Author: Seppo Wickholm, Odont. Lic. Odontological Institution/Center for Public Health – Tobacco Prevention, Stockholm.
§ Tobacco contains both a range of psychoactive substances and a large number of toxic substances , several of which are carcinogenic . It is well known that tobacco can cause and affect the development of various diseases in most organ systems and lead to illness and premature death.
Tobacco has such a central role in the emergence and development of periodontitis. Today periodontitis so common in Sweden that it is regarded as a Public Health issue . It is therefore important that the knowledge of the interaction between general diseases , tobacco and periodontal disease be developed. Continued research on the epidemiological, clinical and cellular level is desirable.
This overview describes the current knowledge levels regarding tobacco use, and also oral and periodontal health.
Peer -reviewed. accepted for publication November 16, 2005
Dental Journal (Year 97) No 15 2005
￼ Tobacco is a major cause of morbidity and death in many parts of the world. If it 's current pattern persists, the number of deaths per year will increase from 3 to 10 million over the next 40 years (equivalent to 1/6 part of all deaths) . Links have been shown between smoking and mortality from lung cancer, bladder cancer, chronic obstructive pulmonary disease ( copd ), and cardiovascular disease [ 2]. There is also a strong correlation between smoking and mouth, pharynx and throat cancer and periodontal disease [3-5] .
In some parts of the world there is both smoking and smokeless tobacco use, snuff/snus. In the Western world it is most common in Sweden and in the United States.  Correlation between snus and oral cancer, cardiovascular disease, type ii diabetes and impact on the fetus during pregnancy has been shown in various studies [7-10 ] . Swedish studies have recently been unable to confirm the link to oral cancer, cardiovascular disease from snus, but they have not been able to rule out the possibility either [11-13]. The health impacts of snus, alone or in combination with smoking , need to be studied further.
Tobacco habits in the population
Tobacco use in Sweden consists essentially of cigarette smoking and snus use. Cigar and pipe smoking is now uncommon. According to the national public health survey, 19 per cent of women and 14 percent of men smoke daily; totalling approximately 1.1 million.  Daily snus use occurred in 22 percent of men and 3 percent of women, totalling 800,000. Annual statistics from CAN showed in 2004 that, among adolescents in grades 9, 5 per cent of boys and 13 per cent of girls smoked daily or almost daily. The number of snus users were at the same time 15 and 3 per cent respectively.  In a survey of all the boys in grade 9 in Stockholm in 1998 more than 2/3 of all snus users reported having smoked . In a retrospective Swedish the results showed that 27 per cent of current smokers and 33 per cent of former smokers also had used snus at some time. 
In addition to the amount of tobacco that the individual uses, the time of exposure is relevant to the effect. Cigarette consumption is counted in number of cigarettes smoked per day and the total exposure over time specified as " pack -years”. Exposure is calculated by multiplying the number of cigarettes per day divided by 20 and multiplied by the number of years the person has smoked. Snus use is counted in units per week. Exposure in a "can -years" is calculated by the average number of cans per week multiplied by the number of years that the individual used snuff .
Toxicology - cigarettes
Cigarettes are probably the single most important cause of toxic chemical exposure and chemically transmitted (non communicable) illness in humans. The main ingredients in
smoke can be divided into 1) those that cause cancer, 2) those that have respiratory effects , or 3) those that affect the cardiovascular system [ 19-21 ] .
The chemicals that are most important for an increased cancer risk are; 1,3 butadiene, aldehydes and other volatile organic combustion products (including benzene ), metals (cadmium , arsenic, chromium, nickel , beryllium and lead) nitrosamines and polycyclic aromatic hydrocarbons. The main contributors to respiratory irritation are acrolein and acetaldehyde.
Cardiovascular disease is mainly caused by exposure to cyanide, arsenic, creosol and carbon monoxide. Only one cigarette per day results in an exposure exceeding the limit for measurable for respiratory and cardiovascular effects .
Toxicology - snus
Snus consists of finely ground tobacco with high humidity (35-60 %) and basic pH (7.8-8.5) [6, 23] .
