Oral Cancer Risk Assessment for Different Types of Smokeless Tobacco Products Sold Worldwide: A Review of Reviews and Meta-analyses

Oral cancer is a highly lethal disease and one of the most debilitating and disfiguring malignancies globally. Head and neck cancers represent the sixth most common cancer worldwide and oral cancer accounts for ∼37% of head and neck cancers with more than 500,000 cases worldwide and are predicted to rise by 62% to 856,000 cases by 2035 (1). According to global cancer statistics, Globocan 2020, cancers of the lip and oral cavity pose an enormous global challenge, with 377,713 new cases and 177,757 deaths accounting for about 3.8% of all cancer cases and 3.6% of cancer deaths globally (2).

Oral cancer is most likely caused by a combination of extrinsic and intrinsic factors acting in concert over a period of time (3, 4). Major risk factors implicated in the etiology of oral cancers are tobacco use (5), areca nut use (6), alcohol consumption (7), ultraviolet radiation, and human papillomavirus (HPV) infection (8). Other factors include poor oral hygiene, low socioeconomic status and genetic factors, occupational exposure (9), weakened immune system, deficiencies in dietary intake, or lack of healthy eating (10). Gender, age, physical activity, and environmental factors may also play a crucial role in the progression of the disease (11, 12). Tobacco and alcohol use are two of the most common risk factors for oral cavity and oropharyngeal cancers (13). As dual use of tobacco products and alcohol act synergistically, and account for 3 of 4 oral cavity cancer cases globally (14, 15).

Smokeless tobacco (SLT) includes a large variety of commercial or noncommercial tobacco preparations used orally or nasally, without combustion. Chewing tobacco, moist snuff, and dry snuff are the three most common types of SLT products used worldwide. The chewing tobacco products mainly include betel quid with tobacco, khaini, zarda, and gutkha. Non-chewing products include oral snuff, nasal snuff, and snus. Snuffed tobacco products are used in either wet or dry form. Use of wet snuff is more common in the Western world, while nasal snuff in dry powder form is used in the South East Asia and Eastern Mediterranean regions (EMR; ref. 16).

The World Health Organization (WHO) South-East Asia Region (SEAR), notably the Indian subcontinent, contains 90% of the world's 250 million SLT consumers and accounts for nearly one third of all cancers (17, 18). SLT use is culturally widely acceptable due to its association with socialization and family tradition in various parts of the world (19). SLT products may be premade (ready-to-use) or custom-made. Premade products range from large factory manufactured products to small cottage industry products, while custom made are assembled by the user or a vendor in market stalls or shops according to one's preferences. Due to the vast heterogeneity and lack of standardization, the chemical formulation or composition of SLT products shows great complexity. Factors for the high prevalence of SLT are its addictive properties, easy accessibility, low cost, and lack of prohibitive legislation (20). This could be the reason that the FDA nicotine reduction strategy, which greatly improved the health consequences of tobacco dependence in smokers, could not be applied to SLT products.

SLT causes cancers of all parts of the oral cavity including the lip, tongue, palate, gum, cheek, buccal gingivae, and floor of the mouth (21), along with esophageal and pancreatic cancer, etc (22). More than 180,000 cases of oral cancer occur every year in SEAR with approximately 90% of which are due to tobacco use (23). The odds of developing oral cancer in SEAR were more than 4 times higher among SLT users than non–tobacco users (24, 25). India has one of the highest incidences of oral cancer and accounts for about 30% of all new cases annually due to the high prevalence of SLT use and betel‐quid chewing (26). Population-based studies from 13 countries showed that the oral cancer incidence rate is increasing, especially among the younger population (27). Other than HPV, an increased incidence of early-onset oral carcinoma in the US has been associated with SLT use, mainly chewing tobacco and snuff (28).

