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Linear no-threshold dogma

I read with great interest the article by Feinendegen published in the January issue of the British Journal of Radiology [1]. This article is courageous because it challenges the dogma of the linear no-threshold dose–effect relationship (LNT) and shows that it is unjustified to use it for assessing risks associated with even the smallest doses of radiation. This dogma could lead to erroneous conclusions with regard to the dangers of diagnostic radiology. Indeed, an article published in The Lancet in 2004 [2] estimated that several hundred lethal cancers in the UK every year could be induced by radiological examinations. This conclusion could increase needless anxiety among patients for whom radiological examinations have been prescribed.

The seriousness of this situation led the French Academy of Sciences and the French Academy of Medicine to join their efforts to review critically the available data. A working party was set up. A report was written, approved and recently released [3]. The report analyses recent progress in radiobiology which has shown that a cell is not passively affected by the accumulation of lesions induced by ionizing radiation. The cell reacts through at least three mechanisms: (a) by fighting against reactive oxygen species (ROS) generated by ionizing radiation; (b) by eliminating injured cells (mutated or unstable), through two mechanisms (i) apoptosis and (ii) death at the time of mitosis of cells whose lesions have not been repaired. (Recent works suggest that there is a threshold of damage below which low doses and dose rates do not activate intracellular signalling and repair systems, a situation leading to cell death); (c) by stimulating or activating DNA repair systems following slightly higher doses of about 5–10 mSv.

Furthermore, intercellular communication systems inform a cell about the presence of an insult in neighbouring cells and the irradiated cell takes this information into account. Modern transcriptional analysis of cellular genes using microarray technology reveals that many genes are activated after doses much lower than those for which mutagenesis is observed and shows that according to the dose and the dose rate it was not the same genes that were transcribed. The cell defences are modulated by these two parameters. The probability of DNA misrepair increases with dose and dose rate. Moreover, it was previously thought that radiocarcinogenesis is initiated by a lesion of the genome affecting at random a few specific targets (proto-oncogenes, suppressor genes, etc.). This relatively simple model has been replaced by a more complex process including genetic and epigenetic lesions, and in which the relationship between the initiated cells and their microenvironment play an essential role. This carcinogenic process is confronted by effective defence mechanisms in the cell, tissue, and the whole organism.

These phenomena suggest the lesser effectiveness per unit dose of low doses determine a practical threshold, 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. The LNT relationship assumes that the probability of mutations is constant per unit dose, irrespective of dose and dose rate. It also assumes that the carcinogenic effect on a cell is not influenced by the number of injured cells and the tissue damage. The conclusion of the report is that these two assumptions are inconsistent with recent experimental and radiobiological data, and that the use of the LNT relationship for assessing the carcinogenic effect of doses below 20 mSv is not based on valid data. The data quoted by Feinendegen are consistent with the conclusions of the French Academies report.

Yours etc.,

M Tubiana

Centre Antoine Béclère, 45 rue des Saints-Pères, Paris 75006, France

Received for publication May 31, 2005. Revision received June 14, 2005. Accepted for publication June 16, 2005.

References

1. Feinendegen LE. Evidence for beneficial low level radiation effects and radiation hormesis. Br J Radiol 2005;78:3–7.[Abstract/Free Full Text]
2. Berrington de Gonzalez A, Darby S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet 2004;363:345–51.[CrossRef][Medline]
3. Tubiana M, (chairman) Aurengo A, Averbeck D, Bonnin A, Le Guen B, Masse R, et al. Dose-effect relationships and estimation of the carcinogenic effect of low doses of ionizing radiation. Académie des Sciences – Académie Nationale de Médecine (Paris). 2005. www.academie-medecine.fr/actualites/rapports.asp [Accessed 22 July 2005].

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