Tobacco and health

From Wikipedia, the free encyclopedia

Male Smoking by Country
Male Smoking by Country[1]
Female Smoking by Country
Female Smoking by Country[2]

The effects of tobacco on health are significant, depending on the way the tobacco is used (smoked, snuffed or chewed) and the amount. Major health effects of smoking, the most common use of tobacco, include an increased risk in lung cancer and cardiovascular disease. The World Health Organization estimated in 2002[3] that in developed countries, 26% of male deaths and 9% of female deaths were attributable to smoking. Similarly, the United States Centers for Disease Control and Prevention describes tobacco use as "the single most important preventable risk to human health in developed countries and an important cause of premature death worldwide."[4]

Contents

[edit] Primary risks

A 1905 advertisement about the dangers of smoking, and calling for its prohibition.
A 1905 advertisement about the dangers of smoking, and calling for its prohibition.

Regular smokers are estimated to live to 2.5[5] to 10[6] years less than nonsmokers.[5] About one-half of male smokers will die of illness due to smoking.[7]

Tobacco related illnesses kill approximately 438,000 USA citizens per year,[8] about 1,205 per day, making it the leading cause of preventable death in the U.S. The World Health Organization has stated that tobacco is set to kill a billion people this century.[9]

The main health risks in tobacco pertain to diseases of the cardiovascular system, in particular smoking being a major risk factor for a myocardial infarction (heart attack), diseases of the respiratory tract such as Chronic Obstructive Pulmonary Disease (COPD) and emphysema, and cancer, particularly lung cancer and cancers of the larynx and mouth. It also increases the risk of developing pancreatic cancer by 75%. Prior to World War I, lung cancer was considered to be a rare disease, which most physicians would never see during their career. With the postwar rise in popularity of cigarette smoking came a virtual epidemic of lung cancer.[10][11]

Currently, among people who have ever smoked any kind of tobacco, almost one in ten will develop lung cancer.[2] One in six men who continue to smoke tobacco will develop lung cancer.[12] This compares to only one case of lung cancer in seventy-five lifelong non-smokers.

Incidence of impotence is approximately 85 percent higher in male smokers compared to non-smokers,[13] and it is a key cause of erectile dysfunction (ED).[14][15] Smoking causes impotence because it promotes arterial narrowing.[16]

A person's increased risk of contracting disease is directly proportional to the length of time that a person continues to smoke as well as the amount smoked. However, if someone stops smoking, then these chances gradually decrease as the damage to their body is repaired.

Diseases linked to smoking tobacco cigarettes include:

The incidence of lung cancer is highly correlated with smoking.
The incidence of lung cancer is highly correlated with smoking.

Cigar and pipe smokers tend to inhale less smoke than cigarette smokers, so their risk of lung cancer is lower but is still several times higher than the risk for nonsmokers[citation needed]. Pipe and cigar smokers are also at risk for cancers of the oral cavity, larynx (voice box), or esophagus, a risk which was widely hypothesized before any link between smoking and cancer was scientifically proved as seen in the news coverage of the tobacco-related cancers of two American presidents; Ulysses S. Grant died in 1885 at age sixty-three after a long and painful public battle with throat cancer which was widely assumed at the time to be the result of his lifelong cigar habit, and Grover Cleveland was diagnosed in 1893 with cancer of the left jaw, which was frequently remarked upon by the press and public as the side where he usually had a cigar clamped. Similarly, cancer of the mouth and jaw is also a risk for chewing tobacco. The benefits of smoking cessation are immediate: blood pressure, heart rate, and temperature return to normal range; heart attack risk decreases; ability to smell and taste is enhanced; circulation improves.

It is generally assumed that the major motivational factor behind smoking is the nicotine it contains. However, the practice of ingesting the smoke from a smoldering leaf generates an enormous number of active chemical compounds, loosely lumped together as 'tar', many of which are biologically reactive and potential health dangers. (Chewing tobacco is also carcinogenic, likely because similar compounds are generated in the practice of curing it; the Nordic snus, which is steam cured and therefore does not generate these compounds, is much less carcinogenic.) There are around 3000 chemicals found in tobacco smoke. Long term exposure to other compounds in the smoke, such as carbon monoxide, cyanide, and other compounds that damage lung and arterial tissue, are believed to be responsible for cardiovascular damage and for loss of elasticity in the alveoli, leading to emphysema and COPD.

