[1] Member of the National Academy of Medicine [2] Corresponding Member of the National Academy of Medicine [3] Member of the Academy of Sciences

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 irradiation.

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 worse 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 the possible risks of low doses (< 100 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 eliminating 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 are 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 whichgenes that were transcribed.

For doses of a few mSv (< 10 mSv), lesions are eliminated by the disappearance of the 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.

3) Immunosurveillance systems are able to eliminate clones of transformed cells, as is shown by tumor cell transplants. The effectiveness of immunosurveillance is also shown by the large increase in the incidence of several types of cancers among immunodepressed subjects (a link seems to exist between a defect in NHEJ DNA repair and immunodeficiency).

These phenomena suggest the lesser effectiveness of low doses, or even of a practical threshold which can be due to either a failure of a low level of damage to sufficiently activate DNA repair mechanisms or to an association between apoptosis + error-free repair + immunosurveillance, to determine a threshold (between 5 and 50 mSv?). The stimulation of the cell defense mechanisms could also cause hormesis by fighting against endogenous mutagenic factors, in particular against reactive oxygen species. Indeed a meta-analysis of experimental data shows that in 40% of animal experiments there is a decrease in the incidence of spontaneous cancers after low doses. This observation has been overlooked so far because the phenomenon was difficult to explain.

These data show that the use of a linear no-threshold relationship is not justified for assessing by extrapolation the risk of low doses from observations made for doses from 0.2 to 5 Sv since this extrapolation relies on the concept of a constant carcinologic carcinogenic effect per unit dose, which is inconsistent with experimental and radiobiological data. This conclusion is in contradiction with those of an article and a draft report [43,118], which justify the use of LNT by several arguments.

1. for doses lower than 10 mGy, there is no interaction between the different physical events initiated along the electron tracks through the DNA or the cell;

2. the nature and the repair of lesions thus caused are not influenced by the dose and the dose rate;

3. cancer is the direct and random consequence of a DNA lesion in a cell apt to divide;

4. LNT model correctly fits the dose-effect relationship for the induction of solid tumors in the Hiroshima and Nagasaki cohort;

5. the carcinogenic effect of doses of about 10 mGy is proven by results obtained in humans in studies on irradiation in utero.

With respect to the first argument, it should be noted that the physico-chemical events are identical but their biological consequence may greatly vary because the cellular defense reactions differ depending on dose and dose rate. The second argument is contradicted by recent radiobiological studies considered in the present report. The third argument does not take into account recent findings showing the complexity of the carcinogenic process and overlooks experimental data. Regarding the fourth argument, it can be noted that besides LNT, other types of dose-effect relationships are also compatible with data concerning solid tumors in atom bomb survivors, and can satisfactorily fit epidemiological data that are incompatible with the LNT concept, notably the incidence of leukemia in these same A-bomb survivors. Furthermore, taking into account the latest available data, the dose-effect relationship for solid tumors in Hiroshima-Nagasaki survivors is not linear but curvilinear between 0 and 2 Sv. Moreover, even if the dose-effect relationship were demonstrated to be linear for solid tumors between, for example, 50 mSv and 3 Sv, the biological significance of this linearity would be open to question. Experimental and clinical data have shown that the dose effect relationship varies widely with the type of tumor and with the age of the individuals - some being linear or quadratic, with or without a threshold. The composite character of a LNT relationship between dose and all solid tumors confirms the invalidity of its use for low doses.

Finally, with regard to irradiation in utero, whatever the value of the Oxford study, some inconsistencies should lead us to be cautious before concluding to a causal relationship from data showing simply an association. Moreover, it is questionable to extrapolate from the fetus to the child and adult, since the developmental state, cellular interactions and immunological control systems are very different.

In conclusion, this report doubts the validity of using LNT in the evaluation of the carcinogenic risk of low doses (< 100 mSv) and even more for very low doses (< 10 mSv). LNT can be a pragmatic tool for assessing the carcinogenic effect of doses higher than a dozen mSv within the framework of radioprotection. However the use of LNT in the low dose or dose rate range is not consistent with the current radiobiological knowledge; LNT cannot be used without challenge for assessing by extrapolation the risks of associated with very low doses (< 10 mSv), nor be used in benefit-risk assessments imposed on radiologists by the European directive 97-43. Biological mechanisms are different for doses lower than a few dozen mSv and for higher doses. The eventual risks in the dose range of radiological examinations (0.1 to 5 mSv, up to 20mSv for some examinations) must be estimated taking into account radiobiological and experimental data. An empirical relationship which is valid for doses higher than 200 mSv may lead to an overestimation of risk associated with doses one hundred fold lower and this overestimation could discourage patients from undergoing useful examinations and introduce a bias in radioprotection measures against very low doses (< 10 mSv).

Decision makers confronted with problems of radioactive waste or risk of contamination, should re-examine the methodology used for the evaluation of risks associated with these very low dose exposures delivered at a very low dose rate. This analysis of biological data confirms the inappropriateness of the collective dose concept to evaluate population irradiation risks.

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