Nicotine exists in tobacco smoke in both the aerosol particles and as a gas.35 The nicotine molecule has two nitrogen atoms to which protons (positively charged sub-atomic particles) can be added. Nicotine can therefore exist in three forms as defined by protonation status: unprotonated, monoprotonated and diprotonated. Unprotonated nicotine is often referred to as ‘ free-base nicotine’, referring to the molecule carrying no charge. Free-base nicotine is the only form that can be readily converted into a gas by vapourisation.35 The pH (a measure of the acid-base balance) of smoke affects the proportion of nicotine that is free-base. The more acidic the smoke, the less nicotine is in its free form. One study of a range of cigarettes describes the proportion of free-base nicotine in the particles as ranging from 1% to 36%, with the higher particle pH resulting in a higher proportion of free-base nicotine.35
Free-base nicotine is proposed to be more readily deposited into the lungs than protonated nicotine.3 Subsequently, it’s believed that decreasing the acidity of smoke increases the amount and/or the rate of nicotine entry into the body through the lungs. However, there is little biological evidence to support this hypothesis. In fact, some studies comparing free-base to protonated nicotine have shown no increase in blood levels of nicotine when a higher proportion of free-base nicotine was consumed.36 ,37However, studies of smokeless tobacco of differing pH showed that nicotine delivery to the blood was higher and faster for products with a higher pH (higher free-base nicotine).38 ,39 Nicotine uptake from smokeless tobacco is absorbed through the mucosa of the mouth (buccal absorption), rather than the lungs. Increasing the pH of the smokeless tobacco has been shown to increase blood nicotine levels and nicotine-induced increases in heart rate and blood pressure.38
Chemicals such as ammonia and ammonium compounds are added to tobacco products to increase the pH,40 which may be increasing the delivery of nicotine to the blood, although this is not supported by biological studies.37Addition of ammonia increases smokers’ satisfaction,40 perhaps by enhancing flavours,41 but the mechanisms by which it does this are not well understood. More information about the role of ammonia in tobacco can be found in Section 126.96.36.199.
Other (non-nicotine) alkaloids in tobacco smoke may also contribute to the addictiveness of tobacco smoke.3 Both nicotine and some non-nicotine alkaloids serve as precursors for the production of carcinogenic N-nitrosamines produced in tobacco and in its emissions after burning.3 ,33
An aldehyde is a carbon-based (organic) molecule that has a carbon atom that is double-bonded to an oxygen and single-bonded to a hydrogen atom.42 Aldehydes of concern in tobacco smoke include acetaldehyde, acrolein (acraldehyde), formaldehyde, crotonaldehyde, propionaldehyde and butyraldehyde.30 ,31 Acetaldehyde, acrolein and formaldehyde are priority toxicants for regulation recommended by the WHO and standard operating procedures for their measurement have been established (see Section 12.5.3).
Aldehydes are often toxic to the respiratory system. Some are also toxic to the cardiovascular system and some damage DNA in tissues such as lung cells.30 ,31 Aldehydes from tobacco smoke are a likely cause of cancer in the lungs and nasal cavity.3
The smallest and simplest aldehyde molecule is formaldehyde; a compound with both cardio-toxic and carcinogenic activity. Formaldehyde is a preservative used in embalming solutions and for preserving dead tissue in laboratories.43 Formaldehyde is toxic to the cardiovascular system and has a genotoxic (mutating DNA to cause cancer) effect in lung cells.3 ,30 ,44 Similarly, acetaldehyde has both genotoxic activity in lung cells and is a cardiovascular toxicant.30 ,44 Acetaldehyde may also contribute to the addictiveness of tobacco by interacting with signalling processes in the brain that affect motivation, reward and stress-related responses.45 However, more studies are needed to confirm this.
Acrolein is a volatile and highly toxic aldehyde.46 Aside from tobacco smoke, people are exposed to acrolein due to the cooking of fatty foods and burning of fossil fuels. But acrolein from tobacco smoke is responsible for much of human exposure. In tobacco smoke, one source of acrolein is the breakdown of glycerol during combustion. Glycerol is often added to tobacco to maintain moisture, but even without this additive, tobacco smoke still contains significant levels of acrolein.46 Compared to non-smokers, smokers have four times the level of biomarkers in their urine that indicate acrolein exposure, and this is reduced by 78% after smoking cessation.47 Acrolein is an irritant to the human respiratory system, toxic to lung cilia and is likely to be a carcinogen in the lungs.3 Acrolein is toxic to the cardiovascular system and causes oxidative stress in the heart and increases cardiovascular disease risk.3 ,30 Animal experiments indicate that acrolein may be involved in the formation of type 2 diabetes and increase the risk of bacterial infections.30
188.8.131.52 Aromatic amines
An aromatic amine is a carbon-based compound consisting of an aromatic ring (of six carbon atoms) attached to an amine (containing a nitrogen atom). Human exposure to aromatic amines has long been associated with bladder cancers and aromatic amines are considered a likely cause of bladder cancer in smokers.3 ,8 ,48 ,49
Of the aromatic amines in tobacco emissions listed in Table 12.4.1, 4-aminobiphenyl is one of the most concerning for human health. One study has estimated that the average smoker consumes 36 µg of 4-aminobiphenyl, 1,309 µg of o-toluidine and 98.2 µg of β-naphthylamine each year. The effects of these three aromatic amines combined cause bladder cancer in 40 out of 100,000 smokers each year.48
Hydrocarbons are carbon-based compounds containing only hydrogen and carbon atoms. Hydrocarbons occur often in nature, particularly in trees and other plants, and make up much of fossil fuels.50 There is a wide range of hydrocarbons, some of which are toxic, damaging various human organs.
Benzene is a long-established carcinogen in humans and the benzene from tobacco smoke is a likely cause of lung cancer and acute myeloid leukaemia in smokers.3 ,51 ,52 Benzene may also damage the cardiovascular system30 and reproductive system.53
1,3-butadiene is of high concern to tobacco regulators and is on the WHO list of chemicals in tobacco emissions proposed for mandatory regulation. 1,3-butadiene from tobacco smoke is a carcinogen that is a likely cause of lung cancer. It is also toxic to the respiratory system. A study from 2003 used data that included measures of individual chemicals in cigarette smoke to compare the potency of 158 toxicants. The contribution of 1,3-butadiene (BDE) to the cancer risk index was over twice that of acrylonitrile, the next highest contributing carcinogen.54
Isoprene, present in the gases of tobacco emissions, causes cancer in mice and rats,55 ,56 and may cause lung cancer in smokers.3 Toluene is toxic to the respiratory system, central nervous system and reproductive system.30
184.108.40.206 Heterocyclic aromatic amines
Heterocyclic aromatic amines are carbon-based compounds containing more than one ring of carbon atoms with one ring containing a nitrogen atom. They are the carcinogenic chemicals that are produced during pyrolysis of tobacco (but are not present in unburned tobacco) and when cooking muscle meats such as beef and pork.3 ,57 ,58 Carcinogenesis (the formation of a cancer) currently is the only suspected toxicity of heterocyclic aromatic amines from tobacco.
