Health effects of tobacco

Pre-cigarette

Concern about health effects of tobacco has a long history. The coughing, throat irritation, and shortness of breath caused by smoking have always been obvious.

Texts on the harmful effects of smoking tobacco were recorded in the Timbuktu manuscripts.^[19]

Pipe smoking gradually became generally accepted as a cause of mouth cancers following work done in the 1700s. An association between a variety of cancers and tobacco use was repeatedly observed from the late 1800s into the early 1920s. An association between tobacco use and vascular disease was reported from the late 1800s onwards.

Gideon Lincecum, an American naturalist and practitioner of botanical medicine, wrote in the early 19th century on tobacco: "This poisonous plant has been used a great deal as a medicine by the old school faculty, and thousands have been slain by it. ... It is a very dangerous article, and use it as you will, it always diminishes the vital energies in exact proportion to the quantity used – it may be slowly, but it is very sure."^[20]

The 1880s invention of automated cigarette-making machinery in the American South made it possible to mass-produce cigarettes at low cost, and smoking became common. This led to a backlash and a tobacco prohibition movement, which challenged tobacco use as harmful and brought about some bans on tobacco sale and use.^[15] In 1912, American Dr. Isaac Adler was the first to strongly suggest that lung cancer is related to smoking.^[21] In 1924, economist Irving Fisher wrote an anti-smoking article for Reader's Digest which said "...tobacco lowers the whole tone of the body and decreases its vital power and resistance ... tobacco acts like a narcotic poison, like opium, and like alcohol, though usually in a less degree".^[22]Reader's Digest for many years published frequent anti-smoking articles.

Prior to World War I, lung cancer was considered to be a rare disease, which most physicians would never see during their career.^[23][24] With the postwar rise in popularity of cigarette smoking, however, came an epidemic of lung cancer.^[25]

Early observational studies

From the 1890s onwards, associations of tobacco use with cancers and vascular disease were regularly reported.^[14] In 1930, Fritz Lickint of Dresden, Germany, published^[18][17] a metaanalysis citing 167 other works to link tobacco use to lung cancer.^[17] Lickint showed that lung cancer sufferers were likely to be smokers. He also argued that tobacco use was the best way to explain the fact that lung cancer struck men four or five times more often than women (since women smoked much less),^[18] and discussed the causal effect of smoking on cancers of the liver and bladder.^[17]

More observational evidence was published throughout the 1930s, and in 1938, Science published a paper showing that tobacco users live substantially shorter lives. It built a survival curve from family history records kept at the Johns Hopkins School of Hygiene and Public Health. This result was ignored or incorrectly explained away.^[14]

An association between tobacco and heart attacks was first mentioned in the 1930; a large case–control study found a significant association in 1940, but avoided saying anything about cause, on the grounds that such a conclusion would cause controversy and doctors were not yet ready for it.^[14]

Official hostility to tobacco use was widespread in Nazi Germany where case-control studies were published in 1939 and 1943. Another was published in the Netherlands in 1948. A case-control study on lung cancer and smoking, done in 1939 by Franz Hermann Müller, had serious weaknesses in its methodology, but study design problems were better addressed in subsequent studies.^[14] The association of anti-tobacco research and public health measures with the Nazi leadership may have contributed to the lack of attention paid to these studies.^[18] They were also published in German and Dutch. These studies were widely ignored.^[26] In 1947 the British Medical Council held a conference to discuss the reason for the rise in lung cancer deaths; unaware of the German studies, they planned and started their own.^[14]

Five case-control studies published in 1950 by researchers from the US and UK did draw widespread attention.^[27] The strongest results were found by "Smoking and carcinoma of the lung. Preliminary report", by Richard Doll and Austin Bradford Hill,^[28][14] and the 1950 Wynder and Graham Study, entitled "Tobacco Smoking as a Possible Etiologic Factor in Bronchiogenic Carcinoma: A Study of Six Hundred and Eighty-Four Proved Cases". These two studies were the largest, and the only ones to carefully exclude ex-smokers from their nonsmokers group. The other three studies also reported that, to quote one, "smoking was powerfully implicated in the causation of lung cancer".^[27] The Doll and Hill paper reported that "heavy smokers were fifty times as likely as non-smokers to contract lung cancer".^[28][27]

Causality

The case-control studies clearly showed a close link between smoking and lung cancer, but were criticized for not showing causality. Follow-up large prospective cohort studies in the early 1950s showed clearly that smokers died faster, and were more likely to die of lung cancer, cardiovascular disease, and a list of other diseases which lengthened as the studies continued^[14]

The British Doctors Study, a longitudinal study of some 40,000 doctors, began in 1951.^[29] By 1954 it had evidence from three years of doctors' deaths, based on which the government issued advice that smoking and lung cancer rates were related^[30][29] (the British Doctors Study last reported in 2001,^[29] by which time there were approximately 40 linked diseases).^[14] The British Doctors Study demonstrated that about half of the persistent cigarette smokers born in 1900–1909 were eventually killed by their addiction (calculated from the logarithms of the probabilities of surviving from 35–70, 70–80, and 80–90) and about two thirds of the persistent cigarette smokers born in the 1920s would eventually be killed by their addiction.

