Radiological Accidents in Georgia
Lecture Module 15 Lecture: Radiological accidents in Georgia Purpose: To present case histories of two radiological accidents that occurred in Georgia and the biodosimetry response Learning objectives: Upon completion of this lecture the participants will know: The background circumstances of the two accidents The biodosimetry results The application of the G-function calculation to compensate for dose protraction A comparison of the dose estimates from the dicentric assay with, where available, results from FISH and electron spin resonance An illustration of follow-up studies showing the relative declines with time of the dicentric and translocation frequencies Duration: 1 hour Observation of 500 metaphases in 2-2.5 days scoring
The dicentric assay 48 h Cell culture Spreading Observation of 500 metaphases in days scoring Dicentrics acentrics Blood Processing 2 x 5 ml blood collected on heparin This slide is a summary reminder of the steps in the dicentric assay which requires 3 days to produce an initial triage dose estimates followed later by full dose estimates. 3 days 500 cells 48 hours 1 day 1 hour 50 cells Dose effect curves WHOLE BODY DOSE
Yield of dicentrics and centric rings per cell 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 6 7 8 9 Dose (Gy) Bare source (n/g=0.86) Lead shield (n/g=5.6) CH2 shield (n/g=0.12) 0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 Cobalt-60 (0.1 Gy/min) Cobalt-60 (0.5 Gy/min) X-Ray (0.1 Gy/min) Caesium (0.5 Gy/min) These are examples of the laboratorys standard acute dose effect curves for various qualities of high and low LET radiation. The most appropriate curve is chosen for converting the aberration frequency obtained from the patients into estimates of absorbed dose. WHOLE BODY DOSE Biological tests (hematological analysis, biochemical data, HLA, etc.)
Summary of the different strategies for dealing with a few or many patients Expertise (Priority to the dose assessment) Emergency w/o population triage (Priority to the medical evaluation) Emergency w population triage (Priority for the distribution in categories) Clinical symptoms Biological tests (hematological analysis, biochemical data, HLA, etc.) Physical dosimetry Biological dosimetry quick but not precise Biological dosimetry very precise Medical team All persons are firstly assessed for clinical signs of overexposure. This is supplemented by a series of blood tests usually available as routine procedures in most clinics and hospitals. Where possible, physical dosimetry by measurements and / or calculations are carried out. At the same time blood samples are taken for biological dosimetry.For events involving just one or a few patients precise biological dosimetry is performed. All information from biological dosimetry, routine blood tests and physics is reported back to the medical team to assist in their clinical decision taking. In the case a large number of patients biological dosimetry will be operated firstly in triage mode, to produce initial dose estimates. Together with the other information that is then available the patients can be prioritised for extending the biological dosimetry to precise dose estimates. Biological dosimetry more precise Clinical decision & treatment Time Time 4 Influence of the number of cells analysed on the precision of dose estimation
Confidence intervals at 95 %: include the true value of the dose The precision of the dose measurement is dependent on the number of cells scored and the number of chromosome aberrations found in the blood sample. This graph illustrates how the 95% confidence limits on the same dose estimate of Gy are reduced by scoring more cells. In triage mode where 50 cells are quickly scored the confidence interval is about 1Gy, sufficient for a first triage. A full dose estimate is based classically on the examination of 250 to 500 cells which takes more time. In this example for 500 cells examined, the confidence interval is about 0.2 Gy. Triage based on 50 cells: 1 hour More precise dose estimation: 2-3 days Dose reconstruction by biological dosimetry for the accident at Lilo (Georgia, 1997)
Between 1997 and 2001 there were 3 radiation accidents in Georgia involving either soldiers or members of the general public. These accidents had a common cause: many radioactives sources were abandoned in some former military camps when the Russian army left Georgia. All 3 accidents were dealt with by an IAEA mission help by a French delegation. Each individual involved in the accidents was assessed for biological dosimetry by cytogenetics. Because, for biological dosimetry, the most interestingevents were the first two in 1997 and 1998 just these are summarized in this presentation. Location in Georgia LILO, 1997