Many heterocyclic aromatic amines show strong gene mutagenic activity in laboratory-grown cells.59-61All of the heterocyclic aromatic amines listed in Table 12.4.1 show carcinogenic activity in rodent experiments. Target organs in the rat include the liver, bladder, intestines and blood vessels.60 ,61 Once heterocyclic aromatic amines are broken down upon entering the body, their metabolites can form DNA adducts—they bind to regions of DNA where they can potentially cause mutations.
220.127.116.11 Polycyclic aromatic hydrocarbons (PAH)
A polycyclic aromatic hydrocarbon (PAH) is a carbon-based molecule that contains only hydrogen and carbon atoms and has multiple aromatic rings (rings of six carbon atoms). PAHs are found in fossil fuels and produced when these fuels, wood, garbage or tobacco are burned.62 Tobacco is a significant source of human exposure to PAHs.63 PAHs are produced by pyrolysis in the burning cigarette.3 Over 500 PAHs have been detected in tobacco smoke.64 They are mostly found in the particulate phase of tobacco smoke, but a small proportion are also detected as gases.3 One study has found that 1 to 1.6 μg of total PAHs are detected in the smoke from the average commercial cigarette under standard FTC machine-smoking conditions (see Section 12.5.1 for details about machine smoking conditions).65 There appears to be an inverse relationship between the levels of PAHs and tobacco-specific nitrosamines (TSNAs). This may be due to the use of different varieties of tobacco, which yield different amounts of these chemicals and also be related to the amount of nitrogen present in the tobacco.3 Both TSNAs and PAHs are highly carcinogenic, so choosing tobacco with lower PAH levels will not necessarily mean a lower level of carcinogens overall.
The FDA includes 16 PAHs in its list of 93 harmful and potentially harmful constituents in tobacco. The WHO’s list only includes benzo[a]pyrene ( Table 12.4.1), which is also proposed for mandatory regulation. Benzo[a]pyrene is classified as a group 1 human carcinogen by the IARC (indicating that the evidence is strong). Ten of the PAHs on the FDA list are being considered by the WHO for addition to its list of regulated chemicals from tobacco smoke.30 Each of the 16 PAHs on the FDA’s list is suspected to be a carcinogen and may be causing cancer in smokers. For most, there are animal studies that show carcinogenic effects.63 PAHs are likely causes of cancer in the lungs, larynx, mouth and cervix of smokers.3 Some are also toxic to the cardiovascular system.
N-nitrosamines are carbon-based compounds that contain two or more nitrogen atoms, and a nitrogen atom double-bonded to an oxygen atom. Most N-nitrosamines are known or suspected carcinogens. Humans are exposed to low levels of N-nitrosamines from many different sources, including foods, chlorinated water and personal care products. Tobacco emissions are a major source of human exposure to N-nitrosamines.66
Tobacco smoke contains volatile and non-volatile N-nitrosamines. A subset of N-nitrosamines are found only in tobacco and emissions from tobacco products— called tobacco-specific nitrosamines (TSNAs).3
N-Nitrosamines are uncommon in fresh tobacco. They are produced in chemical reactions as modifications of alkaloids (such as nicotine) after the plant is harvested or during burning. TSNAs are mainly produced during the processing, curing and storage of tobacco. N-nitrosamine levels in tobacco emissions are influenced by the amount of nitrogen fertiliser used for plant growth, the curing method used, and the variety of tobacco used, with Burley tobacco containing the highest levels (see Section 12.3.3). Growing and curing conditions can therefore be manipulated to reduce the levels of TNSAs in tobacco emissions.3 It is not yet known whether these changes could lead to better health outcomes in smokers.
The IARC has classified two TNSAs as group 1 carcinogens, meaning that there is sufficient evidence to conclude they are carcinogenic to humans.66 ,67 These are N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Both are listed by the WHO as proposed for mandatory regulation (Table 12.4.1). Two tobacco N-nitrosamines are classified into group 2A (probably carcinogenic to humans): NDMA and NDEA. Six others are classified as group 2B (possibly carcinogenic to humans): NDMA, NMEA, NMOR, NPIP and NPYR (see Table 12.4.1 for chemical names).66
NNK is a likely cause of cancer in the lungs, mouth, nose, liver, pancreas and cervix of smokers. NNN is a likely cause of cancer in the nose, mouth and oesophagus of smokers, and other N-nitrosamines are likely causes of nasal, oesophagus and liver cancers.3 Both NNN and NNK can form DNA adducts—where the chemical binds to DNA and potentially causes DNA sequence mutations. Higher levels of NNK or NNN-DNA adducts have been found in the oral cells of smokers with head-and-neck squamous cell carcinoma, indicating the importance of these DNA adducts.68
Phenols are carbon-based compounds containing an aromatic ring of six carbon atoms attached to one or more hydroxyl (-OH, oxygen bound to a hydrogen atom). Phenols are usually acidic, and many are highly toxic. The simplest form of these molecules is called phenol, whereas the term ‘phenols’ refers to a class of similar molecules, of which seven are listed by the FDA as harmful or potentially harmful constituents of tobacco.31 Phenols detected in tobacco emissions, such as phenol, catechol, m- and p-cresol are likely to have formed during the pyrolysis of common tobacco biomass components such as lignin, tyrosine and ethyl cellulose.69 Levels of some phenols, such as resorcinol and hydroquinone, may be increased in smoke with a higher pH (less acidic).3
There is currently insufficient data to support a role for these phenols as causes of specific cancers in smokers, but their relatively high levels in tobacco smoke and their known toxicities from laboratory and animal studies are cause for concern. Phenols found in tobacco emissions that may have carcinogenic activity are catechol, cresols and hydroquinone. Cresols and phenol are also respiratory toxicants and phenol may harm the cardiovascular system.31 Catechol is a co-carcinogen (increases the effects of other carcinogens) that is present at relatively high levels in cigarette smoke.8 Hydroquinone causes? DNA mutations in animal and laboratory experiments and may form DNA adducts.70 ,71
18.104.22.168 Other carbon-based (organic) compounds
There are many other carbon-based chemicals found in tobacco smoke that may be damaging the health of smokers. The WHO includes acetone, acrylonitrile, pyridine and quinoline in its list of chemicals to be measured for tobacco product regulation (Table 12.4.1). The longer FDA list adds 17 more ‘other organic chemicals’ to this in their list of harmful and potentially harmful constituents of tobacco. These include furan, aflatoxin B1 and styrene.
