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Contenu archivé le 2024-05-29

Extended low dose risk estimation for ionising radiation

Final Activity Report Summary - LOWDOSE (Extended low dose risk estimation for ionising radiation)

The main objectives of the low dose cancer modelling studies at the University of Salzburg could be summarised in the effort to take into consideration all biological mechanisms that were relevant for low dose exposure scenarios relating to ionising radiation into multi-stage cancer models. These mechanisms included various protective processes, such as radiation-induced Deoxyribonucleic acid (DNA) repair and radical scavenging, but also possible detrimental, and protective, effects that might arise through cell-to-cell signalling phenomena, i.e. bystander effects.

While our earlier studies focussed on low-dose induction of DNA repair and radical scavenging, the new research successfully implemented protective apoptosis-mediated effects into a multistage model for neoplastic transformation. In this new model apoptosis could eliminate cells with Double strand breaks (DSBs) as well as those with severe chromosome damage, i.e. unrepairable initiated cells. At higher doses the effect was modelled as exponentially disappearing. The dose effect curves were therefore modified at low doses only, as it was found in vitro for bystander effects. The new model was tested on a groundbreaking data set by Redpath et al., as presented in Radiation Research 156, pages 700 to 707, in 2001. These data showed protective effects of low doses of gamma-radiation in a human cell line in vitro, as was earlier discovered by Azzam et al. for a mammalian cell line (Radiation Research 146, 369-373, 1996). In the experiments of Redpath et al., low doses of gamma-radiation, up to 250 mGy approximately, protected against spontaneous neoplastic transformation. This represented a one-dose adaptive response in opposition to the classical two-dose adaptive response. The model with protective apoptosis-mediated bystander effect successfully fit the available data. In case such cell culture studies were relevant to humans, this result would have the dramatic effect that low doses of ionising radiation would not only be non harmful but could also reduce the spontaneous cancer frequency for various cancers.

Another important result was the implementation of detrimental bystander effects into a multistage model for chromosome aberrations. A suitable data set that was related to in vitro irradiation of mammalian cells with alpha-particles was used to test the model. Our results indicated that detrimental bystander effects mainly occurred during post-exposure and that bystander-induced tissue responses might promote pre-existing initiated cells. In case detrimental bystander effects were relevant to low dose exposure scenarios of humans, this result would imply that low doses of ionising radiation could be more harmful than currently anticipated.

During our earlier studies, we implemented protective effects from inducible DNA repair and radical scavengers after exposure to low doses of low Linear energy transfer (low-LET) radiation at low dose rates into deterministic and stochastic cancer models. A new model was developed that extended this approach for high dose rates. This new approach distinguished between background and artificial irradiation with a low dose delivered at high dose rates, as it might be encountered in workplace accidents by nuclear workers. Endogenous DNA damage was also considered as a separate term. The model could be used for risk predictions, e.g. to calculate the lifetime probability of lung cancer.

The most important project achievement was the successful simulation of the data by Redpath et al., as published in Radiation Research 156, in 2001, with a protective apoptosis-mediated bystander effect. Within these model fits it was possible to estimate the time span that the protective effect from apoptosis would be switched on. This paralleled previous experimental findings by Mendonca et al., published in Cancer Research 59, pages 3972 to 3979, in 1999.