Open Access

Global burden of disease due to smokeless tobacco consumption in adults: analysis of data from 113 countries

  • Kamran Siddiqi1Email author,
  • Sarwat Shah1,
  • Syed Muslim Abbas2,
  • Aishwarya Vidyasagaran1,
  • Mohammed Jawad3,
  • Omara Dogar1 and
  • Aziz Sheikh4
BMC Medicine201513:194

DOI: 10.1186/s12916-015-0424-2

Received: 6 May 2015

Accepted: 17 July 2015

Published: 17 August 2015

Abstract

Background

Smokeless tobacco is consumed in most countries in the world. In view of its widespread use and increasing awareness of the associated risks, there is a need for a detailed assessment of its impact on health. We present the first global estimates of the burden of disease due to consumption of smokeless tobacco by adults.

Methods

The burden attributable to smokeless tobacco use in adults was estimated as a proportion of the disability-adjusted life-years (DALYs) lost and deaths reported in the 2010 Global Burden of Disease study. We used the comparative risk assessment method, which evaluates changes in population health that result from modifying a population’s exposure to a risk factor. Population exposure was extrapolated from country-specific prevalence of smokeless tobacco consumption, and changes in population health were estimated using disease-specific risk estimates (relative risks/odds ratios) associated with it. Country-specific prevalence estimates were obtained through systematically searching for all relevant studies. Disease-specific risks were estimated by conducting systematic reviews and meta-analyses based on epidemiological studies.

Results

We found adult smokeless tobacco consumption figures for 115 countries and estimated burden of disease figures for 113 of these countries. Our estimates indicate that in 2010, smokeless tobacco use led to 1.7 million DALYs lost and 62,283 deaths due to cancers of mouth, pharynx and oesophagus and, based on data from the benchmark 52 country INTERHEART study, 4.7 million DALYs lost and 204,309 deaths from ischaemic heart disease. Over 85 % of this burden was in South-East Asia.

Conclusions

Smokeless tobacco results in considerable, potentially preventable, global morbidity and mortality from cancer; estimates in relation to ischaemic heart disease need to be interpreted with more caution, but nonetheless suggest that the likely burden of disease is also substantial. The World Health Organization needs to consider incorporating regulation of smokeless tobacco into its Framework Convention for Tobacco Control.

Background

Smokeless tobacco (SLT) consists of a number of products containing tobacco, which are consumed—without burning—through the mouth or nose [1]. A diverse range of SLT products are available worldwide, varying in their composition, methods of preparation and consumption, and associated health risks (Table 1) [1]. Its use is most prevalent in South and South-East Asia where one-third of tobacco is consumed in smokeless form [2, 3]. Wrapped in a betel leaf with areca nut, slaked lime, and catechu, SLT is often served at social occasions in this region. Other products (e.g. gutkha, khaini) contain slaked lime, areca nut, flavourings, and aromatic substances [4]. A number of products based on powdered tobacco (e.g. snus) are also consumed in Nordic countries and North America. In other parts of world, the most commonly used SLT products (Table 1) include Chimó (Venezuela), Nass (Uzbekistan, Kyrgyzstan), Tambook (Sudan, Chad), and Snuff (Nigeria, Ghana, South Africa).
Table 1

Smokeless tobacco products consumed most commonly across the world

Smokeless tobacco products

Regions (WHO)

Countries (highest consumption)

Other ingredients

Preparation and use

pHa

Nicotinea (mg/g)

Total TSNAa (ng/g)

Snus (Swedish)

Europe (Region A)

Nordic countries (Denmark, Finland, Iceland, Norway, Sweden)

Water, sodium carbonate, sodium chloride, moisturisers, flavouring

A heat treatment process; placed between the gum and upper lip

6.6–7.2

7.8–15.2

601–723

Plug, Snuff (US), Snus (US)

Americas (Region A and B)

US, Canada, Mexico

Sweeteners, liquorice

Plug; air cured

4.7–7.8

3.9–40.1

313–76,500

Dry or moist snuff; finely ground and fire cured

Snus; steam cured

Snuff; kept between lip and gum, dry snuff can be inhaled too

Chimó

Americas (Region B)

Venezuela, Colombia

Sodium bicarbonate, brown sugar, Mamo’n tree ashes

Tobacco paste made from tobacco leaves; placed between the lip or cheek and gum and left there for some time

6.9–9.4

5.3–30.1

9390

Nass (Naswar)

Europe (Region B) and Eastern Mediterranean (Region D)

Uzbekistan, Kyrgyzstan, Tajikistan, Afghanistan, Pakistan, Iran

Lime, ash, flavourings (cardamom), indigo

Sundried and powdered; placed between lip or cheek and gum

8.4–9.1

8.9–14.2

478–1380

Tambook

Eastern Mediterranean (Region D) and Africa (Region D)

Sudan, Chad

Mixed with moist sodium bicarbonate

Fermented and grounded; placed and kept in mouth

7.3–10.1

9.6–28.2

302,000–992,000

Snuff (North and West African)

Africa (Region D)

Nigeria, Ghana, Algeria, Cameroon, Chad, Senegal

Dried tobacco leaves mixed with potassium nitrate and other salts

Dry snuff; finely ground and inhaled as a pinch

9.0–9.4

2.5–7.4

1520–2420

Moist snuff is placed in mouth

Snuff (South African)

Africa (Region E)

South Africa

Dried tobacco leaves mixed with ash

Dry snuff; finely ground and inhaled as a pinch

6.5–10.1

1.2–17.2

1710–20,500

Khaini

South East Asia (Regions B and D) Western Pacific (Region B) Eastern Mediterranean (Region D) Europe (Region A)

India, Bangladesh, Nepal, Bhutan

Slaked lime, menthol, flavourings, areca nut

Shredded; kept in mouth between lips and gum

9.6–9.8

2.5–4.8

21,600–23,900

Zarda

Bangladesh, India, Pakistan, Myanmar, Thailand, Indonesia, Nepal, Maldives, Sri Lanka, UK

Served wrapped in a betel leaf with lime, catechu, areca nuts

Shredded tobacco leaves are boiled with lime and saffron; the mixture is dried then chewed and spat

5.2–6.5

9.5–30.4

5490–53,700

Gutkha

India, Pakistan, Bangladesh, Nepal, Myanmar, Sri Lanka, UK

Betel nut, catechu, flavourings, sweeteners

Commercially manufactured; sucked, chewed, and spat

7.4–8.9

0.2–4.2

83–23,900

WHO World Health Organization, TSNA tobacco-specific nitrosamines

aFigures are adapted from Stanfill et al. [6], Lawler et al. [17], and NIH & CDC 2014 report on smokeless tobacco products [37]

In addition to nicotine, SLT products contain over 30 carcinogens [5] including tobacco-specific nitrosamines (TSNA), arsenic, beryllium, cadmium, nickel, chromium, nitrite, and nitrate. The level of nicotine and carcinogens vary between products (Table 1) [6]. For example, nicotine content among SLT products varies between 0.2 and 40.1 mg/g, compared to commercial filtered cigarettes which contain 16.3 mg/g of nicotine [7]. Their pH also varies, which, being a key determinant of the level of absorption of nicotine and carcinogens, determines its toxicity: the higher the pH, the higher the absorption and, consequently, the higher the toxicity [6]. Such considerations mean that there are substantial variations between different SLT products in the level of risk posed to human health [4, 811]. It is therefore important not to consider SLT as a single product, but rather as groups of products with differences in their toxicity and addictiveness depending upon their carcinogen, nicotine, and pH levels. The diversity in SLT toxicity has been an impediment not only in establishing its global risks to human health, but also in agreeing on international policies for its prevention and control. It is therefore perhaps unsurprising that despite several country-specific studies [1215] no attempt has hitherto been made to estimate its global disease burden.

To overcome these challenges, we developed a novel approach to estimate the global burden associated with the use of SLT products. The determinants of their toxicity (carcinogens and pH) and addictiveness (nicotine) are dependent on preparation methods, ingredients that are added to SLT products, and consumption behaviours. Given that the SLT preparations and consumption patterns are determined by, and vary with, geography and culture [16], it is possible to group them according to their availability in different parts of the world (Table 1). These groups of SLT products, classified according to different geographical regions, will also be distinguishable from each other on the basis of their toxicity, addictiveness, and associated health risks. Hence, the risks were assumed to be highest in those regions and cultures where products are combined with other ingredients, and are prepared and consumed in a way that makes them very alkaline (i.e. a high pH), and rich in nicotine and TSNA [6, 17]. Building on this assumption, we aimed to estimate the worldwide burden of disease attributable to SLT use, measured in terms of disability adjusted life years (DALYs) lost and number of deaths in 2010.

Methods

We used the comparative risk assessment method, which evaluates changes in population health (burden of disease) that result from modifying a population’s exposure to a risk factor [18, 19]. For this, we used 2010 datasets, which provided the most recent global estimates of burden of disease [20]. The estimates were calculated for individual countries and then grouped into 14 World Health Organization (WHO) sub-regions (Additional file 1: Appendix 1) [21]. These were generated through estimating the following:
  1. 1.

    The prevalence of SLT consumption

     
  2. 2.

    Diseases caused by SLT use

     
  3. 3.

    The relative risks of acquiring these diseases

     
  4. 4.

    The population attributable fraction (PAF) for each of these diseases

     
  5. 5.

    The overall burden of these diseases in terms of DALYs lost and deaths

     
  6. 6.

    Proportion of this burden attributable to SLT use

     

Prevalence of smokeless tobacco use

We carried out a systematic literature search (see Additional file 1: Appendix 2 for a detailed description of the methods employed) for the point prevalence (current use) of SLT consumption among all adult (≥15 years) populations, and also for men and women separately. Only one prevalence report was included for one country. Latest national prevalence data collected as part of an international or regional survey were preferred over an older isolated national or a sub-national survey. We used data from the Global Adult Tobacco Survey (GATS), where available [22]. In its absence, other international (WHO STEPwise approach to Surveillance, The Demographic and Health Surveys), regional (Special Europe Barometer), national, and/or sub-national surveys were used to extract prevalence data.