The toxic effects of snus have primarily been linked to tobacco specific nitrosamines (TSNA) and the development of oral cancer. During processing and manufacture of snus nitrosamines are formed, such as 4-(methylnitrosoamine)-1 -( 3-pyridyl )-1- butanone ( NNK ) and N -nitroso-nornicotine ( NNN) [24 , 25]. These levels of TSNA’s were in 1992 at a level of 9μg/g dry weight. In a survey in 2002, the levels down to 1.0 μg/g dry weight. Thus, the total content of TSNA in Swedish snus has been reduced significantly in recent years . Calculations based on 60 per cent absorption and a daily average consumption of 20 g of snuff and an estimated carcinogenic potential for NNK and NNN can give a rough idea of the number of cancer cases due to snus. If a Swedish study would be performed with a 200 000 snus user cohort, the number of cancer cases per year according to this calculation method ought to be approximately 7 [12, 25].
The mucosa of snus users also exposed to other carcinogens such as N - nitrosamine acid, volatile N-nitrosamines, formaldehyde, acetaldehyde and traces of carcinogenic hydrocarbons, and polonium -210.  One possible explanation for the low risk of cancer among snus users is considered to be the presence of antioxidants .
Effects of nicotine
Cigarette smoke is slightly acidic (pH < 7) which means that you have to breathe down the nicotine in the lungs for it to be taken up efficiently into the bloodstream. When nicotine is taken up into the bloodstream there is an almost instant uptake in the lung alveoli and further transport to the brain's reward center. Snus is alkaline (pH> 7) and nicotine in snus is therefore easily absorbed through the oral mucosa.
Tobacco use causes a heavy nicotine addiction (the only real reason for a continuous tobacco use among both smokers and snus users). The addiction created is likened to that created by other psychoactive drugs such as morphine and amphetamine. With time a raised tolerance is developed which means that you have to take more of the drug to achieve the same effect .
Nicotine activates the sympathetic nervous system that results in increased heart rate and elevated blood pressure. Nicotine also increases the levels of circulating catecholamines and free fatty acids. Through its effects on lipid metabolism nicotine may contribute to higher levels of total cholesterol and decreased levels of harmful LDL cholesterol .
Nicotine’s effects at the cellular level in the oral tissues has been the subject of several studies. One of these showed a dose-dependent suppression of chemotaxis and phagocytosis , and increased degranulation and eikosanoidbildning of neutrophils . In another study where fibroblasts exposed to nicotine showed these stunted growth and reduced protein content and damaged cell membranes. The cells exhibited an atypical form and vacuole formation. The toxic effects became irreversible at levels between 10.5 mM and 15.5 mM nicotine . At concentrations greater than 2.5 mM was found that nicotine was toxic to human fibroblasts that were derived from periodontal ligament . Nicotine is highly toxic: The lethal dose is about 1 mg / kg body weight . I am not qualified to translate this part properly, sorry.
Tobacco and associated with periodontal disease
That cigarette smoking is strongly associated with paradontitis has been shown in many studies. When fully controlled for other possible risk factors such as plaque, age and gender it seems smoking may have an independent effect . The increased risk of periodontal disease persists even when adjusting for other forms of tobacco use . An American study calculated that smoking accounted for more than half of all periodontitis among adults . In a Swedish study, the risk of periodontal disease was 2.5 times higher in smokers than non-smokers . In another study, the risk was 2.7 (OR) to suffer from periodontal disease if they were smokers, and 2.0 if they were ex-smokers compared to never users of tobacco. 
Dual use of cigarettes and snus is common. Dual use occurs simultaneously, or a shift from one tobacco product to the other . Among boys in 9th grade more than 2/3 of snus users also smoked. In this group there was an elevation in general risk behavior and a high consumption of alcohol . What alcohol consumption in combined with tobacco use means for the development of periodontal disease has not been investigated. However, an increased risk of periodontal disease among alcohol users has been reported . In persons exposed to approximately 10 pack-years, one can discern an increased incidence of periodontal disease. The existence becomes evident after an exposure of more than 15 pack-years .
Snus and periodontitis
Previous studies in the U.S. have not been able to demonstrate any connection between generalized periodontitis and snus . Snus users have more gingival recession defects (especially in connection to the usual location of the pouch/prilla ) compared with non- users of snus. In a recently published study that included 1,674 patients with an average age of 37 years showed that the proportion of subjects with periodontitis ( ≥ 3 teeth with pocket depth ≥ 5mm ) was 7.4 per cent among snus users compared with 4.7 per cent among non-users. In both smokers and dual users, the proportion was 12.1 per cent. It should be noted that dual use patients smoked significantly less than exclusive smokers. Thus cutting down on smoking while using snus instead is a questionable method to achieve increased periodontal health.
