While more and more information is becoming available on the pathogenesis of smoking-related lung cancer (US Department of Health and Human Services, 2010), a comprehensive understanding of the actual causative agents in smoke and the mechanisms involved is still missing. To some extent, this knowledge gap is related to the lack of a generally accepted laboratory animal model for mainstream smoke (MS) inhalation-inducible lung cancer. Such a model, once

established, could be used for etiological and mechanistic research, for research on diagnostic and therapeutic means, and for the evaluation of modified risk tobacco products. Such models have recently been called for by the US FDA (US Food and Drug Administration Center for Tobacco Products, 2012) and the US IOM (Institute of Medicine, 2012), in particular for comparative PD0332991 supplier assessments. The purpose of bioassays on carcinogenesis is to identify carcinogenic properties of test materials see more in laboratory rodents in order to evaluate a carcinogenic potential for humans (Organisation for Economic Co-operation and Development, 1981 and Organisation for Economic Co-operation and Development,

2009). In line with regulatory guidance for conducting bioassays on carcinogenesis, laboratory rats and mice are most commonly exposed for an appreciable portion of their lifespan. In the case of smoking, a carcinogenic potential has already been established in humans, and bioassays are required to model the human disease pathogenesis to the extent possible for the above-mentioned applications. In terms of lung cancer, laboratory rodents mainly develop peripheral pulmonary adenomas that may progress to adenocarcinomas, while humans may develop various histological types of highly invasive bronchial and bronchiolar-alveolar carcinomas (Schleef et al., 2006) with an increasing fraction of adenocarcinomas over the last decades (Devesa et al., 2005). Despite many years of research, no model for MS-induced lung tumorigenesis

could be established that is generally accepted (Coggins, 2010). However, there are three rather recent developments, which may eventually qualify. (1) Lifetime MS inhalation studies have been recently reported on F344 rats Thalidomide and B6C3F1 mice, in which statistically significant increases in lung tumors were found in females (Hutt et al., 2005 and Mauderly et al., 2004). However, the response for male rats was negative, and male mice were not tested. Furthermore, it seems that these studies have not been repeated anywhere to test for reproducibility. (2) A relatively pronounced increase in lung tumorigenicity in male and female Swiss mice was obtained when MS inhalation exposure was started immediately after birth (Balansky et al., 2007). These results seem to be reproducible in the same laboratory (Balansky et al., 2009), but apparently this study design has not been reproduced in other laboratories.