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Mechanistic study on lung cancer mortality after radon exposure in the Wismut cohort supports important role of clonal expansion in lung carcinogenesis

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Abstract

Lung cancer mortality after radon exposure in the Wismut cohort was analyzed using the two-stage clonal expansion (TSCE) model. A total of 2996 lung cancer deaths among the 58,695 male workers were observed during the follow-up period between 1946 and 2003. Adjustment to silica exposure was performed to find a more accurate estimation of the risk of radon exposure. An additional analysis with the descriptive excess relative risk (ERR) model was carried out for comparison. The TSCE model that best describes the data is nonlinear in the clonal expansion with radon exposure and has a saturation level at an exposure rate of \(d_{\mathrm{r}}\simeq 100\,\text{WLM}{/}\text{yr}\). The excess relative risk decreases with age and shows an inverse exposure rate effect. In comparison with the ERR model, the TSCE model predicts a considerably larger risk for low exposures rates below \(50\,\text{WLM}{/}\text{yr}\). Comparison to other mechanistic studies of lung cancer after exposure to alpha particles using the TSCE model reveals an extraordinary consistency in the main features of the exposure response, given the diversity in the characteristics of the cohorts and the exposure across different studies. This suggests that a nonlinear response mechanism in the clonal expansion, with some level of saturation at large exposure rates, may be playing a crucial role in the development of lung cancer after alpha particle irradiation.

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Notes

  1. One working level, 1 WL, is \(1.3\times 10^5\) MeV of \(\alpha\)-particle energy per liter of air. One WLM of exposure corresponds to one WL during 1 working month or 170 h.

  2. The likelihood ratio test is described in any statistical book covering inference e.g., Dobson and Barnett (2008). For the Akaike information criterion see Akaike (1973). A short review of model selection techniques applied in epidemiological studies can be found in Walsh (2007).

  3. Since the TSCE model is formulated with rate parameters, the silica rate and not the total silica exposure is used as input, similar to the radon exposure rate. These rates are integrated over lifetime to obtain the total risk. It is nevertheless interesting to note that the weekly silica exposure obtained here is of the same order of magnitude as the NIOSH recommended limit for respirable silica of \(0.05\,\mathrm{mg}{/}\mathrm{m}^3\) (NIOSH 1974).

  4. One is inclined to assume that extrapolating the risk with age in a model based on a dynamical process is more reliable than in a purely descriptive model (BEIR 1999). The TSCE model has more flexibility to accommodate different functional forms for the hazard and survival function at different attained ages (Moolgavkar and Venzon 1979; Moolgavkar and Knudson 1981), and may therefore provide more accurate fits to the data on the intermediate and young ages regime.

  5. These models were referred to as exposure-age-concentration and exposure-age-duration models.

  6. Uranium ore dust as a constant term added to the radon response in \(\gamma\) has been used in analyses for lung tumors in rats in Luebeck et al. (1999b), Heidenreich et al. (1999).

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Acknowledgments

We thank the Federal Office for Radiation Protection (BfS) for providing the data on the Wismut cohort. It is a pleasure to thank Michaela Kreuzer, Linda Walsh and Florian Dufey for useful discussions about the cohort, and Jan Christian Kaiser, Reinhard Meckbach and Sascha Zöllner for helpful comments about the models. This work was supported by the European Commission under FP7 project EpiRadBio with Project No. 269553.

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  1. Institute of Radiation Protection, Helmholtz Zentrum München, 85764, Neuherberg, Germany

    I. Zaballa & M. Eidemüller

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Zaballa, I., Eidemüller, M. Mechanistic study on lung cancer mortality after radon exposure in the Wismut cohort supports important role of clonal expansion in lung carcinogenesis. Radiat Environ Biophys 55, 299–315 (2016). https://doi.org/10.1007/s00411-016-0659-0

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