Due to increasing awareness about smoking-related harms and growing regulatory pressures on cigarettes, the global prevalence of smoking is showing a downward trend in the last two decades (29). A systematic analysis of the global burden of disease study results in 204 countries and territories between 1990 and 2019 indicated that the global age-standardized prevalence of smoking had decreased significantly during this period, while the use of SLT products continued unabated during this period (30). Such a trend could be one of the reasons that the incidence of nasopharyngeal cancers has decreased dramatically [estimated annual percentage change (EAPC), –1.5; 95% CI, −1.7 to −1.3) from 1990 to 2017, while the global incidence for lip and oral cavity cancers has shown a substantial increase from 1990 to 2017 (EAPC, 0.26; 95% CI, 0.16–0.37). Globally, the absolute number of lip and oral cavity cancers incidence increased from around 186,000 in 1990 to 389,800 in 2017, which is about 109% increase over 28 years (31).

Great diversity in the preparation and composition of SLT products makes their regulation a big challenge. For example, gutkha is chewing tobacco mixed with areca nut and slaked lime (32), often marketed as a mouth freshener due to added flavors (33). Shammah is a traditional form of fermented chewing tobacco popular in the Middle East (34) while toombak, a homemade oral snuff mainly used in Sudan, is prepared from the tobacco leaves of Nicotiana rustica species having high nicotine content (35). Weak enforcement of regulatory policies and aggressive marketing of SLT products by the tobacco industry worsens the situation (36, 37).

Broadly, reports quantifying the promotion of all types of SLT, as a harm reduction strategy and as a safer alternative to cigarettes, have shown no apparent health benefits at a population level (38). On the other hand, this has caused an increase in the sale of SLT. Because nicotine content in a cigarette stick varies from 0.8 to 13.0 mg/g, while it ranges from 0.8 to 76.0 mg/g in SLT products (39), SLT users absorb 2 to 3 times the amount of nicotine as those who smoke cigarettes (40). This is due to the high alkaline nature of most SLT products providing free nicotine at a high concentration in a short time. Excessive high nicotine concentration makes SLT products highly addictive, and nicotine is also a precursor of carcinogenic tobacco-specific N-nitrosamines (TSNA; refs. 41, 42).

TSNAs are chemically stable compounds under physiologic conditions and are found to be associated with carcinogenicity in humans and experimental animals (43). TSNAs, mainly N’-nitrosonornicotine (NNN) and nicotine-derived nitrosamine ketone (NNK) are listed as group 1 human carcinogens by International Agency for Research on Cancer (3).They are shown to disrupt DNA repair and molecular processes and are the prime cause of oral cancer in SLT users (44–46).

Addictiveness and health hazards of SLT across the globe are largely dependent upon product's chemical composition and its use pattern (47). Globally, the magnitude of cancer risk due to SLT use shows disparity and is highly correlated with the variation in the levels of NNN and NNK present in diverse SLT products sold worldwide (48, 49). Seeing the carcinogenicity of NNN and NNK in humans, the WHO Study Group on Tobacco Product Regulation in 2010 recommended a regulatory limit for maximal total concentration of NNN and NNK as less than 2-μg/g dry weight of tobacco (48) However, the levels of NNN and NNK, per unit dose, in SLT products are much higher as compared with cigarette smoke. While on an average mainstream cigarette smoke contains NNK and NNN in the range of 0.006 to 1.74 μg/g and 0.004 to 2.83 μg/g, respectively, SLT products sold across the world showed NNK levels between 0.019 to 7,870 μg/g and NNN levels between 0.080 to 3080 μg/g against the WHO permissible limit of less than 2 μg/g.

Swedish Match, the principal manufacturer of Swedish moist snuff, adopted a voluntary standard for TSNAs levels, called the GothiaTek standard (50). Table 1 represents comparative data on the type of SLT sold across the world, its preparation process and use, country/WHO region, levels of nicotine, total TSNAs, NNN, and NNK. SLT products viz. shammah, gutkha, toombak, betel quid with tobacco, chewing tobacco (unspecified) along with dry snuff and moist snuff (snus) were found to contain high levels of carcinogenic TSNAs, mainly NNN and NNK in them.