Diseases caused by smokeless tobacco use

A scoping review was carried out to identify associated diseases. A series of focused literature reviews were subsequently carried out to find and assess the evidence of causation between each of these diseases and SLT use. Our search strategies and selection criteria are provided in Additional file 1: Appendix 3. One researcher ran the searches, which were then independently scrutinised by another independent researcher who considered the search results against the pre-specified inclusion and exclusion criteria. Similarly, one researcher extracted data, which were independently crosschecked by another researcher. In particular, we appraised the studies for case definitions for diseases and for assessment methods for measuring exposure to SLT and for investigating the effects of potential confounders. We excluded those diseases (and respective studies) where evidence was not supportive of a causal relationship. Only studies that adequately controlled for smoking and/or alcohol as potential confounders either at the design or the analysis stage were carried forward into the next stage of the analysis (discussed below). Quality was assessed using the Newcastle-Ottawa Scale for assessing the quality of non-randomised studies in meta-analyses [23].

Assessing risk and meta-analyses

Risk estimates (relative risks/odds ratios) and their confidence intervals (CI) were log transformed to produce effect sizes and standard errors, respectively [24]. We carried out random effects meta-analysis using RevMan version 5 to estimate pooled risk estimates. We first obtained country-specific risk estimates (relative risks/odds ratios) for individual diseases by pooling data from the included studies carried out in respective countries. We then extrapolated non-specific global risk estimates by pooling respective country-specific risk estimates. We were mindful that the risk of acquiring diseases varies between countries owing to differences in SLT products used. Therefore, for each disease where good country-specific risk estimates (pooled estimate from a meta-analysis of three or more studies in respective country) were available, we applied these to respective countries and also to those countries and regions where similar SLT products are used. In the absence of good country-specific risk estimates, we used either one of the following two approaches: (a) In countries and regions that use SLT products with moderate to high pH and TSNAs levels, we applied non-specific global estimates (pooled estimate from a meta-analysis of all studies); and (b) in countries and regions where there was either no information available on the SLT products or the information available indicates low levels of pH and TSNA, we did not apply any estimates. Further details on the application of these assumptions across all 14 WHO regions are provided in web Additional file 1: Appendix 4. We only used those pooled relative risks (country or non-specific) that were found to be statistically significant.

Where associations were presented for more than one SLT product in the same paper, we considered these as separate studies for the purpose of meta-analysis. Similarly, where risks were given separately for former and current SLT users, these were also treated as separate studies. We did not attempt to group risks according to gender because very few studies had such sub-group analysis.

Population attributable fraction

PAF is the proportional reduction in disease or mortality that would occur if exposure were reduced to zero [25, 26]. PAF was estimated for each disease for each country for both males and females, using the following formula:
$$ \mathrm{P}\mathrm{A}\mathrm{F}={\mathrm{P}}_{\mathrm{e}}\left({\mathrm{RR}}_{\mathrm{e}}\hbox{--} 1\right)/\left[1+{\mathrm{P}}_{\mathrm{e}}\left({\mathrm{RR}}_{\mathrm{e}}\hbox{--} 1\right)\right] $$
$$ {\mathrm{P}}_{\mathrm{e}}=\mathrm{Prevalence} $$
$$ {\mathrm{RR}}_{\mathrm{e}}=\mathrm{Relative}\ \mathrm{Risk} $$

Overall burden

The overall number of DALYs and deaths for each associated disease for both males and females for each country were extracted from the 2010 Global Burden of Disease study [27, 28].

Attributable burden

The attributable burden (AB), in deaths and DALYs, was estimated for each associated disease for each country for both males and females by multiplying PAF by the overall burden of the disease (B):
$$ \mathrm{AB}=\mathrm{P}\mathrm{A}\mathrm{F}\times \mathrm{B} $$

Results

Prevalence of smokeless tobacco use

We found adult prevalence figures for SLT consumption in 115 countries (Fig. 1). The definition for ‘adult’ ranged from 15, 16, 25, or 35 years at one end to 49, 64, 65, 70, 74, 84, 85, 89, or no age limit at the other. The PRISMA diagram describing the selection of the prevalence reports is provided in Additional file 1: Appendix 5a.
https://static-content.springer.com/image/art%3A10.1186%2Fs12916-015-0424-2/MediaObjects/12916_2015_424_Fig1_HTML.gif
Fig. 1

Smokeless tobacco prevalence among males and females

In general, SLT consumption was higher among males than females (Table 2). Mauritania had the highest prevalence of SLT consumption among females (28.3 %), followed by Bangladesh (27.9 %), Madagascar (19.6 %), India (18.4 %), and Bhutan (17.3 %). Among males, Myanmar (51.4 %), Nepal (37.9 %), India (32.9 %), Uzbekistan (31.8 %), and Bangladesh (26.4 %) had the highest consumption rates. Within Europe, SLT (snus) consumption was high in Sweden (24.0 % males, 7.0 % females) and Norway (20.0 % males, 6.0 % females).
Table 2

Prevalence of smokeless tobacco use in different countries of the world according to WHO sub-regional classification

WHO sub-regions

Country

M

F

Source

Year

Africa (Region D)

Algeria

21

0.4

STEPS [38]

2005

Benin

12.7

5.7

STEPS [38]

2008

Burkina Faso

3.86

DHS [39]

2011

Cameroon

1.94

0.94

DHS [39]

2011

Cape Verde

3.5

5.8

STEPS [38]

2007

Chad

1.9

0.4

STEPS [38]

2008

Comoros

7.72

2.99

DHS [39]

2012

Gabon

0.48

0.34

DHS [39]

2012

Gambia

0.8

1.4

STEPS [38]

2010

Ghana

1.33

0.2

DHS [39]

2008

Guinea

1.4

1.5

STEPS [38]

2009

Liberia

2.3

2.4

DHS [40]

2007

Madagascar

24.66

19.6

DHS [39]

2009

Mali

5

1.2

STEPS [38]

2007

Mauritania

5.7

28.3

STEPS [38]

2006

Niger

4.55

2.3

DHS [39]

2012

Nigeria

3.2

0.5

DHS [40]

2008

Sao Tome & Principe

3.8

1.9

STEPS [38]

2009

Senegal

6.63

0.23

DHS [39]

2011

Sierra Leone

3

12

STEPS [38]

2009

Togo

5.1

2.2

STEPS [38]

2010

Africa (Region E)

Botswana

7.2

14.5

STEPS [38]

2007

Burundi

0.03

0.31

DHS [39]

2011

Congo (Brazzaville)

8.3

1.54

DHS [39]

2012

Congo (Republic)

8.67

3.22

DHS [39]

2013

Cote d'Ivoire

0.61

1.27

DHS [39]

2012

Eritrea

5.8

0.2

STEPS [38]

2004

Ethiopia

1.94

0.2

DHS [39]

2011

Kenya

2.05

1.29

DHS [39]

2008

Lesotho

1.3

9.1

DHS [40]

2009

Malawi

1.9

5

STEPS [38]

2009

Mozambique

10.94

0.82

DHS [39]

2011

Namibia

1.8

2.3

DHS [40]

2006–07

Rwanda

5.8

2.73

DHS [39]

2011

South Africa

2.4

10.9

DHS [41]

2003

Swaziland

2.6

0.8

STEPS [38]

2007

Tanzania

2.03

0.83

DHS [39]

2010

Uganda

2.94

1.5

DHS [39]

2011

Zambia

0.3

1.2

DHS [39]

2007

Zimbabwe

1.6

0.4

DHS [41]

2011

Americas (Region A)

Canada

2

ICS [41]

2011

USA

6.5

0.4

ICS [41]

2010

Americas (Region B)

Argentina

0.1

0.2

GATS [42]

2012

Barbados

0

0.6

STEPS [38]

2007

Brazil

0.6

0.3

GATS [42]

2010

Dominican Republic

1.9

0.3

DHS [40]

2007

Grenada

2.2

0.3

STEPS [38]

2011

Mexico

0.3

0.3

GATS [42]

2009

Paraguay

3

1.6

ICS [41]

2011

St Kitts & Nevisa

0.3

0.1

STEPS [38]

2007

Trinidad & Tobago

0.5

0.3

STEPS [38]

2011

Venezuela

6.2

0.9

ICS [41]

2011

Americas (Region D)

Haiti

2.5

DHS [40]

2005–06

Eastern Mediterranean (Region B)

Libya

2.2

0.1

STEPS [38]

2009

Saudi Arabia

1.3

0.5

STEPS [38]

2004

Tunisia

8.6

2.2

ICS [41]

2005–06

Eastern Mediterranean (Region D)

Egypt

4.8

0.3

GATS [42]

2009

Iraq

1.6

0.3

STEPS [38]

2006

Pakistan

16.3

2.44

DHS [43]

2012–13

Sudan

24.1

1

STEPS [38]

2005

Yemen

15.1

6.2

ICS [41]

2003

Europe (Region A)

Austria

7.8

1.1

SEBS [44]

2012

Belgium

1.1

0.6

SEBS [44]

2012

Cyprus

2.1

0.4

SEBS [44]

2012

Czech Republic

2.5

0.4

SEBS [44]

2012

Denmark

3

1

ICS [41]

2010

Finland

5.5

0.3

ICS [41]

2011

France

1.2

0.6

SEBS [44]

2012

Germany

3.4

3.4

SEBS [44]

2012

Iceland

5.97

ICS [41]

2008

Ireland

2.2

0.9

SEBS [44]

2012

Italy

1.8

1.5

SEBS [44]

2012

Luxembourg

1.8

1

SEBS [44]

2012

Malta

5.5

1.5

SEBS [44]

