Landmark studies on the evidence for the carcinogenicity of tobacco were published in 1950. Comprehensive epidemiological studies over many years have established a clear link between tobacco smoking and a number of cancer types. There are over 60 known carcinogens in cigarette smoke, the most important of which are polycyclic aromatic hydrocarbons, N-nitrosamines, aromatic amines, 1,3-butadiene, benzene, aldehydes, and ethylene oxide due to their carcinogenicity and levels.
Tobacco smoking and tobacco smoke, smokeless tobacco and second-hand tobacco smoke are all classified by the International Agency for Research on Cancer (IARC) as Group 1 carcinogens (carcinogenic to humans). IARC first classified tobacco smoking as a Group 1 carcinogen in 1986, and has since published monographs on the carcinogenic risk of smokeless tobacco, and updated evidence for tobacco smoking. The summary of IARC classifications of evidence for the link between tobacco and specific cancer types can be found in Table 1.
There is sufficient evidence that smoking is a risk factor for 16 cancer types: lung, oral cavity, pharynx, oesophagus, stomach, bowel, liver, pancreas, nasal cavity and paranasal sinuses, larynx, uterine cervix, ovary, urinary bladder, kidney, ureter and bone marrow (myeloid leukaemia). There is limited evidence for a link between tobacco smoking and breast cancer.
There is sufficient evidence that smokeless tobacco (such as chewing tobacco and snuff) are risk factors for cancers of the oral cavity, oesophagus and pancreas.
Table 1. IARC levels of evidence for a link between tobacco and different cancer types
|Risk factor||Sufficient evidence of carcinogenicity||Limited evidence of carcinogenicity||Evidence suggesting lack of carcinogenicity|
|Tobacco smoking||Oral cavity, pharynx, oesophagus, stomach, bowel, liver, pancreas, nasal cavity and paranasal sinuses, larynx, lung, uterine cervix, ovary, urinary bladder, kidney, ureter, bone marrow (myeloid leukaemia)||Female breast||Endometrium (postmenopausal), thyroid|
|Second-hand smoke||Lung||Larynx, pharynx|
|Smokeless tobacco||Oral cavity, oesophagus, pancreas|
|Parental smoking (cancer in the offspring)||Hepatoblastoma||Childhood leukaemia|
Source: IARC 2012
The IARC monograph and US Surgeon General’s report on the health consequences of smoking contain detailed reviews of the epidemiological evidence for the link between tobacco and specific cancer types.
Meta-analyses of the evidence linking tobacco use with cancer show that the risk of developing cancer increases with the amount of tobacco smoked, duration of smoking and earlier starting age.
Studies have also demonstrated that the risk of developing cancer decreases with increased time since quitting. Recent studies have reported that among current smokers, life expectancy drops by 10 years or more. However, adults who quit smoking regained some years of life compared with those who continued to smoke. Adults who had quit smoking at 25 to 34 years of age gained around 10 years, those who quit aged 35 to 44 gained nine years and those who quit aged 45 to 54 gained about six years of life, compared with those who continued to smoke”.
Given that a number of cancer types associated with tobacco use, such as pancreatic cancer, are often diagnosed at an advanced stage and cannot be prevented through any other known lifestyle changes or interventions, avoiding exposure to tobacco smoke is one of the only measures available for actively reducing individual risk.
The U.S. Surgeon General’s report How Tobacco Smoke Causes Disease outlines a number of biological mechanisms involved in the major established pathways of cancer causation by cigarette smoking, involving:
- The exposure of the body to carcinogens in the aerodigestive tract, blood, and urine;
- The formation of covalent bonds between these carcinogens and DNA (known as DNA adducts); and
- The resulting accumulation of permanent mutations in critical genes which lead to uncontrolled cell growth and the development of cancer.
There are over 60 established carcinogens in tobacco smoke. Polycyclic aromatic hydrocarbons (PAH), N-nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN), aromatic amines, 1,3-butadiene, benzene, aldehydes, and ethylene oxide are among the most important carcinogens because of their carcinogenicity and their high levels in cigarette smoke.
A number of these carcinogens, and the products that they are metabolised into, are found in the blood, breath and urine of smokers. Most carcinogens in cigarette smoke require metabolic activation to convert them into the form that binds DNA, forming DNA adducts.
Persistent DNA adducts can cause miscoding during normal DNA replication. Gene mutations can cause the loss of normal functions that control the growth of cells. Ultimately, this uncontrolled growth leads to cancer.
The U.S. Surgeon General’s report outlines the link between a number of tobacco carcinogens and the specific cancer types they are associated with:
- PAH and NNK are major factors in the development of lung cancer.
- The particulate phase of cigarette smoke is linked to cancers of the larynx, potentially due to PAH.
- PAH, NNK, and NNN are the most likely causes of oral cancer.
- N-nitrosamines, as well as acetaldehyde and formaldehyde, are likely candidates for causing nasal tumours.
- NNK, several other N-nitrosamines and furan are carcinogenic in the liver.
- NNK and its major metabolite, known as NNAL, are the only known pancreatic carcinogens in tobacco products.
- NNK and PAH can reach the cervix in humans and are metabolically activated in these tissues.
- 4-aminobiphenyl and 2-naphthylamine are known human bladder carcinogens, and aromatic amines are thought to be the major cause of bladder cancer in smokers.
- The most probable cause of leukaemia in smokers is exposure to benzene.
Further to the action of these specific carcinogens, cigarette smoke causes oxidative damage to cells and alters a range of immunological functions, both of which have the potential to affect tobacco carcinogenesis.
Second-hand tobacco smoke
A study of 2004 data found that in one year, over 600,000 deaths worldwide were attributable to second-hand smoke, accounting for 1.0% of worldwide mortality. The majority (47%) of deaths from second-hand smoke occurred in women, 28% in children, and 26% in men.
Involuntary smoking (exposure to second-hand smoke) is classified by IARC as a Group 1 carcinogen. There is sufficient evidence that exposure to second-hand or ‘environmental’ tobacco smoke causes lung cancer in humans, and some limited evidence for a link between exposure to second-hand smoke and cancers of the larynx and pharynx (see Table 1). Long-term exposure to second-hand tobacco smoke in the home or workplace can elevate lung cancer risk in a non-smoker by up to 30%.
Some studies have suggested that second-hand tobacco smoke may also be a risk factor for cancers of the nasal sinus, naso-pharynx, breast, cervix, bladder and kidney. Pre- and postnatal exposure to second-hand tobacco smoke may also increase the risk of brain tumours, lymphomas, and acute lymphocytic leukaemia in children.
Smoking and alcohol
Smoking and alcohol together have a synergistic effect on upper gastrointestinal and aero-digestive cancer risk, meaning the combined effects exceed the risk from either alone. It has been estimated that over 75% of cancers of the upper aero-digestive tract in developed countries can be attributed to this effect. For example, compared non-smoking non-drinkers, the approximate relative risks for developing mouth and throat cancer are up to seven times greater for those who use tobacco, up to six times greater for those who use alcohol, and 35 times greater for those who are regular heavy users of both tobacco and alcohol.
While alcohol is an independent risk factor for oral, pharyngeal, laryngeal and oesophageal cancers, the risk is significantly higher when combined with tobacco smoke.
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