The U.S. investigation also showed that the risk for former exclusive snus users being affected by paradontitis was 2.3 times higher compared to never users since after adjustment for age, sex , educational level, plaque and smoking. The increased risk was not shown to be statistically certain . In a recently published paper in the USA, the results indicate that snus is a risk factor for severe periodontitis in adults snus users who never smoked. Anywhere in the mouth adjusted OR was = 2.1 (1.2-3.7) , restricted to proximal (to placement of snus) adjusted OR was = 2.1 (1.0 to 4.4) . 
Smoking, parodonial diseases and general diseases
Epidemiological studies have shown a possible correlation between periodontal diseases and general diseases. Many of these diseases are also associated with smoking. This is a parameter that must be taken into account when drawing conclusions from studies in which participants￼ consist of smokers with periodontitis but who also have a general illness. Cardiovascular disease, for example, has a connection with both periodontitis and smoking, independently of each other [40, 41]. Moreover, recent studies have shown that pregnant women with periodontal disease are at a greater risk for having a baby with low birth weight and also premature delivery. This is also the case for smokers [42, 43]. A recent Swedish study showed that it was more common with premature delivery and low birth weight among both snus users and smokers .
Both diabetes type 1 and type 2 is associated with periodontitis , but only Type 2 is related to smoking and snus . It has long been known that general diseases can influence the progression of paradontitis.
Tobacco use and host response in periodontal disease (Prof Rodu, pls help out;)
Pathogenic bacteria in the dental plaque initiates immunological and inflammatory reactions that affect the epithelium, connective tissues, vessels and bonestructure? in the periodontium . Under healthy conditions, there is a balance between the release of lipopolysaccharides and other toxic products from bacteria and the natural defenses from granulocytes, antibodies and others. In some individuals an imbalance between bacterial and host response resulting in tissue degradation. The bacteria stimulate an inflammatory reaction that involves white blood cells, mainly neutrophils . Neutrophils play a major role in the acute inflammation and contains both hydrolytic and proteolytic enzyme [ 45, 46]. Smoking appears to affect the gingival host response by suppressing the natural healing process . 
Neutrophils can produce proteases , including elastase, secreted to fickexsudatet??. Elastase is considered to play an important role in the degradation of various components of the connective tissues . Smoking appears to have an influence on the release of proteases from neutrophils but also the activity of inhibitors such as α1 -antitrypsin and α2 - macroglobulin [ 49, 50]. In a new study of young adults who were periodontally healthy, you could not see any difference in elastic sulphatase activity or concentration of protease inhibitors among smokers . Among smokers with refractory paradontitis, one other study showed an increased elastase activity compared with non-smokers . In smokers with severe periodontal injuries the levels of α1 -antitrypsin and α2 - macroglobulin were reduced in smokers compared with nonsmokers. In a recent study of patients with severe periodontitis healed smokers had higher functional elastase activity in the liquid phase after centrifugation of the samples. More elastase was bound to α1 -antitrypsin. If you also compared the amount of elastase in liquid kefasen with the amount of pellets, the liquid phase almost all of the elastase. This suggests that elastase really has been released from the cells in smokers. This can be explained by the granulocytes seem to get triggered by smoking and thus releasing elastase. 
Collagen gets degraded by matrixmetalloproteaser (MMP) that play an important role in connective tissuedegradation. MMP-8 are released from granulocytes on their way towards the periodontal pockets . The amount of MMP-8 reflects the degree of inflammation in the tissue. The collagenase is initially inactive and is only activated outside the cell. parodontal ligaments appear to be degraded by MMP-8 [ 54, 55].
The levels of collagenase activity is regulated by tissue inhibitors specific to MMPs. High activity of MMP’s and low levels of inhibitors characterize an active disease process .
There are only a few studies on which effects smoking has on MMP levels . The results are inconclusive and give no clear picture of how smoking affects MMP production . Prostaglandine E2 , PGE2 released from monocytes and plays a major role in periodontal disease , and mirror cellular and biological activity [ 57, 58]. No differences were demonstrated in a study regarding smokers, former smokers and non-smokers  while another study could show lower levels of PGE2 in smokers than non-smokers .