2012

Netherlands

0.3

0.1

ICS [41]

2011

Norway

20

6

ICS [41]

2011

Portugal

4.4

1.1

SEBS [44]

2012

Slovenia

1.8

0.4

SEBS [44]

2012

Spain

0.4

0.2

SEBS [44]

2012

Sweden

24

7

ICS [41]

2011

Switzerland

4

1.3

ICS [41]

2011

United Kingdom

1.6

0.5

SEBS [44]

2012

Europe (Region B)

Ajerbaijan

0.3

0

DHS [40]

2006

Armenia

1.8

0

DHS [40]

2005

Bulgaria

0.3

0

SEBS [44]

2012

Georgia

1

0.2

ICS [41]

2010

Kyrgyzstan

7

0.3

ICS [41]

2006

Poland

1

0.1

GATS [42]

2009

Romania

0.4

0.2

GATS [42]

2011

Slovakia

3.9

0.7

SEBS [44]

2012

Uzbekistan

31.8

0.2

DHS [40]

2002

Europe (Region C)

Latvia

5.8

0.9

ICS [41]

2010

Lithuania

1.2

0.2

SEBS [44]

2012

Moldova

0.1

0

DHS [40]

2005

Russia

1

0.2

GATS [42]

2009

Ukraine

0.5

0

GATS [42]

2010

South East Asia (Region B)

Indonesia

1.5

2

GATS [42]

2011

Sri Lanka

24.9

6.9

STEPS [38]

2006

Thailand

1.1

5.2

GATS [42]

2011

South East Asia (Region D)

Bangladesh

26.4

27.9

GATS [42]

2009

Bhutan

21.1

17.3

STEPS [38]

2007

India

32.9

18.4

GATS [42]

2009

Maldives

5.6

2.6

STEPS [38]

2011

Myanmar

51.4

16.1

STEPS [38]

2009

Nepal

37.9

6

DHS [41]

2011

Timor Leste

2.48

1.93

DHS [43]

2009–10

Western Pacific (Region A)

Australia

0.75

0.41

ICS [45]

2004

Western Pacific (Region B)

Cambodia

2.2

14.8

STEPS [38]

2010

China

0.7

0

GATS [42]

2010

Lao People’s Democratic Republic

14.6

1.1

STEPS [38]

2008

Malaysia

0.9

0.6

GATS [42]

2011

Micronesia

22.4

3

STEPS [38]

2002

Mongolia

2.8

0.5

STEPS [38]

2009

Philippines

2.8

1.2

GATS [42]

2009

Vietnam

0.3

2.3

GATS [42]

2010

DHS The Demographic and Health Surveys, ICS Individual Country Survey, GATS Global Adult Tobacco Survey, SEBS The Special Europe Barometer Survey, STEPS STEPwise approach to Surveillance

aPopulations of St Kitts and Nevis are tiny and unlikely to affect our estimates

Diseases caused by smokeless tobacco use

The initial scoping review identified a number of associated diseases, including a range of cancers, cardiovascular diseases (ischaemic heart disease and stroke), periodontal conditions, and adverse pregnancy outcomes. The subsequent more focused systematic reviews identified 53 studies (Table 3) reporting association between SLT consumption and cancers of mouth, pharynx, larynx, oesophagus, lung, and pancreas (39 studies); and cardiovascular diseases, such as ischaemic heart disease and stroke (14 studies). PRISMA flow diagrams describing the selection process of the studies identified in the literature searches are provided in Additional file 1: Appendix 5b,c. The pooled non-specific relative risks were statistically significant for cancers of the mouth, pharynx, and oesophagus (Figs. 2, 3, 4, and 5). Only statistically significant relative risks (country-specific or non-specific) were included in the model to estimate attributable risks. For example, the pooled non-specific relative risk for laryngeal cancer was 1.42 (95 % CI 0.77–2.59), and hence excluded (Additional file 1: Appendix 6). Likewise, none of the country-specific estimates for the USA were statistically significant (Additional file 1: Appendix 4). Based on the above reviews, we assumed that a causal association exists between some SLT products and cancers of the mouth, pharynx, and oesophagus, and ischaemic heart disease.
Table 3

Smokeless tobacco use and risk of cancers, ischaemic heart disease, and stroke—studies included in meta-analysis

Country

Study period

Study design

Exposure status

Inclusion of cigarette/alcohol users

Outcome

Odds ratios/relative risks (95 % confidence intervals)

Comments

Quality assessment (NOS)a

Reference

CANCERS

India

2001–2004

Case–control

Smokeless tobacco with or without additives

No/No

Oral cancer

0.49 (0.32–0.75)

Exclusive SLT users

Selection****

Anantharaman et al. 2007 [46]

Comparability**

Exposure/Outcome*

India

1996–1999

Case–control

Ever SLT users

Yes/Yes

Oral cancer

7.31 (3.79–14.1)

Never drinkers adjusted for smoking

Selection****

Balaram et al. 2002 [47]

9.19 (4.38–19.28)

Never smokers adjusted for alcohol

Comparability**

Exposure/Outcome *

India

1982–1992

Case–control

Tobacco quid chewing

Yes/No

Oral cancer

5.8 (3.6–9.34)

Adjusted for smoking

Selection***

Dikshit & Kanhere 2000 [48]

Pharyngeal cancer

1.2 (0.8–1.8)

Comparability*

Lung cancer

0.7 (0.4–1.22)

Exposure/Outcome*

India

Unclear

Case–control

Chewing tobacco

No/No

Oral cancer

10.75 (6.58–17.56)

Exclusive SLT users

Selection**

Goud et al. 1990 [49]

Comparability*

Exposure/Outcome0

India

1990–1997

Cohort

Current SLT users

No/No

Oral cancer

5.5 (3.3–9.17)

Exclusive SLT users

Selection****

Jayalekshmi et al. 2009 [50]

Former SLT users

9.2 (4.6–18.40)

Comparability*

Exposure/Outcome**

India

1990–1997

Cohort

Current SLT user

Yes/Yes

Oral cancer

2.4 (1.7–3.39)

Adjusted for smoking and alcohol

Selection****

Jayalekshmi et al. 2010 [51]

Former SLT users

2.1 (1.3–3.39)

Comparability*

Exposure/Outcome***

India

May 2005

Case–control

Ever SLT users

No/No

Oral cancer

4.23 (3.11–5.75)

Exclusive SLT users

Selection***

Jayant et al. 1977 [52]

Pharyngeal cancer

2.42 (1.74–3.37)

Comparability**

Laryngeal cancer

2.8 (2.07–3.79)

Exposure/Outcome0

Oesophageal cancer

1.55 (1.15–2.07)

India

1968

Case–control

Tobacco

Yes/No

Oral cancer

4.63 (3.50–6.14)

Exclusive chewers and non-chewers data available

Selection***

Jussawalla & Deshpande 1971 [53]

Pharyngeal cancer

3.09 (2.31–4.13)

Comparability**

Laryngeal cancer

2.29 (1.72–3.05)

Exposure/Outcome0

Oesophageal cancer

3.82 (2.84–5.13)

India

2005–2006

Case–control

Tobacco flakes

Yes/Yes

Oral cancer

7.6 (4.9–11.79)

Adjusted for smoking and alcohol

Selection****

Madani et al. 2010 [54]

Gutkha

12.7 (7–23.04)

Comparability**

Mishiri

3.0 (1.9–4.74)

Exposure/Outcome*

India

Unclear

Case–control

Chewing tobacco

Yes/Yes

Oral cancer

5.0 (3.6–6.94)

Adjusted for smoking and alcohol

Selection****

Muwonge et al. 2008 [55]

Comparability*

Exposure/Outcome*

India

1982–1984

Case–control

Chewing tobacco

Yes/No

Oral cancer

10.2 (2.6–40.02)

Adjusted for smoking

Selection***

Nandakumar et al. 1990 [56]

Comparability**

Exposure/Outcome*

India

1980–1984

Case–control

SLT users

No/No

Oral cancer

1.99 (1.41–2.81)

Exclusive SLT users

Selection**

Rao et al. 1994 [57]

Comparability0

Exposure/Outcome*

India

1952–1954

Case–control

Chewing tobacco

No/No

Oral cancer

4.85 (2.32–10.14)

Exclusive SLT users

Selection***

Sanghvi et al. 1955 [58]

Pharyngeal cancer

2.02 (0.94–4.33)

Comparability**

Laryngeal cancer

0.76 (0.37–1.56)

Exposure/Outcome0

India

1983–1984

Case–control

Snuff (males only)

Yes/Yes

Oral cancer

2.93 (0.98–8.76)

Adjusted for smoking and alcohol; adjusted effect size is only among males

Selection***

Sankaranarayan et al. 1990 [59]

Comparability0

Exposure/Outcome*

India

Not given

Case–control

Tobacco chewing

Yes/Yes

Oropharyngeal cancer

7.98 (4.11–13.58)b

Adjusted for smoking and alcohol

Selection***

Wasnik et al. 1998 [60]

Comparability**

Exposure/Outcome0

India

1991–2003

Case–control

Chewing tobacco

No/No

Oral cancer

5.88 (3.66–7.93)

Exclusive SLT users

Selection****

Subapriya e al. 2007 [61]

Comparability**

Exposure/Outcome**

India

1950–1962

Case–control

Tobacco with or without paan or lime

Yes/No

Oral and oropharyngeal cancer

41.90 (34.20–51.33)

Exclusive chewer data available

Selection**

Wahi et al. 1965 [62]

Note: data of habit was not available for the whole cohort

Comparability**

Exposure/Outcome0

Pakistan

1996–1998

Case–control

Naswar

Yes/Yes

Oral cancer

9.53 (1.73–52.50)

Adjusted for smoking and alcohol

Selection***

Merchant et al. 2000 [63]

Paan with tobacco

8.42 (2.31–30.69)