Many research articles in the previous years have indicated the link between SLT and oral cancer but the present systematic review, for the first time, describes the levels of risk estimates of oral cancer associated with the major individual type of SLT products sold across the five WHO regions. It also reports the WHO region-wise oral cancer risk estimates associated with different SLT products and compiles data on the global pattern of different types of SLT product use and the concentration of nicotine, total TSNAs, NNN, and NNK in them.

An electronic search was conducted on PubMed and Google Scholar for articles published between January 1, 2010 to August 5, 2021 using the key phrases “oral cancer”, “oral squamous cell carcinoma”, “smokeless tobacco”, “chewing tobacco”, “betel quid”, “snuff”, “snus”, “gutkha/gutka”, “toombak”, and “shammah”. The references of relevant articles were manually searched for additional eligible citations. This comprehensive review presents pooled data from the different studies.

Author, A.K. Gupta extracted data through this literature search and identified studies. Duplicate records were removed, and the reference lists of the selected articles were screened for additional relevant articles. Titles and abstracts of papers identified through the search strategy were reviewed and relevant articles, potentially fulfilling the inclusion criteria, were retrieved in full text. A second reviewer (R. Mehrotra) screened the titles and abstracts of the retrieved articles to identify the relevance of the articles to the objectives of this review. Two authors, A.K. Gupta and M. Kanaan, independently assessed the eligibility of the selected data to assure quality and minimize biases. Figure 1 provides the detailed strategy of the study selection process using PRISMA guidelines.

• Oral cancer had to be one of the outcomes of SLT use in the adult population.

• Articles presented only as reviews, systematic reviews, and meta-analyses.

• Studies providing OR/risk ratio (RR) estimates with corresponding 95% confidence intervals (CI).

• Articles published in English.

• Studies not designed to investigate SLT association with oral cancer.

• Articles published before year 2010.

• Articles published in languages other than English.

For articles meeting the eligibility criteria, the following information was extracted: the study authors with the date of publication, region of the study, the type of SLT, period of study, OR/RR estimates, and corresponding 95% CI. Information was extracted by one author A.K. Gupta and checked by another author, M. Kanaan (Supplementary Table S1).

The region of the study was classified as global or as one of the WHO regions, namely, the American Region (AMR), EMR including Pakistan, European Region (EUR), African Region (AFR), and South-East Asian Region (SEAR). The type of tobacco was classified as: any type of SLT, if not explicitly specified which type, shammah (Arabian chewing tobacco), toombak (Sudanese dipping tobacco), gutkha (Indian chewing tobacco), betel quid with tobacco, chewing tobacco (unspecified), dry snuff, and moist snuff (snus). If a review article had been updated, then the updated review estimates were used and if two reviews cite the same source, then the one reporting pooled estimates was used.

We used forest plot graphs to represent the OR/RR estimates and 95% CI. Results were stratified by WHO region and by tobacco type. No overall pooled analysis was conducted. If a previous review reported individual studies without pooling the results, these were pooled if the estimates were provided together with 95% CI or other information to enable pooling the results. All studies were systematic reviews with meta-analysis except for one study on toombak where the combined OR estimates were not reported and thus were calculated (see Supplementary Method).

Article does not contain any studies involving human or animal participants.

The data generated in this study are available upon request from the first author A.K. Gupta.

Articles, published in the last decade, i.e., from 2010 to 2021 and reporting the oral cancer risk estimates in the association of the SLT product, were selected for the present review. After removing duplicate records, titles and abstracts of 74 records were retrieved through the selected databases. The reference lists of the included articles were screened for 4 additional articles. All 78 articles were reviewed thoroughly. After removing 52 irrelevant articles, 26 were selected for the full-text study, of which, 17 which did not meet the selection criteria, were excluded. Figure 1 demonstrates the flowchart of the study selection process for SLT use and oral cancer risk using PRISMA guidelines. Oral potentially malignant disorders are abbreviated as OPMD in Fig. 1.

