Saturday, April 30, 2016

Appendix Part 2

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 immunosuppressed subjects (a link seems to exist between a defect in NHEJ DNA repairs 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 or 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 finding 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 20 mSv 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 hundredfold 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.