Comparability**

Exposure/Outcome*

Sweden

1973–2002

Cohort

Snus

Yes/Yes

Oral and pharyngeal combined

3.10 (1.50–6.41)

Adjusted for smoking and alcohol

Selection**

Roosar et al. 2008 [64]

Comparability**

Outcome***

India

1993–1999

Case–control

Chewing tobacco

Yes/Yes

Oral cancer

5.05 (4.26–5.99)

Adjusted for smoking and alcohol

Selection***

Znaor et al. 2003 [65]

Pharynx

1.83 (1.43–2.34)

Comparability**

Oesophagus

2.06 (1.62–2.62)

Exposure/Outcome*

Norway

1966–2001

Cohort

Chewing tobacco plus oral snuff

No/No

Oral cancer

1.1 (0.5–2.42)

Adjusted for smoking, might be confounded by alcohol use

Selection***

Bofetta et al. 2005 [66]

Oesophageal cancer

1.4 (0.61–3.21)

Comparability*

Pancreatic cancer

1.67 (1.12–2.49)

Exposure/Outcome***

Lung cancer

0.80 (0.61–1.05)

Sweden

1988–1991

Case–control

Oral snuff

Yes/Yes

Oral cancer

1.4 (0.8–2.45)

Adjusted for smoking and alcohol

Selection**

Lewin et al. 1998 [67]

Larynx

0.9 (0.5–1.62)

Comparability**

Oesophagus

1.2 (0.7–2.06)

Exposure/Outcome*

Pharynx

0.7 (0.4–1.22)

Sweden

1969–1992

Cohort

Snus

No/No

Oral cancer

0.8 (0.4–1.60)

Exclusive SLT users

Selection***

Luo et al. 2007 [68]

Lung cancer

0.8 (0.5–1.28)

Comparability*

Pancreatic cancer

2 (1.20–3.33)

Exposure/Outcome***

Sweden

2000–2004

Case–control

Oral snuff

Yes/Yes

Oral

0.70 (0.3–1.63)

Adjusted for smoking and alcohol

Selection***

Rosenquist et al 2005 [69]

Comparability**

Exposure/Outcome**

Sweden

1980–1989

Case–control

Oral snuff

Yes/Yes

Oral cancer

0.8 (0.5–1.28)

Adjusted for smoking and alcohol

Selection**

Schildt et al. 1998 [70]

Comparability**

Exposure/Outcome***

USA

1972–1983

Case–control

Oral snuff

Yes/Yes

Oral cancer

0.8 (0.4–1.60)

Not clear if adjusted for smoking and alcohol

Selection**

Mashberg et al. 1993 [71]

Chewing tobacco

1 (0.7–1.43)

Comparability0

Exposure/Outcome*

USA

Not given

Case–control

SLT use

Yes/Yes

Oral cancer

0.90 (0.38–2.13)

Adjusted for smoking and alcohol

Selection***

Zhou et al. 2013 [15]

Pharyngeal cancer

1.59 (0.84–3.01)

Comparability**

Laryngeal cancer

0.67 (0.19–2.36)

Exposure/Outcome*

India

2001–2004

Case–control

Chewing tobacco

No/No

Pharyngeal cancer

3.18 (1.92–5.27)

Exclusive SLT users

Selection***

Sapkota et al. 2007 [72]

Laryngeal cancer

0.95 (0.52–1.74)

Comparability**

Exposure/Outcome*

Pakistan

1998–2002

Case–control

Snuff dipping

No/No

Oesophageal cancer

4.1 (1.3–12.93)

Adjusted for areca nut

Selection***

Akhtar et al. 2012 [73]

Quid with tobacco

14.2 (6.4–31.50)

Comparability**

Exposure/Outcome**

India

2008–2012

Case–control

Nass chewing

No/No

Oesophageal cancer

2.88 (2.06–4.03)

Exclusive SLT users

Selection***

Dar et al. 2012 [74]

Gutkha chewing

2.87 (0.87–9.47)

Comparability**

Exposure/Outcome**

India

2007–2011

Case–control

Oral snuff

Yes/Yes

Oesophageal cancer

3.86 (2.46–6.06)

Adjusted for smoking and alcohol

Selection**

Sehgal et al. 2012 [75]

Comparability**

Exposure/Outcome*

India

2011–2012

Case–control

Chewing tobacco

Yes/Yes

Oesophageal cancer

2.63 (1.53–4.52)

Adjusted for smoking and alcohol

Selection***

Talukdar et al. 2013 [76]

Comparability**

Exposure/Outcome*

Sweden

1995–1997

Case–control

Oral snuff

Yes/Yes

Oesophageal cancer (adenocarcinoma)

1.2 (0.7–2.06)

Adjusted for smoking and alcohol

Selection***

Lagergren et al. 2000 [77]

(Squamous cell carcinoma)

1.4 (0.9–2.18)

Comparability**

Exposure/Outcome*

Sweden

1969–1993

Cohort

Oral snuff

Yes/No

Oesophageal cancer (Adenocarcinoma)

1.3 (0.8–2.11)

Adjusted for smoking

Selection**

Zendehdel et al. 2008 [78]

(Squamous cell carcinoma)

1.2 (0.8–1.80)

Comparability*

Exposure/Outcome**

Sweden

1974–1985

Cohort

SLT users

No/NA

Lung cancer

0.90 (0.20– 4.05)

Adjusted for age, region of origin

Selection***

Bolinder et al. 1994 [79]

Comparability*

Outcome**

Morocco

1996–1998

Case–control

SLT users

Yes/No

Lung cancer

1.05 (0.28–3.94)

Adjusted for smoking

Selection**

Sasco et al. 2002 [80]

Comparability**

Exposure/Outcome**

USA

1977–1984

Case–control

SLT users

Yes/No

Oesophageal cancer

1.2 (0.1–14.40)

Adjusted for smoking

Selection***

Brown et al. 1988 [81]

Comparability**

Exposure/Outcome**

USA

1986–1989

Case–control

SLT users

Yes/No

Pancreatic cancer

1.4 (0.5–3.92)

Adjusted for smoking

Selection***

Alguacil & Silverman 2004 [82]

Comparability*

Exposure/Outcome**

USA

2000–2006

Case–control

Chewing tobacco

Yes/Yes

Pancreatic cancer

0.6 (0.3–1.20)

Adjusted for smoking and alcohol

Selection****

Hassan et al. 2007 [83]

Oral snuff

0.5 (0.1–2.5)

Comparability**

Exposure/Outcome*

CARDIOVASCULAR DISEASES (ischaemic heart disease and stroke)

52 countries

1999–2003

Case–control

Chewing tobacco

No/Yes

Myocardial infarction

1.57 (1.24–1.99)

Adjusted for diabetes, abdominal obesity, hypertension, exercise, diet

Selection****

Teo et al. 2006 [29]

Comparability**

Exposure/Outcome*

Pakistan

2005–2011

Case–control

Dippers only (Naswar)

No/NA

Myocardial infarction

1.46 (1.20–1.77)

Adjusted for age, sex, region, ethnicity

Selection****

Alexander 2013 [84]

Chewers only (Paan/ Supari/ Gutkha)

1.71 (1.46–2.00)

Comparability**

Exposure/Outcome**

Bangladesh

2006–2007

Case–control

Ever SLT users

No/NA

Myocardial infarction, Angina pectoris

2.8 (1.1–7.13)

Adjusted for age, sex, hypertension

Selection***

Rahman & Zaman 2008 [85]

Comparability**

Exposure/Outcome*

Bangladesh

2010

Case–control

Ever SLT users

No/NA

Myocardial infarction, Angina pectoris

0.77 (0.52–1.14)

Adjusted for age, hypertension, diabetes, acute psycho-social stress

Selection****

Rahman et al. 2012 [86]

Comparability**

Exposure/Outcome*

Sweden

1998–2005

Case–control

Current SLT users

No/NA

Myocardial infarction

0.73 (0.35–1.52)

Exclusive SLT users

Selection***

Hergens et al. 2005 [87]

Former SLT users

1.2 (0.46–3.13)

Comparability**

Exposure/Outcome**

Sweden

1978–2004

Cohort

Ever SLT users

No/NA

Myocardial infarction

0.99 (0.90–1.10)

Adjusted for age, BMI, region of residence

Selection**

Hergens et al. 2007 [88]

Comparability**

Exposure/Outcome***

Sweden

1989–1991

Case–control

Regular SLT users

Yes/NA

Myocardial infarction

1.01 (0.66–1.55)c

Adjusted for age, education, smoking

Selection***

Huhtasaari et al. 1992 [89]

Comparability**

Exposure/Outcome*

Sweden

1991–1993

Case–control

Former SLT users

No/NA

Myocardial infarction

1.23 (0.54–2.82)

Exclusive SLT users

Selection****

Huhtasaari et al. 1999 [90]

Comparability**

Exposure/Outcome**

Sweden

1988–2000

Cohort

Daily SLT users

No/NA

Ischaemic heart disease

1.41 (0.61–3.28)

Adjusted for BMI, physical activity, diabetes, hypertension

Selection****

Johansson et al. 2005 [91]

Comparability**

Exposure/Outcome**

Sweden

1985–1999

Case–control

Current SLT users

No/NA

Myocardial infarction

0.82 (0.46–1.46)

Adjusted for BMI, physical activity, education, cholesterol

Selection****

Wennberg et al. 2007 [92]

Former SLT users

0.66 (0.32–1.36)

Comparability**

Exposure/Outcome**

Sweden

1985–2000

Case–control

Regular SLT users

No/NA

Stroke

0.87 (0.41–1.83)

Adjusted for diabetes, hypertension, education, marital status, cholesterol

Selection****

Asplund et al. 2003 [93]

Comparability**

Exposure/Outcome**

Sweden

1978–2003

Cohort

Ever SLT users

No/NA

Stroke

1.02 (0.92–1.13)