Most of the chemicals listed in Table 12.4.1 are carcinogenic and/or respiratory toxins. Chlorinated dioxins/furans, ethyl carbamate, ethylene oxide and nitrobenzene are also classified as reproductive or developmental toxins.31 Ethylene oxide and ethylene carbamate are carcinogens that are likely to be a cause of lung cancer in smokers.3 Furan in cigarette smoke is a likely cause of liver cancer in smokers.3 Caffeic acid can cause kidney cancer in animal experiments, although humans are exposed to considerable levels of caffeic acid through their diet as well as smoking.72 Coumarin (1,2-benzopyrone) has toxic activity on the liver and kidneys and was banned as a food additive in the United States in 1954.73 Acrylonitrile is a compound that is highly toxic at low doses. It does not occur naturally but is made by industrial processes. The FDA classifies acrylonitrile as a carcinogen and respiratory toxicant. A study from 2003 used data that included measures of individual chemicals in cigarette smoke to compare the potency of 158 toxicants. The contribution of acrylonitrile to the cancer risk index was the second-highest of all tested.54 Aflatoxin B1 is a toxin produced by fungal infections of tobacco plants. It is classified as a group 1 carcinogen by the IARC.74 Acrylamide is found in tobacco smoke and also formed when carbohydrate foods are cooked at high temperatures. Inhalation of acrylamide can irritate the respiratory system and long-term exposure may lead to nerve damage. There is data from animal experiments demonstrating the formation of cancer, nerve damage and reproductive toxicity with acrylamide exposure.75
The WHO lists the inorganic gases ammonia, carbon monoxide, hydrogen cyanide and nitric oxides to be measured in tobacco smoke ( Table 12.4.1). The longer FDA list also includes hydrazine, 2-nitropropane and selenium. Of these inorganic substances, ammonia, hydrogen cyanide, hydrazine and selenium may be toxic to the respiratory tract. Hydrazine and 2-nitropropane have carcinogenic activity.31
Ammonium compounds are often added to tobacco to increase the pH of smoke and may be making smoking more addictive (see Section 12.6.2 for more information). Hydrogen cyanide is a toxic gas that affects the cardiovascular, respiratory and central nervous systems. Chronic exposure of smokers to hydrogen cyanide in smoke may lead to impaired wound healing, fertility issues and other conditions.30
The carbon monoxide in tobacco smoke is of particular concern due to its many effects on human health. Carbon monoxide is a cardiovascular toxicant, which binds to haemoglobin in the blood, displacing oxygen. This reduces oxygen delivery through the blood. Carbon monoxide also causes damage to blood vessel walls, and promotes the progression of atherosclerosis (hardening of the arteries) and other cardiovascular diseases.30
22.214.171.124 Metals, metalloids and radionuclides
Toxic metals and metalloids can be detected in the particle phase of tobacco smoke. A metalloid is an element that has properties of both metals and non-metals. The WHO recommends testing of the metalloid arsenic and metals cadmium, lead and mercury in tobacco emissions ( Table 12.4.1).30 The FDA adds beryllium, chromium, cobalt and nickel to this list as harmful or potentially harmful substances, as well as radioactive polonium-210, uranium-235 and uranium-238.31
All of these elements are considered carcinogenic based on animal and laboratory experiments.31 Arsenic, beryllium, cadmium and polonium-210 are IARC group 1 carcinogens, meaning there is sufficient evidence that they are carcinogenic to humans.3 ,8 ,72 ,76 Lead, nickel and cobalt are group 2B carcinogens (possibly carcinogenic to humans).76 Polonium is a potent carcinogen and has been detected in the lungs of smokers and former smokers.77 Whether polonium in the lungs of smokers has impacts on human health is currently unknown due to insufficient data.78
Lead and cadmium are of particular concern in tobacco smoke as they are at relatively higher levels than the other metals.3 Cadmium is a respiratory toxicant, promoting oxidative injury and emphysema. Cadmium, lead and mercury have toxic effects on reproduction and development. Cadmium exposure in pregnant women may also affect the development of their children.3
126.96.36.199 Additives and flavours
Tobacco manufacturers add numerous chemicals to the tobacco to control moisture, add flavour, manipulate free nicotine levels and other reasons. These additives often contribute to the toxicity, addictiveness and attractiveness of tobacco products. See Section 12.6 for more information.
12.4.4 Emission from tobacco that is not combusted (set alight)
Tobacco that is not directly lit on fire does not undergo combustion— a chemical reaction described in Section 188.8.131.52. Waterpipe tobacco and heated tobacco products are heated but not directly set alight, therefore do not undergo combustion. However, waterpipe emissions are a mix of emissions from the heated tobacco and the burning coals that heat them, which are undergoing combustion. Therefore the emissions from waterpipe contain the chemical products of combustion of the coals as well as emissions from the heated tobacco.
Heated tobacco products, not to be confused with e-cigarettes/vapes, produce emissions from pyrolysis and other chemical reactions that occur at lower temperatures. However, pyrolysis is responsible for the production of many of the toxic chemicals in tobacco emissions (see Section 184.108.40.206). Currently, there is debate as to whether the emissions from heated tobacco products should be referred to as smoke or another term.
Products collectively known as ‘smokeless tobacco’ include those used orally and nasally. The emissions from these products are all the chemicals that move out of tobacco and have the potential to be absorbed into the cells of the body. These products are not heated at all, but the emissions may be modified by saliva or other bodily excretions, before uptake into the body.
220.127.116.11 Emissions from waterpipes
A typical waterpipe consists of numerous elements that are necessary for the heating of tobacco using burning coals. The tobacco is placed in the ‘head’ and often covered with perforated foil or a screen. Heated coals are placed over the top of the tobacco and a cover (wind guard) with air holes may sit over this, which keeps the burn rate and temperature low by restricting the flow of air. With suction from the mouthpiece through the hose, emissions are pulled down through the ‘body’, moving through the water in the bowl before inhalation through the hose ( Figure 12.4.2).79
Figure 12.4.2 Diagram of a hookah waterpipe.
Source: Smackware, Public domain, via Wikimedia Commons.
The water in a waterpipe cools the emissions and may reduce the concentration of some chemicals. Experiments comparing waterpipes used with and without the water have shown that the water reduces the concentration of nicotine in the emissions by half, but does not reduce carbon monoxide and many other toxic chemicals.80
The tobacco in a typical waterpipe is not directly set on fire, presumably because it is so moist that it will not burn in a self-sustaining manner. However, heated tobacco produces emissions are inhaled by waterpipe users.81 The burning coals heat the tobacco unevenly, ranging from about 450°C near the heat source to 50°C furthest from it.82 These temperatures are generally lower than would be found in cigarettes or tobacco pipes (non-water), which may change the range of chemicals produced in waterpipe emissions. However, the temperature is sufficient for pyrolysis to occur in parts of the tobacco. Chemicals produced from the burning charcoal, which is undergoing combustion, are also present in the mainstream emissions coming from a waterpipe.82
Emissions from waterpipes used with tobacco include aldehydes, carbon monoxide, nicotine, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons and lead.83 ,84 See Section 12.4.3 for more details about these chemicals. The charcoal is the source of most of the carbon monoxide and polycyclic aromatic hydrocarbons (such as benzo[a]pyrene) found in waterpipe smoke.85 ,86
Waterpipe tobacco can be heated by an electrical heating element as an alternative to the heated charcoal, which may reduce the harmful emissions from the charcoal. These electrical elements may reduce some toxicants, such as carbon monoxide and polycyclic aromatic hydrocarbons. However, nicotine and many other toxic chemicals remain at similar levels in the emissions from electrically-heated waterpipe tobacco compared to charcoal-heated.86
See Section 12.2.5 for more information about the tobacco used in waterpipes and Section 3.27.5 for the health effects of smoking tobacco in a waterpipe.
