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RADIATION-INDUCED STRUCTURAL CHROMOSOME ABERRATIONS IN MAMMALIAN SOMATIC CELLS

Objective

1. CHROMOSOME ABERRATIONS IN PERIPHERAL BLOOD LYMPHOCYTES OF RADIATION THERAPY PATIENTS MEASURED AS BIOLOGICAL INDICATORS OF GENETIC DAMAGE IN MAN AFTER PARTIAL BODY IRRADIATION.
2. ACCURATE ESTIMATION OF DOSE EFFECT RELATIONSHIP FOR CHROMOSOME ABERRATIONS INDUCED IN HUMAN LYMPHOCYTES AT LOW DOSES OF X RAYS.

Dose effect relationships for the induction of chromosome aberrations have been well established for irradiation in vitro but are still relatively scarce after in vivo inhomogeneous exposure such as expected after accidental irradiation. For that purpose information can be obtained from patients undergoing therapy under well controlled technical conditions. An advantage of this procedure is that the patients provide their own control and that chromosomal aberration yields can be followed in the same person after increasing dose levels. In this study cytogenetic observations were mainly made on patients receiving radiotherapyfor malignant glioma, uterine cancer or prostatic cancer.

The yield of dicentric chromosomes and ring chromosomes observed in the blood lymphocytes sampled prior to the first radiotherapy treatment was found to be much higher in the pelvic tumour group than usually reported in the controls (0.88% versus 0.078%). This may be related to diagnostic exposures and/or unknown medical treatments received by some patients during the period preceding the detection of their cancer. However, the yield of dicentrics observed in the glioblastoma group prior to the first radiotherapy session was found to be in complete agreement with the values usually reported in the controls. Here, anomalies were infrequent after irradiation too, probably because of the highly localised exposures as well as the low number of lymphocytes present in the irradiated regions.

On the basis of the maximum likelihood method a linear dose response relationship was fitted through the experimental points for the pelvic tumours and a linear quadratic dose response relationship for the glioblastomas. According to these relationships the dose D at the target volumes inducing 10 dicentrics and ring chromosomes per 100 cells can be estimated to 58 Gy for glioblastomas. This is considerably higher than those found for mammary carcinoma (15 Gy), pelvic tumours (5.62 Gy) or after in vitr o irradiation (1 Gy).

For a uniform irradiation, the distribution of aberrations among the cells is Poisson. For partial body exposure or nonuniform exposure, the aberrations are distributed among the cells with a variance greater than that predicted by Poisson distribution. By examining the magnitude of this overdispersion, it is theoretically possible to estimate approximately the proportion of the body exposed and its average dose.

Our results indicate that in the case of fractionated exposures, confined to a small volume of the body, it is not possible to estimate the total dose administered and that the method only provides an estimate of the proportion of the lymphocytes irradiated. By comparison to the dose (1 Gy) necessary to produce in blood samples irradiated in vitro 10 dicentrics or ring chromosomes one can estimate that this proportion is 17% for the pelvic tumours and about 10% after 4 X 2.5 Gy to about 20% after 12 X 2.5 Gy for glioblastomas.
A study, funded by CEC, was set up essentially to study the effects of low X-ray doses using cells from 4 subjects and the results (Lloyd et al, Int. J. Radiat. Biol. 53, 4, 1988) were compatible with a possible threshold at doses less than 20 mGy. This was later extended (still to be published) to blood from a further 20 subjects. Despite large numbers of cells being analyzed the statistical uncertainties on the data were fairly large. Nevertheless a similar conclusion of a threshold could still be drawn. If the low dose response is really linear as has been the usual assumption in radiobiology, it is remarkable that three studies have all shown, albeit each not significantly, evidence for a low dose plateau in response and a reduction below the control value at 10 mGy or less.

The present project forms an extension of this work to obtain data using low doses of high LET radiation. Samples of blood from 4 subjects will be irradiated at the Fast Neutron Facility at the Reactor Centre Petten, The Netherlands. Expertise from NRPB, together with the staff at the Reactor Centre will be used in the dosimetry. Eight doses (0, 0.25, 0.5, 0.8, 1.25, 2.5, 12.5 and 62.5 mGy) will be used and the incident neutrons have a mean energy of 1.0 MeV. The irradiated samples will be taken to Leiden for culturing for metaphase preparations using a standard protocol. Many replicate slides will be prepared, coded and distributed between the six participating laboratories for microscope analysis. After scoring the data will be decoded and evaluated by statistical programs at NRPB.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

CENTRE D'ETUDES DE L'ENERGIE NUCLEAIRE
Address
Parc Seny Rue Charles Lemaire 1
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Belgium