Adjusted for age, BMI, region of residence

Selection**

Hergens et al. 2008 [94]

Comparability**

Exposure/Outcome***

Sweden

1998–2005

Cohort

Current SLT users

No/NA

Ischaemic heart disease

0.85 (0.51–1.42)

Adjusted for age, hypertension, diabetes, cholesterol

Selection***

Hansson et al. 2009 [95]

Former SLT users

Stroke

1.07 (0.56–2.04)

Comparability**

1.18 (0.67–2.08)

Exposure/Outcome**

1.35 (0.65–2.82)

Sweden

1991–2004

Cohort

SLT users

No/NA

Myocardial infarction

0.75 (0.3–1.87)

Adjusted for age, diabetes, occupation, hypertension, physical activity, BMI, marital status

Selection***

Janzon et al. 2009 [96]

Stroke

0.59 (0.2–1.5)

Comparability**

Exposure/Outcome**

BMI body mass index, NA not applicable, NOS Newcastle-Ottawa Scale, SLT smokeless tobacco

aNOS for assessing the quality of non-randomised studies in meta-analyses based on selection, comparability, and exposure/outcome. Number of stars (*) indicates the number of criteria met for each of these three categories [23]

bEffect sizes are for oral and pharyngeal cancers combined and were included in the meta-analysis for oral cancer only

cBased on parameter estimate and standard error reported in paper

https://static-content.springer.com/image/art%3A10.1186%2Fs12916-015-0424-2/MediaObjects/12916_2015_424_Fig2_HTML.gif
Fig. 2

Random effects model showing relative risk for mouth cancer for smokeless tobacco use

https://static-content.springer.com/image/art%3A10.1186%2Fs12916-015-0424-2/MediaObjects/12916_2015_424_Fig3_HTML.gif
Fig. 3

Random effects model showing relative risk for pharyngeal cancer for smokeless tobacco use

https://static-content.springer.com/image/art%3A10.1186%2Fs12916-015-0424-2/MediaObjects/12916_2015_424_Fig4_HTML.gif
Fig. 4

Random effects model showing relative risk for oesophageal cancer for smokeless tobacco use

https://static-content.springer.com/image/art%3A10.1186%2Fs12916-015-0424-2/MediaObjects/12916_2015_424_Fig5_HTML.gif
Fig. 5

Random effects model showing relative risk for ischaemic heart disease for smokeless tobacco use

Relative risks

Based on 32 studies, the estimated pooled non-specific relative risk for mouth (oral cavity, tongue, and lip) cancers was 3.43 (95 % CI 2.26–5.19) (Fig. 2). Studies from South-East Asia indicated an increased risk of oral cancer for SLT use whereas results from studies pertaining to Europe and the Americas did not substantiate such an association. For cancers of the pharynx, pooled non-specific relative risk was 2.23 (95 % CI 1.55–3.20), based on ten studies (Fig. 3). For oesophageal cancers, no clear increased risk was present in studies in the USA, whereas a pooled estimate reported a relative risk of 2.17 (95 % CI 1.70–2.78) (Fig. 4). For ischaemic heart disease, no good country-specific risk estimates were available (Fig. 5). However, we found one large case–control study (INTERHEART study) [29] conducted in 52 countries from all regions showing a statistically significant risk of ischaemic heart disease (adjusted odds ratio 1.57, 95 % CI 1.24–1.99) among SLT users.

Applying risk estimates

For cancers in general, pooled country-specific risk estimates obtained from Sweden and the USA were applied to Europe A and Americas A, respectively. For South-East Asia B and D and Western Pacific B regions, country-specific estimates from India were applied. There were a few exceptions to this rule, because some countries (UK, Mexico, Pakistan, China, Mongolia) differed in their SLT consumption patterns from their respective regions (see Additional file 1: Appendix 4 for details). In short, country-specific risk estimates for cancers could only be fully applied to five regions. For the remaining nine regions, our findings were imputed either by applying statistically significant non-specific risk estimates or none at all (Additional file 1: Appendix 4). In case of ischaemic heart disease, Sweden was the only country with a pooled country-specific relative risk (0.98, 95 % CI 0.90–1.07) obtained from a good number (more than three) of studies. For 11 out of 14 regions, we used a large multi-country study (INTERHEART)—conducted in 52 countries—to apply and deduce risk estimates. The three regions (Europe A and C and Americas D) were excluded, as these were not among those regions included in the INTERHEART study (Additional file 1: Appendix 4). There was one exception (UK) where INTERHEART study estimates were applied because SLT products consumed in the UK commonly originate from South Asia.

Attributable burden

The attributable burden of SLT use is outlined in Table 4. Our estimates indicate that in 2010, SLT use led to 1,711,539 DALYs lost and 62,283 deaths due to cancers of mouth, pharynx, and oesophagus, and, based on data from the benchmark 52 country INTERHEART study, 4,725,381 DALYs lost and 204,309 deaths from ischaemic heart disease. In total, SLT use caused the loss of 6,436,920 DALYs and 266,592 deaths. The figures show that three-quarters of these deaths and loss of DALYs were among males. This disease burden was found to be distributed across all WHO sub-regions. However, nearly 85 % of the total burden attributable to SLT use was in South-East Asia, with India alone accounting for 74 % of the global burden, followed by Bangladesh (5 %).
Table 4

Number of DALYs lost and deaths from SLT use in 2010, by WHO sub-region as defined in Additional file 1: Appendix 1

WHO sub-regionsa

Mouth cancer

Pharyngeal cancer

Oesophageal cancer

Ischaemic heart disease

All causes

 

M

F

All

M

F

All

M

F

All

M

F

All

M

F

All

DEATHS

Africa D

86

36

123

15

2

17

157

77

233

2323

751

3074

2581

866

3448

Africa E

155

85

240

19

12

31

389

252

641

1202

923

2125

1765

1272

3037

Americas A

0

0

0

0

0

0

0

0

0

10,240

649

10,889

10,240

649

10,889

Americas B

90

11

102

28

3

31

74

9

83

1030

291

1321

1222

314

1536

Americas D

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Eastern Mediterranean B

11

1

12

1

0

2

4

1

5

441

74

515

457

76

534

Eastern Mediterranean D

933

254

1187

604

59

663

1012

129

1141

7401

926

8327

9950

1368

11,318

Europe A

66

13

78

16

2

18

244

38

282

539

145

684

865

197

1062

Europe B

146

3

148

57

1

58

260

2

262

5506

156

5662

5969

162

6130

Europe C

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

South-East Asia B

438

396

835

129

58

187

243

139

382

3205

1852

5057

4016

2445

6461

South-East Asia D

11,527

6459

17,987

12,715

3485

16,200

15,247

5625

20,873

117,523

45,047

162,570

157,013

60,617

217,630

Western Pacific A

0

0

0

0

0

0

0

0

0

69

36

104

69

36

104

Western Pacific B

134

159

293

22

34

56

51

63

114

3167

814

3981

3374

1070

4443

Worldwide

13,586

7418

21,003

13,608

3656

17,264

17,680

6336

24,016

152,647

51,662

204,309

197,520

69,072

266,592

DALYs

Africa D

2516

1046

3562

452

65

517

4119

1906

6024

64,043

19,116

83,159

71,130

22,132

93,262

Africa E

4926

2293

7220

573

349

922

10,159

6290

16,449

33,502

21,109

54,610

49,159

30,042

79,201

Americas A

0

0

0

0

0

0

0

0

0

172,206

7213

179,419

172,206

7213

179,419

Americas B

2311

230

2541

734

63

797

1717

176

1893

22,252

4728

26,980

27,014

5197

32,210

Americas D

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Eastern Mediterranean B

285

36

321

33

9

43

86

20

106

9841

1383

11,224

10,246

1448

11,694

Eastern Mediterranean D

29,240

7669

36,909

16,446

1800

18,247

27,777

3613

31,390

187,394

21,544

208,938

260,857

34,627

295,483

Europe A

1514

224

1738

369

45

414

4949

545

5494

8397

1491

9888

15,230

2304

17,534

Europe B

4439

60

4499

1704

20

1724

6460

56

6517

115,640

1991

117,631

128,243

2128

130,371

Europe C

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

South-East Asia B

10,968

7741

18,709

3217

1487

4704

5608

2983

8591

66,969

29,913

96,881

86,762

42,124

128,886

South-East Asia D

351,752

179,051

530,803

338,976

107,041

446,017

400,770

143,146

543,916

290,6993

938,528

3,845,521

3,998,491

1,367,766

5,366,257

Western Pacific A

0

0

0

0

0

0

0

0

0

1024

340

1364

1024

340

1364

Western Pacific B

3700

3567

7267

615

794

1409

1313

1485

2797

72,936

16,830

89,766

78,564

22,675

101,239

Worldwide

411,652

201,918

613,569

363,120

111,673

474,793

462,957

160,219

623,177

3,661,195

1,064,186

4,725,381

4,898,924

1,537,996

6,436,920

Discussion

We have found that SLT is consumed worldwide and that its use results in substantial, potentially avoidable, morbidity and mortality. However, owing to marked differences in the types of products available, patterns of consumption, and associated risks, there are substantial differences in the attributable burden between regions and countries. In particular, SLT consumption in South-East Asia leads to a much greater burden of disease than in Sweden, despite its use being equally prevalent. This is due to the much lower levels of TSNA and pH in SLT products in Sweden compared to those found in SLT in South-East Asia [6]. Similarly, SLT products used in the USA have lower risk estimates than for those used in South-East Asia.

We found that more than six million DALYs were lost and over a quarter of a million deaths occurred in 2010 owing to SLT consumption. However, our estimates require cautious interpretation because of a number of potential limitations.

