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Smokeless Tobacco PERSONAL HABITS AND INDOOR COMBUSTIONS volume 100 e A review of humAn cArcinogens This publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 29 September-6 October 2009 LYON, FRANCE - 2012 iArc monogrAphs on the evAluAtion of cArcinogenic risks to humAns SMOKELESS TOBACCO Smokeless tobacco was considered by a previous IARC Working Group in 2004 (IARC, 2007a). Since that time, new data have become available, these have been incorporated into the Monograph, and taken into consideration in the present evaluation. 1. Exposure Data 1.2 Chemical composition of smokeless tobacco 1.1 Smokeless tobacco products The tobacco used in a particular product has The term smokeless tobacco implies use of a decisive influence on its chemical composition, unburned tobacco in the finished products. A and varies with tobacco species, growing, curing, variety of smokeless tobacco products are avail­ processing and storage. During product manu­ able, for oral or nasal use. Products intended for facture, tobacco is blended to achieve a specific oral use are sucked, chewed (dipped), gargled or nicotine content and pH. The pH strongly applied to the gums or teeth, while fine tobacco influences the concentration of unprotonated mixtures are usually inhaled into the nostrils. nicotine, the bioavailable form of nicotine, Table 1.1 summarizes for each smokeless while the nitrite/nitrate content strongly influ­ tobacco product its mode of use, the main ingre­ ences the levels of carcinogenic nitrosamines dients included, the WHO regions in which in the product. Other tobacco components are the product is used, and some specification alkaloids which include nicotine (85–95% of of the countries is which the product is used total alkaloids), terpenes, polyphenols, phytos­ most commonly or specifically DHHS,( 2001; terols, carboxylic acids, aromatic hydrocarbons, IARC, 2007a; European Commission, 2008). aldehydes, ketones, amines, nitriles, N- and Smokeless tobacco products that contain areca O-heterocyclic hydrocarbons, pesticides, and nut are commonly used in India, other coun­ metallic compounds. Flavour-type additives tries in South Asia, and in migrant populations are also present (Bates et al., 1999). Ammonia, from these countries. These products may be ammonium carbonate and sodium carbonate are mentioned here for comparison but are reviewed applied to control nicotine delivery by raising pH in the Monograph on Betel Quid and Areca Nut and subsequently the level of unprotonated nico­ in this volume. tine which is most readily absorbed through the mouth into the bloodstream (Djordjevic et al., 1995). 265 266 IARC MONOGRAPHS – 100E MONOGRAPHSIARC 100E – Table 1.1 Smokeless tobacco products, ingredients, and use by WHO region Tobacco product Mode Ingredients WHO Region of use AFRO AMRO EMRO EURO SEARO WPRO Oral use Betel quid with tobaccoa Chewing Betel leaf, areca nut, slaked lime, tobacco in various X X X forms Chimó Sucking Paste of crushed and boiled tobacco leaves, sodium Xb bicarbonate, sugar, wood ash, flavourings Chewing tobacco Chewing See Tobacco chewing gum Chewing tobacco twist/ Chewing Dark, air- or fire-cured tobacco leaves treated with Xc roll tobacco extract, flavourings Creamy snuff Other Finely ground tobacco with aromatic substances X (manufactured commercially) Dry snuff Sucking Fire- or air-cured, fermented powdered tobacco Xd Xc Xe Xf Xg Gudhaku Other Paste of powdered tobacco and molasses Xg Gul Other Powdered tobacco, molasses and other ingredients Xg Gutkaa Sucking Sun-dried finely chopped tobacco, areca nut, slaked X lime, catechu, flavourings, sweeteners (manufactured commercially) Iq’mik Chewing Fire-cured tobacco leaves with punk ash Xh Khaini Sucking Sun-dried or fermented coarsely crushed tobacco leaves Xi Khiwam Chewing Paste of tobacco extract, spices, additives Xj Loose leaf Chewing Small strips of air-cured, shredded cigar tobacco leaves Xc X (manufactured commercially) Maraş Sucking Sun-dried powdered tobacco leaves, wood ash, water Xk Mawaa Chewing Sun-cured areca nut, crushed tobacco leaves, slaked lime Xj Mishri Sucking Tobacco toasted on hot metal plate and powdered Xg Moist snuff Sucking Air- or fire-cured tobacco, processed into fine particles Xc Xl (fine-cut) or strips (long-cut), with stem and seeds Naswar/nass Sucking Sun-dried, powdered tobacco, ash, oil, flavourings, Xd Xm X colourings, slaked lime (optional) Plug chewing tobacco Chewing Heavy-grade or cigar tobacco top leaves immersed in Xc liquorice or sugar, pressed into a plug Red tooth powder Other Fine tobacco powder, many additional ingredients X (manufactured commercially) Shammah Sucking Powdered tobacco, lime, ash, black pepper, oils, Xn X flavourings Snus - See moist stuff Xc Xl