Public awareness

In 1953, scientists at the Sloan-Kettering Institute in New York City demonstrated that cigarette tar painted on the skin of mice caused fatal cancers.^[26] This work attracted much media attention; the New York Times and Life both covered the issue. The Reader's Digest published an article entitled "Cancer by the Carton".^[26]: 14

On January 11, 1964, the United States Surgeon General's Report on Smoking and Health was published; this led millions of American smokers to quit, the banning of certain advertising, and the requirement of warning labels on tobacco products.

These results were first widely accepted in the medical community, and publicized among the general public, in the mid-1960s.^[14] The medical community's resistance to the idea that tobacco caused disease has been attributed to bias from nicotine-dependent doctors, the novelty of the adaptations needed to apply epidemiological techniques and heuristics to non-infectious diseases, and tobacco industry pressure.^[14]

The health effects of smoking have been significant for the development of the science of epidemiology. As the mechanism of carcinogenicity is radiomimetic or radiological, the effects are stochastic. Definite statements can be made only on the relative increased or decreased probabilities of contracting a given disease. For a particular individual, it is impossible to definitively prove a direct causal link between exposure to a radiomimetic poison such as tobacco smoke and the cancer that follows; such statements can only be made at the aggregate population level. Tobacco companies have capitalized on this philosophical objection and exploited the doubts of clinicians, who consider only individual cases, on the causal link in the stochastic expression of the toxicity as actual disease.^[31]

There have been multiple court cases against tobacco companies for having researched the health effects of tobacco, but having then suppressed the findings or formatted them to imply lessened or no hazard.^[31]

After a ban on smoking in all enclosed public places was introduced in Scotland in March 2006, there was a 17 percent reduction in hospital admissions for acute coronary syndrome. 67% of the decrease occurred in non-smokers.^[32]

Mortality

Smoking is the cause of about 5 million deaths per year.^[43] This makes it the most common cause of preventable early death.^[44] One study found that male and female smokers lose on average of 13.2 and 14.5 years of life, respectively.^[45] Another found a loss of life of 6.8 years.^[46] Each cigarette that is smoked is estimated to shorten life by an average of 11 minutes.^[47][48][49] At least half of all lifelong smokers die earlier as a result of smoking.^[29] Smokers are three times as likely to die before the age of 60 or 70 as non-smokers.^[29][50][51]

In the United States, cigarette smoking and exposure to tobacco smoke accounts for roughly one in five,^[52] or at least 443,000 premature deaths annually.^[53] To put this into context, ABC's Peter Jennings (who would later die at 67 from complications of lung cancer due to his life-long smoking habit) famously reported that in the US alone, tobacco kills the equivalent of three jumbo jets full of people crashing every day, with no survivors.^[54] On a worldwide basis, this equates to a single jumbo jet every hour.^[55]

A 2015 study found that about 17% of mortality due to cigarette smoking in the United States is due to diseases other than those usually believed to be related.^[56]

It is estimated that there are between 1 and 1.4 deaths per million cigarettes smoked. In fact, cigarette factories are the most deadly factories in the history of the world.^[57][58] See the below chart detailing the highest-producing cigarette factories, and their estimated deaths caused annually due to the health detriments of cigarettes.^[57]

• 
  Share of deaths from smoking, 2017^[59]
• 
  The number of deaths attributed to smoking per 100,000 people in 2017^[60]

Cancer

Share of cancer deaths attributed to tobacco in 2016^[61]

The primary risks of tobacco usage include many forms of cancer, particularly lung cancer,^[62] kidney cancer,^[63] cancer of the larynx and head and neck,^[64][65] bladder cancer,^[66] cancer of the esophagus,^[67] cancer of the pancreas^[68] and stomach cancer.^[69] Studies have established a relationship between tobacco smoke, including secondhand smoke, and cervical cancer in women.^[70] There is some evidence suggesting a small increased risk of myeloid leukemia,^[71] squamous cell sinonasal cancer, liver cancer, colorectal cancer, cancers of the gallbladder, the adrenal gland, the small intestine, and various childhood cancers.^[69] The possible connection between breast cancer and tobacco is still uncertain.^[72]

