We were commissioned by the Ministry of Health and Care Services to update the 2014 report on health risks from snus use. The report presents updated figures on snus use in Norway, and assesses exposure and risk. The report is limited to the use of Swedish snus.
Health effects of constituents of snus
Tobacco specific nitrosamines (TSNA)
The tobacco-specific nitrosamines N-Nitrosonornicotine (NNN) and 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as the NNK degradation product 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are important and potent carcinogens in tobacco. A number of studies have unequivocally shown that laboratory animals develop cancer after exposure to NNN, NNK and NNAL. In many cell types, including cells in the liver, lungs and oral cavity, these nitrosamines can be converted into reactive products by activation or detoxification enzymes. These metabolic transformation products can bind to DNA and cause irreversible damage. This may be an early step in cancer development. Both animal and human cells are capable of forming such DNA binding products. This indicates that the mechanism of cancer development in humans is similar to that seen in laboratory animals. International Agency for Research on Cancer (IARC) classifies NNK and NNN as carcinogenic to humans. This is based on evidence from studies in cell lines and animals, and population studies which have found a correlation between the degree of exposure to NNK and NNN and cancer risk in smokers.
Nicotine is one of the most important active substances in tobacco and has considerable addictive potential. Nicotine acts primarily by stimulating nicotinic cholinergic receptors and secondly by increased release of various signaling molecules in and outside the central nervous system. The nicotinic cholinergic receptors activate multiple cellular signaling pathways involved in physiological functions. However, nicotine activation of these receptors will also mediate many of the undesirable effects of nicotine.
Nicotine and addiction: Nicotine is highly addictive and it is nicotine that mediates addiction in tobacco use. Withdrawal symptoms when trying to quit smoking are the typical signs that nicotine use leads to physical dependence. The use of nicotine also leads to development of nicotine tolerance. In some individuals, nicotine addiction can develop very quickly. There are indications that differences in nicotine dependence in the population may be related to genetic predisposition.
Nicotine and cancer: There is insufficient data from animal studies to conclude if nicotine is a complete carcinogen or not. Cell studies have shown that nicotine activates a number of signaling cascades in the cells that are relevant in terms of whether nicotine can promote cancer development (promoter effect) when such development is first initiated by known carcinogens. Experimental studies in animals indicate that nicotine may be a promoter, that is, nicotine may promote already initiated cancer development. Animal studies have shown that nicotine can reduce the effects of cancer treatments by growth factor receptor blockade, chemotherapy and radiation therapy.
Lung development: Nicotine use during pregnancy will also expose the unborn child to nicotine. Several animal studies have shown that nicotine exposure during pregnancy has harmful effects on lung development and lung function after birth.
Immune system: Nicotine has a variety of immunological effects of both stimulant and suppressive nature. The effects are likely to be affected by the amount and duration of exposure, route of exposure, organ systems involved in the immune response, stage and type of disease, and the degree of autoimmune and inflammatory mechanisms involved. Gender, age and disease manifestations may alter the effects of nicotine.
Cardiovascular effects: Nicotine exposure increases heart rate and blood pressure. Nicotine can reduce insulin sensitivity, which in turn can increase the risk of atherosclerosis. Overall, nicotine may contribute to an increased risk of cardiovascular disease both in smokers and snus users.
Cognitive functions and mental health: Animal studies and human studies have shown that nicotine can alter cognitive functions. This is especially true when exposed during pregnancy through maternal nicotine use, as well as during childhood and adolescence where the brain is developing and thus extra vulnerable. Hypotheses have been made that nicotine use may alleviate mental disorders by enhancing cognitive functions (the self-medication hypothesis), while other data indicate that nicotine may be a risk factor for mental illness since it affects some of the same biological mechanisms underlying such disease. There are also studies indicating that there are common genes that provide vulnerability to nicotine addiction and mental illness.
Snus cause changes in the oral mucosa (snus-induced lesion) in rats, as well as an increased number of cancers outside the oral cavity compared with those found in animals not exposed to snus. In animal studies with mice, exposure to snus or nicotine alone seems to affect the ability of the blood vessels to repair and to heal wounds. Exposure to snus in animal studies affects the immune system by reducing the white blood cell count and altering levels of various inflammatory markers. Such changes may affect the body’s defence and repair when exposed to illnesses or harmful effects.
We have prepared systematic reviews of available research on health risks from use of Swedish snus. Most studies were included in the report on snus from the Norwegian Institute of Public Health in 2014. The new studies have strengthened the conclusions of the previous report that the use of snus may increase the risks of some serious adverse health outcomes and some less serious adverse health outcomes, as shown in the results section.
The carcinogenic properties of the constituents, as shown in animal studies and cell studies, support the results of the population studies.
Available studies, on which we have based our conclusions, have varying design and length of follow-up. All follow-up studies identified the tobacco habits at the start of the studies, that is whether the participants used or had used snus, whether they smoked or had smoked, whether they neither smoked nor used snus, or both used snus and smoked (alternating or simultaneously).
