Portal de Periódicos da CAPES

Dose–effect relationship and estimation of the carcinogenic effects of low doses of ionizing radiation: The joint report of the Académie des Sciences (Paris) and of the Académie Nationale de Médecine

2005; Elsevier BV; Volume: 63; Issue: 2 Linguagem: Inglês

10.1016/j.ijrobp.2005.06.013

1879-355X

Maurice Tubiana,

Radioactivity and Radon Measurements

The assessment of the carcinogenic effect of low doses of ionizing radiation is of crucial importance for all those who use X-rays or radionuclides for diagnosis or therapy, including the many physicians who prescribe X-ray examinations. It also concerns health physicists, public health specialists, and all those who are occupationally exposed to ionizing radiation. Over the past 20 years the French Ministry of research has twice asked the Académie des Sciences to carry out a critical review of the available data regarding the effects of low doses of ionizing radiation on health. The Académie Nationale de Médecine has also published a few analyses of the data. In 2003 the two Academies decided to join their efforts for an update of two main topics: the dose–carcinogenic effect relationship and the carcinogenic effect of low doses. A working party was set up; its report was accepted after a few modifications suggested by the reviewers and it was released in March 2005 (1Tubiana M, Aurengo A, Averbeck D, et al. Dose–effect relationships and estimation of the carcinogenic effect of low doses of ionizing radiation. Paris: Académie des Sciences–Académie Nationale de Médecine; 2005. English text: Feb. 2005; www.academie-medecine.fr/actualites/rapports.asp.Google Scholar). The main points that are discussed in the report are the following: Epidemiologic studies have been unable to detect in humans a significant increase of cancer incidence for doses below about 100 mSv. The only method for estimating the possible risks of such low doses is extrapolation from carcinogenic effects observed between 0.2 and 3 Sv. In the 1960s, the International Commission of Radioprotection introduced the linear no threshold (LNT) relationship because it allows the addition of sequential irradiation delivering low or high doses of radiation received by an individual whatever the dose rate and the fractionation. Thus it greatly simplifies accounting in radioprotection, as has the introduction of the quantities "equivalent dose" and "effective dose." However, gradually LNT has been interpreted as meaning that the carcinogenic risk is proportional to the dose and that even the smallest dose induces a cancer risk. Thus the LNT has been used for assessing the effect of low and very low doses. This procedure has become a dogma in many radioprotection circles and has caused controversy over the past decade. With regard to the study of radiocarcinogenesis, the meta-analyses of experimental animal data have not evidenced significant cancer excess for doses below 100 mSv. They do show, however, the existence of a dose below which no excess in tumor incidence is detectable, which suggests the existence of a practical threshold. Furthermore, most of the dose–effect relationships are not linear but rather linear-quadratic or quadratic. Moreover, a hormesis is observed in approximately 40% of the experiments. Therefore, the lack of evidence of a carcinogenic effect for doses below 100 mSv in humans or animals has two possible explanations: (1) the carcinogenic effect is too small to be detected by statistical analysis; (2) there is no effect and a threshold exists. These data challenge the validity of LNT for assessing the carcinogenic effect of low doses, and the hypotheses on which LNT is implicitly based should be reexamined. The LNT model postulates that the cell reactions are identical regardless of dose rate and dose, which implies that the probabilities of death and mutation (per unit dose) and the contribution to carcinogenesis of each physical event remains constant, irrespective of the number of lesions in the cell and in the neighboring cells. This constancy implicitly postulates several hypotheses: (1) In the range of the doses and dose rates under consideration, there is no chemical or biologic interaction between the effects caused by the various tracks of ionizing particles in a cell. (2) Any absorbed dose of energy in a cell nucleus leads to a proportional probability of mutation. The probabilities of error-free repair or misrepair (per dose unit) do not vary with the dose. Similarly, the probability of apoptosis is constant irrespective of dose and dose rate. (3) Any deoxyribonucleic acid (DNA) lesion has the same probability of giving rise to a cancer, irrespective of the number of other lesions in the same cell and the neighboring cells. The conclusion of the report is that these hypotheses are not consistent with current radiobiological knowledge. The cells do not remain passive when they are irradiated either by solar ultraviolet or by ionizing radiation. Several types of defense mechanisms have been identified; moreover, 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, without modification of the genome, numerous genes are activated or inhibited after doses much lower than those for which mutagenesis is observed. Moreover, depending on the dose and the dose rate, not the same genes are transcribed. The oxidative stress provoked by the irradiation induces defense mechanisms against the reactive oxygen species; the effectiveness of these defenses varies with dose. The dose rate influences the effectiveness of DNA repair and of mutagenesis. The DNA damage decreases when the dose rate is lower. However, in humans with congenital diseases affecting DNA repair or when cells are irradiated in vitro at a low temperature which blocks enzymatic systems, the yield of damage does not decrease with dose rate. For low doses (<100 mSv), the extent of mutagenic misrepairs is small but