Table 1.1 (continued) Tobacco product Mode Ingredients WHO Region of use AFRO AMRO EMRO EURO SEARO WPRO Saffa - Toomback rolled into a ball Xq Tobacco tablet Sucking Compressed powdered tobacco, mint, eucalyptus Xc Toombak Sucking Dried, fermented, ground and matured tobacco leaves, Xq sodium bicarbonate Tuibur Other Tobacco water Xr Zarda Chewing Tobacco leaves boiled with lime and spices until dry, X X colourings; chewed with areca nut and spices Nasal use Dry snuff Sniffing Fire-cured, fermented and powdered tobacco Xs X Xt X Liquid snuff Sniffing Powered tobacco mixed with ash from plants, oil, lemon Xu juice, herbs a These products contain areca nut and are reviewed in theMonograph on Betel Quid and Areca Nut in this volume. b Specific to Venezuela, used by young boys and urban teenagers c Used in the USA d Used principally in South Africa; dry snuff is mostly inhaled. e Common in North Africa, notably in Tunisia asneffa f Used in Germany, Georgia and the United Kingdom g Used as dentifrice, mostly by women, in various parts of India h Specific to native American tribes of North-West Alaska i Used in India, Bangladesh and Nepal j Specific to India k Specific to remote regions of Turkey l Used in Sweden, Norway and Finland m Common in Afghanistan, Islamic Republic of Iran, Pakistan and central Asia n Common in the Middle East, particularly in Saudi Arabia and Yemen o Used in Sweden and Denmark p Specific to Japan (new product) q Specific to Sudan, used by men r Specific to eastern States of India s Used by several tribes in South Africa, namely Bantus Smokeless tobacco t Used in the United Kingdom u Specific to tribes in East Africa AFRO, African Region; AMRO, Regions of the Americas; EMRO, Eastern Mediterranean Region; EURO, European Region; SEARO, South East Asian Region, WPRO, Western Pacific Region; the countries included in each region are available at http://www.who.int/about/regions/en/ 267 IARC MONOGRAPHS – 100E 1.2.1 Nicotine content in smokeless tobacco measured were 135 and 17.8 μg/g tobacco, respec­ tively. In home-made toombak from Sudan, The majority of commercial tobacco prod­ values as high as 3085 and 7870 μg/g dry wt ucts are made from N. tabacum species, grown tobacco, respectively, have been reported (Idris throughout the world with an alkaloid content et al., 1991; Prokopczyk et al., 1995). that varies greatly. In randomly cultivated vari­ eties examined, the alkaloid content ranged (b) N-Nitrosamino acids between 0.17 and 4.93%. The amino acids present in tobacco, and N. rustica species is cultivated in eastern probably also the proteins with secondary Europe, Asia Minor and Africa, and the cured amino groups, are amenable to N-nitrosation. leaves may contain up to 12% nicotine. Toombak Since 1985, numerous studies have reported the from Sudan, which contains N. rustica tobacco, presence of N-nitrosamino acids in smokeless had the highest reported levels of nicotine (Idris tobacco products (IARC, 2007a). et al., 1991; Prokopczyk et al., 1995). In 17 brands To date, 11 N-nitrosamino acids have been iden­ of moist snuff from the USA, the nicotine content tified in smokeless tobacco: N-nitrososarcosine ranged from 0.47 to 3.43%.The nicotine content (NSAR), N-nitrosoazetidine-4-carboxylic of Swedish snus ranges from 0.5–1.7% (Idris acid (NAzCA), 3-(methylnitrosamino)propi­ et al., 1998; Stepanov et al., 2008). onic acid (MNPA), 4-(methylnitrosamino) butyric acid (MNBA), N-nitrosoproline 1.2.2 Carcinogenic compounds in smokeless (NPRO), N-nitrosohydroxyproline tobacco (NHPRO), N-nitrosopipecolic acid (NPIC), Multiple carcinogens have been identified in N-nitrosothiazolidine-4-carboxylic acid smokeless tobacco (IARC, 2007a) including: (NTCA), N-nitroso-2-methylthiazolidine­ 4-carboxylic acid (MNTCA), (a) Tobacco-specific N-nitrosamines 4-(methylnitrosamino)-4-(3-pyridyl)butyric Tobacco-specific N-nitrosamines include acid (iso-NNAC) and 2-(methylnitrosamino)­ the carcinogens N′-nitrosonornicotine (NNN), 3-phenylpropionic acid (MNPhPA) (Ohshima and 4-(methylnitrosamino)-1-(3-pyridyl)-1­ et al., 1985; Tricker & Preussmann, 1988; butanone (NNK). Hoffmann et al., 1995). Of these, NSAR, MNPA, Tobacco-specific N-nitrosamines are formed MNBA and NAzCA have been established as from tobacco alkaloids (nicotine, nornicotine, carcinogens in experimental animals. anatabine, anabasine, and nitrite) primarily The concentration of N-nitrosamino acids during tobacco curing, fermentation and ageing. depends on the nitrate or nitrite content of The nitrate or nitrite content, the mode of curing tobacco; they are formed during prolonged and the various steps of processing are the main storage, particularly under adverse conditions of determining factors for the yields of tobacco-
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