The techniques of “mechanistic modeling”, represented by the two-stage clonal expansion model, do not only claim to give an at least qualitatively correct picture of the biological mechanisms of carcinogenesis but also promise to infer quantitative estimates of the underlying biokinetic parameters by fitting the relevant models to e.g. epidemiological data. In this respect the article by Eidemüller et al. arrived at a surprising result which has not been addressed in the discussion. Given that the parameter δ=αμ₀ and hence the cell division rate α was kept constant, the fitted dose and age dependence of the clonal expansion rate δ can only be due to either the rate for cell inactivation or differentiation, β, or the transformation rate μ with dose and age. Realistic values of μ being orders of magnitude smaller than either α or β, this effect can only be due to a dependence of β on both age and dose.
As far as the age dependence is concerned, δ decreases with age and an increase of β with age seems entirely plausible.
As far as the dose dependence is concerned, an increase of δ requires a reduction of β with dose which seems rather unusual. In the discussion it is speculated that the increase of the clonal expansion rate may have its roots in the bystander effect. However, the biological experiments cited (refs. 31–38 of the article) which tested the bystander effect either report an increase of cell death or mutation after irradiation, but certainly not a decrease as suggested by the model.
If the result were robust it might rather be interpreted in terms of immortalization of the clones, which is known to be a characteristic of cancer cells.
However given that the model considerably departs from anterior models (refs. 20, 21 of the article) which were designed to include the bystander effect and explicitly assumed a dose dependence of δ or α, it would be interesting to know whether the new model really fits the data significantly better than the older ones, e.g. in terms of the AIC.