Lung cancer risk is highly affected by smoking, with up to 90% of cases being caused by tobacco smoking.^[73] Risk of developing lung cancer increases with number of years smoking and number of cigarettes smoked per day.^[74] Smoking can be linked to all subtypes of lung cancer. Small-cell carcinoma (SCLC) is the most closely associated with almost 100% of cases occurring in smokers.^[75] This form of cancer has been identified with autocrine growth loops, proto-oncogene activation and inhibition of tumour suppressor genes. SCLC may originate from neuroendocrine cells located in the bronchus called Feyrter cells.^[76]

The risk of dying from lung cancer before age 85 is 22.1% for a male smoker and 11.9% for a female smoker, in the absence of competing causes of death. The corresponding estimates for lifelong nonsmokers are a 1.1% probability of dying from lung cancer before age 85 for a man of European descent, and a 0.8% probability for a woman.^[77]

Pulmonary

Since establishing causation through experimental trials was not possible due to ethical restrictions, a lengthy study was conducted in order to establish the strong association necessary to allow for legislative action against tobacco consumption.

In smoking, long term exposure to compounds found in the smoke (e.g., carbon monoxide and cyanide) are believed to be responsible for pulmonary damage and for loss of elasticity in the alveoli, leading to emphysema and chronic obstructive pulmonary disease (COPD). COPD caused by smoking is a permanent, incurable (often terminal) reduction of pulmonary capacity characterised by shortness of breath, wheezing, persistent cough with sputum, and damage to the lungs, including emphysema and chronic bronchitis.^[78] The carcinogen acrolein and its derivatives also contribute to the chronic inflammation present in COPD.^[79]

Cardiovascular disease

Smoking can cause atherosclerosis, leading to coronary artery disease and peripheral arterial disease.

Tobacco stains on primarily the second and third fingers of a heavy smoker

Inhalation of tobacco smoke causes several immediate responses within the heart and blood vessels. Within one minute the heart rate begins to rise, increasing by as much as 30 percent during the first 10 minutes of smoking. Carbon monoxide in tobacco smoke exerts negative effects by reducing the blood's ability to carry oxygen.^[80]

Smoking also increases the chance of heart disease, stroke, atherosclerosis, and peripheral vascular disease.^[81][82] 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.^[83][84]

Exposure to tobacco smoke is known to increase oxidative stress in the body by various mechanisms, including depletion of plasma antioxidants such as vitamin C.^[85]

Recent research by American biologists has shown that cigarette smoke also influences the process of cell division in the cardiac muscle and changes the heart's shape.^[86]

The usage of tobacco has also been linked to Buerger's disease (thromboangiitis obliterans), the acute inflammation and thrombosis (clotting) of arteries and veins of the hands and feet.^[87]

Although cigarette smoking causes a greater increase in 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.^[88][89] As for second-hand smoke, 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 in a cigar smoking event, the amount of ETS (i.e. second-hand smoke) produced is sufficient to be a health concern for those regularly required to work in those environments."^[90]

Smoking tends to increase blood cholesterol levels. Furthermore, the ratio of high-density lipoprotein (HDL, also known as the "good" cholesterol) to low-density lipoprotein (LDL, also known as the "bad" cholesterol) tends to be lower in smokers compared to non-smokers. Smoking also raises the levels of fibrinogen and increases platelet production (both involved in blood clotting) which makes the blood thicker and more likely to clot. Carbon monoxide binds to hemoglobin (the oxygen-carrying component in red blood cells), resulting in a much stabler complex than hemoglobin bound with oxygen or carbon dioxide—the result is permanent loss of blood cell functionality. Blood cells are naturally recycled after a certain period of time, allowing for the creation of new, functional red blood cells. However, if carbon monoxide exposure reaches a certain point before they can be recycled, hypoxia (and later death) occurs. All these factors make smokers more at risk of developing various forms of arteriosclerosis (hardening of the arteries). As the arteriosclerosis progresses, blood flows less easily through rigid and narrowed blood vessels, making the blood more likely to form a thrombosis (clot). Sudden blockage of a blood vessel may lead to an infarction (stroke or heart attack). However, it is also worth noting that the effects of smoking on the heart may be more subtle. These conditions may develop gradually given the smoking-healing cycle (the human body heals itself between periods of smoking), and therefore a smoker may develop less significant disorders such as worsening or maintenance of unpleasant dermatological conditions, e.g. eczema, due to reduced blood supply. Smoking also increases blood pressure and weakens blood vessels.^[91]

Renal

In addition to increasing the risk of kidney cancer, smoking can also contribute to additional renal damage. Smokers are at a significantly increased risk for chronic kidney disease than non-smokers.^[92] A history of smoking encourages the progression of diabetic nephropathy.^[93]