First, our analysis was limited to those countries and diseases for which reliable prevalence and risk data were available, respectively. Most global tobacco surveys that reported on SLT consumption did not include all countries in the world. While global figures on smoking prevalence were available, we did not find any SLT prevalence figures for almost half of all countries. Where SLT prevalence figures were available, two countries (Micronesia and Saint Kitts & Nevis) were excluded from the final estimates owing to an absence of data for cancers in the 2010 Global Burden of Disease study. Moreover, for certain disease outcomes, e.g. adverse reproductive and oral health effects, poor quality as well as limited quantity of evidence precluded their inclusion.

Second, lack of country-specific risk estimates leads to considerable uncertainty. Despite several countries reporting SLT consumption, most did not have any reliable information on the types of SLT products used and on their associated health risks. For example, studies from several African countries reported high SLT consumption (Table 2), but provided little information on their hazard profile. There is some evidence, mainly from Sudan [30], that products used in Africa tend to have a higher pH than those used in Europe or in the USA. However, we did not find any data on the risks associated with widespread SLT use in southern parts of Africa. Likewise, various forms of SLT have been used in parts of South America (Brazilian rapê or Venezuelan chimó) for many years, yet there are no studies on the health effects of such products. In the absence of country-specific risk estimates, we assumed that in general those populations that consume similar SLT products are likely to share similar health risks and susceptibilities. We extrapolated and applied risk estimates to most countries included in our analysis on that basis (Additional file 1: Appendix 4). For cancer, our extrapolation was based on estimates obtained from several studies; for ischaemic heart diseases, extrapolations were mostly based on a single although large multi-country study (INTERHEART). As a result, almost three-quarters of the estimated SLT disease burden, which is attributed to ischaemic heart disease, is uncertain. Therefore, a cautious interpretation would be to exclude ischaemic heart disease burden figures from our estimates. However, in estimating these figures we had already excluded those regions and their respective countries that were not included in INTERHEART study. As a pointer on future research, our study highlights the need to study risk of SLT consumption on ischaemic heart diseases across the spectrum of SLT products and consumption behaviours. In time, this will produce more country-specific risk estimates, which would undoubtedly improve the reliability of our estimates presented here.

Third, the disease burden observed in 2010 is unlikely to be a consequence of SLT consumption in recent years. Therefore, our prevalence figures, obtained in surveys carried out in the last decade and used in the estimates, could be problematic. However, we assumed that the SLT consumption rates have remained stable over the last 30–40 years in these countries. We consider this as a safe assumption given that SLT use is not a new trend and historically embedded in culture and tradition in many countries, most remarkably in South Asia [31]. Consumption trends based on repeated youth surveys in India and Bangladesh suggest that SLT use has remained stable over the last decade [32]. Evidence from Sweden suggests that while more people are using snus now than 25 years ago, the consumption trends, compared to cigarette use, have essentially remained stable in this period [33, 34].

Finally, the age range of the adult sampling frames used in different SLT prevalence surveys varied, which could also increase uncertainty. The main difference between two of the key categories used was in the adult range starting from either ≥15 years or ≥25 years. Given that the risk of cancers and ischemic heart disease accumulates after many years of use well beyond young adult age, it may not have made much of a difference to our burden of disease estimates.

For the seven countries in South-East Asia region D, we estimated that 55,060 deaths caused by cancers of mouth, pharynx, and oesophagus, could be attributed to SLT in 2010. This is a little higher than the estimates from a recent study in which 50,000 deaths were attributed to SLT in eight South Asian countries [4]. This discrepancy may be explained by the fact that we used the most recent, updated prevalence and burden of disease figures.

Our estimate does not include economic impact. However, given the nature of the associated diseases, it is likely that the SLT use imposes a huge economic burden on weak health systems and poor economies. Moreover, owing to higher consumption of SLT among people of lower socio-economic status and inequitable access to health care in low-income and middle-income countries, its use is likely to contribute to driving disadvantaged sections of these societies into further poverty. A disproportionate impact on the male population (more than 70 % of disease burden due to SLT is in males) is also likely to have a disproportionate economic impact on societies in terms of reduced workforce contributions by men. On the other hand, effective legislation, policy, and preventive programmes could avert this burden due to SLT.

The signatories of the WHO’s Framework Convention on Tobacco Control should, in addition to the focus on reducing smoking consumption and related harm, now also consider the need to regulate production, marketing, and labelling of SLT products. This is particularly necessary in those countries where prevalence is high and SLT products are manufactured at a large scale without any checks on the carcinogenic level of their ingredients [35]. In countries where its use is largely limited to immigrant populations (such as in the UK) [36], strict regulation and taxation policies should be enforced which prevent import of SLT products and sale by local shops.

SLT is an important health issue, applying to a large part of the world. The data presented here are the most comprehensive gathered and brought together thus far. However, considerable uncertainties remain pertaining to risk estimation of different diseases associated with SLT use. Therefore more research is needed to investigate the newly established and previously known adverse health outcomes pertaining to SLT, particularly within countries where prevalence is high but no research evidence of risk estimation is available. Moreover, more descriptive questions about the type of SLT products and the pattern of use should be introduced into national surveys and publications of such findings encompassing all the regions.

Conclusions

Our study, a first attempt to assess global burden of disease due to SLT, estimates that more than six million DALYs are lost and over a quarter of a million deaths occur each year owing to its consumption. There is a need to build on the insights obtained from efforts to reduce cigarette smoking-related harm and to investigate strategies to reduce use of SLT and decrease the substantial associated burden of harm.

Abbreviations

CI: 

Confidence intervals

DALYs: 

Disability-adjusted life years

DHS: 

Demographic and Health Surveys

GATS: 

Global Adult Tobacco Survey

ICS: 

Individual Country Survey

PAF: 

Population attributable fraction

SEBS: 

Special Europe Barometer Survey

SLT: 

Smokeless tobacco

STEPS: 

STEPwise Approach to Surveillance

TSNA: 

Tobacco-specific nitrosamines

WHO: 

World Health Organization

Declarations

Funding

This study was funded by grants received from Leeds City Council, Leeds, UK and Medical Research Council, UK (MC_PC_13081).

Ethics approval

No ethics approval was required for this study.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Health Sciences, Hull York Medical School, University of York
(2)
Fatima Memorial Hospital College of Medicine and Dentistry, Fatima Memorial System
(3)
Department of Primary Care and Public Health, Imperial College London, Charing Cross Campus
(4)
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh

