Fig. 8.

Molecular effects in the lungs (in vivo and in vitro), including cell stress. A. Consistency in the molecular effects of cigarette smoke in the lungs. Correlation of gene expression responses as fold changes in 3R4F exposure vs. sham in the rat and mouse in vivo studies. Red lines represent fit from linear model. ${\mathit{R}}_{\mathit{a}\mathit{l}\mathit{l}}^2$ and ${\mathit{R}}_{\mathit{s}\mathit{i}\mathit{g}}^2$ are the coefficients of determination for all or the significantly affected genes, respectively. B–D. Evaluation of biological impact on lung tissue by using a causal network enrichment approach based on transcriptomics data. Relative biological impact factors are represented for each group vs. sham. E–G. Network enrichment analysis of the oxidative stress network. Bars show the overall NPA on the basis of transcriptomic data; error bars indicate 95 % confidence intervals. Three statistical measures are shown: The red star indicates statistical significance with respect to biological replicatesl the green star (o statistic) indicates significance with respect to permutation of genes downstream of the network nodes; and the blue star (k statistic) indicates significance with respect to permutation of the network topology (p < 0.05). THS, Tobacco Heating System; CHTP, Carbon Heated Tobacco Product; NPA, network perturbation amplitude; OECD, Organisation for Economic Co-operation and Development Test Guideline.