Influenza

A study of an outbreak of an (H1N1) influenza in an Israeli military unit of 336 healthy young men to determine the relation of cigarette smoking to the incidence of clinically apparent influenza, revealed that, of 168 smokers, 68.5 percent had influenza, as compared with 47.2 percent of nonsmokers. Influenza was also more severe in the smokers; 50.6 percent of them lost work days or required bed rest, or both, as compared with 30.1 percent of the nonsmokers.^[94]

According to a study of 1,900 male cadets after the 1968 Hong Kong A2 influenza epidemic at a South Carolina military academy, compared with nonsmokers, heavy smokers (more than 20 cigarettes per day) had 21% more illnesses and 20% more bed rest, light smokers (20 cigarettes or fewer per day) had 10% more illnesses and 7% more bed rest.^[95]

The effect of cigarette smoking upon epidemic influenza was studied prospectively among 1,811 male college students. Clinical influenza incidence among those who daily smoked 21 or more cigarettes was 21% higher than that of non-smokers. Influenza incidence among smokers of 1 to 20 cigarettes daily was intermediate between non-smokers and heavy cigarette smokers.^[95]

Surveillance of a 1979 influenza outbreak at a military base for women in Israel revealed that influenza symptoms developed in 60.0% of the current smokers vs. 41.6% of the nonsmokers.^[96]

Smoking seems to cause a higher relative influenza-risk in older populations than in younger populations. In a prospective study of community-dwelling people 60–90 years of age, during 1993, of unimmunized people 23% of smokers had clinical influenza as compared with 6% of non-smokers.^[97]

Smoking may substantially contribute to the growth of influenza epidemics affecting the entire population.^[94] However, the proportion of influenza cases in the general non-smoking population attributable to smokers has not yet been calculated.

Mouth

Perhaps the most serious oral condition that can arise is that of oral cancer. However, smoking also increases the risk for various other oral diseases, some almost completely exclusive to tobacco users. 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."^[90] Pipe smoking involves significant health risks,^[98][99] particularly oral cancer.^[100] Roughly half of periodontitis or inflammation around the teeth cases are attributed to current or former smoking. 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. Smokers have significantly greater loss of bone height than nonsmokers, and the trend can be extended to pipe smokers to have more bone loss than nonsmokers.^[101]

Smoking has been proven to be an important factor in the staining of teeth.^[102][103] Halitosis or bad breath is common among tobacco smokers.^[104] Tooth loss has been shown to be 2^[105] to 3 times^[106] higher in smokers than in non-smokers.^[107] In addition, complications may further include leukoplakia, the adherent white plaques or patches on the mucous membranes of the oral cavity, including the tongue.^[108]

• 
  Smoker's lines
• 
  Smoking and its effects on the skin
• 
  Smoker's tongue
• 
  Dental radiograph showing bone loss in a 32 year old heavy smoker

Infection

Smoking is also linked to susceptibility to infectious diseases, particularly in the lungs (pneumonia). Smoking more than 20 cigarettes a day increases the risk of tuberculosis by two to four times,^[109][110] and being a current smoker has been linked to a fourfold increase in the risk of invasive disease caused by the pathogenic bacteria Streptococcus pneumoniae.^[111] It is believed that smoking increases the risk of these and other pulmonary and respiratory tract infections both through structural damage and through effects on the immune system. The effects on the immune system include an increase in CD4+ cell production attributable to nicotine, which has tentatively been linked to increased HIV susceptibility.^[112]

Smoking increases the risk of Kaposi's sarcoma in people without HIV infection.^[113] One study found this only with the male population and could not draw any conclusions for the female participants in the study.^[114]

Impotence

The incidence of impotence (difficulty achieving and maintaining penile erection) is approximately 85 percent higher in male smokers compared to non-smokers.^[115] Smoking is a key cause of erectile dysfunction (ED).^[12][115] It causes impotence because it promotes arterial narrowing and damages cells lining the inside of the arteries, thus leading to reduce penile blood flow.^[116]

Female infertility

Smoking is harmful to the ovaries, potentially causing female infertility, and the degree of damage is dependent upon the amount and length of time a woman smokes. Nicotine and other harmful chemicals in cigarettes interfere with the body's ability to create estrogen, a hormone that regulates folliculogenesis and ovulation. Also, cigarette smoking interferes with folliculogenesis, embryo transport, endometrial receptivity, endometrial angiogenesis, uterine blood flow and the uterine myometrium.^[117] Some damage is irreversible, but stopping smoking can prevent further damage.^[118][119] Smokers are 60% more likely to be infertile than non-smokers.^[120] Smoking reduces the chances of in vitro fertilization (IVF) producing a live birth by 34% and increases the risk of an IVF pregnancy miscarrying by 30%.^[120]