References

  1. CDC. Smokeless Tobacco Fact Sheets. Prepared for the 3rd International Conference on Smokeless tobacco: advancing Science and Protecting Public Health. Stockholm, Sweden: National Cancer Institute, CDC and Prevention & Stockholm Centre of Public Health; 2002.
  2. SEARO. WHO: report on oral tobacco use and its implications in South East Asia. New Delhi: SEARO; 2004.Google Scholar
  3. Palipudi K, Rizwan SA, Sinha DN, Andes LJ, Amarchand R, Krishnan A, et al. Prevalence and sociodemographic determinants of tobacco use in four countries of the World Health Organization: South-East Asia region: findings from the Global Adult Tobacco Survey. Indian J Cancer. 2014;51:S24–32.PubMedGoogle Scholar
  4. Boffetta P, Hecht S, Gray N, Gupta P, Straif K. Smokeless tobacco and cancer. Lancet Oncol. 2008;9:667–75.View ArticlePubMedGoogle Scholar
  5. International Agency for Research on Cancer. Smokeless tobacco products. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 89. Lyon, France: International Agency for Research on Cancer; 2008.
  6. Stanfill SB, Connolly GN, Zhang L, Jia LT, Henningfield JE, Richter P, et al. Global surveillance of oral tobacco products: total nicotine, unionised nicotine and tobacco-specific N-nitrosamines. Tob Control. 2011;20:e2.View ArticlePubMedGoogle Scholar
  7. Malson JL, Sims K, Murty R, Pickworth WB. Comparison of the nicotine content of tobacco used in bidis and conventional cigarettes. Tob Control. 2001;10:181–3.PubMed CentralView ArticlePubMedGoogle Scholar
  8. Critchley JA, Unal B. Health effects associated with smokeless tobacco: a systematic review. Thorax. 2003;58:435–43.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Gupta PC, Ray CS, Sinha DN, Singh PK. Smokeless tobacco: a major public health problem in the SEA region: a review. Indian J Public Health. 2011;55:199–209.View ArticlePubMedGoogle Scholar
  10. Gupta PC, Sreevidya S. Smokeless tobacco use, birth weight, and gestational age: population based, prospective cohort study of 1217 women in Mumbai, India. BMJ. 2004;328:1538.PubMed CentralView ArticlePubMedGoogle Scholar
  11. 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 CentralView ArticlePubMedGoogle Scholar
  12. Gupta PC, Subramoney S. Smokeless tobacco use and risk of stillbirth: a cohort study in Mumbai, India. Epidemiology. 2006;17:47–51.View ArticlePubMedGoogle Scholar
  13. England LJ, Kim SY, Shapiro-Mendoza CK, Wilson HG, Kendrick JS, Satten GA, et al. Maternal smokeless tobacco use in Alaska Native women and singleton infant birth size. Acta Obstet Gynecol Scand. 2012;91:93–103.View ArticlePubMedGoogle Scholar
  14. Tomar SL. Is use of smokeless tobacco a risk factor for cigarette smoking? The U.S. experience. Nicotine Tob Res. 2003;5:561–9.View ArticlePubMedGoogle Scholar
  15. Zhou J, Michaud DS, Langevin SM, McClean MD, Eliot M, Kelsey KT. Smokeless tobacco and risk of head and neck cancer: evidence from a case–control study in New England. Int J Cancer. 2013;132:1911–7.PubMed CentralView ArticlePubMedGoogle Scholar
  16. Napier AD, Ancarno C, Butler B, Calabrese J, Chater A, Chatterjee H, et al. Culture and health. Lancet. 2014;384:1607–39.View ArticlePubMedGoogle Scholar
  17. Lawler TS, Stanfill SB, Zhang L, Ashley DL, Watson CH. Chemical characterization of domestic oral tobacco products: total nicotine, pH, unprotonated nicotine and tobacco-specific N-nitrosamines. Food Chem Toxicol. 2013;57:380–6.View ArticlePubMedGoogle Scholar
  18. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected major risk factors and global and regional burden of disease. Lancet. 2002;360:1347–60.View ArticlePubMedGoogle Scholar
  19. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2224–60.PubMed CentralView ArticlePubMedGoogle Scholar
  20. Horton R, Chan M, Kim J, Watts C, Cairncross S. Global Burden of Disease Study 2010. Lancet. 2012;380:2053–260.View ArticlePubMedGoogle Scholar
  21. World Health Organization. The World Health Report 2002: reducing risks, promoting healthy life. Geneva: World Health Organization; 2002.Google Scholar
  22. CDC. Global Tobacco Surveillance System Data. www.cdc.gov/tobacco/global/gtss/.
  23. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp].
  24. Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med. 2000;19:3127–31.View ArticlePubMedGoogle Scholar
  25. Rockhill B, Newman B, Weinberg C. Use and misuse of population attributable fractions. Am J Public Health. 1998;88:15–9.PubMed CentralView ArticlePubMedGoogle Scholar
  26. Öberg M, Jaakkola MS, Woodward A, Peruga A, Prüss-Ustün A. Worldwide burden of disease from exposure to second-hand smoke: a retrospective analysis of data from 192 countries. Lancet. 2011;377:139–46.View ArticlePubMedGoogle Scholar
  27. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2197–223.View ArticlePubMedGoogle Scholar
  28. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095–128.View ArticlePubMedGoogle Scholar
  29. Teo KK, Ounpuu S, Hawken S, Pandey MR, Valentin V, Hunt D, et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case–control study. Lancet. 2006;368:647–58.View ArticlePubMedGoogle Scholar
  30. Idris AM, Ibrahim Y, Warnakulasuriya K, Cooper D, Johnson N, Nilsen R. Toombak use and cigarette smoking in the Sudan: estimates of prevalence in the Nile state. Prev Med. 1998;27:597–603.View ArticlePubMedGoogle Scholar
  31. Siddiqi K, Gupta PC, Prasad VM, Croucher R, Sheikh A. Smokeless tobacco use by south Asians. Lancet Glob Health. 2013;1:e71.View ArticlePubMedGoogle Scholar
  32. Sinha DN, Palipudi KM, Jones CK, Khadka BB, Silva PD, Mumthaz M, et al. Levels and trends of smokeless tobacco use among youth in countries of the World Health Organization South-East Asia Region. Indian J Cancer. 2014;51:S50–53.PubMedGoogle Scholar
  33. Norberg M, Malmberg G, Ng N, Broström G. Who is using snus? - Time trends, socioeconomic and geographic characteristics of snus users in the ageing Swedish population. BMC Public Health. 2011;11:929–9.PubMed CentralView ArticlePubMedGoogle Scholar
  34. Rodu B, Stegmayr B, Nasic S, Cole P, Asplund K. Evolving patterns of tobacco use in northern Sweden. J Intern Med. 2003;253:660–5.View ArticlePubMedGoogle Scholar
  35. Khan A, Huque R, Shah SK, Kaur J, Baral S, Gupta PC, et al. Smokeless tobacco control policies in South Asia: a gap analysis and recommendations. Nicotine Tob Res. 2014;16:890–4.View ArticlePubMedGoogle Scholar
  36. Panesar SS, Gatrad R, Sheikh A. Smokeless tobacco use by south Asian youth in the UK. Lancet. 2008;372:97–8.View ArticlePubMedGoogle Scholar
  37. National Cancer Institute and Centers for Disease Control and Prevention. Smokeless tobacco and public health: a global perspective. Bethesda, MD: US Department of Health and Human Services, Centres for Disease Control and Prevention, and National Institute of Health, National Cancer Institute; 2014.
  38. STEPS Country Reports [http://www.who.int/chp/steps/reports/en/].
  39. Sreeramareddy CT, Pradhan P, Sin S. Prevalence, distribution, and social determinants of tobacco use in 30 sub-Saharan African countries. BMC Med. 2014;12:243.PubMed CentralView ArticlePubMedGoogle Scholar
  40. Ansra DL, Arnold F, Kishor S, Hsia J, Kaufmann R. Tobacco use by men and women in 49 countries with demographic and health surveys. DHS Comparative Reports No 31. Calverton, MD: ICF International; 2013.Google Scholar
  41. World Health Organization. WHO report on the global tobacco epidemic, 2013: enforcing bans on tobacco advertising, promotion and sponsorship. Geneva: WHO; 2013.Google Scholar
  42. GATS (Global Adult Tobacco Survey) [http://www.who.int/tobacco/surveillance/gats/en/].
  43. Sreeramareddy CT, Pradhan PM, Mir IA, Sin S. Smoking and smokeless tobacco use in nine South and Southeast Asian countries: prevalence estimates and social determinants from Demographic and Health Surveys. Popul Health Metr. 2014;12:22.PubMed CentralView ArticlePubMedGoogle Scholar
  44. Agaku IT, Filippidis FT, Vardavas CI, Odukoya OO, Awopegba AJ, Ayo-Yusuf OA, et al. Poly-tobacco use among adults in 44 countries during 2008-2012: evidence for an integrative and comprehensive approach in tobacco control. Drug Alcohol Depend. 2014;139:60–70.View ArticlePubMedGoogle Scholar
  45. Australian Institute of Health and Welfare. 2004 National Drug Strategy Household Survey: first results. Canberra: Australian Institute of Health and Welfare; 2005.Google Scholar
  46. Anantharaman D, Chaubal PM, Kannan S, Bhisey RA, Mahimkar MB. Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator. Carcinogenesis. 2007;28:1455–62.View ArticlePubMedGoogle Scholar
  47. Balaram P, Sridhar H, Rajkumar T, Vaccarella S, Herrero R, Nandakumar A, et al. Oral cancer in southern India: the influence of smoking, drinking, paan-chewing and oral hygiene. Int J Cancer. 2002;98:440–5.View ArticlePubMedGoogle Scholar
  48. Dikshit RP, Kanhere S. Tobacco habits and risk of lung, oropharyngeal and oral cavity cancer: a population-based case–control study in Bhopal, India. Int J Epidemiol. 2000;29:609–14.View ArticlePubMedGoogle Scholar
  49. Goud ML, Mohapatra SC, Mohapatra P, Gaur SD, Pant GC, Knanna MN. Epidemiological correlates between consumption of Indian chewing tobacco and oral cancer. Eur J Epidemiol. 1990;6:219–22.View ArticlePubMedGoogle Scholar
  50. Jayalekshmi PA, Gangadharan P, Akiba S, Nair RRK, Tsuji M, Rajan B. Tobacco chewing and female oral cavity cancer risk in Karunagappally cohort, India. Br J Cancer. 2009;100:848–52.PubMed CentralView ArticlePubMedGoogle Scholar
  51. Jayalekshmi PA, Gangadharan P, Akiba S, Koriyama C, Nair RRK. Oral cavity cancer risk in relation to tobacco chewing and bidi smoking among men in Karunagappally, Kerala, India: Karunagappally cohort study. Cancer Sci. 2011;102:460–7.View ArticlePubMedGoogle Scholar
  52. Jayant K, Balakrishnan V, Sanghvi LD, Jussawalla DJ. Quantification of the role of smoking and chewing tobacco in oral, pharyngeal, and oesophageal cancers. Br J Cancer. 1977;35:232–5.PubMed CentralView ArticlePubMedGoogle Scholar