18.104.22.168 Emissions from heated tobacco (‘heat-not-burn’) products
Rather than setting alight the tobacco, heated tobacco products apply heat to tobacco to produce emissions (described further in Chapter 18C). The heating system uses an external heat source that liberates nicotine and other chemicals from specially designed cigarette-like sticks containing reconstituted tobacco sheet or loose leaf tobacco (see Section 12.2.8).87-89 Features of some heated tobacco products include lower- and higher-temperature variants, capacity to heat both tobacco and liquid, use of a metallic mesh punctured with tiny holes to heat a sealed liquid cap, and features that allow users to customise the temperature and manage the aerosol and flavour output.87
Heated tobacco products should not be confused with e-cigarettes (vapes), which do not contain tobacco. Most e-cigarettes heat a liquid to produce an aerosol, which often includes nicotine that is derived from tobacco plants (see Section 18B.1).
Heated tobacco products generally heat tobacco to lower than 600°C using a battery-powered heating system. Tobacco companies often claim that their devices do not heat above 350°C.89 This produces an aerosol that, like the smoke aerosols from combusted tobacco, contains particles that float in gases. The tobacco industry maintains that the aerosol produced by heated tobacco products is not smoke and sometimes erroneously refers to it as a “vapour”.90 ,91 These aerosol emissions are not accurately described as vapours, which are defined as chemicals in their gaseous state (at a temperature in which they can be liquified with added pressure). In fact, the aerosols emitted by cigarettes and other combusted tobacco products share much in common with the aerosols produced by heated tobacco products.
While some chemicals in smoke from combusted products are produced in the combustion reactions, many more are produced by pyrolysis. Pyrolysis is a chemical reaction that is best described as decomposition driven by heat (see Section 22.214.171.124). Pyrolysis of tobacco mostly occurs between 100°C and 500°C,10 ,14 with the majority of volatile products produced between 200°C and 350°C.15 Many of the toxic chemicals produced during the use of conventional burned tobacco products are made by pyrolysis. There is evidence that pyrolysis is occurring in heated tobacco products, in that charring is consistently observed in the tobacco plugs after use92 and polycyclic aromatic hydrocarbons are detected, which are produced when tobacco is pyrolysed.3 It is therefore quite feasible that heated tobacco products would produce emissions containing similar toxic products to those produced by pyrolysis in combusted tobacco products.
The emissions from commonly used heated tobacco products were shown to produce similar levels of addictive nicotine as conventional cigarettes.88 ,89 ,93-95 Harmful reactive oxygen compounds (such as hydrogen peroxide), and a range of carbonyl compounds (including toxic aldehydes such as acrolein,89 formaldehyde, acetaldehyde and butyraldehyde),93 ,96 pyrene, benzo[a]pyrene and other carcinogenic polycyclic aromatic hydrocarbons89 ,94 have been found in emissions from heated tobacco products. However, they are usually at lower levels than in the smoke from conventional cigarettes. Carcinogenic tobacco-specific nitrosamines were found in the emissions of heated tobacco products96 at levels 50 to 100 times higher than those in e-cigarette emissions but approximately 10 times lower than conventional cigarette emissions.97 Gases found in heated tobacco product emissions include toxic carbon monoxide and nitric oxide88 ,94 ,96 but carbon monoxide levels were considerably lower than in emissions from conventional cigarettes.89 More information about the individual chemicals in these emissions can be found below in Section 12.4.3.
Emissions from common heated tobacco products, therefore, contain a broad range of the toxic chemicals found in cigarette smoke, but most at lower levels. For some of these chemicals, it has been shown that their concentrations in heated tobacco product emissions lie in between those of e-cigarettes and cigarette smoke. However, there are studies showing similar health risks from the use of heated tobacco products and factory-made cigarettes (see InDepth 18C for more information). It should therefore not be assumed that a lower amount of specific chemicals in heated tobacco product emissions will lead to a reduction in the harm to health caused by their use.
126.96.36.199 Emission from smokeless tobacco
Smokeless tobacco refers to tobacco products that are chewed, sucked or placed in the mouth or nose.98 Chewed tobacco is a loose-leaf, plug tobacco or twist. Oral snuff is ground tobacco that may be in a bag, held in place in the mouth and sucked.98 Snus is a type of moist snuff that is placed between the user’s cheek and gums, or behind the upper or lower lip, whereas dry or liquid snuff may be used nasally.67 Broad generalisations about the emissions and health risks can be problematic due to the wide variety of these products and the ways they are used.99 Sales of smokeless tobacco products have been banned in Australia since 1991.100 See Section 12.2.9 for more information about the tobacco used in these products and for the prevalence of use, health effects and regulation of smokeless tobacco products.
Smokeless tobacco products are not heated and therefore do not undergo combustion, pyrolysis chemical reactions, distillation or other processes that create many of the chemicals found in smoke.67 These products, however, do have emissions: the chemicals released from the product during use. Nicotine and other chemicals in these emissions are absorbed through the oral or nasal mucous membranes of the user and enter the bloodstream, circulating throughout the body. Oral smokeless tobacco products are mixed with saliva through chewing or sucking. Saliva contains compounds that can modify the pH of the solution as well as start the process of digestion, where large carbon-based (organic) components are broken down into smaller, more water-soluble compounds. The emission from oral smokeless tobacco may therefore be modified before entering the body’s cells and bloodstream, however, these modifications remain poorly characterised due to a lack of research.