Nine studies fulfilling all the eligibility criteria for inclusion were finally included in the current review. Of these, three reviews evaluated the risk of oral cancer with the use of all types of SLT products combined (51–53). Three reported OR estimates for betel quid with tobacco (51, 54, 55). Dry snuff was evaluated for high risk of oral cancer in three studies (51, 56, 57). Two studies mentioned chewing tobacco (without specifying the type; refs. 51, 56), while one study each was found on shammah (58), gutkha (51), toombak (59), and snus (51). All the selected studies are systematic reviews with meta-analysis and OR estimates were adjusted for confounding factors mainly smoking except for one study (ref. 59; Supplementary Table S1).

Data analysis of all included studies together indicated that the individual product that showed the highest association (OR, 38.74; 95% CI, 19.50–76.96) was shammah, followed by oral snuff (OR, 11.80; 95% CI, 8.45–16.49), gutkha (OR, 8.67; 95% CI, 3.59–20.93), tobacco with betel quid (OR, 7.74; 95% CI, 5.3–11.13), toombak (calculated OR, 4.72; 95% CI, 2.88–7.73; see Supplementary Method), and unspecified chewing tobacco (OR, 4.72; 95% CI, 3.13–7.11). Overall, all selected SLT product types, except snus, were found to have a strong association with oral cancer incidence across the globe. Figure 2 represents a forest plot of the included studies showing ORs and 95% CI for the association between the types of SLT products and the risk of oral cancer.

Region-wise analysis of SLT products showed that the overall global OR for oral cancer for all SLT types combined, ranged from 3.53 (95% CI, 2.76–4.52) to 3.94 (95% CI, 2.70–5.75). In general, region-wise oral cancer risk estimates, for all types combined, were highest for EMR with OR ranging from 1.28 (95% CI, 1.05–1.57) to 14.52 (95% CI, 7.69–27.41), followed by SEAR with OR 4.44 (95% CI, 3.51–5.61) to 5.67 (95% CI, 3.83–8.40) and for AMR, OR 0.95 (95% CI, 0.71–1.25) to 4.72 (95% CI, 0.66–33.69), while it was not statistically significant for EUR with OR 0.94 (95% CI, 0.71–1.25). For further details, see Fig. 3, which represents a forest plot of included studies by the WHO region.

A strong positive association of betel quid with tobacco and oral cancer was seen globally OR 7.18 (95% CI, 5.489.41; ref. 51) while for Asian studies risk estimates for betel quid with tobacco range from OR 7.10 (95% CI, 4.49–11.22) to 7.74 (5.38–11.13; refs. 54, 55), toombak and shammah use for EMR, showed highest oral cancer risk estimate with OR 4.72 (95% CI, 2.88–7.73; ref. 56) and OR 38.74 (95% CI, 19.50–76.96) respectively (58). Risk estimates for snuff-type products vary significantly among various WHO regions. In EUR and AMR, dry snuff and snus are more prevalent. Global oral cancer risk estimates for oral snuff showed OR 4.18 (95% CI, 2.37–7.38; ref. 51) while for AMR, OR was 3.01 (95% CI, 1.63–5.55; 56). Naswar, used in EMR was shown to have a high OR value of 11.80 (95% CI, 8.45–16.49; ref. 57). Globally, chewing tobacco, is shown to have a high oral cancer risk with OR 4.37 (95% CI, 3.27–5.84) as compared with non-chewing SLT products with OR 1.56 (95% CI, 1.04–2.35; ref. 51; Fig. 3).