Psychological

American Psychologist stated, "Smokers often report that cigarettes help relieve feelings of stress. However, the stress levels of adult smokers are slightly higher than those of nonsmokers, adolescent smokers report increasing levels of stress as they develop regular patterns of smoking, and smoking cessation leads to reduced stress. Far from acting as an aid for mood control, nicotine dependency seems to exacerbate stress. This is confirmed in the daily mood patterns described by smokers, with normal moods during smoking and worsening moods between cigarettes. Thus, the apparent relaxant effect of smoking only reflects the reversal of the tension and irritability that develop during nicotine depletion. Dependent smokers need nicotine to remain feeling normal."^[121]

Pregnancy

A number of studies have shown that tobacco use is a significant factor in miscarriages among pregnant smokers, and that it contributes to a number of other threats to the health of the fetus. It slightly increases the risk of neural tube defects.^[157]

Environmental tobacco smoke exposure and maternal smoking during pregnancy have been shown to cause lower infant birth weights.^[158]

Studies have shown an association between prenatal exposure to environmental tobacco smoke and conduct disorder in children. As well, post-natal tobacco smoke exposure may cause similar behavioral problems in children.

Drug interactions

Smoking is known to increase levels of liver enzymes that break down drugs and toxins. That means that drugs cleared by these enzymes are cleared more quickly in smokers, which may result in the drugs not working. Specifically, levels of CYP1A2 and CYP2A6 are induced:^[159][160] substrates for 1A2 include caffeine and tricyclic antidepressants such as amitriptyline; substrates for 2A6 include the anticonvulsant valproic acid.

Multigenerational effects

Other harm

Protein AZGP1

Studies suggest that smoking decreases appetite, but did not conclude that overweight people should smoke or that their health would improve by smoking. This is also a cause of heart diseases.^[161] Smoking also decreases weight by overexpressing the gene AZGP1, which stimulates lipolysis.^[162]

Smoking causes about 10% of the global burden of fire deaths,^[163] and smokers are placed at an increased risk of injury-related deaths in general, partly due to also experiencing an increased risk of dying in a motor vehicle crash.^[164]

Smoking increases the risk of symptoms associated with Crohn's disease (a dose-dependent effect with use of greater than 15 cigarettes per day).^{[165][166][167][168]} There is some evidence for decreased rates of endometriosis in infertile smoking women,^[169] although other studies have found that smoking increases the risk in infertile women.^[170] 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,^[171] but overall the evidence is unconvincing.^[172]

Current research shows that tobacco smokers who are exposed to residential radon are twice as likely to develop lung cancer as non-smokers.^[173] As well, the risk of developing lung cancer from asbestos exposure is twice as likely for smokers than for non-smokers.^[174]

New research has found that women who smoke are at significantly increased risk of developing an abdominal aortic aneurysm, a condition in which a weak area of the abdominal aorta expands or bulges, and is the most common form of aortic aneurysm.^[175]

Smoking leads to an increased risk of bone fractures, especially hip fractures.^[176] It also leads to slower wound-healing after surgery, and an increased rate of postoperative healing complication.^[177]

Tobacco smokers are 30-40% more likely to develop type 2 diabetes than non-smokers, and the risk increases with the number of cigarettes smoked. Furthermore, diabetic smokers have worse outcomes than diabetic non-smokers.^[178][179]

Claimed benefits

Against the background of the overwhelmingly negative effects of smoking on health, some observational studies have suggested that smoking might have specific beneficial effects, including in the field of cardiovascular disease.^[180][181] Interest in this epidemiological phenomenon has also been aroused by COVID-19.^[181] Systematic review of reports that suggested smokers respond better to treatment for ischemic stroke provided no support for such claims.^[180]

Claims of surprising benefits of smoking, based on observational data, have also been made for Parkinson's disease,^[181] as well as a variety of other conditions, including basal-cell carcinoma,^[182] malignant melanoma,^[182] acute mountain sickness,^[183] pemphigus,^[184] celiac disease,^[185] and ulcerative colitis,^[186] among others.^[187]

Tobacco smoke has many bioactive substances, including nicotine, that are capable of exerting a variety of systemic effects.^[181] Surprising correlations may also stem from non-biological factors such as residual confounding (that is to say, the methodological difficulties in completely adjusting for every confounding factor that can affect outcomes in observational studies).^[181]

Chemical carcinogens

Benzopyrene diol epoxide, an extremely carcinogenic (cancer-causing) metabolite of benzopyrene, a polycyclic aromatic hydrocarbon produced by burning tobacco

Benzopyrene, a major mutagen in tobacco smoke, in an adduct to DNA^[201]

