Current status of biodosimetry based on standard cytogenetic methods

Knowledge about dose levels in radiation protection is an important step for risk assessment. However, in most cases of real or suspected accidental exposures to ionizing radiation (IR), physical dosimetry cannot be performed for retrospective estimates. In such situations, biological dosimetry has been proposed as an alternative for investigation. Briefly, biodosimetry can be defined as individual dose evaluation based on biological endpoints induced by IR (so-called biomarkers). The relationship between biological endpoints and absorbed dose is not always straightforward: nausea, vomiting and diarrhoea, for example, are the most well-known biological effects of individual irradiation, but a precise correlation between those symptoms and absorbed dose is hardly achieved. The scoring of unstable chromosomal-type aberrations (such as dicentrics and rings) and micronuclei in mitogen-stimulated peripheral blood, up till today, has been the most extensively biodosimetry assay employed for such purposes. Dicentric assay is the gold standard in biodosimetry, since its presence is generally considered to be specific to radiation exposure; scoring of micronuclei (a kind of by-product of chromosomal damages) is easier and faster than that of dicentrics for dose assessment. In this context, the aim of this work is to present an overview on biodosimetry based on standard cytogenetic methods, highlighting its advantages and limitations as tool in monitoring of radiation workers’ doses or investigation into accidental exposures. Recent advances and perspectives are also briefly presented.     

Use of unstable chromosome aberrations for biological dosimetry after the first postirradiation mitosis

The loss of unstable chromosome aberrations after the first postirradiation mitosis makes their use difficult in radiation dosimetry. We describe here a method which, in a cell population observed at this stage, allows retrospective estimation of the frequencies of the unstable aberrations induced at the time of irradiation, and their use as a dosimeter. The laws controlling the behavior of unstable aberrations during mitosis were defined from a large-scale experiment on irradiated human lymphocytes. For cells undergoing the first, second, or third mitosis after irradiation, relationships were determined between the frequency, at irradiation time, of acentric fragments not arising from formation of dicentrics or rings, and the ratio of dicentrics and centric rings appearing without acentric fragments to the total number of dicentrics plus rings. On the basis of this ratio, the method described here provides an assessment of the postirradiation mitotic activity in a cell population. This assessment permitted estimation of the cell distribution and frequency of dicentrics plus centric rings, and of the frequency of acentric fragments at the time of irradiation. The use of this method for retrospective dosimetry after whole-body irradiation under various conditions of exposure is illustrated.     

A novel 210Po-based α-particle irradiator for radiobiological experiments with retrospective α-particle hit per cell determination

A new experimental design for α-particle irradiation of cells in vitro is described where the α-particle irradiator is based on a ²¹⁰Po radioactive source. In the described set-up cells are grown directly on an α-particle detector and irradiation is done from below. For an irradiated cell dish the number of α-particle traversals through each individual cell is scored by using retrospective track etch dosimetry and an accurate technique for individual cell relocation. Calibration experiments characterizing the new irradiator system are presented. Received: 16 November 1999 / Accepted: 9 March 2000     

Mutation and inactivation of cultured mammalian cells exposed to beams of accelerated heavy ions. I. Irradiation facilities and methods.

This paper, which is the first of four covering the inactivation of clonogenic capacity and induction of mutation in cultured mammalian cells, deals briefly with the general aims of the work and describes the irradiation techniques used. Human diploid fibroblasts and V79 Chinese hamster cells were irradiated as monolayers with ions of helium, boron or nitrogen at LET's in the range 20 to 479 keV micrometer-1 in H2O. The physical aspects of the irradiation including measurement of ion energies, dosimetry and uniformity of dose and also the methods of handling large numbers of samples are described in detail. Subsequent papers will present the biological methods and results and a biophysical analysis of the data.     

The cytogenetic indication of irradiation in persons exposed to the action of the factors in the Chernobyl accident]

363 men who have been working under conditions of additional irradiation in terms from few hours to some months were cytogenetically examined to define individual irradiation. In 111 men with the known dose of irradiation (5-140 cGy), the results of cytogenetic evaluation indicated, as a rule, a less intensive irradiation than physical dosimetry. This could be caused by elimination of chromosome aberrations, individual sensitivity, peculiar irradiation situation, or in some cases by incorrect evaluation of dose. In 252 men with the unknown dose of irradiation a tentative level was determined as based on frequency of metaphases with chromosome type aberrations. According to the study the absorbed dose was below 25 cGy in 209 cases, 26-50 cGy in 39 cases, and reached 51-90 cGy in 4 cases.     