The level of TSNAs in SLT products plays a significant role in carcinogen exposure levels. Thus, the difference in the magnitude of oral cancer risks can be correlated with the variation in the levels of NNN and NNK present in SLT products (49). TSNA levels vary from 0.08 μg/g to as high as 992 μg/g in the selected SLT products. Figure 4 indicates that high levels of TSNAs are present in SLT products with a high RR for oral cancer. Figure 4 (a) presents TSNAs values on the log scale while the original TSNAs levels in μg/g are presented on the right-hand side of the y-axis. (b) OR and corresponding 95% CIs estimates are based on review studies from the same region that the SLT product TSNAs values are based. The OR estimates for zarda and khaini are not product specific but those for all types of chewing tobacco from SEAR (54). For gutkha, dry snuff, and snus the OR estimates are based on global pooled estimates (51), whereas for naswar (a nasal snuff) these are based on EMR estimates only (57).

According to a recent study, published in Lancet Public Health, of the total 273·9 million tobacco chewers (age 15 and above) in the world, about 228·2 million live in SEAR (30). Over the past several decades, it has been seen that SLT use has increased by nearly 50% in low-and-middle-income countries while declining in high-income countries (60). Tobacco chewing and betel quid with tobacco are the two most prevalent forms of SLT use in Asia (61). In India, the majority of SLT users consume chewing tobacco (11.6% khaini, 8.2% gutkha preparations, 6.2% betel quid with tobacco, 4.7% oral snuff, and 4.4% other SLT products; ref. 51). Gutkha use has been gaining popularity in Europe and US in the last two decades due to its easy availability, low cost and extensive marketing (62). In the US, the sale of SLT products increased by 5.8% between 2011 and 2016, but declined by 3.9% from 2016 to 2019; however, the sale of snus consistently increased while the sale of chewing tobacco, dry snuff, and dissolvable decreased during this period (63).

A recent Centers for Disease Control and Prevention (CDC) report indicated that the incidence of cancers of the oral cavity and pharynx (all sites), not associated with HPV, increased in the US during 2007–2016 (64). In 2018, an estimated 120,000 new patients with oral cancer were diagnosed with 72,000 deaths in India alone (65). Studies revealed that a higher risk of oral cancer was observed for SLT products sold before 1990 (OR, 6.6; 95% CI, 5.3–8.2) as compared with that sold after 1990 (OR, 3.0; 95% CI, 2.3–3.9; ref. 17). Dry snuff sold in the US and Western Europe, before 2000, was shown to have higher relative risks for oral cancers (RR, 8; 95% CI, 2.7–20.0; ref. 66). This is due to improvement in the quality of manufactured tobacco products. Most SLT products sold in the US after 1990, achieved TSNAs levels below 20 ppm as compared with generally high TSNAs levels (above 100 ppm) in earlier SLT products, sold before 1990 (67). Previous studies showed that snus had an association with an increased risk of oral or pancreatic cancer as compared with non–tobacco users (68, 69). However, the current prevalence statistics and epidemiologic data on snus use, in the European population, do not indicate an increased risk of oral cancer compared with cigarettes (70).

More than 50% of oral cancers are attributable to using SLT products in Sudan and India compared with about 4% in US men (65). Literature studies show that toombak has a major role in the etiology of oral/oropharyngeal cancer in Sudan (71, 72) and sub-Saharan Africa (73). Oral cancer occurrence is about 3 to 6 times higher in North-East Nigeria than reported for the US and Europe, mainly due to the use of dry snuff (OR, 10; 95% CI, 4.1–4.3; refs. 74, 75). Oral cancer is the third most common malignancy in Saudi Arabia mainly due to the use of shammah, the traditional form of chewing tobacco prevalent in the Middle East, Yemen, and Sudan (76). A review of studies by Awan and Patil showed that in the SEAR, the oral cancer risk estimates (OR) for betel quid varied from 3.1 to 15.7 (95% CI, 11.0–22.1) and from 1.2 (95% CI, 1.0–1.4) to 12.9 (95% CI, 7.5–22.3) for chewing tobacco (43).

The frequency of SLT use was also seen to vary substantially across countries and by sex, age, ethnic origin, and socioeconomic characteristics within a country (77). A linear dose–response association was observed between oral cancer and chewing tobacco regarding age at initiation, duration, and frequency of chewing per day (78).