Smoke, or any partially burnt organic matter, contains carcinogens (cancer-causing agents). The potential effects of smoking, such as lung cancer, can take up to 20 years to manifest themselves. Historically, women began smoking en masse later than men, so an increased death rate caused by smoking amongst women did not appear until later. The male lung cancer death rate decreased in 1975 — roughly 20 years after the initial decline in cigarette consumption in men. A fall in consumption in women also began in 1975^[202] but by 1991 had not manifested in a decrease in lung cancer-related mortalities amongst women.^[203]

Smoke contains several carcinogenic pyrolytic products that bind to DNA and cause genetic mutations. Particularly potent carcinogens are polycyclic aromatic hydrocarbons (PAH), which are toxicated to mutagenic epoxides. The first PAH to be identified as a carcinogen in tobacco smoke was benzopyrene, which has been shown to toxicate into an epoxide that irreversibly attaches to a cell's 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. Similarly, acrolein, which is abundant in tobacco smoke, also irreversibly binds to DNA, causes mutations and thus also cancer. However, it needs no activation to become carcinogenic.^[204]

There are over 19 known carcinogens in cigarette smoke.^[205] The following are some of the most potent carcinogens:

• Polycyclic aromatic hydrocarbons are tar components produced by pyrolysis in smoldering organic matter and emitted into smoke. Several of these PAH's are already toxic in their normal form, however, many of then can become more toxic to the liver. Due to the hydrophobic nature of PAH's they do not dissolve in water and are hard to expel from the body. In order to make the PAH more soluble in water, the liver creates an enzyme called Cytochrome P450 which adds an additional oxygen to the PAH, turning it into a mutagenic epoxides, which is more soluble, but also more reactive.^[206] 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. The DNA contains the information on how the cell function; in practice, it contains the recipes for protein synthesis. If the mutation inhibits programmed cell death, the cell can survive to become a cancer, a cell that does not function like a normal cell. The carcinogenicity is radiomimetic, i.e. similar to that produced by ionizing nuclear radiation. Tobacco manufacturers have experimented with combustion less vaporizer technology to allow cigarettes to be consumed without the formation of carcinogenic benzopyrenes.^[207] Although such products have become increasingly popular, they still represent a very small fraction of the market, and no conclusive evidence has shown to prove or disprove the positive health claims.
• Acrolein is a pyrolysis product that is abundant in cigarette smoke. It gives smoke an acrid smell and an irritating, tear causing effect and is a major contributor to its carcinogenicity. Like PAH metabolites, acrolein is also an electrophilic alkylating agent and permanently binds to the DNA base guanine, by a conjugate addition followed by cyclization into a hemiaminal. The acrolein-guanine adduct induces mutations during DNA copying and thus causes cancers in a manner similar to PAHs. However, acrolein is 1000 times more abundant than PAHs in cigarette smoke and is able to react as is, without metabolic activation. Acrolein has been shown to be a mutagen and carcinogen in human cells. The carcinogenicity of acrolein has been difficult to study by animal experimentation, because it has such a toxicity that it tends to kill the animals before they develop cancer.^[204] Generally, compounds able to react by conjugate addition as electrophiles (so-called Michael acceptors after Michael reaction) are toxic and carcinogenic, because they can permanently alkylate DNA, similarly to mustard gas or aflatoxin. Acrolein is only one of them present in cigarette smoke; for example, crotonaldehyde has been found in cigarette smoke.^[208] Michael acceptors also contribute to the chronic inflammation present in tobacco disease.^[79]
• 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 gasses. Switching to Indirect fire curing has been shown to reduce nitrosamine levels to less than 0.1 parts per million.^[209][210]

Sidestream tobacco smoke, or exhaled mainstream smoke, is particularly harmful. Because exhaled smoke exists at lower temperatures than inhaled smoke, chemical compounds undergo changes which can cause them to become more dangerous. As well, smoke undergoes changes as it ages, which causes the transformation of the compound NO into the more toxic NO₂. Further, volatilization causes smoke particles to become smaller, and thus more easily embedded deep into the lung of anyone who later breathes the air.^[211]

Radioactive carcinogens

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. The presence of polonium-210 in mainstream cigarette smoke has been experimentally measured at levels of 0.0263–0.036 pCi (0.97–1.33 mBq),^[212][213] which is equivalent to about 0.1 pCi per milligram of smoke (4 mBq/mg); or about 0.81 pCi of lead-210 per gram of dry condensed smoke (30 Bq/kg).