Lilo is a small city located 25 km east of the capital Tbilisi. Lilo military training center
1997: 11 Georgian soldiers developed radiation induced skin lesions and acute radiation syndrome 12 radioactive sources (Cs-137, Co-60, Ra-226) abandoned at different locations in a former training Russian military camp, some in this underground shelter. The most irradiated victim (33 patches on his body) LILO: accident circumstances (1)
Source container seems to have been opened by patient AN, but the source remained inside for some time. Then the source was placed in pocket of EPs coat. The coat was borrowed regularly leading to irradiation of other persons. TK and CG shared the same room with AN and EP and all used the coat, with the source in a pocket, as a night time bed blanket. Irradiation occurred from mid 1996 to April 1997 Discovery of the exposures was in August 1997 Fuller details of the circumstances and the patients clinical conditions can be found in the IAEA book (2002) describing this event. LILO: accident circumstances (2)
11 people with different levels of expsoure The 4 most exposed people were hospitalized in France, the 7 others in Germany All patients in France suffered from lymphopenia and nausea AN suffered from contractures affecting the hands and lesions on the abdomen TK displayed a deep lesion on the right thigh EP displayed 33 patches on the trunk and thighs CG had hand and thigh lesions Fuller details of the circumstances and the patients clinical conditions can be found in the IAEA book (2002) describing this event. Results of the dicentric analyses
First dose estimations obtained in October 1997 for the 4 most seriously irradiated soldiers hospitalized in the Curie Institute and Percy Hospital , Paris (cases 1 to 4) and for the 7 others hospitalized in Ulm University Clinic (cases 5 to 11). Estimates of averaged whole body doses were made by reference to Co-60 calibration curves. Patients 1 and 2 showed significant overdispersion of their dicentric distributions (the u- test statistic). Analyses made in October 1997 Details of biological dosimetry by cytogenetics for the 4 most irradiated patients
4 patients hospitalized in France Analyses performed by 23/10/1997 Dicentric distribution Case Cells DicCrAce u-test Adu Eli God Kak Dic = dicentrics; Cr = centric rings; Ace = excess acentrics Lymphopenia was already present before the patients' arrival in France. Consequently, the integrated equivalent whole-body doses may be underestimations of the true doses because the dicentric aberration is unstable and is removed more rapidly with lymphopenia. For the first two patients the u-test indicated overdispersion, consistent with heterogeneous irradiation, even though the proportion of cells with several anomalies was relatively low. Moreover, there was a lot (13% and 14%) of cells with dicentrics without an accompanying acentric. This percentage is abnormally high for acute irradiations and may be explained by the fact that during cell division, dicentrics have a 50% chance of passing from the mother cell to one of the two daughter cells. The accompanying acentric fragments, on the other hand, are lost during the division. This suggests that an exposure of relatively low intensity took place, either continuously or at repeated intervals for several days, weeks, or months, thus allowing partial replenishment of the lymphocyte population. For patients 3 and 4 who also had received heterogeneous exposure, as shown by their skin lesions, the dicentric distributions surprisingly showed no evidence of overdispersion.It is possible that the lymphopaenia led to the most highly irradiated cells being lost first and by the time that they came to analysis lymphocytes containing only a single aberration were seen. 12 Protracted/chronic exposure : correction by the G-function
Initial dose-effect curve : Y= c + D +D2 For a protracted exposures the acute curve is modified by the G-function G(x) = 2/x2 [x-1+exp(-x)] where x= t/t0 t= the actual exposure time t0=2h The circumstances of the event were clearly that the men had been irradiated on many different occasions, i.e.,fractionated exposures and many single events were likely to have been protracted, typically over several hours. This non-acute nature of their exposures therefore needs to be considered in arriving at more realistic dose estimates. The acute in vitro calibration curve is modified by the G-function which is applied to the D2 term of the yield equation which represents the dose rate and dose fractionation sensitive component of the induced aberrations (see the lecture on statistical techniques). However this procedure in practice only operates for exposures of a few hours duration. For longer times G(x) tends to zero so that the dose-effect curve becomes simply linear Y = D as shown by the blue curve in the graph. . Modified dose-effect curve : Y= c + D +G(x)D2 Correction of cytogenetics results and comparison with ESR data
