, 2004). In lifetime MS inhalation study with B6C3F1 mice, only
female mice were used with the idea of increasing the statistical power of the study (Hutt et al., 2005). It remains to be determined whether female mice would indeed be more susceptible to MS-induced lung tumorigenesis. The average relative MS-induced increase in tumor multiplicity beyond control was similar at the end of the 18-month inhalation study to that after the shorter-term 5 + 4-month schedule (Curtin et al., 2004, Stinn et mTOR inhibitor al., 2010 and Stinn et al., 2012). A relative increase of this size was also found in A/J mice pretreated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and in KrasLA2 transgenic mice in a 5 + 4-month schedule, even though this increase was obtained on a much higher overall level of tumor multiplicity in the transgenic mice ( Takahashi et al., 2010). In the current study, the most pronounced effect was observed for adenomas in female mice (6-fold increase over control); for the combined adenomas and carcinomas in female mice, a 5-fold increase was observed. This was about half of the increase observed in a 30-month MS inhalation study with female B6C3F1 mice ( Hutt et al., 2005), which, however, only used one high MS concentration and has not been reproduced to date. It is
noteworthy, though, that MS inhalation in these more recent studies was shown to be tumorigenic in both resistant and susceptible mouse strains as well in transgenic mice. The B6C3F1 mouse is considered to be resistant to lung tumorigenesis selleck chemicals llc (multiplicity of 0.1 for spontaneous tumors at an age of approximately Leukocyte receptor tyrosine kinase 32 months), while A/J mice are rather susceptible (average multiplicity of 1–2 for males and females at approximately 20 months of age, Fig. 8). Another life-time MS inhalation study with female B6C3F1 mice was more or less negative, although a numerically higher tumor incidence was reported for the MS-exposed compared to the sham-exposed mice ( Henry and Kouri, 1986). In the latter study,
mice were nose-only exposed to intermittent short daily periods of high MS concentrations, which is different to the whole-body 6-h continuous exposure to diluted MS concentrations in the more recent positive study ( Hutt et al., 2005). Interestingly, an average relative increase in tumor multiplicity of approximately 2.5-fold was observed after exposure to high concentrations of ETSS ( Witschi, 2005), similar to that observed in MS inhalation studies as discussed above. This rather robust increase in relative tumor multiplicity by smoke inhalation in the A/J mouse model is remarkable, although much higher dynamic effects (up to 50-fold) were observed after administering individual carcinogens (Shimkin and Stoner, 1975).