[edit] Radioactive components of tobacco

In addition to chemical, nonradioactive carcinogens, tobacco and tobacco smoke contain small amounts of lead-210 (210Pb) and polonium-210 (210Po) both of which are radioactive carcinogens. Lead 210 is a product of the decay of radium-226 and, in turn, its decay product, radon-222; lead 210 then decays to bismuth-210 and then to polonium 210, emitting beta particles in both steps. Tarry particles containing these elements lodge in the smokers' lungs where airflow is disturbed; the concentration found where bronchioles bifurcate is 100 times higher than that in the lungs overall. This gives smokers much more intense exposure than would otherwise be encountered. Polonium 210, for instance, emits high energy alpha particles which, because of their large mass, are considered to be incapable of penetrating the skin more than 40 micrometres deep, but do considerable damage (estimated at 100 times as much chromosome damage as a corresponding amount of other radiation) when a process such as smoking causes them to be emitted within the body, where all their energy is absorbed by surrounding tissue. (Lead 210 also emits gamma rays).

The radioactive elements in tobacco are accumulated from the minerals in the soil, as with any plant, but are also captured on the sticky surface of the tobacco leaves in excess of what would be seen with plants not having this property. As might be expected, the radioactivity measured in tobacco varies widely depending on where and how it is grown. One study found that tobacco grown in India averaged only 0.09 pCi per gram of polonium-210, whereas tobacco grown in the United States averaged 0.516 pCi per gram. Another study of Indian tobacco, however, measured an average of 0.4 pCi of polonium 210 per cigarette, which also would be approximately a gram of tobacco. One factor in the difference between India and the United States may be the extensive use of apatite as fertilizer for tobacco in the United States, because it starves the plant for nitrogen, thereby producing more flavorful tobacco; apatite is known to contain radium, lead 210, and polonium 210. This would also account for increased concentration of these elements compared to other crops, which do not use this mineral as fertilizer.

The presence of polonium-210 in mainstream cigarette smoke has been experimentally measured at levels of 0.0263 - 0.036 pCi,[28] which is equivalent to about 0.1 pCi per milligram of smoke; or about 0.81 pCi of lead 210 per gram of dry condensed smoke. The amount of polonium 210 inhaled from a pack of 20 cigarettes is therefore about 0.72 pCi. This seems to be independent of any form of filtering or 'low tar' cigarette. This concentration results in a highly significant increase in the body burden of these compounds. Compared to nonsmokers, heavy smokers have four times greater radioisotope density throughout their lungs. The polonium 210 content of blood in smokers averages 1.72 pCi per kilogram, compared to 0.76 pCi per kilogram in nonsmokers. Higher concentrations of polonium 210 are also found in the livers of smokers than nonsmokers. Polonium 210 is also known to be incorporated into bone tissue, where the continued irradiation of bone marrow may be a cause of leukemia, although this has not been proved as yet.

Research by NCAR radiochemist Ed Martell determined that radioactive compounds in cigarette smoke are deposited in "hot spots" where bronchial tubes branch. Since tar from cigarette smoke is resistant to dissolving in lung fluid, the radioactive compounds have a great deal of time to undergo radioactive decay before being cleared by natural processes. Indoors, these radioactive compounds linger in secondhand smoke, and therefore greater exposure occurs when these radioactive compounds are inhaled during normal breathing, which is deeper and longer than when inhaling cigarettes. Damage to the protective epithelial tissue from smoking only increases the prolonged retention of insoluble polonium 210 compounds produced from burning tobacco. Martell estimated that a carcinogenic radiation dose of 80-100 rads is delivered the lung tissue of most smokers who die of lung cancer.[29]

In other experiments, the alpha particle dosage from polonium 210 received by smokers of two packs a day was measured at 82.5 millirads per day, which would total 752.5 rads per 25 years, 150 times higher than the approximately 5 rem received from natural background radiation over 25 years.[citation needed] Other estimates of the dosage absorbed over 25 years of heavy smoking range from 165 to 1,000 rem, all significantly higher than natural background. In the case of the less radioactive Indian tobacco referred to above, the dosage received from polonium 210 is about 24 millirads a day, totalling 219 rads over 25 years or still about 40 times the natural background radiation exposure. In fact, all these numbers of total body burden are misleadingly low, because the dosage rate in the immediate vicinity of the deposited polonium 210 in the lungs can be from 100 to 10,000 times greater than natural background radiation. Lung cancer is seen in laboratory animals exposed to approximately one fifth of this total dosage of polonium 210.