Most SLT users have limited awareness of its association with oral cancer due to a lack of knowledge of its harmful constituents and high use due to cultural traditions/ religious norms (79). According to the Global Adult Tobacco Survey in India (GATS, 2016–17), the prevalence of SLT use is very high, especially in females, which could be due to a lack of awareness and knowledge about the health hazards of the SLT product used (80). In the Indian subcontinent, betel quid chewing, with added tobacco has a much higher RR in women (OR, 14.6; 95% CI, 7.6–27.8; ref. 55). Globally, gender-wise sub-group analysis showed a higher risk for females with (OR, 5.8; 95% CI, 2.9–11.6), as compared with males (OR, 2.7; 95% CI, 1.7–4.3; ref. 51).

High nicotine content in SLT products is responsible for the increased levels of TSNAs, which are primarily formed during tobacco fermentation and storage, especially at elevated temperature and moisture (81). A global surveillance study across 113 countries from five WHO regions over the past 10 years, indicated that diverse SLT products sold worldwide seem to contain high levels of carcinogenic TSNAs (52). Maximum concentrations of NNN and NNK content for toombak products from Sudan were found to be 3,085 and 7,870 μg/g respectively, which were remarkably higher than most of the products sold worldwide (82). Average levels of NNN, in a brand of khaini, marketed as snus, were 22.9 and 2.6-μg/g tobacco respectively (83). Khaini, sold in South Asia, contains alarmingly high levels of NNN (39.4–76.9 μg/g) and NNK (2.34–28.4 μg/g; ref. 84). Snuff sold in America was shown to have TSNAs levels as high as 76.5 μg/g, while NNN (0.37–42.6 μg/g) and NNK (0.38–9.9 μg/g; ref. 85). The literature did not report levels of TSNAs in shammah, showing the highest OR. On average, NNN and NNK levels showed an almost 70-fold variation with NNN concentrations ranging from 0.09 to 76.9 μg/g while NNK levels ranged from 0.04 to 28.4 μg/g in all selected SLT products (6). Fermented SLT products, like toombak, shammah, dry snuff, khaini, gutkha, have been found to contain higher levels of TSNA than pasteurized products like snus (84). Shammah, a highly fermented product with high nicotine content (86), is made under long anaerobic conditions so more nitrite is generated which increases TSNA concentration. However, no study was found reporting the TSNA levels in shammah (34). The OR of developing oral cancer, for shammah users was 38.7 (95% CI, 19.5–77.0) which was nearly 39 times higher than non-shammah users (58). Studies showed that NNN and NNK levels for toombak were about 100 folds higher than most of the products sold worldwide (87, 88). Oral cancer risk estimate for toombak use was significantly high among users in comparison with controls (OR, 3.8; 95% CI, 1.7–8.6; ref. 89). A report showed that US snus had high TSNAs with NNN and NNK as high as 42.55 and 9.95 μg/g, respectively (90). Dry snuff, the major factor for tongue carcinoma in the US, is shown to contain high TSNAs levels (91). On the other hand, Swedish snus made with improved manufacturing techniques has low oral cancer risks due to low levels of NNN and NNK (92). Thus, the levels of nicotine and TSNAs showed several hundred-fold variations across different product types and substantial vendor-to-vendor variation within some product categories (93).

Thus, SLT products with higher NNN concentration pose higher cancer risks, so reducing the levels of carcinogenic nitrosamines in finished SLT products could prove a beneficial strategy to reduce OR risk for oral cancer (94, 95).

For the protection of public health, FDA has proposed a tobacco product standard rule, which states that the mean level of NNN in any batch of finished SLT product should not exceed 1.0 μg/g of tobacco (on a dry weight basis) at any time through the product's labelled expiration date (96). However, constituent regulation and control of SLT products lag far behind cigarettes, mainly due to non-standardized production and storage methods, greater heterogeneity, and the lack of strict legal policies for SLT (39).