Initial Doses (Gy) 1 1.2 2 1.6 3 0.7 4 0.5 5 0.1 6 0.3 7 8 9 10 11 Corrected Doses (Gy) 4.2 5.9 1.5 1.1 0.2 0.6 0.7 4.1 Doses by ESR (Gy) ND 4.5 1.4 1.5 0.7 1.3 0.1 0.4 Taking into account the probable mix between chronic and repeated exposure during several months, a simplifying assumption was made that the most appropriate dose response to use for dose estimation was Y = D and not to attempt a more sophisticated analysis involving the G function, as duration information on the protracted individual exposures was inadequate. The table shows the initial averaged whole body doses based on the acute dose response curve and then the recalculated (corrected) values based on the linear term only. It became possible in some cases to obtain teeth and /or bone samples which were sent to the Institute of Biophysics, Moscow for measurement by electron spin resonance (ESR). This technique provides an integrated total dose received by the tooth or piece of bone and is not subject to dose rate modification. It is analagous to a monitoring badge permanently worn in the same place and therefore provides a measurement of dose at that point. Given that exposures were heterogeneous the point dose estimate is also an approximation of the true integrated dose. Nevertheless it was gratifying to note that particularly for the most severe cases the corrected cytogenetic values were closer than the initial values to the ESR results. Nevertheless, regarding the very complex story of irradiation, it is better to consider the results obtained by the application of G-function and the ESR as a working hypothesis rather thantrue values. ND = not done Some follow-up data An occasional follow-up blood sampling of the 4 patients treated in France was possible and this demonstrated the well known decline with time in the frequency of the dicentric type of aberration. Each was sampled 4 times and there was a complete disappearance of dicentrics for three of the patients occuring either in the 3rd or 4th samples, whereas in person Eli the dicentrics were more persistent. This is a good illustration of the variability in dicentric persistence and the unsuitability of the dicentric as a biological dosemeter long after irradiation. Comparison of dicentric and translocation yields when patients were first sampled
The figure shows the respective level of dicentrics, reciprocal and total translocations scored in October 1997 in the blood lymphocytes of the 4 most irradiated victims. Overall there is a good level of agreement. For God no difference was seen in the doses estimated by dicentric or translocation yields. For Kak and Eli, a higher dose was assessed using translocations, but the difference was not statistically significant. For patient Adu however, a higher dose was estimated using dicentrics. To explain these discrepancies, one can assume that the heterogeneity of exposure differed from one patient to another. This has modified the distribution of translocations in unstable cells and consequently the relative disappearance of dicentrics compared to translocations during the time from first exposure to first blood sampling, exacerbated by the lymphopaenia FISH follow-up More interesting is the FISH follow-up which was made with the 4 patients. The translocations in stable cells were scored. In contrast to the dicentric persistence presented in a previous slide, no decline in the frequency of two-way translocations was observed for three of the 4 patients. For patient Kak, the frequency of translocations decreased two months after the first blood sample was taken, but the confidence interval included the initial value of the translocations yield. This has illustrated that generally there is a better persistence of translocations which makes them better suited for retrospective dosimetry. After four years, and considering the initial lymphopenia, it is assumed that the blood was repopulated by lymphocytes coming from bone marrow. Therefore these results suggest that in 3 cases the irradiation of bone marrow was relatively homogeneous and the dose was similar to that of the peripheral blood lymphocyte pool. Conclusion Complex exposure scenario Exposures protracted
Delayed discovery Dicentric assay still possible Linear dose response curve used Reasonable agreement with ESR Follow-up dicentrics reduced with time Greater stability of translocations Translocations probably reflect the bone marrow dose The second accident Dose reconstruction by biological dosimetry for the accident at Matkhoji (Georgia, 1998) The location MATKHOJI, 1998 Matkhoji is a small village, 300 km west of the capital,Tbilisi. Key-dates in the IAEA mission to Georgia 1.
