Dose estimation after a mixed field exposure: Radium-223 and intensity modulated radiotherapy.

INTRODUCTION: Radium-223 dichloride ([223Ra]RaCl2), a radiopharmaceutical that delivers α-particles to regions of bone metastatic disease, has been proven to improve overall survival of men with metastatic castration resistant prostate cancer (mCRPC). mCRPC patients enrolled on the ADRRAD clinical trial are treated with a mixed field exposure comprising radium-223 (223Ra) and intensity modulated radiotherapy (IMRT). While absorbed dose estimation is an important step in the characterisation of wider systemic radiation risks in nuclear medicine, uncertainties remain for novel radiopharmaceuticals such as 223Ra. METHODS: 24-Colour karyotyping was used to quantify the spectrum of chromosome aberrations in peripheral blood lymphocytes of ADRRAD patients at incremental times during their treatment. Dicentric equivalent frequencies were used in standard models for estimation of absorbed blood dose. To account for the mixed field nature of the treatment, existing models were used to determine the ratio of the component radiation types. Additionally, a new approach (M-FISHLET), based on the ratio of cells containing damage consistent with high-LET exposure (complex chromosomal exchanges) and low-LET exposure (simple exchanges), was used as a pseudo ratio for 223Ra:IMRT dose. RESULTS: Total IMRT estimated doses delivered to the blood after completion of mixed radiotherapy (after 37 IMRT fractions and two [223Ra]RaCl2 injections) were in the range of 1.167 ± 0.092 and 2.148 ± 0.096 Gy (dose range across all models applied). By the last treatment cycle analysed in this study (four [223Ra]RaCl2 injections), the total absorbed 223Ra dose to the blood was estimated to be between 0.024 ± 0.027 and 0.665 ± 0.080 Gy, depending on the model used. Differences between the models were observed, with the observed dose variance coming from inter-model as opposed to inter-patient differences. The M-FISHLET model potentially overestimates the 223Ra absorbed blood dose by accounting for further PBL exposure in the vicinity of metastatic sites. CONCLUSIONS: The models presented provide initial estimations of cumulative dose received during incremental IMRT fractions and [223Ra]RaCl2 injections, which will enable improved understanding of the doses received by individual patients. While the M-FISHLET method builds on a well-established technique for external exposures, further consideration is needed to evaluate this method and its use in assessing non-targeted exposure by 223Ra after its localization at bone metastatic sites.

Radiation exposures in pregnancy, health effects and risks to the embryo/foetus-information to inform the medical management of the pregnant patient.

Generally, intentional exposure of pregnant women is avoided as far as possible in both medical and occupational situations. This paper aims to summarise available information on sources of radiation exposure of the embryo/foetus primarily in medical settings. Accidental and unintended exposure is also considered. Knowledge on the effects of radiation exposure on the developing embryo/foetus remains incomplete-drawn largely from animal studies and two human cohorts but a summary is provided in relation to the key health endpoints of concern, severe foetal malformations/death, future cancer risk, and future impact on cognitive function. Both the specific education and training and also the literature regarding medical management of pregnant females is in general sparse, and consequently the justification and optimisation approaches may need to be considered on a case by case basis. In collating and reviewing this information, several suggestions for future basic science research, education and training, and radiation protection practice are identified.

The harmonization process to set up and maintain an operational biological and physical retrospective dosimetry network: QA QM applied to the RENEB network.

PURPOSE: The European Network of Biological and Physical Retrospective Dosimetry 'RENEB' has contributed to European radiation emergency preparedness. To give homogeneous dose estimation results, RENEB partners must harmonize their processes. MATERIALS AND METHODS: A first inter-comparison focused on biological and physical dosimetry was used to detect the outliers in terms of dose estimation. Subsequently, trainings were organized to improve both tools dose estimation. A second inter-comparison was performed to validate training efficiency. Simultaneously, based on ISO standards, a QA&QM manual on all dosimetry assays was produced which states a common basis and harmonized procedures for each assay. The evaluation of the agreement of RENEB partners to follow the QA&QM manual was performed through a questionnaire. The integration of new members into the network was carried out in the same way, whatever the assays. RESULTS: The training courses on biological and physical dosimetry were judged to be successful because most of the RENEB members' dose estimates improved in the second inter-comparison. The QA&QM manual describes the consensus for the minimum requirements and the performance criteria for both dosimetry assays. The questionnaire revealed that the whole network capacity currently can manage between 15 and 3800 samples once. CONCLUSION: The methodology used to harmonize all dosimetry practice within the network RENEB was highly successful. The network is operational to manage a mass casualty radiation accident for immediate dose assessment.