Nicotine is the main addictive chemical present in smokeless tobacco products.67 Nicotine is found in moist snuff and chewing tobacco at similar levels to conventional cigarettes101 but concentrations across products and brands differ widely. A study of 31 popular brands of smokeless tobacco in the US showed that total nicotine levels in unused products ranged from 8.77 to 18.16 mg/g of the product, and free nicotine ranged from 0.48 to 6.99 mg/g of the product.102 A study of nicotine in smokeless tobacco emissions, using artificial saliva, found that nicotine release was dependent on the form and cut of the smokeless tobacco products, with a slower release observed for snus and loose-leaf, compared to chopped and loose moist snuff smokeless tobacco.103
Nicotine is absorbed into the body more slowly from oral snuff and chewing tobacco than from cigarettes, but it reaches similar peak levels in the blood.101 ,104 Unlike nicotine from cigarettes that quickly drops in concentration, nicotine levels in the blood plateau after the use of these smokeless tobacco products.101 The rate of nicotine delivery across mucous membranes, which affects its addictive properties, can be increased by a higher (less acidic) pH level in smokeless tobacco (see Section 188.8.131.52). The pH levels of smokeless tobacco products vary widely, from pH 5 to 8.105 For products that mix with saliva, pH may be affected by the buffering chemicals present in the saliva, which could increase the pH of tobacco emissions with a low pH.104 However, there is evidence that manipulation of the pH of moist snuff by manufacturers is the primary means by which the rate of nicotine delivery is controlled.104
Most of the research on smokeless tobacco chemicals has detected them in the unused product, rather than its emissions.67 Chemicals found in various types of smokeless tobacco products include toxic and carcinogenic chemicals such as N-nitrosamines, aldehydes, benzofluoranthenes, lactones, benzo[a]pyrene, aldehydes, arsenic, cadmium, polonium and uranium.67 ,105 Additives, which often remain a trade secret, may include menthol, methyl or ethyl salicylate, β-citronellol, 1,8-cineole or benzyl benzoate. There is a wide variety in the amount of N-nitrosamines found in different brands of smokeless tobacco.67 Some Swedish Snus manufacturers use processes that minimise the amount of N-nitrosamines in their products.67
In the absence of comprehensive studies of the chemicals emitted from smokeless tobacco products during their use, biomarkers provide evidence that these chemicals enter the body. Biomarker studies have shown that users of smokeless tobacco products are exposed to nicotine,106 carcinogenic N-nitrosamines such as NNN and NNAL (see Section 184.108.40.206),106 ,107 polycyclic aromatic hydrocarbons and volatile organic compounds.108 People who only use smokeless tobacco have higher concentrations of “total nicotine equivalent” biomarker and tobacco-specific N-nitrosamines than exclusive cigarette smokers. Conversely, they had lower biomarker levels for polycyclic aromatic hydrocarbons and volatile organic compounds than cigarette smokers.108
Relevant news and research
For recent news items and research on this topic, click here. (Last updated April 2022)
1. World Health Organization. Partial guidelines for implementation of articles 9 and 10 of the WHO Framework Convention on Tobacco Control. 2013. Available from: https://www.who.int/fctc/guidelines/Guideliness_Articles_9_10_rev_240613.pdf.
2. Borgerding M and Klus H. Analysis of complex mixtures--cigarette smoke. Experimental and Toxicologic Pathology, 2005; 57 Suppl 1:43-73. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16092717
3. US Department of Health and Human Services. A report of the Surgeon General: How tobacco smoke causes disease. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53017/.
4. International Agency for Research on Cancer, Tobacco Smoking. IARC Monographs on the evaluation of carcinogen risk of chemicals to humans. Vol. 38 Vol. 38.Lyon: World Health Organization; 1986. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Tobacco-Smoking-1986.
5. Daher N, Saleh R, Jaroudi E, Sheheitli H, Badr T, et al. Comparison of carcinogen, carbon monoxide, and ultrafine particle emissions from narghile waterpipe and cigarette smoking: Sidestream smoke measurements and assessment of second-hand smoke emission factors. Atmospheric Environment, 2010; 44(1):8-14. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20161525
6. US Department of Health and Human Services. The health consequences of involuntary exposure to tobacco smoke: a report of the Surgeon General. Atlanta, Georgia: US Dept. of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2006. Available from: http://www.cdc.gov/tobacco/data_statistics/sgr/sgr_2006/index.htm.
7. National Research Council (US) Committee on Passive Smoking, Environmental tobacco smoke: Measuring exposures and assessing health effects. Washington (DC): National Academies Press (US); 1986. Available from: https://www.ncbi.nlm.nih.gov/books/NBK219205/
8. International Agency for Research on Cancer Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Volume 83. Lyon: International Agency for Research on Cancer 2004. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Tobacco-Smoke-And-Involuntary-Smoking-2004.
9. Bridge DP and Corn M. Contribution to the assessment of exposure of nonsmokers to air pollution from cigarette and cigar smoke in occupied spaces. Environmental Research, 1972; 5(2):192-209. Available from: https://www.ncbi.nlm.nih.gov/pubmed/5036964
10. Ermala P and Holsti LR. On the burning temperatures of tobacco. Cancer Research, 1956; 16(6):490-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/13343119
11. Baker RR. Smoke generation inside a burning cigarette: modifying combustion to develop cigarettes that may be less hazardous to health. Progress in energy and Combustion Science, 2006; 32:373-85. Available from: https://www.sciencedirect.com/science/article/abs/pii/S036012850600013X
12. McAdam K, Eldridge A, Fearon IM, Liu C, Manson A, et al. Influence of cigarette circumference on smoke chemistry, biological activity, and smoking behaviour. Regulatory Toxicology and Pharmacology, 2016; 82:111-26. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27634061
13. Boslaugh SE. Pyrolysis: chemical reaction, in Britannica 2014. Available from: https://www.britannica.com/science/pyrolysis.
14. Baker RR. A review of pyrolysis studies to unravel reaction steps in burning tobacco. Journal of Analytical and Applied Pyrolysis, 1987; 11:555-73. Available from: https://www.sciencedirect.com/science/article/abs/pii/0165237087850544
15. Oja V, Hajaligol MR, and Waymack BE. The vaporization of semi-volatile compounds during tobacco pyrolysis. Journal of Analytical and Applied Pyrolysis, 2006; 76(1-2):117-23. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0165237005001646
16. Kondratiev VN. Combustion: chemical reaction, in Britannica 2007. Available from: https://www.britannica.com/science/combustion.
17. Cartanya-Hueso A, Lidon-Moyano C, Fu M, Perez-Ortuno R, Ballbe M, et al. Comparison of TSNAs concentration in saliva according to type of tobacco smoked. Environmental Research, 2019; 172:73-80. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30771628
18. Ohshima H, Nair J, Bourgade MC, Friesen M, Garren L, et al. Identification and occurrence of two new N-nitrosamino acids in tobacco products: 3-(N-nitroso-N-methylamino)propionic acid and 4-(N-nitroso-N-methylamino)butyric acid. Cancer Letters, 1985; 26(2):153-62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/3978605
19. Piade JJ, Roemer E, Dempsey R, Hornig G, Deger Evans A, et al. Toxicological assessment of kretek cigarettes: Part 2: kretek and American-blended cigarettes, smoke chemistry and in vitro toxicity. Regulatory Toxicology and Pharmacology, 2014; 70 Suppl 1:S15-25. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25497993
20. Rosenberry ZR, Pickworth WB, and Koszowski B. Large cigars: Smoking topography and toxicant exposure. Nicotine & Tobacco Research, 2018; 20(2):183-91. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27798089
21. Hamad SH, Johnson NM, Tefft ME, Brinkman MC, Gordon SM, et al. Little cigars vs 3R4F cigarette: Physical properties and HPHC yields. Tobacco Regulatory Science, 2017; 3(4):459-78. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29911130
22. Jablonski JJ, Maines JH, Cheetham AG, and Gillman IG. Comparative levels of carbonyl delivery between mass-market cigars and cigarettes. Regulatory Toxicology and Pharmacology, 2019; 108:104453. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31473262
23. Klepeis NE, Ott WR, and Repace JL. The effect of cigar smoking on indoor levels of carbon monoxide and particles. Journal of Exposure Analysis and Environmental Epidemiology, 1999; 9(6):622-35. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10638847
24. Hoffman D and Hoffman I. Cigar smoke: chemistry and toxicology. Smoking and tobacco control monograph No. 9, 1998. Available from: https://cancercontrol.cancer.gov/sites/default/files/2020-06/m9_3.pdf.