Photodimerization of uracil in films and their use for dosimetry of genetically active ultraviolet irradiation

On the basis of the known photodimerization of uracil it is proposed to use its films obtained by sublimation in vacuum for the dosimetry of genetically active UV radiation. Experimental estimations are presented of radiation dose rate resulting in a change of uracil optical density delta D/D0 under irradiation due to photodimerization for erythemal lamp lo-30. The data obtained are used for dosimetry of lethal damage of Chlamydomonas reinhardii. Estimations are also presented of the sun radiation dose rate which induce uracil photodimerization on the earth surface and in the extraterrestrial atmosphere.     

Estimation and reduction of the radiation dose to the fetus from external-beam radiotherapy

The appearance of a malignant disease during pregnancy is relatively rare. The use of external-beam radiation therapy is limited to non-pelvic tumors which are usually located above the diaphragm. However, supradiaphragmatic radiotherapy unavoidably exposes the fetus to secondary radiation due to head leakage, scatter from the machine and scatter produced inside the patient. This fetal exposure may be associated with an elevated risk for the development of deterministic harmful effects and/or carcinogenesis. The decision about the administration of radiotherapy in a pregnant patient is influenced by the fetal dose which must always be estimated before the patient’s treatment course. The methods employed for fetal dosimetry in external-beam radiotherapy are described in this review study. Direct dose measurements using thermoluminescent dosemeters or large ionization chambers placed on physical phantoms may be used. Monte Carlo simulations on computational phantoms may also provide accurate fetal dose calculations. The physical and/or computational phantoms need to simulate the full-scatter geometry of the pregnant patient. Typical fetal dose values attributable to radiation therapy for brain tumors, head and neck cancer, breast carcinoma and Hodgkin lymphoma at the first, second and third trimesters of gestation are presented. The effectiveness of different shielding devices for fetal dose reduction in radiotherapy is discussed. The effect of the dimensions and setup of the shielding material on the radiation dose received by the fetus is described. Moreover, practical methods for reducing the fetal dose by selecting the appropriate irradiation parameters are presented.     

Preliminary investigation on the use of the MOSFET dosimeter in proton beams

Metal Oxide Semiconductor (MOS) device structures can be used to measure ionizing radiation through the mechanism of hole trapping in the oxide layer leading to changing of electrical characteristic of the device. They are a new type of direct reading semiconductor dosimeters. Due to their extremely small physical size, ability to permanently store the accumulated dose, dose-rate independence and their ease of use make them very promising for in vivo dosimetry. They are attractive for dosimetry in small radiation fields used in modern radiation oncology modalities, as conformal radiotherapy, IMRT, stereotactic radiotherapy/radiosurgery and proton therapy. Preliminary results on the use of commercial MOSFET dosimeters (TN-502RD, Thomson & Nielsen Electronics Ltd, Canada) irradiated on therapeutic 62 MeV proton beams are presented. Linearity with absorbed dose, sensibility and energy dependence were investigated. Moreover, the possibility to use of MOSFET dosimeters in order to measure the Output Factors (OF) for very small irradiation fields was verified. The comparison of OF obtained using MOSFETs and other dosimetry systems is reported.     

Protocol for X-ray dosimetry and exposure arrangements employed in studies of late somatic effects in mammals

A number of European laboratories studying the late effects of ionizing radiation in animals have established an effective cooperation within the European Late Effects Project Group (EULEP) since 1970. To facilitate the exchange of biological results several techniques, including quality control of the experimental animals, pathology and dosimetry, have to be standardized. The most important aspects of the procedures for X-irradiation and dosimetry of small animals are summarized. These include recommendations on irradiation conditions, dosimetry methods, characteristics of phantoms and factors affecting X-ray dosimetry. X-irradiation procedures employed by the participating institutes are described and the results of five X-ray dosimetry intercomparisons are reported. The introduction of a common dosimetry protocol has resulted in improvements in exposure arrangements and absolute dosimetry.     

