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Carcinogenic effects of low radiation doses and underlying mechanisms

Objective


The progress achieved by the various participants can be summarized as follows:

1. AZL: The computer programs LifePrep and LifeStat have been developed to serve as a standard tool for the analysis of dose-effect relationships in animal models and are available to other groups working on in-vivo carcinogenesis. The program has been applied to tumour induction data in WAG-Rij rats after fractionated irradiation in order to study mammary carcinogenesis in view of radiation protection questions in general or the risk for tumour induction in large scale breast screening programs in particular.
2. ENEA: Studies on the induction of epithelial tumours in mice after irradiation with fission neutrons did not reveal any marked influence of the time regimen of neutron irradiation on survival and tumour induction at low doses. This agrees with the results of an experiment on the effect of dose fractionation of fission neutrons on neoplastic transformation of exponentially cells. Concerning the genetic predisposition to carcinogenesis the restriction length polymorphism of telomere-like sequences appear to be different in the CBA/Cne and CBA/H mouse colonies. In addition an experimental approach has been followed consisting of a bi-directional selective breeding for susceptibility and resistance to two-stage carcinogenesis, initiated by DMBA and promoted with TPA.
3. ITRI-TNO: The study of mammary cancer induction in rats after single dose and fractionated gamma irradiation with and without hormone administration has been completed as far as the collection of tumours is concerned.
4. CEA: The aim of the work is to identify the potential co-carcinogenic effect of combined exposure to irradiation and various occupational and/or environmental inhaled airborne pollutants. The effort was focused mainly on ozone in rats after pulmonary irradiation, either globally by fission neutrons or locally after inhalation of radon 222 and its short lived decay products. The role of cytochrome P450 1A1 (CYP 1A1) was investigated during co-carcinogenesis produced by inducers of this enzyme. Different groups of rats were treated by intramuscular injections of various chemical compounds to induce soft tissue tumours, mainly rhabdomyosarcomas and fibrosarcomas, at the site of injection to constitute a bank of neoplastic and pre-neoplastic lesions.
5. GSF: The analysis methods for tumour induction in animals are performed in subsequent steps, notably the Kaplan-Meier estimators, the Cox regression for a joint analysis and the use of analytical function. The applicability of the mathematical methods is illustrated on a lifetime experiment with Spraque-Dawley rats on the induction of carcinomas and sarcomas after irradiation with gamma rays and fission neutrons. This experiment confirms that for these two classes of neoplasms there are differences in radiation sensitivity, which lead to different dose response and different RBE values.
6. IVVO-TNO: The histopathological examinations of mammary tumours in rats treated with radiation and hormones have been completed. In addition to the benign (fibroadenomas) and malignant tumours (carcinomas), other neoplastic lesions have been observed.
IN THIS JOINT PROPOSAL THE EMPHASIS IS PLACED ON THE CARCINOGENIC EFFECTS OF LOW DOSES OF RADIATION AND THE UNDERLYING MECHANISMS. THE INFLUENCE OF VARIOUS EXPOSURES OR HOST CONDITIONS ON THE PROBABILITY OF CANCER DEVELOPMENT WILL BE STUDIED. THE PROJECT INVOLVES THE ANALYSIS OF DATA FROM RECENTLY ACCOMPLISHED EXPERIMENTS, THE COMPLETION OF ON-GOING EXPERIMENTAL STUDIES, AND THE PERFORMANCE OF A LIMITED SELECTION OF NEW SERIES. THIS LAST ACTIVITY IS PARTICULARLY IMPORTANT TO TEST WELL FOUNDED HYPOTHESES OF RADIATION ACTION BASED ON THE RESULTS OF CELLULAR AND MOLECULAR BIOLOGY STUDIES. THE ASSESSMENT OF THE RISK OF EXPOSURE OF MAN TO IONIZING RADIATION REQUIRES THE KNOWLEDGE OF THE PROBABILITIES OF BOTH FATAL AND NON-FATAL CANCERS INDUCED BY RADIATION. THESE PROBABILITIES ARE ESTIMATED, WHENEVER POSSIBLE, RELYING ON EPIDEMIOLOGICAL STUDIES. HOWEVER, THE DETAILED DOSE-EFFECT RELATIONSHIPS, IN PARTICULAR REGARDING THE LOWER DOSE-RANGES THE INFLUENCE OF DOSE RATE FOR HIGH-LET RADIATION, THE ROLE OF RADIATION QUALITY, DIFFERENCES IN SENSIVITY OF SUBPOPULATIONS, TRANSMISSION OF CARCINOGENIC EFFECTS THROUGH SUCCESSIVE GENERATIONS, AND THE INFLUENCE OF HOST FACTORS, SUCH AS THE SPECIES, AGE, SEX, AND HORMONAL STATUS OF THE IRRADIATED INDIVIDUAL CAN NOT BE OBTAINED FROM HUMAN EPIDEMIOLOGY ALONE. ALSO, HORMONAL STATUS OF THE IRRADIATED INDIVIDUAL CAN NOT BE OBTAINED FROM HUMAN EPIDEMIOLOGY ALONE. ALSO, THE IMPORTANT QUESTIONS ARISING FROM COMBINED EXPOSURES TO RADIATION AND OTHER CARCINOGENS AND PROMOTORS AND INHIBITORS, CANNOT BE UNRAVELED BY HUMAN EPIDEMOLOGY BECAUSE OF THE COMPLEXITY OF OUR ENVIRONMENT AND ITS RAPID CHANGES. FURTHERMORE, THE FOLLOWING SUBJECTS NEED SPECIAL RESEARCH EFFORTS : THE INHERENT RADIOSENSIVITY OF INDIVIDUAL ORGANS AND THE IDENTIFICATION OF MOLECULAR MARKERS ASSOCIATED WITH SPECIFIC NEO PLASTIC LESIONS. THIS LATTER INFORMATION HAS AT THIS MOMENT MAINLY A PREDIC TIVE VALUE, BUT WITH IMPROVED BIOTECHNICAL PROCEDURES MODIFICATION OF THE RADIATION EFFECT CAN BE ENVISAGED. NEW INSIGHTS INTO CARCINOGENESIS EMERGING FROM MOLECULAR BIOLOGICAL INVESTIGATIONS, MAY PROVIDE, BY IDENTIFICATION OF A VARIETY OF STEPS AND PATHWAYS, MUCH NEEDED INFORMATION ON THE SENSIVISY TO RADIATION AMONG DIFFERENT CELL TYPES, AND ON CELL CYCLE DEPENDENCE. FOR ALL THESE REASONS THE USE OF BIOLOGICAL MODEL SYSTEMS SUITABLE TO STUDY THE VARIOUS ASPECTS OF RADIATION CARCINOGENESIS IS ESSENTIAL, AND IN PARTICULAR ANIMAL STUDIES.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Rijksuniversiteit Leiden
Address
10,Rijnsburgerweg
2333 AA Leiden
Netherlands

Participants (5)

Commissariat à l'Energie Atomique (CEA)
France
Address
Centre D'études De Fontenay-aux-roses
92265 Fontenay-aux-roses
Ente per le Nuove Tecnologie l'Energia e l'Ambiente (ENEA)
Italy
Address
Via Anguillarese 301
00060 Santa Maria Di Galeria Roma
GSF-RESEARCH CENTER FOR ENVIRONMENT AND HEALTH
Germany
Address
Ingolstaedter Landstrasse 1
85764 Oberschleissheim
Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek
Netherlands
Address
310,Utrechtseweg
6800 ES Arnhem
Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek
Netherlands
Address
501,Laan Van Westenenk 501
7300 AH Apeldoorn