  53. Jussawalla DJ, Deshpande VA. Evaluation of cancer risk in tobacco chewers and smokers: an epidemiologic assessment. Cancer. 1971;28:244–52.View ArticlePubMedGoogle Scholar
  54. Madani AH, Jahromi AS, Dikshit M, Bhaduri D. Risk assessment of tobacco types and oral cancer. Am J Pharmacol Toxicol. 2010;5:9–13.View ArticleGoogle Scholar
  55. Muwonge R, Ramadas K, Sankila R, Thara S, Thomas G, Vinoda J, et al. Rote of tobacco smoking, chewing and alcohol drinking in the risk of oral cancer in Trivandrum, India: A nested case–control design using incident cancer cases. Oral Oncol. 2008;44:446–54.View ArticlePubMedGoogle Scholar
  56. Nandakumar A, Thimmasetty KT, Sreeramareddy NM, Venugopal TC, Rajanna, Vinutha AT, et al. A population-based case control investigation on cancers of the oral cavity in Bangalore, India. British Journal of Cancer. 1990;62:847–51.
  57. Rao DN, Ganesh B, Rao RS, Desai PB. Risk assessment of tobacco, alcohol and diet in oral cancer: a case–control study. Int J Cancer. 1994;58:469–73.View ArticlePubMedGoogle Scholar
  58. Sanghvi LD, Rao KC, Khanolkar VR. Smoking and chewing of tobacco in relation to cancer of the upper alimentary tract. Br Med J. 1955;1:1111–4.PubMed CentralView ArticlePubMedGoogle Scholar
  59. Sankaranarayanan R, Duffy SW, Padmakumary G, Day NE, Nair MK. Risk factors for cancer of the buccal and labial mucosa in Kerala, southern India. J Epidemiol Community Health. 1990;44:286–92.PubMed CentralView ArticlePubMedGoogle Scholar
  60. Wasnik KS, Ughade SN, Zodpey SP, Ingole DL. Tobacco consumption practices and risk of oro-pharyngeal cancer: a case–control study in Central India. Southeast Asian J Trop Med Publ Health. 1998;29:827–34.Google Scholar
  61. Subapriya R, Thangavelu A, Mathavan B, Ramachandran CR, Nagini S. Assessment of risk factors for oral squamous cell carcinoma in Chidambaram, Southern India: a case–control study. Eur J Cancer Prev. 2007;16:251–6.View ArticlePubMedGoogle Scholar
  62. Wahi PN, Kehar U, Lahiri B. Factors influencing oral and oropharyngeal cancers in India. Br J Cancer. 1965;19:642–60.PubMed CentralView ArticlePubMedGoogle Scholar
  63. Merchant A, Husain SS, Hosain M, Fikree FF, Pitiphat W, Siddiqui AR, et al. Paan without tobacco: an independent risk factor for oral cancer. Int J Cancer. 2000;86:128–31.View ArticlePubMedGoogle Scholar
  64. Roosaar A, Johansson AL, Sandborgh-Englund G, Axell T, Nyren O. Cancer and mortality among users and nonusers of snus. Int J Cancer. 2008;123:168–73.View ArticlePubMedGoogle Scholar
  65. Znaori A, Brennan P, Gajalakshmi V, Mathew A, Shanta V, Varghese C, et al. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer. 2003;105:681–6.View ArticleGoogle Scholar
  66. Boffetta P, Aagnes B, Weiderpass E, Andersen A. Smokeless tobacco use and risk of cancer of the pancreas and other organs. Int J Cancer. 2005;114:992–5.View ArticlePubMedGoogle Scholar
  67. Lewin F, Norell SE, Johansson H, Gustavsson P, Wennerberg J, Biörklund A, et al. Smoking tobacco, oral snuff, and alcohol in the etiology of squamous cell carcinoma of the head and neck: a population-based case-referent study in Sweden. Cancer. 1998;82:1367–75.View ArticlePubMedGoogle Scholar
  68. Luo J, Ye W, Zendehdel K, Adami J, Adami H-O, Boffetta P, et al. Oral use of Swedish moist snuff (snus) and risk for cancer of the mouth, lung, and pancreas in male construction workers: a retrospective cohort study. Lancet. 2007;369:2015–20.View ArticlePubMedGoogle Scholar
  69. Rosenquist K, Wennerberg J, Schildt EB, Bladstrom A, Hansson BG, Andersson G. Use of Swedish moist snuff, smoking and alcohol consumption in the aetiology of oral and oropharyngeal squamous cell carcinoma. A population-based case–control study in southern Sweden. Acta Otolaryngol. 2005;125:991–8.View ArticlePubMedGoogle Scholar
  70. Schildt EB, Eriksson M, Hardell L, Magnuson A. Oral snuff, smoking habits and alcohol consumption in relation to oral cancer in a Swedish case–control study. Int J Cancer. 1998;77:341–6.View ArticlePubMedGoogle Scholar
  71. Mashberg A, Boffetta P, Winkelman R, Garfinkel L. Tobacco smoking, alcohol drinking, and cancer of the oral cavity and oropharynx among U.S. veterans. Cancer. 1993;72:1369–75.View ArticlePubMedGoogle Scholar
  72. Sapkota A, Gajalakshmi V, Jetly DH, Roychowdhury S, Dikshit RP, Brennan P, et al. Smokeless tobacco and increased risk of hypopharyngeal and laryngeal cancers: A multicentric case–control study from India. Int J Cancer. 2007;121:1793–8.View ArticlePubMedGoogle Scholar
  73. Akhtar S, Sheikh AA, Qureshi HU. Chewing areca nut, betel quid, oral snuff, cigarette smoking and the risk of oesophageal squamous-cell carcinoma in South Asians: a multicentre case–control study. Eur J Cancer. 2012;48:655–61.View ArticlePubMedGoogle Scholar
  74. Dar NA, Bhat GA, Shah IA, Iqbal B, Makhdoomi MA, Nisar I, et al. Hookah smoking, nass chewing, and oesophageal squamous cell carcinoma in Kashmir, India. [Erratum appears in Br J Cancer. 2013;108(7):1552 Note: Kakhdoomi MA [corrected to Makhdoomi MA]]. Br J Cancer. 2012;107:1618–23.PubMed CentralView ArticlePubMedGoogle Scholar
  75. Sehgal S, Kaul S, Gupta BB, Dhar MK. Risk factors and survival analysis of the esophageal cancer in the population of Jammu, India. Indian J Cancer. 2012;49:245–50.View ArticlePubMedGoogle Scholar
  76. Talukdar FR, Ghosh SK, Laskar RS, Mondal R. Epigenetic, genetic and environmental interactions in esophageal squamous cell carcinoma from northeast India. PLoS One. 2013;8:e60996.PubMed CentralView ArticlePubMedGoogle Scholar
  77. Lagergren J, Bergstrom R, Lindgren A, Nyren O. The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia. Int J Cancer. 2000;85:340–6.View ArticlePubMedGoogle Scholar
  78. Zendehdel K, Nyren O, Luo J, Dickman PW, Boffetta P, Englund A, et al. Risk of gastroesophageal cancer among smokers and users of Scandinavian moist snuff. Int J Cancer. 2008;122:1095–9.View ArticlePubMedGoogle Scholar
  79. Bolinder G, Alfredsson L, Englund A, de Faire U. Smokeless tobacco use and increased cardiovascular mortality among Swedish construction workers. Am J Public Health. 1994;84:399–404.PubMed CentralView ArticlePubMedGoogle Scholar
  80. Sasco AJ, Merrill RM, Dari I, Benhaim-Luzon V, Carriot F, Cann CI, et al. A case–control study of lung cancer in Casablanca, Morocco. Cancer Causes Control. 2002;13:609–16.View ArticlePubMedGoogle Scholar
  81. Brown LM, Blot WJ, Schuman SH, Smith VM, Ershow AG, Marks RD, et al. Environmental factors and high risk of esophageal cancer among men in coastal South Carolina. J Natl Cancer Inst. 1988;80:1620–5.View ArticlePubMedGoogle Scholar
  82. Alguacil J, Silverman DT. Smokeless and other noncigarette tobacco use and pancreatic cancer: a case–control study based on direct interviews. Cancer Epidemiol Biomarkers Prev. 2004;13:55–8.View ArticlePubMedGoogle Scholar
  83. Hassan MM, Abbruzzese JL, Bondy ML, Wolff RA, Vauthey JN, Pisters PW, et al. Passive smoking and the use of noncigarette tobacco products in association with risk for pancreatic cancer: a case–control study. Cancer. 2007;109:2547–56.PubMed CentralView ArticlePubMedGoogle Scholar
  84. Alexander M. Tobacco use and the risk of cardiovascular diseases in developed and developing countries. Cambridge: University of Cambridge; 2013.Google Scholar
  85. Rahman MA, Zaman MM. Smoking and smokeless tobacco consumption: possible risk factors for coronary heart disease among young patients attending a tertiary care cardiac hospital in Bangladesh. Public Health. 2008;122:1331–8.View ArticlePubMedGoogle Scholar
  86. Rahman MA, Spurrier N, Mahmood MA, Rahman M, Choudhury SR, Leeder S. Is there any association between use of smokeless tobacco products and coronary heart disease in Bangladesh? PLoS One. 2012;7:e30584.PubMed CentralView ArticlePubMedGoogle Scholar
  87. Hergens MP, Ahlbom A, Andersson T, Pershagen G. Swedish moist snuff and myocardial infarction among men. Epidemiology. 2005;16:12–6.View ArticlePubMedGoogle Scholar
  88. Hergens MP, Alfredsson L, Bolinder G, Lambe M, Pershagen G, Ye W. Long-term use of Swedish moist snuff and the risk of myocardial infarction amongst men. [Erratum appears in J Intern Med. 2007;262(5):590]. J Intern Med. 2007;262:351–9.View ArticlePubMedGoogle Scholar
  89. Huhtasaari F, Asplund K, Lundberg V, Stegmayr B, Wester PO. Tobacco and myocardial infarction: is snuff less dangerous than cigarettes? BMJ. 1992;305:1252–6.PubMed CentralView ArticlePubMedGoogle Scholar
  90. Huhtasaari F, Lundberg V, Eliasson M, Janlert U, Asplund K. Smokeless tobacco as a possible risk factor for myocardial infarction: a population-based study in middle-aged men. J Am Coll Cardiol. 1999;34:1784–90.View ArticlePubMedGoogle Scholar
  91. Johansson S-E, Sundquist K, Qvist J, Sundquist J. Smokeless tobacco and coronary heart disease: a 12-year follow-up study. [Erratum appears in Eur J Cardiovasc Prev Rehabil. 2007;14(5):722]. Eur J Cardiovasc Prev Rehabil. 2005;12:387–92.View ArticlePubMedGoogle Scholar
  92. Wennberg P, Eliasson M, Hallmans G, Johansson L, Boman K, Jansson JH. The risk of myocardial infarction and sudden cardiac death amongst snuff users with or without a previous history of smoking. J Intern Med. 2007;262:360–7.View ArticlePubMedGoogle Scholar
  93. Asplund K, Nasic S, Janlert U, Stegmayr B. Smokeless tobacco as a possible risk factor for stroke in men - a nested case–control study. Stroke. 2003;34:1754–9.View ArticlePubMedGoogle Scholar
  94. Hergens M-P, Lambe M, Pershagen G, Terent A, Ye W. Smokeless tobacco and the risk of stroke.[Erratum appears in Epidemiology. 2009;20(3):471]. Epidemiology. 2008;19:794–9.View ArticlePubMedGoogle Scholar
  95. Hansson J, Pedersen NL, Galanti MR, Andersson T, Ahlbom A, Hallqvist J, et al. Use of snus and risk for cardiovascular disease: results from the Swedish Twin Registry. J Intern Med. 2009;265:717–24.View ArticlePubMedGoogle Scholar
  96. Janzon E, Hedblad B. Swedish snuff and incidence of cardiovascular disease. A population-based cohort study. BMC Cardiovasc Disord. 2009;9:21.PubMed CentralView ArticlePubMedGoogle Scholar

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