Research by NCAR radiochemist Ed Martell suggested that radioactive compounds in cigarette smoke are deposited in "hot spots" where bronchial tubes branch, that tar from cigarette smoke is resistant to dissolving in lung fluid and that radioactive compounds have a great deal of time to undergo radioactive decay before being cleared by natural processes. Indoors, these radioactive compounds can linger in secondhand smoke, and greater exposure would occur 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 to the lung tissue of most smokers who die of lung cancer.^{[214][215][216]}

Smoking an average of 1.5 packs per day gives a radiation dose of 60-160 mSv/year,^[217][218] compared with living near a nuclear power station (0.0001 mSv/year)^[219][220] or the 3.0 mSv/year average dose for Americans.^[220][221] Some of the mineral apatite in Florida used to produce phosphate for U.S. tobacco crops contains uranium, radium, lead-210 and polonium-210 and radon.^[222][223] The radioactive smoke from tobacco fertilized this way is deposited in lungs and releases radiation even if a smoker quits the habit. The combination of carcinogenic tar and radiation in a sensitive organ such as lungs increases the risk of cancer.

In contrast, a 1999 review of tobacco smoke carcinogens published in the Journal of the National Cancer Institute states that "levels of polonium-210 in tobacco smoke are not believed to be great enough to significantly impact lung cancer in smokers."^[224] In 2011 Hecht has also stated that the "levels of ²¹⁰Po in cigarette smoke are probably too low to be involved in lung cancer induction".^[225]

Oxidation and inflammation

Free radicals and pro-oxidants in cigarettes damage blood vessels and oxidize LDL cholesterol.^[226] Only oxidized LDL cholesterol is taken-up by macrophages, which become foam cells, leading to atherosclerotic plaques.^[226] Cigarette smoke increases proinflammatory cytokines in the bloodstream, causing atherosclerosis.^[226] The pro-oxidative state also leads to endothelial dysfunction,^[226] which is another important cause of atherosclerosis.^[227]

Nicotine

Nicotine molecule

Nicotine, which is contained in cigarettes and other smoked tobacco products, is a stimulant and is one of the main factors leading to continued tobacco smoking. Nicotine is a highly addictive psychoactive chemical. When tobacco is smoked, most of the nicotine is pyrolyzed; a dose sufficient to cause mild somatic dependency and mild to strong psychological dependency remains. 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. There is also a formation of harmane (a MAO inhibitor) from the acetaldehyde in cigarette smoke, which seems to play an important role in nicotine addiction^[228] probably by facilitating dopamine release in the nucleus accumbens in response to nicotine stimuli. According to studies by Henningfield and Benowitz, nicotine is more addictive than cannabis, caffeine, alcohol, cocaine, and heroin when considering both somatic and psychological dependence. However, due to the stronger withdrawal effects of alcohol, cocaine and heroin, nicotine may have a lower potential for somatic dependence than these substances.^[229][230] About half of Canadians who currently smoke have tried to quit.^[231] McGill University health professor Jennifer O'Loughlin stated that nicotine addiction can occur as soon as five months after the start of smoking.^[232]

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.^[233] 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.^[234]

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,^[91] heart and respiration 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 led to the 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.

Recent evidence has shown that smoking tobacco increases the release of dopamine in the brain, specifically in the mesolimbic pathway, the same neuro-reward circuit activated by addictive substances such as heroin and cocaine. This suggests nicotine use has a pleasurable effect that triggers positive reinforcement.^[235] One study found that smokers exhibit better reaction-time and memory performance compared to non-smokers, which is consistent with increased activation of dopamine receptors.^[236] Neurologically, rodent studies have found that nicotine self-administration causes lowering of reward thresholds—a finding opposite that of most other addictive substances (e.g. cocaine and heroin).

The carcinogenity of tobacco smoke is not explained by nicotine per se, which is not carcinogenic or mutagenic, although it is a metabolic precursor for several compounds which are. In addition, it inhibits apoptosis, therefore accelerating existing cancers.^[237] Also, NNK, a nicotine derivative converted from nicotine, can be carcinogenic.

It is worth noting that nicotine, although frequently implicated in producing tobacco addiction, is not significantly addictive when administered alone.^[238] The addictive potential manifests itself after co-administration of an MAOI, which specifically causes sensitization of the locomotor response in rats, a measure of addictive potential.^[239]

Second-hand smoke

Posted sign to avoid passive smoking in York University, Toronto, Ontario, Canada

Second-hand smoke is a mixture of smoke from the burning end of a cigarette, pipe or cigar, and the smoke exhaled from the lungs of smokers. It is involuntarily inhaled, lingers in the air hours after cigarettes have been extinguished, and may cause a wide range of adverse health effects, including cancer, respiratory infections and asthma.^[240] Non-smokers who are exposed to second-hand smoke at home or work are thought, due to a wide variety of statistical studies, to increase their heart disease risk by 25–30% and their lung cancer risk by 20–30%. Second-hand smoke has been estimated to cause 38,000 deaths per year, of which 3,400 are deaths from lung cancer in non-smokers.^[241]

