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STUDY OF RADIOBIOLOGICAL EFFECTS AT LOW DOSES

Objective

Description of research work
The research programme is a continuation of one which expired in 1989, and aims to provide information to enlarge our knowledge and understanding of the biological action of radiation, and so to tackle specialized problems relevant in the context of radiological protection. The general aims of the work carried out in this contract are the study of the dose-effect relationship at low radiation doses; the interaction mechanisms and the influence of dose rate and radiation quality and the important biological parameters for well identified endpoints in vivo and in vitro.
Studies of dose response relationships for radiation carcinogenesis after single and fractionated neutron doses were performed. This involved over 2000 female BC3F1 mice irradiated with 2 different radiation qualities. The study focussed on tumour incidence (age adjusted), life span shortening, and time to tumour appearance. Mortality rates for specific causes of death indicated that the risk of death with ovarian tumours was appreciably increased below 0.1 Gy for both neutrons and X-rays. For other solid tumours the minimum doses producing a significant increase of the risk were 8 Gy respectively.

A parallel analysis of lymphoma and myeloid leukaemia incidence data in about 3000 BC3F1 male mice irradiated with single acute doses of X-rays and fussion neutrons was performed. For malignant lymphoma the data the data was well described and values are in agreement with those expected from the haematopoetic cell survival. This agrees with the hypothesis that such cells are responsible for the lymphomas. In irradiated BC3F1 mice myeloid leukaemia is a more rare event, nevertheless the dose response curves are very similar in shape to those reported for CBA/H and RF/Un mice.

Research also showed that liver tumour can be induced in mice with very different spontaneous incidences (ie CBA/Cne 67%, BC3F1 11%). Based on these findings the influence of radiation quality (ie X-rays and fission neutrons) on the induction of such tumours in BC3F1 mice was investigated. For both radiation qualities the final incidence appeared to increase with the dose in a wide dose range.

Studies of in vivo and in vitro transformation per surving cell were performed. The mechanisms of tumour induction at the cellular level were studied in order to obtain an estimation of the risk of neoplastic transformation per cell in vivo. The risk was estimated for both dysplastic lesions and tumours.

The transplantation technique used for studies of harderian gland tumours was applied to the in v ivo study of hepatocyte survival and the risk of neoplastic transformation per surviving cell in the mouse. The data for CBA/Cne mice was consistent with a linear quadratic dose effect relationship while for BC3F1 mice a simple quadratic expression provided a better fit to the experimental points.

Further experimental work was performed to compare the transforming effectiveness of equal doses delivered to C3H10T1/2 cells following either acute or fractionated irradiation protocols. Results confirmed that the neutron dose fractionation does not significantly influence survival compared to acute irradiation.

Late somatic effects of total lymphoid irradiation (TLI) were investigated in BC3F1 mice using a fractionated protocol. In particular, using a mouse population with a high natural lymphoma incidence it was intended to investigate whether the expected depression of this tumour following irradiation was associated with other tumour types or shortening of the life span. Results indicate the presence of a relevant incidence of skin cancers which appeared to be the most likely cause of life shortening of the treated mice together with kidney degenerative disease.

Based on previous finding with liver tumours the influence of radiation quality and age at irradiation on the induction of such tumours were investigated in BC3F1 male mice. A marked age dependence was demonstrated for radiation induced liver cancer tumours with a higher susceptibility in young than in old mice. Age dependence also appears to affect neutron relative biological effectiveness (RBE) relative to X-rays for the induction of liver neoplasms. The RBE value for prenatal irradiation is about 2 times higher than for young adult animals irradiated at comparable low doses.

The obtain experimental evidence on the influence of exposure prolongation on the effectiveness of low neutron doses, an in vivo study of the carcinogenic effect of fractionated doses of fission neutrons and of X-rays was ca rried out. About 2000 BC3F1 male mice were given each 5 equal daily dose fractions corresponding to cumulating doses of 2.5 cGy to 70 cGy for fission neutrons and of 25 cGy to 300 cGy for X-rays. Irradiated and control animals were followed up for their life span. After spontaneous death a complete necropsy was performed. Experimental data are being analyzed with respect to life span shortening and the induction of selected tumour types which include lymphoma and myeloid leukaemia.

In vitro studies of neoplastic transformation induced by radiation and chemicals are frequently carried out using different cell lines. The C3H10T1/2 mouse embryo fibroblast system is a very useful tool for these studies as it allows a close quantitative determination of the dose effect relationships for this end point. The system has yielded interesting information on the effect of radiation dose rate. Some experiment with neutrons have indicated the possibility of an enhanced transforming potential of fractionated doses or low dose rates in the dose range of 0 to 1 Gy in comparison to single acute exposures. A series of experiments using this system have been initiated.
This purpose responds to the main objective of radiation protection, that is to achieve and maintain appropriate safe conditions for justified activities involving human exposure. Such a goal rests on the possibility of establishing unambiguous correlations between the physical quantities characterizing the irradiation and the susceptibility of biological tissues and organs to biological effects of major severity.

In this context, it is widely recognized that animal studies are a very important tool concerning the study of the biological consequences of exposure to radiation and, in particular, the mechanisms of radiation induced carcinogenesis. They often represent the only reliable source of information relating to the important aspects of the biological response to radiation in vivo, for example the shape of the dose-effect relationship at low doses, the influence of radiation quality and the time modalities of the dose administration. Recent studies have indicated a concordance of relative risk estimates for the induction of some cancer types between humans and mice, suggesting that extrapolation between species can be considered, and have encouraged further studies in this direction.

Fast neutrons represent a particularly important problem, as, in the present situation, no useful estimate of RBE can be obtained from available human data of cancer mortality. Furthermore, they pose special important questions, some of which may have far reaching radiation protection implications. Among these, the variation in carcinogenic and mutagenic effectiveness consequent to a protraction of exposure deserves particular attention. Differences in RBE for tumour induction in various organs and tissues also call for careful consideration.

The present programme uses low doses of different radiation qualities and various modes of irradiation on different experimental model systems for suitable endpoints, including life shortening and tumour induction in experimental animals. In particular, in order to obtain further evidence on the enhanced effectiveness of prolongated low neutron dose exposures (low dose rate or fractionation), the present activity includes, as a substantial part, an experimental in vivo study of the carcinogenic effect of fractionate doses of fission neutrons and, for comparison, also of X-rays on long-living BC3F1 male mice.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Comitato Nazionale per la Ricerca e per lo Sviluppo dell'Energia Nucleare e delle Energie Alternative
Address
Viale Regina Margherita 125
00198 Roma
Italy