4 August 1998 : Georgia requested assistance from the IAEA for radioactives sources found in and near Matkhoji. 10~14 August : IAEA teamidentified problems and needs. ThreeCs-137 sources found: 150 GBq in a pit in a field 65 m from the main road dose rate: 0.15 mSv/h at 1 m. 3.3 GBq in an empty yard 4 m of the same road; dose rate: 0.3 mSv/h at 1 m. 0.17 GBq in a barn; dose rate: 15 Sv/h at 1 m. The pit was used as a swimming pool mainly by children and the empty yard as a playground. In the barn, the source was found close to the place where cows were milked each day. Key-dates 2. 13 August :IAEA requested France to perform biodosimetry. 14 August : Difficulties for local medical team to identify thecritical individuals. 18 August : France offered to send a physicist and a physician to help the Georgian medical team to identify thecritical persons. 16 September: Hematological screening by local medical team on 800 suggested that 60 people could have received 0.2 Gy. 12~17 October 1998 :Georgia requested help through IAEA anda French team of two physicians, a physicist and a translator went to Georgia. French teams decisions
To collect information about the circumstances of the exposure directly from the Matkhoji people and the Georgian authorities. To make blood cell counts on local people, to detect leucopaenia. To blood sample some tens of people for biological dosimetry. People sampled: children using the pit and playground and people living in the barn. Timetable of the biodosimetry in Paris
Quick triage: 50 cells per case: Saturday 17th October (day 0) 85 blood samples arrive in Paris First blood cultures Sunday 18th October (d1) Second blood cultures Monday 19th October (d2) Mitotic block and harvesting of the first cultures after 48 h Tuesday 20th October (d3) Mitotic block and harvesting of the second cultures after 50 h Wednesday 21st October (d4) Staining slides and starting triage scoring Thursday 22nd October to Monday 26 October (d5 - 7) Completed scoring, using six observers and an image analysis system Full analyses: increased scoring to 250 cells per case: From Tuesday 27th October to Thursday 17th December 1998 In view of the need to assess 85 people promptly, the biodosimetry was firstly made in triage mode.Processing all the blood samples and the triage scoring was completed in 7 days. The second phase was to increase the statistical precision by increasing the number of cells scored to 250 per case. This was achieved for all patients but two. The blood samples had been transportedbadly and so there was considerable variation in the mitotic indices. Summary of biodosimetry results
First triage step : 85 individuals, mainly children On a basis of 50 cells scored per individual 1 blood sample with two cells carrying one dicentrics each; 1 blood sample with a cell carrying one dicentric; 1 blood sample with a cell carrying two dicentrics. 82 blood samples with no dicentrics Conclusion : the dose estimation is within the Gy range The triage data showed few dicentrics. This seemed to be in accord with the normal haematological data obtained in Matkhojiby the IAEA mission. The second phase of dose examination confirmed the triage phase. The Paris laboratorys spontaneous dicentrics frequency in a normal population is about 1 dicentrics per 2000 cell. Therefore in the lymphocytes scored in these 85 people one would expect to observe 10 or 11 dicentrics. The number of dicentrics observed was significantly higher than the control value suggesting that the group had been irradiated. In addition,in the person with the most dicentrics a tricentric was observed. Dicentric yields distribution
The majority (68 ) persons had no dicentrics in 250 cells. Nine had 1 dicentric (0.004 / cell) which falls essentially on the 95th percentile on the population mean. Three people had 2 dicentrics and 5 people, including one with a tricentric, had 4 dicentrics (0.012 / cell). Matkhojl - Conclusions
Biodosimetry indicated no individual whole-body dose above0.3Gy. The highest doses were mostly to children who played in theformer military camp close to the radioactive sources. From the local investigations it was impossible to reconstructprecise individual exposures. The haematology was normal, but this would only exclude doses >1 Gy. The biodosimetry was the most quantitative technique possible andthe results were good news for the people examined and moregenerally the whole population of Matkhoji. Publications on the Georgian accidents: An IAEA book on the Lilo event: The Radiological Accident in Lilo STI/PUB/1097, 103 pp.; 39 figures; 2000, ISBN Two journal papers: Suspicion of radiological overexposures in Georgia (1998): The role of IPSN- P. Voisin, L. Lebaron-Jacobs, J.-F. Bottollier-Depois and P. Gourmelon. Radioprotection Volume 36, Numro 2, 2001. Study of the tools available in biological dosimetry to estimate the dose in case of accidental complex overexposure to ionizing radiation: the Lilo accident - Roy L., Gregoire E., Durand V., Buard V., Delbos M., Paillole N., Sorokine-Durm I., Gourmelon P., Voisin P.. Int. J. Rad. Biol.,1-10, 2006.