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SUMMARYThe objective of this review is to support tobacco scientists when evaluating information published on smoking machines, and on cigarette mainstream smoke (in vivo and in vitro) exposure systems and collection devices. The intriguing development of smoking machines (mainly for cigarettes) is followed for more than 170 years -from the first simple set-ups in the 1840s to the sophisticated and fully automated analytical smoking machines available today. Systems for the large-scale production of smoke (condensate) for preparative work are equally considered. The standardization of machine smoking methods and test pieces has solved several technical problems and produced sensible rules but, at the same time, given rise to new controversies like the compatibility of artificial and human smoking, and the implementation of more intense machine smoking regimes. Adequate space is allotted for the discussion of configurations for in vivo smoke exposure of rodent and non-rodent species and the machines generating the required smoke (condensate). Covered as well is the field of in vitro toxicity testing, including the increasingly informative new techniques of air-liquid interface exposure, which are becoming more and more refined with the use of organotypic cultures and genetic analyses. The review is completed by the examination of the considerable variety of mainstream smoke collection devices (filters and traps) developed over time -some for very specific purposes -and refers to the perpetual problem of artifact formation by aging.

Smoking, especially cigarette smoking, is the most common form of tobacco consumption world-wide. It is generally accepted that smoking carries health risks for smokers. The combustion and pyrolysis products of tobacco generated during smoking are considered to be responsible for the harmful effects. Smokeless tobacco, another wide-spread form of tobacco use, is not subjected to burning and produces no combustion or pyrolysis products. Therefore, there is an increasingly intense debate about the potential role of smokeless tobacco in reducing the harm of tobacco use.An overview is presented on the different types of smokeless tobaccos consumed around the world. Commercial products differ widely in composition and patterns of use. The smokeless tobaccos of the Western world (Europe and North America) need to be clearly distinguished from those popular in Asia, Africa and South America. The modern smokeless tobaccos used in Europe and North America are reviewed regarding their chemical composition and toxicological properties. Agents of concern found in smokeless tobacco, especially the tobacco specific N-nitrosamines, are dealt with in particular.The epidemiological evidence is summarized concerning a wide range of health outcomes. Published reviews and studies are presented and interpreted regarding non-neoplastic oral diseases, various forms of cancer, circulatory diseases, several other diseases and pregnancy outcome. While many of the epidemiological studies have weaknesses and data are often inconsistent it is quite obvious that smokeless tobacco use is much less risky for consumers than smoking. In fact, for modern forms of European moist snuff such as Swedish snus, which is subject to strict quality standards, there is evidence for - if any - only very limited serious health risk.The ongoing public discussion centers around the influence smokeless tobacco may have on smoking rates (initiation or cessation) and the occurrence of tobacco specific diseases - with Sweden being a revealing example. There is an interesting controversy regarding product and marketing regulations for smokeless tobaccos in the European Union.

Tobacco additives play an important role in the manufacturing and for the quality of tobacco products, particularly cigarettes and roll-your-own tobaccos. Attention is increasingly given to the potential effects of additives on consumer behavior and health. This review is intended to compile, collate and - to some degree - evaluate the wealth of pertinent scientific information available from the published literature and other special sources. At first, the reasons are set forth for the use of additives in cigarette manufacturing. In response to the growing controversy over the attractiveness and addictiveness of smoking, the clarification of terms and concepts is followed by a detailed discussion of two kinds of substances with particular relevance: Additives like ammonium compounds that are claimed to increase nicotine availability, and additives that are claimed to increase nicotine addictiveness.The composition and toxicity of mainstream smoke of cigarettes with and without additives are assessed in several respects. The potentials of pyrolysis studies are explored by looking at a number of key studies and some basic considerations regarding in vitro and in vivo toxicity testing are addressed. Five major literature reviews on additives published between 1994 and 2004, and the results of several comprehensive experimental studies covering a large range of additives, released between 2002 and 2012, are dealt with in detail. Single tobacco additives of particular importance (menthol, glycerol, 1,2-propylene glycol, sorbitol, sugars, cocoa, licorice, citric acid, triacetin, and ammonium compounds) are discussed in dedicated chapters, which are generally subdivided into special sections: Use and toxicological assessment; inclusion level in cigarettes, transfer and pyrolysis; attractiveness and addictiveness; effect on cigarette mainstream smoke composition; effect on cigarette mainstream smoke toxicity. Epidemiological findings and data obtained by the biomonitoring of smokers consuming cigarettes with and without additives are compiled and interpreted specifically for American blend cigarettes, Virginia cigarettes, “French” (dark) cigarettes and menthol cigarettes whereby the focus is on the effects of additives on smoking topography and potential health risks.Opinionated reviews were published in recent years that are compromised by arbitrary selection of sources and unbalanced views. Leaving those unconsidered, the aggregated scientific knowledge shows that tobacco additives have only occasional and limited effects on cigarette mainstream smoke composition, which are almost never reflected in the results of toxicological in vitro assays or in vivo studies. This supports the conclusion that tobacco additives are not likely to increase the known health risks of smoking. There is also no evidence for sustaining claims that certain additives increase nicotine availability or nicotine addictiveness.

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The tobacco-specific nitrosamines (TSNA) N-nitrosonornicotine (NNN) and 4-(N-methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) as well as the volatile N-nitrosamines N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) were determined in the indoor air of a poorly ventilated office where extensive smoking took place. Under these conditions, moderate to heavy smoking resulted in indoor air concentrations of 7.6-20.0 ppm carbon monoxide, 109-290 ppb nitrogen oxides and 58.5-132 μg/m^3 nicotine. The N-nitrosamine concentrationes were (in nanograms/cubic meter): not detected (nd)-6.0 NNN, nd-13.5NNK, 7.9-45.0 NDMA and 3.5-27.0 ng/m^3 NPYR. Occupation of the office by a nonsmoker for 1 h would result in a maximum exposure to 0.01 pg TSNA and 0.03 pg volatile N-nitrosamines.