25. Mottola G. 10 things every cigar smoker should know. 2017. Available from: https://www.cigaraficionado.com/article/10-things-every-cigar-smoker-should-know-19531.
26. Gupta PC and Asma S. Bidi smoking and public health. Nee Delhi: Ministry of Health and Family Welfare, Government of India, 2008. Available from: https://www.healis.org/pdf/special-report/Bidi_smoking_and_public_health.pdf.
27. Rahman M and Fukui T. Bidi smoking and health. Public Health, 2000; 114(2):123-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10800151
28. Ahamad T and Alshehri SM. TG-FTIR-MS (Evolved Gas Analysis) of bidi tobacco powder during combustion and pyrolysis. Journal of Hazardous Materials, 2012; 199-200:200-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22119196
29. World Health Organization. Tobacco product regulation: basic handbook. Geneva: WHO, 2018. Available from: https://www.who.int/publications/i/item/tobacco-product-regulation-basic-handbook.
30. World Health Organization. Report on the scientific basis of tobacco product regulation: Seventh report of a WHO study group. Geneva: WHO, 2019. Available from: https://www.who.int/publications/i/item/who-study-group-on-tobacco-product-regulation-report-on-the-scientific-basis-of-tobacco-product-regulation-seventh-report-of-a-who-study-group.
31. Food and Drug Administration. Harmful and potentially harmful constituents in tobacco products and tobacco smoke: Established list. 2012. Available from: https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/harmful-and-potentially-harmful-constituents-tobacco-products-and-tobacco-smoke-established-list.
32. Rogers K. Alkaloid. Britannica, 2002. Available from: https://www.britannica.com/science/alkaloid.
33. Zhang X, Wang R, Zhang L, Ruan Y, Wang W, et al. Simultaneous determination of tobacco minor alkaloids and tobacco-specific nitrosamines in mainstream smoke by dispersive solid-phase extraction coupled with ultra-performance liquid chromatography/tandem orbitrap mass spectrometry. Rapid Communications in Mass Spectrometry, 2018; 32(20):1791-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29964303
34. Hukkanen J, Jacob P, 3rd, and Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacological Reviews, 2005; 57(1):79-115. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15734728
35. Pankow JF, Tavakoli AD, Luo W, and Isabelle LM. Percent free base nicotine in the tobacco smoke particulate matter of selected commercial and reference cigarettes. Chemical Research in Toxicology, 2003; 16(8):1014-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12924929
36. Ebajemito JK, McEwan M, Gale N, Camacho OM, Hardie G, et al. A randomised controlled single-centre open-label pharmacokinetic study to examine various approaches of nicotine delivery using electronic cigarettes. Scientific Reports, 2020; 10(1):19980. Available from: https://www.ncbi.nlm.nih.gov/pubmed/33235307
37. van Amsterdam J, Sleijffers A, van Spiegel P, Blom R, Witte M, et al. Effect of ammonia in cigarette tobacco on nicotine absorption in human smokers. Food and Chemical Toxicology, 2011; 49(12):3025-30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22001171
38. Wilhelm J, Mishina E, Viray L, Paredes A, and Pickworth WB. The pH of smokeless tobacco determines nicotine buccal absorption: Results of a randomized crossover trial. Clinical Pharmacology and Therapeutics, 2022; 111(5):1066-74. Available from: https://www.ncbi.nlm.nih.gov/pubmed/34826137
39. Fant RV, Henningfield JE, Nelson RA, and Pickworth WB. Pharmacokinetics and pharmacodynamics of moist snuff in humans. Tobacco Control, 1999; 8(4):387-92. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10629244
40. Stevenson T and Proctor RN. The secret and soul of Marlboro: Phillip Morris and the origins, spread, and denial of nicotine freebasing. American Journal of Public Health, 2008; 98(7):1184-94. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18511721
41. Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). Final opinion on additives used in tobacco products. European Commission, Health & Food Safety, Directorate C: Public Health 2016. Available from: http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_051.pdf.
42. Rogers K. Aldehyde: chemical compound. Britannica, 2008. Available from: https://www.britannica.com/science/aldehyde.
43. The Editors of Encyclopaedia Britannica. Formaldehyde: chemical compound. Britannica, 1998. Available from: https://www.britannica.com/science/formaldehyde.
44. Zhang S, Chen H, Wang A, Liu Y, Hou H, et al. Assessment of genotoxicity of four volatile pollutants from cigarette smoke based on the in vitro gammaH2AX assay using high content screening. Environmental Toxicology and Pharmacology, 2017; 55:30-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28818740
45. Brancato A, Lavanco G, Cavallaro A, Plescia F, and Cannizzaro C. Acetaldehyde, motivation and stress: Behavioral evidence of an addictive menage a trois. Frontiers in Behavioral Neuroscience, 2017; 11:23. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28232795
46. Stevens JF and Maier CS. Acrolein: sources, metabolism, and biomolecular interactions relevant to human health and disease. Molecular Nutrition & Food Research, 2008; 52(1):7-25. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18203133
47. Carmella SG, Chen M, Zhang Y, Zhang S, Hatsukami DK, et al. Quantitation of acrolein-derived (3-hydroxypropyl)mercapturic acid in human urine by liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry: effects of cigarette smoking. Chemical Research in Toxicology, 2007; 20(7):986-90. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17559234
48. Talaska G. Aromatic amines and human urinary bladder cancer: exposure sources and epidemiology. Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews, 2003; 21(1):29-43. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12826031
49. US Department of Health and Human Services, The health consequences of smoking: a report of the Surgeon General. Atlanta, Georgia: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health 2004. Available from: http://www.cdc.gov/tobacco/data_statistics/sgr/index.htm.
50. Carey FA and Rogers K. Hydrocarbon: chemical compound. Britannica, 2008. Available from: https://www.britannica.com/science/hydrocarbon.
