snus now above 75% complete. Bidis, water pipe tobacco and western pipe tobacco are 40–50% complete, with many of the missing data points being filled by the assumption of combustible tobacco values for toxin emissions. Heat-not-burn devices, electronic cigarettes, NRT and non-tobacco pouches are around 50% complete, with the epidemiological analysis accounting for most of the missing data points. As such, their position on the relative risk hierarchy is determined mostly by the LCR analysis. The lowest data completeness scores are cigarillos and cut tobacco, which have only 20% of the data points complete. For cut tobacco, the dataset has mostly been assumed from combustible cigarettes in both the LCR and epidemiological analysis and taking account of this assumption the data completeness score is 100%. For cigarillos, most of the dataset for the LCR (toxin emissions) analysis was assumed from combustible cigarettes and there is no data for this product in the epidemiological analysis. Overall, data completeness has increased from 2020, but there are still significant gaps to fill and therefore, there remains a level of uncertainty due to missing data in the scores of most products.
This update of the nicotine products relative risk assessment adds new data to the analysis, filling in some of the data gaps in the first iteration, and expands its scope to include smokeless tobacco from outside the United States and Europe.
The overall order of products in the relative risk hierarchy is consistent with the original analysis completed in 2020, although some product categories have shifted one place up or down the scale. Notably, western pipe and water pipe tobacco have inversed, as well as U.S. dipping and U.S. chewing tobacco, heat-not-burn and snus, and non-tobacco pouches and NRT. These changes are driven by new data and adjustments to the scope of the categories, for example the limitation of the chewing and dipping tobacco category to U.S. varieties only and the creation of the smokeless (rest of world) and bidis category.
Overall, the data completeness for the epidemiological analysis has increased from 33% in 2020 to 54% in this update and the LCR analysis from 57% to 68% across all the categories of nicotine products. While this is a reasonable increase in the completeness of both analyses, there are still gaps that could affect the position of products in the spectrum moving forward.
In the LCR analysis, the seven highest scoring products have remained in the same position as in the 2020 iteration, and none have changed by more than 1%. Bidis enter the spectrum between combustible cigarettes and cut tobacco, although only one data point was available for the toxin emissions on bidis and the rest of the data was filled based on the assumption that bidis would emit at least the same toxins as a combustible cigarette. The heat-not-burn and electronic cigarette products have shifted higher on the scale in the LCR analysis. This shift can be attributed to incorporation of data from new studies published since 2020 and completion of the data sets, which are now both 100% complete compared to only 91% and 50% previously. The ingestible categories have all shifted slightly higher on the scale, in part due to the change in methodology where ingestible NRT data now serves as the referent. The exception to this is the non-tobacco pouches which have shifted lower due to new data on their toxin content. The rest of world smokeless category enters the scale with a lower LCR than any of the combustible products, but higher than the reduced-risk categories. The range, represented by the error bars, for the smokeless (rest of world) category is very broad, due to the variety of Indian and south Asian smokeless tobacco products that comprise this category and their wide range of measured toxin content. Some products have measured toxin content on par with combustibles, whereas some have toxin contents on par with the lower risk products.
The overall order of the nicotine products in the epidemiological analysis in this update is identical to the 2020 iteration, with the sole exception of cigars which are now above U.S. dipping and chewing tobacco. This change can be explained primarily by the limitation of this category to U.S. varieties of dipping and chewing tobacco, resulting in the removal of data for other types of chewing and dipping tobacco associated with higher risk ratios. This update brings the epidemiological analysis more in line with the order observed for the toxin emissions data, where U.S. dipping and U.S. chewing tobacco are both below cigars and sit much closer to the newer products.