Whether the quantities of these elements are sufficient to cause cancer is still a matter of debate. Most studies of carcinogenicity of tobacco smoke involve painting tar condensed from smoke onto the skin of mice and monitoring for development of tumors of the skin, a relatively simple process. However, the specific properties of polonium 210 and lead 210 and the model for their action, as described above, do not permit such a simple assay and require more difficult studies, requiring dosage of the mice in a manner mimicking smoking behavior of humans and monitoring for lung cancer, more difficult to observe as it is internal to the mouse.

Some researchers suggest that the degree of carcinogenicity of these radioactive elements is sufficient to account for most, if not all, cases of lung cancer related to smoking. In support of this hypothetical link between radioactive elements in tobacco and cancer is the observation that bladder cancer incidence is also proportional to the amount of tobacco smoked, even though nonradioactive carcinogens have not been detected in the urine of even heavy smokers; however, urine of smokers contains about six times more polonium 210 than that of nonsmokers, suggesting strongly that the polonium 210 is the cause of the bladder carcinogenicity, and would be expected to act similarly in the lungs and other tissue. Furthermore, many of the lung cancers contracted by cigarette smokers are adenocarcinomas, which are characteristic of the type of damage produced by alpha particle radiation such as that of polonium 210. It has also been suggested that the radioactive and chemical carcinogens in tobacco smoke act synergistically to cause a higher incidence of cancer than each alone.

However, the view that polonium 210 is responsible for many cases of cancer in tobacco smokers is disputed by at least one researcher.[30][31]

[edit] Other carcinogens

There are over 19 known carcinogens in cigarettes.[32] The following are some of the most potent carcinogens:

  • Polynuclear aromatic hydrocarbons are produced by pyrolysis in smoldering organic matter and emitted into smoke. Many of them are highly carcinogenic and mutagenic, because they are toxicated to mutagenic epoxides. The first PAH to be identified as a carcinogen in tobacco smoke was benzopyrene, which been shown to toxicate into a diol epoxide and then permanently attach to nuclear DNA, which may either kill the cell or cause a genetic mutation. If the mutation inhibits programmed cell death, the cell can survive to become a cancer cell. Tobacco manufacturers have experimented with combustionless vaporizer technology to allow cigarettes to be consumed without the formation of carcinogenic benzopyrenes.[33]
  • Nitrosamines are a group of carcinogenic compounds found in cigarette smoke but not in uncured tobacco leaves. Nitrosamines form on flue-cured tobacco leaves during the curing process through a chemical reaction between nicotine and other compounds contained in the uncured leaf and various oxides of nitrogen found in all combustion gases. Switching to indirect-fire curing has been shown to reduce nitrosamine levels to less than 0.1 parts per million.[34][35]
  • The carcinogenity of tobacco smoke is not explained by nicotine per se, which is not carcinogenic or mutagenic. It can be a synergistic carcinogen, however.

[edit] Nicotine Addiction and Genetic Factors

According to three separate studies commissioned by governments in the US and Europe scientists have identified a genetic link that makes people more likely to become addicted to tobacco. This genetic variation causes individuals to smoke more cigarettes, makes it harder for them to quit and increases their likelihood of developing lung cancer by up to 80%. [36]

Genetic markers of more than 35,000 people (mostly smokers and ex-smokers) were surveyed by scientists in three separate studies and all three zoned in on the same set of genetic differences. The genetic variations of note encode nicotine receptors on cells and was identified on a region of chromosome 15. [37] Possessing a single copy of the mutation raises an individuals risk of lung cancer by approximately 30%, while possessing two copies can raise that figure to about 80%.

[edit] Nicotine and addiction

Because of their nicotine addiction, many smokers find it difficult to cease smoking despite their knowledge of ill health effects.
Because of their nicotine addiction, many smokers find it difficult to cease smoking despite their knowledge of ill health effects.