51. Fiebelkorn S and Meredith C. Estimation of the leukemia risk in human populations exposed to benzene from tobacco smoke using epidemiological data. Risk Analysis, 2018; 38(7):1490-501. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29266361
52. Korte JE, Hertz-Picciotto I, Schulz MR, Ball LM, and Duell EJ. The contribution of benzene to smoking-induced leukemia. Environmental Health Perspectives, 2000; 108(4):333-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10753092
53. U.S. Environmental Protection Agency. Benzene; CASRN 71-43-2. Integrated Risk Information System (IRIS) U.S. Environmental Protection Agency Chemical Assessment Summary: EPA, 2003. Available from: https://iris.epa.gov/static/pdfs/0276_summary.pdf.
54. Fowles J and Dybing E. Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke. Tobacco Control, 2003; 12(4):424-30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14660781
55. National Toxicology Program. NTP Toxicology and carcinogenesis studies of isoprene (CAS No. 78-79-5) in F344/N rats (inhalation studies). National Toxicology Program Technical Report Series, 1999; 486:1-176. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12571689
56. International Agency for Research on Cancer. IARC Monographs on the evaluation of carcinogenic risks to humans: some industrial chemicals. 60 Lyon, France: IARC, 1994. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Some-Industrial-Chemicals-1994.
57. Zhang L, Wang L, Li Y, Xia Y, Chang CM, et al. Evaluation of tobacco smoke and diet as sources of exposure to two heterocyclic aromatic amines for the U.S. population: NHANES 2013-2014. Cancer Epidemiology, Biomarkers & Prevention, 2020; 29(1):103-11. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31575556
58. Heterocyclic amine. 2010. Available from: https://www.sciencedirect.com/topics/medicine-and-dentistry/heterocyclic-amine.
59. Nagao M and Sugimura T. Carcinogenic factors in food with relevance to colon cancer development. Mutation Research, 1993; 290(1):43-51. Available from: https://www.ncbi.nlm.nih.gov/pubmed/7694098
60. Sugimura T. Overview of carcinogenic heterocyclic amines. Mutation Research, 1997; 376(1-2):211-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9202758
61. Turesky RJ. Heterocyclic aromatic amine metabolism, DNA adduct formation, mutagenesis, and carcinogenesis. Drug Metabolism Reviews, 2002; 34(3):625-50. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12214671
62. Centers for Disease Control and Prevention. Polycyclic aromatic hydrocarbons (PAHs) factsheet. 2017. Available from: https://www.cdc.gov/biomonitoring/PAHs_FactSheet.html.
63. International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans: some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures. Monographs on the Evaluation of Carcinogenic Risks to Human, 92 Lyon, France: IARC, 2010. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Some-Non-heterocyclic-Polycyclic-Aromatic-Hydrocarbons-And-Some-Related-Exposures-2010.
64. Rodgman A and Perfetti T. The composition of cigarette smoke: A catalogue of the polycyclic aromatic hydrocarbons. Eiträge zur Tabakforschung International, 2016; 22(1):13-69. Available from: https://cyberleninka.org/article/n/650361/viewer
65. Ding YS, Trommel JS, Yan XJ, Ashley D, and Watson CH. Determination of 14 polycyclic aromatic hydrocarbons in mainstream smoke from domestic cigarettes. Environmental Science & Technology, 2005; 39(2):471-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15707046
66. Gushgari AJ and Halden RU. Critical review of major sources of human exposure to N-nitrosamines. Chemosphere, 2018; 210:1124-36. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30208538
67. International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans: Smokeless tobacco and some tobacco-specific N-Nitrosamines. 89 Lyon, France: IARC, 2007. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Smokeless-Tobacco-And-Some-Tobacco-specific-Em-N-Em--Nitrosamines-2007.
68. Khariwala SS, Ma B, Ruszczak C, Carmella SG, Lindgren B, et al. High level of tobacco carcinogen-derived DNA damage in oral cells is an independent predictor of oral/head and neck cancer risk in smokers. Cancer Prevention Research, 2017; 10(9):507-13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28679497
69. Kibet JK, Khachatryan L, and Dellinger B. Phenols from pyrolysis and co-pyrolysis of tobacco biomass components. Chemosphere, 2015; 138:259-65. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26091866
70. Leanderson P and Tagesson C. Cigarette smoke-induced DNA-damage: role of hydroquinone and catechol in the formation of the oxidative DNA-adduct, 8-hydroxydeoxyguanosine. Chemico-Biological Interactions, 1990; 75(1):71-81. Available from: https://www.ncbi.nlm.nih.gov/pubmed/2114224
71. McGregor D. Hydroquinone: an evaluation of the human risks from its carcinogenic and mutagenic properties. Critical Reviews in Toxicology, 2007; 37(10):887-914. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18027166
72. International Agency for Research on Cancer. Monographs on the evaluation of carcinogenic risks to humans: some naturally occurring substances: food items and constituents, heterocyclic aromatic amines and mycotoxins. 56 Lyon, France: IARC, 1993. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Some-Naturally-Occurring-Substances-Food-Items-And-Constituents-Heterocyclic-Aromatic-Amines-And-Mycotoxins-1993.
73. Food & Drug Administration. Food for human consumption (continued) part 189 -- Substances prohibited from use in human food. 2020. Available from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=189.130.
74. Marchese S, Polo A, Ariano A, Velotto S, Costantini S, et al. Aflatoxin B1 and M1: Biological properties and their involvement in cancer development. Toxins, 2018; 10(6). Available from: https://www.ncbi.nlm.nih.gov/pubmed/29794965
75. Centers for Disease Control and Prevention. Acrylamide factsheet. CDC, 2017. Available from: https://www.cdc.gov/biomonitoring/Acrylamide_FactSheet.html.
76. International Agency for Research on Cancer. Agents classified by the IARC monographs, volumes 1–129. Lyon, France: IARC, Available from: https://monographs.iarc.who.int/list-of-classifications.