This update of the relative risk hierarchy is broadly in agreement with previous work that estimated the relative harms of nicotine products. Compared to the spectrum presented by Nutt and colleagues, the overall order of the products is the same except for pipes, cigars and water pipe tobacco, which in our spectrum appear as water pipe, western pipe and cigars (from highest to lowest)17. Another point of divergence is that our spectrum suggests that there is a larger difference in risk between combustibles and other nicotine products. While the risk spectrum of Nutt and colleagues shows a significant drop in risk from cigarettes and small cigars to pipes and other combustibles, followed by an incremental decrease in risk down to electronic cigarettes, followed by a significant drop to NRT, our spectrum shows a high risk across much of the combustible and smokeless (rest of world) categories, with incremental decreases from cigarillos down to cigars, followed by a significant gap between cigars and the other product categories (U.S. chewing and dipping tobacco, snus, heat-not-burn, electronic cigarettes, NRT and non-tobacco pouches). This is more consistent with the division of products proposed by Abrams and colleagues, defining “extreme toxicity” as the combustible categories, “much less harm” as the smokeless tobacco (U.S./European), e-cigarettes and NRT grouping, and then “no harm” applying to non-users of any products10. In agreement with this categorization, we define two categories of products; those associated with high risk and those associated with reduced risk of tobacco-related diseases.
The high risk nicotine products category includes combustible cigarettes, cut tobacco, bidis, cigarillos, water pipe tobacco, western pipe tobacco, smokeless (rest of world) and cigars. All products in the high risk category have a combined risk score of between 40 and 100, and are associated with significant harm to health supported by the results of both analyses. The higher risk associated with these products is driven by high levels of toxin exposure, which significantly harm their users health.
Cigars occupy the lowest position in the high risk products group at 40. Despite being a combustible product, cigars are often consumed without inhalation into the lungs, which may be a factor determining the lower risk observed in epidemiological analyses. While the epidemiological analysis is based on real-world consumption, the toxin emissions analysis models only the toxin content and number of puffs per day, without accounting for how the toxins are absorbed into the body. On the other hand, the smokeless (rest of world) category shows much higher cancer risk than any of the other products in the epidemiological analysis, compared with the toxin content analysis. This may be driven by the difference in the varieties represented. In the toxin emissions analysis, studies include varieties of Indian smokeless tobacco, betel quid, zarda and gul, whereas in the epidemiological analysis the products represented are nass, mishri, paan/betel quid, pan-tobacco, khaini, zarda, mawa and gutka.
The reduced risk products are U.S. chewing and dipping tobacco, snus, heat-not-burn, electronic cigarettes, NRT and non-tobacco nicotine pouches. All of these products have a combined risk score of less than 10. The reduced risk category equates to the “much less harm” category defined by Abrams and colleagues, and all products therein carry significantly reduced risk compared with the combustible products. In the epidemiological analysis, the reduced risk products were found to carry a non-statistically significant risk of cancer compared with non-use of any nicotine product, based on the data available. The lifetime cancer risk also shows a significant drop between products in the high risk category and those in the reduced risk category.
This study has a number of limitations, the first of which is the availability of the input data. While there are fewer missing data in this iteration than in the 2020 version, there are still gaps which could give rise to error. For this reason, it is important to interpret the results in the context of the data completeness scores highlighted throughout the presentation of the data. Secondly, there is also a risk of error arising from a lack of accountability of products that have not been studied in the scientific literature. The sample selection bias of this study determines that we are only able to represent products for which data was available, which may not correlate with what is currently on the market. Thirdly, the study methodology is limited to average consumption patterns and usage of a single nicotine product. Therefore, it does not represent the potential risk associated with higher consumption levels of the products or dual/poly-use of the products. Fourthly, the epidemiological meta-analysis combines odds ratios for several diseases, which effectively generalizes a multitude of diseases to “cancer” and “non-cancer” categories. While generalization of multiple datasets is not unprecedented in meta-analyses, where calculation of odds ratios for all-cause mortality often involves a similar process, it is important to note that these values must be interpreted carefully. For example, if the generalized cancer risk ratio is 2, the lung cancer ratio may still be much higher or the risk for stomach cancer much lower, as is the case for combustible cigarettes. The risk ratios derived here are meaningless at the level of individual diseases and should not be used as an indicator for specific disease risk. Rather they give an indication of the average risk across a wide variety of diseases, when several confounders are accounted for.