The current review is to bring attention to the prevention community to the risks of individual SLT product for risk of oral cancer. Most carcinogenic SLT types sold across the various geographic regions worldwide, mainly shammah, toombak, gutkha, betel quid with tobacco, dry snuff were found to be associated with high oral cancer risks. Data analysis indicated that the shammah showed the highest association (OR, 38.7; 95% CI, 19.5–77.0), followed by oral snuff (OR, 11.8; 95% CI, 8.4–16.4), gutkha (OR, 8.7; 95% CI, 3.6–20.9), tobacco with betel quid (OR, 7.7; 95% CI, 5.3–11.1), toombak (OR, 4.7; 95% CI, 2.9–7.7) and unspecified chewing tobacco (OR, 4.7; 95% CI, 3.0–7.1). The difference in the magnitude of oral cancer risks has been found to correlate highly with regional variation in the SLT product type which showed great diversity and heterogeneity in its composition, usage and manufacturing process. A decrease in smoking and the prevalence of lung cancer in the US shows the effectiveness of decades of public education and tobacco control policies (97). However, the rising incidence of oral cancer across the world, primarily associated with SLT use, indicates that the tobacco control policies do not have a more prominent effect on SLT usage. The huge variation in the levels of carcinogenic TSNAs, especially NNN and NNK, in diverse types of SLT products, hinders the comparability of results from evaluating the global risks estimate of SLT to human health across the globe. It is imperative to develop and effectively implement strategies for monitoring TSNA levels in SLT products. There is a critical need for systematic surveillance of all types of SLT products through legal control of the permissible TSNA levels. Global standards for testing and measuring TSNAs levels in all types of SLT products, with effective measures to minimize the levels of TSNA, can significantly help reduce oral cancer risk associated with individual SLT products.

The high concentration of TSNAs, mainly NNN and NNK, in diverse types of SLT products is the major causative factor for the development of oral cancer. Applying a grassroots approach to lower the levels of carcinogenic TSNAs at various stages of SLT production, right from its growth, processing, manufacturing, and storage, could prove to be a beneficial strategy. This includes the use of tobacco plant varieties having low levels of nitrate and TSNAs precursors, decreasing the use of nitrate fertilizers and chemical pesticides while growing tobacco, avoiding microbial contamination during tobacco processing, air-curing of leaves instead of fire curing under controlled conditions, use of newer technologies like heat treatment, pasteurization for tobacco processing and avoiding tobacco fermentation etc. can significantly lower the concentration of carcinogenic TSNAs in the finished SLT products (39).

As the majority of oral cancer are preventable through risk factors intervention, creating awareness about their carcinogenicity among consumers, constituent's disclosure along with their health hazard information on all SLT products may play a key factor in reducing oral cancer incidence in the future. Strict regulatory measures are to be taken for the additives and flavoring agents in SLT products, which make them palatable and more appealing especially amongst youth (98).

For the first time, the World Health Assembly, in 2007, passed a resolution on oral health and oral cancer prevention to be an integral part of national cancer control programs. The WHO global oral health program was launched to work for the capacity building in oral cancer prevention in different countries, inter-country exchange and the development of global surveillance systems for oral cancer and risk factors. With the establishment of more cancer registries across the globe and their secondary data analysis, the surveillance of SLT products should become easier.

K. Siddiqi reports grants from National Institute of Health Research outside the submitted work. No disclosures were reported by the other authors.

A.K. Gupta: Conceptualization, resources, data curation, investigation, methodology, writing–original draft, writing–review and editing. M. Kanaan: Software, formal analysis, validation, investigation, methodology, writing–review and editing. K. Siddiqi: Supervision, investigation, visualization, project administration. D.N. Sinha: Conceptualization, visualization, project administration. R. Mehrotra: Formal analysis, supervision, writing–original draft, project administration, writing–review and editing.

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