Nicotine is a stimulant and is one of the main factors leading to continued tobacco smoking. Although the amount of nicotine inhaled with tobacco smoke is quite small (most of the substance is destroyed by the heat) it is still sufficient to cause physical and/or psychological dependence. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. Despite the design of various cigarettes advertised and even tested on machines to deliver less of the toxic tar, studies show that when smoked by humans instead of machines, they deliver the same net amount of smoke. Ingesting a compound by smoking is one of the most rapid and efficient methods of introducing it into the bloodstream, second only to injection, which allows for the rapid feedback which supports the smokers' ability to titrate their dosage. On average it takes about ten seconds for the substance to reach the brain. As a result of the efficiency of this delivery system, many smokers feel as though they are unable to cease. Of those who attempt cessation and last three months without succumbing to nicotine, most are able to remain smoke free for the rest of their lives[38]. There exists a possibility of depression in some who attempt cessation, as with other psychoactive substances. Depression is also common in teenage smokers; teens who smoke are four times as likely to develop depressive symptoms as their nonsmoking peers [39].

Although nicotine does play a role in acute episodes of some diseases (including stroke, impotence, and heart disease) by its stimulation of adrenaline release, which raises blood pressure[40], heart rate, and free fatty acids, the most serious longer term effects are more the result of the products of the smouldering combustion process. This has enabled development of various nicotine delivery systems, such as the nicotine patch or nicotine gum, that can satisfy the addictive craving by delivering nicotine without the harmful combustion by-products. This can help the heavily dependent smoker to quit gradually, while discontinuing further damage to health.

[edit] Smoking and cardiovascular disease

Smoking also increases the chance of heart disease. Several ingredients of tobacco lead to the narrowing of blood vessels, increasing the likelihood of a blockage, and thus a heart attack or stroke. According to a study by an international team of researchers, people under 40 are five times more likely to have a heart attack if they smoke.[41]

[edit] Oral health

Perhaps the most serious oral condition that can arise from tobacco smoking is that of oral cancer. However, smoking also increases the risk for various other oral diseases, some almost completely exclusive to smokers. Roughly half of periodontitis cases are attributed to current or former smoking. Smokers experience widespread periodontal destruction and have significantly greater loss of bone height. Smokeless tobacco causes gingival recession and white mucosal lesions. Up to 90% of periodontitis patients who are not helped by common modes of treatment are smokers.[42] Smoking has been proven to be an important factor in the staining of teeth.[43][44] Halitosis is common among tobacco smokers. Other oral diseases that are known to have strong links to smoking are leukoplakia, Snuff Dipper's lesions and smoker's palate. In addition, many smokers report a loss of taste sensation and/or salivary changes.[citation needed]

Tooth loss has been shown to be 2[45] to 3 times[46] higher in smokers than in non-smokers.[47]

[edit] Physical and psychological effects on smokers

Smokers report a variety of physical and psychological effects from smoking tobacco. Those new to smoking will experience nausea, dizziness, and rapid heart beat. The unpleasant symptoms will eventually vanish over time, with repeated use, as the body builds a tolerance to the chemicals in the cigarettes, such as nicotine.

In many respects, nicotine acts on the nervous system in a similar way to caffeine. Some writings have stated that smoking can also increase mental concentration; one study documents a significantly better IQ on the normed Advanced Raven Progressive Matrices test after smoking.[48] Most smokers say they enjoy smoking, which is part of the reason why many continue to do so even though they are aware of the health risks. Taste, smell, and visual enjoyment are also major contributions to the enjoyment of smoking, in addition to camaraderie with other smokers. Ironically, chronic exposure to tobacco smoke may inhibit one's sense of taste and smell, rendering him or her less able to enjoy these aspects of tobacco smoking.

Most smokers, when denied access to nicotine, exhibit symptoms such as irritability, jitteriness, dry mouth, and rapid heart beat.[49] Longer abstinence may lead to insomnia and even mild depression. The onset of these symptoms is very fast, nicotine's half-life being only 1 hour. Withdrawal symptoms can appear even if the smoker's consumption is very limited or irregular, appearing after only 4-5 cigarettes in most adolescents. An ex-smoker's chemical dependence to nicotine will cease after approximately ten to twenty days, although the brain's number of nicotine receptors is permanently altered,[citation needed] and the psychological dependence may linger for months or even many years. Unlike illicit recreational drugs and alcohol, nicotine does not measurably alter a smoker's motor skills, cognition, judgement, or language abilities while under the influence of the drug, but nicotine withdrawal symptoms such as irritability and incapacity to concentrate can have an influence on these aspects. Tobacco withdrawal has been shown to cause clinically significant distress.[50]

The majority of these effects are due to nicotine withdrawal,[49] and so smokers who are not addicted to nicotine will not suffer from them.

