Biologically-based models cancer

Fig. 3.9. Biologically-based model of the cancer induction process used to estimate the dose-response relationship of chemicals causing stochastic effects (Andersen etal., 1987).

Risk Assessment. This model successfully described the disposition of chloroform in rats, mice and humans following various exposure scenarios and developed dose surrogates more closely related to toxicity response. With regard to target tissue dosimetry, the Corley model predicts the relative order of susceptibility to chloroform toxicity consequent to binding to macromolecules (MMB) to be mouse > rat > human. Linking the pharmacokinetic parameters of this model to the pharmacodynamic cancer model of Reitz et al. (1990) provides a biologically based risk assessment model for chloroform. 

The QSARs for the potency of the active aromatic amines in Salmonella typhimurium were not suitable to differentiate the inactives from the actives, and appropriate QSAR models were derived. The QSAR models specific for the separation were based on electronic and steric terms, and hydrophobicity was not found to be significant (Benigni et al., 1998). This result is analogous to that obtained for the rodent carcinogenicity of amines (see above), and provides further evidence of the similarity of the mechanisms of action in Salmonella and rodents. This similarity obviously applies only to the first steps of the process by which the aromatic amines provoke cancer on one side (rodents), and mutations on the other side (bacteria). Once the initial insult to the cells has occurred, the process follows different pathways in the two biological systems the strength of the QSAR model is that it is able to describe quantitatively the first step, which appears to be rate limiting in both systems. 

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