The good correlations of some Akt inhibitor BAL markers for lung tissue damage, such as LDH release or total protein, with γ-H2AX as a marker for DSB might indicate a link between tissue damage and occurrence of profound DNA damage with mutagenic potential. If not adequately repaired, DSB may lead to genomic instability, cell death, or cancer (Jeggo and Lobrich, 2007). Comparing the mean group data on genotoxicity marker expression in alveolar lining cells with the group means of the histopathology data from the carcinogenicity study, there were comparable patterns for γ-H2AX and 8-OH-dG and thus induction of DSB and oxidative DNA damage and tumor incidences

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the standard analysis procedure with one section per lung lobe). There was also high correlation of the mean histopathologic inflammation score three months after the first particle instillation with tumor incidences in the carcinogenicity study part (see Kolling et al., 2008 and Kolling et al., 2011), irrespective of the differences in the administered particle mass doses, thus providing a link between particle exposure, particle-driven inflammation, induction of DNA damage, and lung tumor development. In conclusion, the present study has demonstrated that immunohistochemical detection and quantification of local genotoxicity in vivo in pulmonary alveolar lining cells by using appropriate genotoxicity markers is feasible, and identified γ-H2AX and 8-OH-dG as sensitive genotoxicity markers that are able to distinguish particles with different genotoxic

potencies. In addition, their expression three months after the first particle exposure corresponded well with the inflammatory and finally carcinogenic potential of the particles, and they might thus be sensitive predictors of tumor development. Furthermore, this study demonstrated that L-NAME HCl different genotoxic events, especially induction of DSB and oxidative DNA base lesions, seem to play an important role in particle-induced lung tumor development at high particle doses. As data were obtained from animals that had been treated intratracheally at high dose levels, with total lung loads amounting to >3 mg/lung, strong and persistent lung inflammation was induced. Therefore, these results cannot conclusively answer the question as to whether secondary inflammation-dependent mechanisms only or also particle-specific primary mechanisms of genotoxicity participate in lung tumor induction by MNP. At severe particle overload in the lung, secondary mechanisms may overwhelm and confuse potentially existing primary genotoxic events, thus preventing a clear distinction between the different primary and secondary genotoxic mechanisms.