Some studies suggest that a link exists between smoking and mental illness, citing the high incidence of smoking amongst those suffering from schizophrenia[51] and the possibility that smoking may alleviate some of the symptoms of mental illness,[52] but these have not been conclusive.

[edit] Epidemiology of smoking

A team of British scientists headed by Richard Doll carried out a longitudinal study of 34,439 medical specialists from 1951 to 2001, generally called the "British doctors study."[53] The study demonstrated that smoking decreased life expectancy by up to 10 years and that almost half of the smokers died from diseases possibly caused by smoking (cancer, heart disease, and stroke).

In the UK, the impact of smoking is felt most keenly by the lower social classes, which are known to have lower life expectancy than those in wealthier classes. Half the difference in survival to age 70 between social classes I and V is estimated to be due to the higher smoking prevalence in the lower class group.[54]

[edit] Tobacco and reproduction

[edit] Effects of smoking on sperm cells

There is increasing evidence that the harmful products of tobacco smoking kill sperm cells.[55][56] Therefore, some governments require manufacturers to put warnings on packets. Smoking tobacco increases intake of cadmium, because the tobacco plant absorbs the metal. Cadmium, being chemically similar to zinc, may replace zinc in the DNA polymerase, which plays a critical role in sperm production. Zinc replaced by cadmium in DNA polymerase can be particularly damaging to the testes.[57]

[edit] Spontaneous abortion

A number of studies have shown that tobacco use is a significant factor in spontaneous abortions among pregnant smokers, and that it contributes to a number of other threats to the health of the fetus.[58] Second-hand smoke appears to present an equal danger to the fetus, as one study noted that "heavy paternal smoking increased the risk of early pregnancy loss."[59]

[edit] SIDS

Secondhand smoke is connected to Sudden Infant Death Syndrome (SIDS). Infants who die from Sudden Infant Death Syndrome tend to have higher concentrations of nicotine and cotinine (a biological marker for secondhand smoke exposure) in their lungs than those who die from other causes. While smoking during pregnancy increases the risk of Sudden Infant Death Syndrome, infants exposed to secondhand smoke after birth are also at a greater risk of Sudden Infant Death Syndrome whether or not the parent(s) smoked during pregnancy. The nicotine obtained from smoking travels through a women into her breast milk, thus giving nicotine to her child,[60]

[edit] Risks by kind of tobacco

[edit] Low tar/light cigarettes

There is no credible evidence that "Low Tar," "Light," or "Ultra Light" cigarettes are safer than regular cigarettes.[61]

Most of these terms refer to the type of filter that is used, and can vary depending on the brand. In some countries, the use of the word "Light" to refer to cigarettes has been banned.

According to the United States' Federal Government’s National Cancer Institute (NCI), light cigarettes provide no benefit to smoker's health.[62]

[edit] Cigar vs cigarette smoking

Although cigarette smoking causes a greater increase of the risk of cancer than cigar smoking, cigar smokers still have an increased risk for many health problems, including cancer, when compared to non-smokers.[63][64] The National Institutes of Health, through the National Cancer Institute, determined in 1998 that "cigar smoking causes a variety of cancers including cancers of the oral cavity (lip, tongue, mouth, throat), esophagus, larynx, and lung."[65] Relative risk for cigar-only smokers of all-cause mortality is 1.02 for 1-2 cigars/day, 1.08 for 3-4 cigars/day, and 1.17 for 5+ cigars/day. The NIH study concerned those who smoked at least one cigar per day, and stated "The health risks associated with less than daily smoking (occasional smokers) are not known."[65] Though most cigar smokers do not inhale, those that do have risks of lung cancer similar to cigarette smokers. Increased risk for heart attack is less for cigar smokers, but still present. As for Environmental Tobacco Smoke (ETS, or "Second-hand Smoking"), the NIH study points to the large amount of smoke generated by one cigar, saying "cigars can contribute substantial amounts of tobacco smoke to the indoor environment; and, when large numbers of cigar smokers congregate together in a cigar smoking event, the amount of ETS produced is sufficient to be a health concern for those regularly required to work in those environments."[65]

[edit] Pipe smoking

Pipe smoking involves significant health risks,[66][67][68] particularly oral cancer.[69][70]