High frequency of simple and complex chromosome aberrations detected in the Tokai-mura survivor four and five years after the 1999 criticality accident.

In September 1999 a criticality accident occurred in a uranium processing plant in Tokai-mura, Japan. During the accident, three workers (A, B and C) were exposed to high acute doses of neutrons and γ-rays: workers A and B fatally and worker C to an estimated whole body absorbed dose of 0.81 Gy neutrons and 1.3 Gy γ-rays. We obtained fixed peripheral blood lymphocytes (PBL) preparations from worker C approximately four and five years after the accident and assayed by 24 colour karyotyping (M-FISH) to determine the frequency and complexity of chromosome aberrations present. We observed a high frequency of simple reciprocal translocations, which we used to provide a rough estimation of dose and, in addition, for the assessment of the emergence of any clinically-relevant clonal exchanges. We did not observe any evidence of clonality but did find some evidence suggesting chromosome 1 as being preferentially involved in exchanges in stable cells. We also detected a relatively high frequency of damaged cells containing complex chromosome aberrations, of both the stable and unstable types. Qualitatively these complex aberrations were consistent with those observed to be induced after exposure to low doses of high-LET radiation or moderate doses of low-LET radiation, supporting the suggestion that heavily damaged cells can be quite long-lived in vivo.

DNA and chromosomal damage in response to intermittent extremely low-frequency magnetic fields.

Considerable controversy still exists as to whether electric and magnetic fields (MF) at extremely low frequencies are genotoxic to humans. The aim of this study was to test the ability of alternating magnetic fields to induce DNA and chromosomal damage in primary human fibroblasts. Single- and double-strand breaks were quantified using the alkaline comet assay and the gammaH2AX-foci assay, respectively. Chromosomal damage was assayed for unstable aberrations, sister chromatid exchange and micronuclei. Cells were exposed to switching fields - 5min on, 10min off - for 15h over the range 50-1000microT. Exposure to ionizing radiation was used as a positive-effect calibration. In this study two separate MF exposure systems were used. One was based on a custom-built solenoid coil system and the other on a commercial system almost identical to that used in previous studies by the EU REFLEX programme. With neither system could DNA damage or chromosomal damage be detected as a result of exposure of fibroblasts to switching MF. The sensitive gammaH2AX assay could also not detect significant DNA damage in the MF-exposed fibroblasts, although the minimum threshold for this assay was equivalent to an X-ray dose of 0.025Gy. Therefore, with comparable MF parameters employed, this study could not confirm previous studies reporting significant effects for both the alkaline and neutral comet assays and chromosomal aberration induction.

Evidence for significant heritability of apoptotic and cell cycle responses to ionising radiation.

Genetic factors are likely to affect individual cancer risk, but few quantitative estimates of heritability are available. Public health radiation protection policies do not in general take this potentially important source of variation in risk into account. Two surrogate cellular assays that relate to cancer susceptibility have been developed to gain an insight into the role of genetics in determining individual variation in radiosensitivity. These flow cytometric assays for apoptosis induction and cell cycle delay following radiation are sufficiently sensitive to distinguish lymphocytes from a healthy donor population from those of a sample of obligate carriers of ATM mutations (P = 0.01 and P = 0.02, respectively). Analysis of 54 unselected twin pairs (38 dizygotic, 16 monozygotic) indicated much greater intrapair correlation in response in monozygotic than in dizygotic pairs. Structural equation modelling indicated that models including unique environmental factors only fitted the data less well than those incorporating two or more of additive genetic factors, common environmental factors and unique environmental factors. A model incorporating additive genetic factors and unique environmental factors yielded estimates of heritability for the two traits of 68% (95% CI 40-82%, cell cycle) and 59% (95% CI 22-79%, apoptosis). Thus, these data suggest that genetic factors contribute significantly to human variation in these two measures of radiosensitivity that relate to cancer susceptibility.