Documents of the NRPB: Volume 10 , No. 3

Genetic Heterogeneity in the Population and its Implications for Radiation Risk: Report of an Advisory Group on Ionising Radiation

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Summary:	The conclusions of the report are given below.
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Conclusions

Please note that the paragraph numbering from the full published document has been retained but that the references to other parts of the document have not been included here.

117. Judgements on the extent to which genetic factors influence the response of humans to ionising radiation are fraught with difficulty. There is a large body of information that provides evidence of the existence of genetic subgroups with increased radiosensitivity, but there are few quantitative datasets on which to estimate the true prevalence of such individuals or the degree to which their risk of radiation-induced cancer is enhanced. For these reasons, the judgements made in this document must be regarded as interim and the calculations provided are essentially illustrative. A further source of uncertainty is that most of the data available relate to responses at high doses and high dose rates of radiation rather than the low doses and low dose rates of prime importance in radiological protection.
118. There is abundant evidence that individuals exist in the population with a range of sensitivities to the cytotoxic effect of ionising radiation. These include individuals with certain cancer-prone syndromes and individuals with no known syndrome whose cells have been found to be markedly radiosensitive. In both cases, there is usually an association with defective DNA repair. Current knowledge of the role of DNA damage in carcinogenesis suggests that many of these individuals will also be hypersensitive to the induction of radiation-induced cancer. Such individuals are, however, extremely rare in the population.
119. In addition to these, a small proportion of individuals show highly radiosensitive responses to radiotherapy. A figure of 5% has been quoted for breast cancer cases. There is some evidence of increased sensitivity to cell killing in response to ionising radiation in such individuals. While there may conceivably be an associated risk of radiation-induced cancer, there are no data that bear on this point and the understanding of the mechanisms underlying radiosensitive responses to radiotherapy is too limited to make predictions.
120. There is also cytogenetic evidence of increased radiosensitivity in many cancer-prone conditions, in 30%-40% of breast cancer patients and about 5% of healthy controls. However, the significance of these findings in relation to tumorigenic risk is, at present, unknown and many further studies are required before they should be taken into account in population risk evaluation.
121. Current knowledge indicates that the majority of known cancer-prone conditions expressed in families are associated with inherited mutations of tumour suppressor genes. For these, there are good reasons for predicting tumorigenic radiosensitivity via deletion of the normal allele. This is borne out in studies of animal models and from limited data from humans receiving radiotherapy. There is no a priori reason for assuming that cells with mutant suppressor genes will be sensitive to the lethal effects of ionising radiation, so tests for hypersensitivity to cell killing may be of no predictive value in these cases.
122. There is only limited evidence for an enhanced risk of radiogenic cancer in individuals carrying highly penetrant cancer predisposing genes and for its magnitude. Here, it is suggested that a figure of tenfold be used as an estimate of the likely average increase in risk, but it is acknowledged that the risk for individual conditions could be higher or lower than this. A major uncertainty identified in this report is the prevalence and impact of heritable cancer disorders of low penetrance.
123. Models that take account of heterogeneity in genetic predisposition and radiosensitivity applied to breast cancer indicate that for most populations the likely variation in breast cancer risk at the population level due to such heterogeneity is small. In certain selected populations where cancer-prone disorders are more common, the excess cancer risk due to such heterogeneity could be appreciable, although only when the prevalence is high and the underlying predisposition to cancer and the radiosensitivity are both much larger (by factors of 100 or more) than in the general population.
124. Most of the information currently available suggests that individuals with a genetic predisposition to spontaneously arising cancer are also predisposed to radiation-induced cancer. On this assumption, it is judged that such individuals would not bear a greater proportion of the total cancer burden after additional radiation exposure than they already do without it (say around 5%). As far as these conditions are concerned, variation in their contribution to cancer would not result in an appreciable distortion of current estimates of population risk for radiation-induced cancer. Nevertheless, it is not possible to exclude the existence of individuals for whom the risk of radiation-induced cancer is not accompanied by spontaneous cancer-proneness. Variation in the proportion of such individuals could distort the risk estimated for an irradiated population far in excess of their actual numbers. Moreover, their individual risk would also be greater. Unfortunately, there is no immediate prospect of being able to recognise such individuals should they exist.
125. As far as individual risk is concerned, the increased risk to rare highly-cancer-prone individuals subjected to, say, an occupational radiation exposure would not be detectable because the risk of spontaneous cancer to that individual is so high. In absolute terms, this genetically determined risk may, however, be significantly higher than that experienced by a 'normal' individual subjected to the same dose. This bears some ethical consideration.
126. In radiotherapy, the increased risk of a radiogenic cancer in cancer-prone individuals may be substantial and there may be an additional increase in detriment resulting from a shortened latency period. Other therapies, if they exist, should certainly be considered in such cases.
127. There are considerable advances needed, both technical and in the understanding of cancer genetics, before genetic testing for individual hypersensitivity to the carcinogenic action of ionising radiation becomes feasible. Validation would be a difficult and time-consuming process. While there is little to be gained in identifying such individuals where environmental doses are concerned, there may be an advantage in possessing such information in the context of radiotherapy and certain diagnostic exposures. There are, of course, ethical problems associated with the use of genetic testing information which are becoming widely appreciated and which fall outside the remit of this report.
128. In conclusion, the present state of scientific knowledge offers no rational way to alter the currently accepted philosophy, standards and procedures of radiological protection to take account of the likely above-average radiation risk to certain genetically predisposed members of the population. In the course of time, however, it is considered probable that such individuals will be identifiable. The ethical problems that this will present may have implications for radiological protection.

Last reviewed: 29 August 2008