77. Zaga V, Cattaruzza MS, Martucci P, Pacifici R, Trisolini R, et al. The "Polonium In Vivo" study: Polonium-210 in bronchial lavages of patients with suspected lung cancer. Biomedicines, 2020; 9(1). Available from: https://www.ncbi.nlm.nih.gov/pubmed/33374630
78. Laking GR. Human exposure to radioactivity from tobacco smoke: systematic review. Nicotine & Tobacco Research, 2019; 21(9):1172-80. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30060241
79. Cobb C, Ward KD, Maziak W, Shihadeh AL, and Eissenberg T. Waterpipe tobacco smoking: an emerging health crisis in the United States. American Journal of Health Behavior, 2010; 34(3):275-85. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20001185
80. El Hourani M, Salman R, Talih S, Saliba NA, and Shihadeh A. Does the bubbler scrub key toxicants from waterpipe tobacco smoke? Measurements and modeling of CO, NO, PAH, nicotine, and particulate matter uptake. Chemical Research in Toxicology, 2020; 33(3):727-30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31957423
81. Shihadeh A, Schubert J, Klaiany J, El Sabban M, Luch A, et al. Toxicant content, physical properties and biological activity of waterpipe tobacco smoke and its tobacco-free alternatives. Tobacco Control, 2015; 24 Suppl 1:i22-i30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25666550
82. Shihadeh A. Investigation of mainstream smoke aerosol of the argileh water pipe. Food and Chemical Toxicology, 2003; 41(1):143-52. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12453738
83. Jaccard G, Tafin Djoko D, Korneliou A, and Belushkin M. Analysis of waterpipe aerosol constituents in accordance with the ISO standard 22486. Toxicology Reports, 2020; 7:1344-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/33102137
84. Schubert J, Hahn J, Dettbarn G, Seidel A, Luch A, et al. Mainstream smoke of the waterpipe: does this environmental matrix reveal as significant source of toxic compounds? Toxicology Letters, 2011; 205(3):279-84. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21712083
85. Monzer B, Sepetdjian E, Saliba N, and Shihadeh A. Charcoal emissions as a source of CO and carcinogenic PAH in mainstream narghile waterpipe smoke. Food and Chemical Toxicology, 2008; 46(9):2991-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18573302
86. El Hourani M, Talih S, Salman R, Karaoghlanian N, Karam E, et al. Comparison of CO, PAH, nicotine, and aldehyde emissions in waterpipe tobacco smoke generated using electrical and charcoal heating methods. Chemical Research in Toxicology, 2019; 32(6):1235-40. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31038931
87. World Health Organization. Heated tobacco products information sheet. WHO, 2020. Viewed: Available from: https://www.who.int/publications/i/item/WHO-HEP-HPR-2020.2.
88. Lopez AA, Hiler M, Maloney S, Eissenberg T, and Breland AB. Expanding clinical laboratory tobacco product evaluation methods to loose-leaf tobacco vaporizers. Drug and Alcohol Dependence, 2016; 169:33-40. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27768968
89. Food & Drug Administration. PMTA cover sheet: Technical project lead review for IQOS Tobacco Heating System (THS). FDA, 2017. Available from: https://www.fda.gov/media/124247/download.
90. Ploom UK. What are heated tobacco / T-vapour products? JTI UK, Available from: https://www.ploom.co.uk/faq/9/.
91. Philip Morris International. IQOS heated tobacco products. Available from: https://www.pmi.com/smoke-free-products/iqos-our-tobacco-heating-system.
92. Davis B, Williams M, and Talbot P. iQOS: evidence of pyrolysis and release of a toxicant from plastic. Tobacco Control, 2019; 28(1):34-41. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29535257
93. Salman R, Talih S, El-Hage R, Haddad C, Karaoghlanian N, et al. Free-base and total nicotine, reactive oxygen species, and carbonyl emissions from IQOS, a heated tobacco product. Nicotine & Tobacco Research, 2019; 21(9):1285-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30476301
94. Auer R, Concha-Lozano N, Jacot-Sadowski I, Cornuz J, and Berthet A. Heat-not-burn tobacco cigarettes: Smoke by any other name. JAMA Internal Medicine, 2017; 177(7):1050-2. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28531246
95. Farsalinos KE, Yannovits N, Sarri T, Voudris V, and Poulas K. Nicotine delivery to the aerosol of a heat-not-burn tobacco product: comparison with a tobacco cigarette and e-cigarettes. Nicotine & Tobacco Research, 2018; 20(8):1004-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28637344
96. Eaton D, Jakaj B, Forster M, Nicol J, Mavropoulou E, et al. Assessment of tobacco heating product THP1.0. Part 2: Product design, operation and thermophysical characterisation. Regulatory Toxicology and Pharmacology, 2018; 93:4-13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29080851
97. Leigh NJ, Palumbo MN, Marino AM, O'Connor RJ, and Goniewicz ML. Tobacco-specific nitrosamines (TSNA) in heated tobacco product IQOS. Tobacco Control, 2018; 27(Suppl 1):s37-s8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30242043
98. Australian Competition & Consumer Commission. Smokeless tobacco products. Available from: https://www.productsafety.gov.au/products/health-lifestyle/personal/tobacco-related-products/smokeless-tobacco-products.
99. World Health Organization. Report on the scientific basis of tobacco product regulation: Fifth report of a WHO study group. WHO, 2015. Available from: https://apps.who.int/iris/bitstream/handle/10665/161512/9789241209892.pdf?sequence=1&isAllowed=y.
100. Chapman S and Wakefield M. Tobacco control advocacy in Australia: reflections on 30 years of progress. Health Education and Behavior, 2001; 28(3):274-89. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11380049
101. Benowitz NL. Pharmacology of smokeless tobacco use: Nicotine addiction and nicotine–related health consequences, in Smokeless tobacco or health: an international perspective. Smoking and tobacco control monograph No. 2 Bethesda, MA: National Cancer Institute, Department of Health and Human Services; 1992. Available from: https://cancercontrol.cancer.gov/sites/default/files/2020-08/m02_complete.pdf.
102. Hatsukami DK, Stepanov I, Severson H, Jensen JA, Lindgren BR, et al. Evidence supporting product standards for carcinogens in smokeless tobacco products. Cancer Prevention Research, 2015; 8(1):20-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25524878
103. Miller JH, Danielson T, Pithawalla YB, Brown AP, Wilkinson C, et al. Method development and validation of dissolution testing for nicotine release from smokeless tobacco products using flow-through cell apparatus and UPLC-PDA. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 2020; 1141:122012. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32065955
104. Tomar SL and Henningfield JE. Review of the evidence that pH is a determinant of nicotine dosage from oral use of smokeless tobacco. Tobacco Control, 1997; 6(3):219-25. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9396107
105. Brunnemann KD and Hoffmann D. Chemical composition of smokeless tobacco products in Smokeless tobacco or health: an international perspective. Smoking and tobacco control monograph No. 2 Bethesda, MA: National Cancer Institute, Department of Health and Human Services; 1992. Available from: https://cancercontrol.cancer.gov/sites/default/files/2020-08/m02_complete.pdf.
106. Prasad GL, Jones BA, Chen P, and Gregg EO. A cross-sectional study of biomarkers of exposure and effect in smokers and moist snuff consumers. Clinical Chemistry and Laboratory Medicine, 2016; 54(4):633-42. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26495926
107. Xia B, Blount BC, Guillot T, Brosius C, Li Y, et al. Tobacco-specific nitrosamines (NNAL, NNN, NAT, and NAB) exposures in the US Population Assessment of Tobacco and Health (PATH) study wave 1 (2013-2014). Nicotine & Tobacco Research, 2021; 23(3):573-83. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32716026
108. Cheng YC, Reyes-Guzman CM, Christensen CH, Rostron BL, Edwards KC, et al. Biomarkers of exposure among adult smokeless tobacco users in the Population Assessment of Tobacco and Health study (wave 1, 2013-2014). Cancer Epidemiology, Biomarkers & Prevention, 2020; 29(3):659-67. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31988072