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Comment on “Lung Cancer Mortality (1950–1999) among Eldorado Uranium Workers: A Comparison of Models of Carcinogenesis and Empirical Excess Risk Models, M. Eidemüller et al., PLoS ONE 7(8):e41431“

Posted by Dufey on 08 Oct 2012 at 15:59 GMT

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.

No competing interests declared.

Response to comment from Dr. Florian Dufey

Eidemueller replied to Dufey on 31 Oct 2012 at 17:52 GMT

We thank Dr. Florian Dufey for his interesting remarks. He is correct that the implementation of the exposure dependence on the identifiable TSCE parameters effectively modifies 'beta', the parameter describing apoptosis or differentiation. Although the TSCE model can determine the clonal expansion rate 'gamma' with good precision, there is usually only a weak indication whether this could be due to a change in the proliferation rate of 'alpha' or 'beta' (as noted, 'mu' is usually much smaller than 'alpha' or 'beta'). This is the case also for the Eldorado cohort. Assuming that 'beta' increases with exposure implies the cell division rate of pre-neoplastic cells increases faster for the Eldorado cohort (and all other cohorts with exposure to alpha-radiation, to which the TSCE model has been fitted). For realistic values of parameter ranges, the deviance is equal to or slightly higher than with a constant value of 'alpha'. Different possible mechanisms for such exposure dependences are discussed by Jacob and Jacob, Radiat. Environ. Biophys. 104, 265-273 (2004) and Heidenreich and Paretzke, Radiat. Res. 170, 613-617 (2008).

In Ref. 20, the TSCE model was fitted to the Colorado Uranium Miners using a logarithmic function for the clonal expansion rate 'gamma' on the exposure rate. Although the overall exposure dependence of 'gamma' is roughly similar to our study; we think the parameterization of 'gamma' in our study allows better mechanistic separations of low and high exposure rate effects.

Ref. 21 (the lung cancer risk for Mayak workers, using TSCE and ERR models) observed an increase of the clonal expansion rate with a similar leveling term, as in our study. However Mayak workers were exposed to plutonium. An updated analysis of the Mayak workers is underway within the EU project EpiRadBio ( It will be valuable to compare risk estimates and mechanisms from radon and plutonium exposure when this work is complete.

No competing interests declared.