Within the EU MULTIBIODOSE project, the automated micronucleus (MN) assay was optimised for population triage in large-scale radiological emergencies. For MN scoring, two approaches were applied using the Metafer4 platform (MetaSystems, Germany): fully automated scoring and semi-automated scoring with visual inspection of the gallery of MN-positive objects. Dose-response curves were established for acute and protracted whole-body and partial-body exposures. A database of background MN yields was set up, allowing determination of the dose detection threshold in both scoring modes. An analysis of the overdispersion of the MN frequency distribution σ(2)/µ obtained by semi-automated scoring showed that the value of this parameter represents a reliability check of the calculated equivalent total body dose in case the accident overexposure is a partial-body exposure. The elaborated methodology was validated in an accident training exercise. Overall, the semi-automated scoring procedure represents important added value to the automated MN assay.

The data demonstrate that the MULTIBIODOSE approach of applying multiparametric tools to radiation emergencies is valid and effective.

A technician involved in the maintenance of X-ray equipment visited the occupational medicine service with complaints of skin lesions, apparently caused by an accidental exposure three months earlier. To estimate the dose received by the technician in the accident, biodosimetry was performed 6 and 18 months post-exposure with the dicentric and micronucleus assays. Part of the latest blood sample was also used for retrospective dosimetry by fluorescence in situ hybridisation (FISH) analysis for translocations. The data obtained 6 and 18 months post-exposure indicate that both dicentrics and micronuclei disappear with a half-time of 1 y. After correction for delayed blood sampling, dose values of 0.75 Gy (95% confidence limits 0.56-1.05 Gy) from dicentrics and 0.96 Gy (95% confidence limits 0.79-1.18 Gy) from micronuclei were obtained. FISH analysis of translocations resulted in a dose estimate of 0.79 Gy (95% confidence limits 0.61-0.99 Gy). The satisfactory agreement between the three cytogenetic endpoints supports the use of the micronucleus assay for triage purposes in the case of large scale radiological accidents and provides further evidence for the valid use of FISH for translocations as a reliable retrospective biological dosimeter.

The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G 2 assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (Po0.001). Using the 90th percentile of the G 2 scores of the healthy individuals as a cutoff value for chromosomal radiosensitivity, 26% of the cancer patients were radiosensitive compared with 9% of the healthy controls (P ¼ 0.008). The mean number of radiation-induced chromatid breaks and the proportion of radiosensitive individuals were highest for oral cavity cancer patients (1.26 breaks per cell, 38%) and pharynx cancer patients (1.27 breaks per cell, 35%). The difference between patients and controls was most pronounced in the lower age group (p50 years, 1.32 breaks per cell, 38%) and in the non-and light smoking patient group (p10 pack-years, 1.28 breaks per cell, 46%). In conclusion, enhanced chromosomal radiosensitivity is a marker of genetic predisposition to head and neck cancer, and the genetic contribution is highest for oral cavity and pharynx cancer patients and for early onset and non-and light smoking patients.

External source radiotherapy and beta radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha emitters is attractive because of the high linear energy transfer (LET) and short path length, allowing higher tumour cell kill and lower toxicity to healthy tissues. We assessed the relative biological efficacy (RBE) of alpha RIT (in vitro) compared to external gamma irradiation with respect to induction of apoptosis in B chronic lymphocytic leukaemia (B-CLL) and induction of chromosomal damage in healthy donor B and T lymphocytes. The latter was measured by a micronucleus assay. 213Bi was eluted from a 225Ac generator and conjugated to CD20 antibody (rituximab) with CHX-A"-DTPA as a chelator. B-CLL cells from five patients were cultured for 24 h in RPMI/10% FCS while exposed to 213Bi conjugated to CD20 antibody or after external 60Co gamma irradiation. Binding assays were performed in samples of all patients to calculate the total absorbed dose. Apoptosis was scored by flow cytometric analyses of the cells stained with annexin V-FITC and 7-AAD. Apoptosis was expressed as % excess over spontaneous apoptosis in control. Full dose range experiments demonstrated 213Bi-conjugated CD20 antibody to be more effective than equivalent doses of external gamma irradiation, but showed that similar plateau values were reached at 10 Gy. The RBE for induction of apoptosis in B-CLL was 2 between 1.5 and 7 Gy. The micronucleus yield in lymphocytes of healthy volunteers was measured to assess the late toxicity caused by induction of chromosomal instability. While gamma radiation induced a steady increase in micronucleus yields in B and T cells, the damage induced by 213Bi was more dramatic, with RBE ranging from 5 to 2 between 0.1 Gy and 2 Gy respectively. In contrast to gamma irradiation, 213Bi inhibited mitogen-stimulated mitosis almost completely at 2 Gy. In conclusion, high-LET targeted alpha particle exposure killed B-CLL cells more effectively than did external gamma irradiation at a low dose (RBE=2), while a plateau was reached at a high dose. Long-term toxicity on healthy B and T lymphocytes was systematically higher for the alpha emitter (RBE=5 to 2).