This update of the relative risk hierarchy defines two categories of products, high risk and reduced risk nicotine products. None of the nicotine products assessed in this study were found to have zero risk, and not using any nicotine product would be the only way to eliminate all risks associated with them. However, the results of this analysis are supportive of the potential to reduce harms caused by high-risk nicotine products by switching to reduced risk products. While it is very important to remain vigilant to new data about novel nicotine products, and to be ready to develop these products with a view to reducing health risks further, reduced risk products can be an effective compromise for reducing the harms of nicotine consumption via combustible tobacco, while giving users the freedom to switch from high risk products on their own terms.
There is a growing body of data demonstrating that nicotine replacement can be a powerful tool for smoking cessation while carrying minimal risks to the user. Indeed, NRT is a widely accepted treatment for smoking cessation. There is also accumulating evidence for other low risk products, such as electronic cigarettes, in their potential to help people who would not otherwise succeed with NRT93. Beyond the scientific literature, the potential of reduced risk products is further borne out in real-world data. In Sweden, the use of snus rose dramatically between the 1940s and 1960s in the male population and smoking rates decreased sharply94. This smoking trend continues to the present day and the smoking rate in Sweden is only 5% of the population, the lowest in Europe, while around 20% still use snus94. The result for public health is that in 2020 Swedish men also had the lowest incidence of tobacco-related cancers across Europe95.
While this study does not cover the efficacy of reduced risk products for driving smoking cessation, the results are consistent with the real-world data from Sweden suggesting that switching from high risk to reduced risk nicotine products could lead to a decrease in tobacco-related disease in the long-term.
This update of the nicotine products relative risk assessment reinforces the conclusions of the first iteration of the study and previous work in this space. Combustible products, as well as the new categories of bidis and smokeless tobacco from the rest of the world, carry the highest risk of tobacco-related disease. At the other end of the spectrum, lower toxicity smokeless and non-combustible nicotine products carry a significantly reduced risk of tobacco-related disease for their users according to the best available evidence.
The review protocol is not published in a register but can be found in the previous version of this publication.
Open Science Framework: Extended data for “Nicotine Products Relative Risk Assessment: An Updated Systematic Review and Meta-analysis.” https://osf.io/pndyu/?view_only=5b9e5eacb62043208bb8919cd6fddbdf
Supporting Information:
◦ Supplement 1: The keywords used in the systematic literature searches
◦ Supplement 2: Sensitivity analyses of the weighting system applied to the relative risk hierarchy.
◦ Supplement 3: Analysis data points used in the lifetime cancer risk analysis (including those carried over from the 2020 iteration).
◦ Supplement 4: Analysis data points used in epidemiological risk analysis
◦ Supplement 5: Full list of studies included in the epidemiological and lifetime cancer risk analyses from the 2020 and 2022 iteration
◦ Supplement 6: References for the number of puffs assumptions for each inhalable product.
Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).
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Are the rationale for, and objectives of, the Systematic Review clearly stated?
Yes
Are sufficient details of the methods and analysis provided to allow replication by others?
Partly
Is the statistical analysis and its interpretation appropriate?
Partly
Are the conclusions drawn adequately supported by the results presented in the review?
Partly
References
1. Boffetta P, Straif K: Use of smokeless tobacco and risk of myocardial infarction and stroke: systematic review with meta-analysis.BMJ. 2009; 339: b3060 PubMed Abstract | Publisher Full TextCompeting Interests: The reviewers are employees of Altria Client Services LLC.
Reviewer Expertise: Tobacco product research, clinical studies, epidemiological evidence, biomarkers, long-term health effects.
Are the rationale for, and objectives of, the Systematic Review clearly stated?
Yes
Are sufficient details of the methods and analysis provided to allow replication by others?
Yes
Is the statistical analysis and its interpretation appropriate?
I cannot comment. A qualified statistician is required.
Are the conclusions drawn adequately supported by the results presented in the review?
Yes
References
1. Nutt DJ, Phillips LD, Balfour D, Curran HV, et al.: Estimating the harms of nicotine-containing products using the MCDA approach.Eur Addict Res. 2014; 20 (5): 218-25 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed.
Alongside their report, reviewers assign a status to the article:
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