[edit] Beneficial effects of smoking

Tobacco has sometimes been reported to have isolated positive effects on certain medical conditions, presumably due to the biological effects of nicotine. Most notably, some studies have found that patients with Alzheimer's disease are more likely not to have smoked than the general population, which has been interpreted to suggest that smoking offers some protection against Alzheimer's. However, the research in this area is limited and the results are conflicting; some studies show that smoking increases the risk of Alzheimer's disease. A recent review of the available scientific literature concluded that the apparent decrease in Alzheimer risk may be simply due to the fact that smokers tend to die before reaching the age at which Alzheimer normally occurs. "Differential mortality is always likely to be a problem where there is a need to investigate the effects of smoking in a disorder with very low incidence rates before age 75 years, which is the case of Alzheimer's disease," it stated, noting that smokers are only half as likely as non-smokers to survive to the age of 80.[71]

Other findings include:

  • Former and current smokers have a lower incidence of Parkinson's disease compared to people who have never smoked,[72][73] although the authors stated that it was more likely that the movement disorders which are part of Parkinson's disease prevented people from being able to smoke than that smoking itself was protective. Another study considered a possible role of nicotine in reducing Parkinson's risk: nicotine stimulates the dopaminergic system of the brain, which is damaged in Parkinson's disease.[74]
  • A protective effect of current smoking against ulcerative colitis, although smoking increases the risk of Crohn's disease, the other form of inflammatory bowel disease.[75]
  • Smoking reduces the risk of Kaposi's sarcoma in people without HIV infection.[76]
  • There is some evidence for decreased rates of endometriosis in infertile smoking women,[77] although other studies have found that smoking increases the risk in infertile women.[78] There is little or no evidence of a protective effect in fertile women.
  • Some preliminary data from 1996 suggested a reduced incidence of uterine fibroids,[79] but overall the evidence is unconvincing.[80]
  • There is limited evidence that smoking reduces the incidence of pregnancy-induced hypertension,[81] but not when the pregnancy is with more than one baby (i.e. it has no effect on twins etc.).[82] Smoking does, however, increase the likelihood of almost every other pregnancy-related health risk to both mother and child, and is the single most preventable cause of illness and death among mothers and infants in the developed world.[83]
  • A very large percentage of schizophrenics smoke tobacco as a form of self medication. [84][85][86][87] The high rate of tobacco use by the mentally ill is a major factor in their decreased life expectancy, which is about 25 years shorter than the general population.[88] Following the observation that smoking improves condition of people with schizophrenia, in particular working memory deficit, nicotine patches had been proposed as a way to treat schizophrenia.[89]
  • Preliminary reports suggest that smoking can decrease the incidence of acne prophylactically. This was seen by a decreased percentage ratio of patients needing acne medication versus the percentage of entire population of smokers. (A smaller percentage of patients who smoked needed medication than found in the population as a whole).[90]

[edit] Incidental problems

An indirect public health problem posed by cigarettes is that of accidental fires, usually linked with consumption of alcohol. Numerous cigarette designs have been proposed, some by tobacco companies themselves, which would extinguish a cigarette left unattended for more than a minute or two, thereby reducing the risk of fire. However the tobacco companies have historically resisted this idea, on the grounds that the nuisance involved in having to relight a cigarette left untouched for too long would reduce their sales. In fact, untreated tobacco formed into a cigarette will extinguish itself relatively quickly if left alone, and as a result cigarette tobacco is treated chemically to allow it to smolder indefinitely.[citation needed]

[edit] See also

[edit] Notes

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[edit] References

  • Joint Committee on Smoking and Health. Smoking and health: physician responsibility; a statement of the Joint Committee on Smoking and Health. Chest 1995; 198:201- 208
  • Boffetta, P., Agudo, A., Ahrens, W., Benhamou, E., Benhamou, S., Darby, S.C., Ferro, G., Fortes, C., Gonzalez, C.A., Jockel, K.H., Krauss, M., Kreienbrock, L., Kreuzer, M., Mendes, A., Merletti, F., Nyberg, F., Pershagen, G., Pohlabeln, H., Riboli, E., Schmid, G., Simonato, L., Tredaniel, J., Whitley, E., Wichmann, H.E., Saracci, R. 1998. Multicenter case-control study of exposure to environmental tobacco smoke and lung cancer in Europe. J. Natl. Cancer Inst. 90:1440-1450.

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