Appendix

Academie des Sciences (Academy of Sciences) Academie nationale de Medecine (National Academy of Medicine)

Dose-effect relationships and estimation of the carcinogenic effects of low doses of ionizing radiation

March 6, 2005
Andre Aurengo (Rapporteur), Dietrich Averbeck and Andre Bonnin (all members of the Academie nationale de medecine)

Roland Masse (membre correspondant de l'Academie nationale de medecine)

Roger Monier, Maurice Tubianal (Chairman) (members of the Academie des Sciences)

Bernard Le Guen, Florent de Vathaire

Executive Summary

The assessment of carcinogenic risks associated with doses of ionizing radiation from 0.2 Sv to 5 Sv is based on numerous epidemiological data.

However, the doses which are delivered during medical X-ray examinations are much lower (from 0.1 mSv to 20 mSv). Doses close to or slightly higher than these can be received by workers or by populations in regions of high natural background radiation.

Epidemiological studies have been carried out to determine the possible carcinogenic risk of doses lower than 100 mSv and they have not been able to detect statistically significant risk even on large cohorts or populations.

Therefore these risks are at worst low since the highest limit of the confidence interval is relatively low. It is highly unlikely that putative carcinogenic risks could be estimated or even established for such doses through case-control studies or the follow-up of cohorts. Even for several hundred thousands of subjects, the power of such epidemiological studies would not be sufficient to demonstrate the existence of a very small excess in cancer incidence or mortality adding to the natural cancer incidence which, in non-irradiated populations, is already very high and fluctuates according to lifestyle. Only comparisons between geographical regions with high and low natural irradiation and with similar living conditions could provide valuable information for this range of doses and dose rates. The results from the ongoing studies in Kerala (India) and China need to be carefully analyzed.

Because of these epidemiological limitations, the only method for estimating teh possible risks of low doses (< 010 mSv) is by extrapolating from carcinogenic effects observed between 0.2 and 3 Sv. A linear no-threshold relationship (LNT) describes well the relation between the dose and the carcinogenic effect in this dose range where it could be tested. However, the use of this relationship to assess by extrapolation the risk of low and very low doses deserves great caution. Recent radiobiological data undermine the validity of estimations based on LNT in the range of doses lower than a few dozen mSv which leads to the questioning of the hypotheses on which LNT is implicitly based: 1) the constancy of the probability of mutation (per unit dose) whatever the dose or dose rate, 2) the independence of the carcinogenic process which after the initiation of a cell evolves similarly whatever the number of lesions present in neighboring cells and the tissue.

Indeed 1) progress in radiobiology has shown that a cell is not passively affected by the accumulation of lesions induced by ionizing radiation. It reacts through at least three mechanisms: a) by fighting against reactive oxygen species (ROS) generated by ionizing radiation and by any oxidative stress, b) by eliminating injured cells (mutated or unstable), through two mechanisms i) apoptosis which can be initiated by doses as low as a few mSv thus elimiating cells whose genome has been damaged or misrepaired, ii) death at the time of mitosis cells whose lesions have not been repaired.

Recent works suggest that there is a threshold of damage under which low doses and dose rates do not activate intracellular signaling and repair systems, a situation leading to cell death c) by stimulating or activating DNA repair systems following slightly higher doses of about ten mSv.

Furthermore, intercellular communication systems inform a cell about the presence of an insult in neighboring cells. Modern transcriptional analysis of cellular genes using microarray technology reveals that many genes area activated following doses much lower than those for which mutagenesis is observed. These methods were a source of considerable progress by showing that according to the dose and the dose rate it was not the same genes which genes that were transcribed.

For doses of a few mSv (< 10 mSv), lesions are eliminated by the disappearance of cells. For slightly higher doses damaging a large number of cells (therefore capable of causing tissue lesions), the repair systems are activated. They permit cell survival but may generate misrepairs and irreversible lesions. For low doses (< 100 mSv), the number of mutagenic misrepairs is small but its relative importance, per unit dose, increases with the dose and dose rate. The duration of repair varies with the complexity of the damage and their number. Several enzymatic systems are involved and a high local density of DNA damage may lower their efficacy. At low dose rates the probability of misrepair is smaller. The modulation of the cell defense mechanisms according to the dose, dose rate, the type and number of lesions, the physiological condition of the cell, and the number of affected cells explains the large variations in radiosensitivity (variations in cell mortality or probability of mutations per unit dose) according to the dose and the dose rate that have been observed. The variations in cell defense mechanisms are also demonstrated by several phenomena: initial cell hypersensitivity during irradiation, rapid variations in radiosensitivity after short and intense irradiation at a very high dose rate, adaptive responses which cause a decrease in radiosensitivity of the cells during hours or days following a first low dose irradiation, etc.

2) Moreover, it was thought that radiocarcinogenesis was initiated by a lesion of the genome affecting at random a few specific targets (proto-oncogenes, suppressor genes, etc.). This relatively simple model, which provided a theoretical framework for the use of LNT, has been replaced by a more complex process including genetic and epigenetic lesions, and in which the relation between the initiated cells and their microenvironment plays an essential role. This carcinogenic process is confronted by effective defense mechanisms in the cell, tissue, and the organism. With regard to tissue, the mechanisms which govern embryogenesis and direct tissue repair after an injury seem to play an important role in the control of cell proliferation. This process is particularly important when a transformed cell is surrounded by normal cells. These mechanisms could explain the lesser efficacy of heterogeneous irradiation, i.e., local irradiations through a grid as well as the absence of a carcinogenic effect in humans or experimental animals contaminated by small quantities of a-emitter radionuclides. The latter data suggest the existence of a threshold. This interaction between cells could also help to explain the difference in the probability of carcinogenesis according to the tissues and the dose, since the death of a large number of cells disorganizes the tissue and favors the escape from tissue controls of an initiated cell.