The current US Surgeon General's Report concludes that there is no established risk-free level of exposure to second-hand smoke. Short exposures to second-hand smoke are believed to cause blood platelets to become stickier, damage the lining of blood vessels, decrease coronary flow velocity reserves, and reduce heart rate variability, potentially increasing the risk of heart attack. New research indicates that private research conducted by cigarette company Philip Morris in the 1980s showed that second-hand smoke was toxic, yet the company suppressed the finding during the next two decades.^[240]

Chewing tobacco

Chewing tobacco has been known to cause cancer, particularly of the mouth and throat.^[242] According to the International Agency for Research on Cancer, "Some health scientists have suggested that smokeless tobacco should be used in smoking cessation programmes and have made implicit or explicit claims that its use would partly reduce the exposure of smokers to carcinogens and the risk for cancer. These claims, however, are not supported by the available evidence."^[242] Oral and spit tobacco increase the risk for leukoplakia, a precursor to oral cancer.^[243]

Cigars

Like other forms of smoking, cigar smoking poses a significant health risk depending on dosage: risks are greater for those who inhale more when they smoke, smoke more cigars, or smoke them longer.^[89] The risk of dying from any cause is significantly greater for cigar smokers, with the risk particularly higher for smokers less than 65 years old, and with risk for moderate and deep inhalers reaching levels similar to cigarette smokers.^[244] The increased risk for those smoking 1–2 cigars per day is too small to be statistically significant,^[245] and the health risks of the 3/4 of cigar smokers who smoke less than daily are not known^[246] and are hard to measure. Although it has been claimed that people who smoke few cigars have no increased risk, a more accurate statement is that their risks are proportionate to their exposure.^[88] Health risks are similar to cigarette smoking in nicotine addiction, periodontal health, tooth loss, and many types of cancer, including cancers of the mouth, throat, and esophagus. Cigar smoking also can cause cancers of the lung and larynx, where the increased risk is less than that of cigarettes. Many of these cancers have extremely low cure rates. Cigar smoking also increases the risk of lung and heart diseases such as chronic obstructive pulmonary disease.^[89]

Hookahs

A sign forbidding the use of cigarettes, e-cigarettes and hookah in Tbilisi, Georgia

A common belief among users is that the smoke of a hookah (waterpipe, narghile) is significantly less dangerous than that from cigarettes.^[247] The water moisture induced by the hookah makes the smoke less irritating and may give a false sense of security and reduce concerns about true health effects.^[248] Doctors at institutions including the Mayo Clinic have stated that use of hookah can be as detrimental to a person's health as smoking cigarettes,^[249][250] and a study by the World Health Organization also confirmed these findings.^[251]

Each hookah session typically lasts more than 40 minutes, and consists of 50 to 200 inhalations that each range from 0.15 to 0.50 liters of smoke.^[252][253] In an hour-long smoking session of hookah, users consume about 100 to 200 times the smoke of a single cigarette;^[252][254] A study in the Journal of Periodontology found that water pipe smokers were marginally more likely than regular smokers to show signs of gum disease, showing rates 5-fold higher than non-smokers rather than the 3.8-fold risk that regular smokers show.^[255] According to USA Today, people who smoked water pipes had five times the risk of lung cancer of non-smokers.^[256]

A study on hookah smoking and cancer in Pakistan was published in 2008. Its objective was "to find serum CEA levels in ever/exclusive hookah smokers, i.e. those who smoked only hookah (no cigarettes, bidis, etc.), prepared between 1 and 4 times a day with a quantity of up to 120 g of a tobacco-molasses mixture each (i.e. the tobacco weight equivalent of up to 60 cigarettes of 1 g each) and consumed in 1 to 8 sessions". Carcinoembryonic antigen (CEA) is a marker found in several forms of cancer. Levels in exclusive hookah smokers were lower compared to cigarette smokers although the difference was not as statistically significant as that between a hookah smoker and a non-smoker. Also, the study concluded that heavy hookah smoking (2–4 daily preparations; 3–8 sessions a day; >2 hrs to ≤ 6 hours) substantially raises CEA levels.^[257] Hookah smokers were nearly 6 times more likely to develop lung cancer than healthy non-smokers in Kashmir (India).^[258]

Dipping tobacco

Dipping tobacco, commonly referred to as snuff, is also put in the mouth, but it is a flavored powder. it is placed between the cheek and gum. Dipping tobacco does not need to be chewed for the nicotine to be absorbed. First-time users of these products often become nauseated and dizzy. Long-term effects include bad breath, yellowed teeth, and an increased risk of oral cancer.

Users of dipping tobacco are believed to face less risk of some cancers than are smokers, but are still at greater risk than people who do not use any tobacco products.^[259] They also have an equal risk of other health problems directly linked to nicotine, such as increased rate of atherosclerosis.