its relative importance, per dose unit, increases with the dose and dose rate. Several enzymatic systems are involved in DNA repair, 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 physiologic condition of the cell, and the number of affected cells explains the large variations in radiosensitivity (variations in cell mortality or in the probability of mutations per dose unit) depending on the dose and the dose rate that have been observed. The radiation-induced cell mortality (per dose unit) varies during the cell cycle, although the probability of DNA damage is the same. This change in mortality is therefore mainly attributable to differences in the probability of error-free repair depending on the cell-cycle phase. The variations in cell defense mechanisms are also demonstrated by several phenomena: (1) initial cell hypersensitivity during irradiation, which decreases and disappears as a result of the activation of repair systems for doses higher than 0.5 Gy; (2) rapid variations in radiosensitivity after short and intense irradiation at a very high dose rate; (3) adaptive responses that cause a decrease in radiosensitivity of the cells during hours or days following a first low preconditioning dose of radiation. Most of the cells with unrepaired or misrepaired DNA lesions are eliminated either by mitotic death when the lesions have not been repaired, or by triggering apoptosis. The efficacy of the elimination of potentially mutant cells varies with the dose, the cell line, and the tissue. In the case of intestinal crypt cells after gamma irradiation, apoptosis reaches a plateau at doses of 200 to 400 mGy. In vitro, the damaged cells disappear at very low doses, but this is not the case at doses above approximately 10 mSv. The experiments of Rothkamm (2Rothkamm K. Lobrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.Proc Natl Acad Sci USA. 2003; 100: 4973-4975Crossref PubMed Scopus (1349) Google Scholar) have shown that after a low dose, 24 h after the irradiation no cell with a double-strand break (DSB) can be detected; this disappearance can be due either to cell death caused by the absence of repair, or to a combination of error-free repair and apoptosis. These data strongly suggest the existence of a practical threshold, but the present data do not allow one to define at what dose or dose rate the mutational effects of an irradiation become trivial, probably somewhere between 10 and 50 mGy. It would be important to assess more precisely this level because X-ray examinations deliver doses ranging from 0.1 mGy to 30 mGy. However, the level of this practical threshold may vary with the type of cell and the age of the individual. Epidemiologic and experimental data show that age is a main parameter and that young age is associated with a greater susceptibility to radiocarcinogenesis. The third hypothesis on which LNT is based, namely that carcinogenesis is purely a stochastic phenomenon caused by a damage of cell DNA, is not consistent with the data that have accumulated during the past decade. It was thought that radiocarcinogenesis was initiated by lesions 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 one, including genetic and epigenetic lesions, and in which the relationship between the initiated cells and their microenvironment plays an essential role. This carcinogenic process is counteracted by effective defense mechanisms not only in the cell, but also in the tissues and the organism. The mechanisms that govern embryogenesis and direct tissue repair after injury appear to play also an important role in the control of cell proliferation. This control is particularly effective when a transformed cell is surrounded by normal cells. These mechanisms could explain the lower 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 α-emitter radionuclides. The latter data suggest the existence of a threshold. Several cytokines such as transforming growth factor-beta intervene in the process. Finally, immunosurveillance also contributes to the defenses against carcinogenesis, which may explain why, in experimental animals, radiocarcinogenesis is caused by much lower doses after a whole-body irradiation than after a localized irradiation. The effectiveness of immunosurveillance in humans is also shown by the large increase in the incidence of several types of cancers among immunodepressed patients. The conclusion of the report is that while LNT may be useful for the administrative organization of radioprotection, its use for assessing carcinogenic risks induced by low doses, such as those delivered by diagnostic radiology or the nuclear industry, is not based on valid scientific data. For example, the results of the Berrington article estimating the number of lethal cancers induced by X-ray examinations published in The Lancet (2004) (3Berrington de Gonzalez A. Darby S. Risk of cancer from diagnostic X-rays Estimates for the UK and 14 other countries.Lancet. 2004; 363: 345-351Abstract Full Text Full Text PDF PubMed Scopus (1334) Google Scholar) should be considered with great caution. This type of data triggers unjustified anxiety among patients who have had radiologic or nuclear medicine examinations. From a practical point of view, two recommendations can be made. First, with regard to X-ray examinations, efforts should be mainly focused on the reduction of the dose delivered to pregnant women, infants, and young children, because for them the risk may be significant although probably quite small. Second, in radiotherapy, efforts should be made to reduce the amount of normal tissue receiving high doses, and the data suggest that doses per session higher than about 150 mGy may be carcinogenic. Fortunately, modern radiotherapy techniques enable the radiation oncologist to achieve this goal. The aim should not be to reduce the integral dose but rather to reduce the volume of normal tissue receiving high doses per fraction.