We rarely know how long the individuals who answered that they were using snus, had used snus before they were included in the study. Neither do we know how many of those who used snus at the start of the study, still used snus at the time of follow-up. Some may have quit, some may have changed to higher / lower consumption, and some may have switched to smoking or started to smoke in addition to using snus. Those who, at the start of their studies, said that they did not use snus or other tobacco products may also have started later, and may have used snus (or smoked or both) for many years before the risk analysis was conducted.
For some health outcomes (cancer of the pancreas, colon and rectum) we have a follow-up time of up to 36 years, and it is possible that some would have answered differently to questions about their tobacco habits at the end of the study than they did at the start of the study. For several of the health risks that we have considered, it takes a long time before the disease has progressed so far that the diagnosis is made. For example, more than half of those diagnosed with pancreatic, colon and rectal cancer are over 70 years of age. With increasing age, there is a greater chance of dying from other causes, making any risk associated with snus use more difficult to estimate in older age groups. Long follow-up time will therefore have both strengths and weaknesses. We must also remember that people who choose to use snus may be different from those who choose not to use snus in many other respects. We do not have a complete overview of the factors that may be involved, and thus we do not have an overview of whether and how these factors may influence the same health outcomes.
There has been an increase in the use of Swedish snus in Norway in recent decades, especially among young adults, and especially among young women during the last decade. The majority of snus users are former smokers, but in the past 15 years there has been an increase in the proportion of snus users without prior smoking experience. In the period 2016-2018, 33% of men and 40% of women had not smoked before starting snus use. This is an increase from the period 2004-2006, when 23% of men and 12% of women who had used snus had never smoked.
Studies in animals and cells have shown that tobacco-specific nitrosamines are carcinogenic. Nicotine cause a variety of effects that may have adverse health consequences of varying severity.
Research on the health risks associated with use of Swedish snus in humans mainly comes from observational studies. Even with the inherent limitations of such studies, we conclude that systematically summarized research shows that the use of Swedish snus:
Women who use Swedish snus during pregnancy have:
One study found that use of Swedish snus reduced the risk of getting Parkinson’s disease. For many other health outcomes, there was too little information to conclude whether snus affects the risk of adverse health outcomes or in which direction.
The new studies have strengthened the conclusions of the report from the Norwegian Institute of Public health 2014 that use of snus increases the risks of some serious adverse health outcomes and some less serious adverse health outcomes.
We have described the prevalence of the use of snus in Norway. Furthermore, we have presented the effects (and possible mechanisms for these) of the important constituents nicotine and carcinogenic tobacco-specific nitrosamines as well as experimental animal studies of Swedish snus.
We have conducted systematic reviews of the health risks from using Swedish snus compared to not using tobacco products. Systematic literature searches have identified new studies in addition to the studies included in the National Institute of Public Health’s report on snus from 2014. We have described the studies, and evaluated and presented the studies’ internal validity (quality / risk of bias). If it had been possible we would have performed meta-analyses.
Since snus is known to contain carcinogens, it is unethical to conduct randomized controlled long-term trials. Therefore, observational studies, and preferably prospective cohort studies, are the best available studies we have on health risks associated with the use of snus. When we summarize health risks in accordance with international standards for systematic reviews, we grade our confidence in the effect estimates using the GRADE approach.
According to this approach, observational studies start and rarely achieve higher ratings than “low confidence” in the effect estimate. Therefore, most of the results on health risks in this report – which are from observational studies – are referred to by statements indicating that we have low confidence in the effect estimates (according to GRADE), and conclusions are similarly formulated with the words “It is possible that the use of snus leads to..” That does NOT mean that the cohort studies that have assessed the health risks of using Swedish snus are less trustworthy than cohort studies in general. For example, information we have about risks from smoking and risks from air pollution also comes from observational studies.
Some of the risk estimates show large effects and some other results have established a dose-response relationship (which means that a larger dose produces a larger response). In those cases, we have upgraded to “moderate confidence” in the effect estimate, with conclusions formulated as “it is likely that the use of snus increases the risk of ….”
Many of the risk estimates for the use of Swedish snus have wide confidence intervals, including the possibilities of both a considerable reduction in risk and a considerable increase in risk. Then we are uncertain whether the use of snus will affect the outcome in question and if so in which direction, and we downgrade to very low confidence in the effect estimate. It is very important to distinguish between cases when we have such wide confidence intervals that we do not know whether or in which direction the outcome is affected, and when narrow confidence intervals indicate little or no effect. The final conclusion builds on the statistical results, as the assessment of whether something is important also depends on the outcome that is considered (for example, there is a difference between feeling nauseous and developing cancer). How many who are affected by an increased risk depends on the background risk in the population. We have explained our assessments in the relevant chapters. Here is a simplified table with the statements we have used.