An inbreeding model of associative overdominance during a population bottleneck

Associative overdominance, the fitness difference between heterozygotes and homozygotes at a neutral locus, is classically described using two categories of models: linkage disequilibrium in small populations or identity disequilibrium in infinite, partially selfing populations. In both cases, only equilibrium situations have been considered. In the present study, associative overdominance is related to the distribution of individual inbreeding levels (i.e., genomic autozygosity). Our model integrates the effects of physical linkage and variation in inbreeding history among individual pedigrees. Hence, linkage and identity disequilibrium, traditionally presented as alternatives, are summarized within a single framework. This allows studying nonequilibrium situations in which both occur simultaneously. The model is applied to the case of an infinite population undergoing a sustained population bottleneck. The effects of bottleneck size, mating system, marker gene diversity, deleterious genomic mutation parameters, and physical linkage are evaluated. Bottlenecks transiently generate much larger associative overdominance than observed in equilibrium finite populations and represent a plausible explanation of empirical results obtained, for instance, in marine species. Moreover, the main origin of associative overdominance is random variation in individual inbreeding whereas physical linkage has little effect.     

Results of and prospects for methods of determination of the frequency of mutant cells for glycophorin A and T-cell receptor loci to estimate long-term genotoxic effect of ionizing radiation

The usage of two methods for assessment of somatic gene mutations for the purpose of biological dosimetry and estimation of consequences of irradiation at long time after the exposure has been discussed. The determination of cells bearing mutated glycophorin A (GPA) locus is a reliable method for biodosimetry at both short and long time after the acute irradiation according to our results and the data of other authors. For prolonged exposure, the GPA-method is less informative than in cases of acute irradiation. The determination of mutant cell frequency at T-cell receptor (TCR) locus may be used only at short time after the irradiation. Meanwhile, the TCR-method is more sensitive and informative for biodosimetry of recent irradiation than the GPA test. The both methods may be used for individual assessment of long-term health consequences after the irradiation, because persons with elevated frequencies of mutant cells may represent a group at high risk in respect to oncological diseases.     

Study of genetic control of radiosensitivity

The results of radiation genetics studies are reviewed. The first series of studies concerned the role of heterogeneity of the human population for radiosensitivity of chromosomes in determining the pattern of dose-response relationships; correctness of extrapolation of averaged experimental data to low doses was demonstrated. In the second series of experiments, the radiation-induced adaptive response and the contribution of different factors, including genetic ones, to its formation in human cells were studied. A conclusion was made about impossibility of extrapolating data obtained for cell cultures to an organism as a whole or to a population. The third part of the study was of applied character: cytogenetic methods of biological dosimetry were used to estimate the doses of internal and external irradiation of children living on the territory of the Bryansk oblast contaminated after the Chernobyl accident. The results are discussed in the context of the present-day concepts of genetic control of sensitivity to environmental factors.     

Measurement of absorbed doses from X-ray baggage examinations to tooth enamel by means of ESR and glass dosimetry

The contribution of radiation from X-ray baggage scans at airports on dose formation in tooth samples was investigated by electron spin resonance (ESR) dosimetry and by glass dosimetry. This was considered important, because tooth samples from population around the Semipalatinsk Nuclear Test Site (SNTS), Kazakhstan, had been transported in the past to Hiroshima University for retrospective dose assessment of these residents. Enamel samples and glass dosimeters were therefore examined at check-in time at Kansai airport (Osaka, Japan), Dubai airport (Dubai, United Arab Emirates) and Domodedovo airport (Moscow, Russia). These airports are on the route from Kazakhstan to Japan. Three different potential locations of the samples were investigated: in pocket (without X-ray scans), in a small bag (with four X-ray scans) and in large luggage (with two X-ray scans). The doses obtained by glass and ESR dosimetry methods were cross-compared. As expected, doses from X-ray examinations measured by glass dosimetry were in the μGy range, well below the ESR detection limit and also below the doses measured in enamel samples from residents of the SNTS.     

The observed relationship between the occurrence of acute radiation effects and leukemia mortality among A-bomb survivors

In an analysis of a follow-up study of a fixed population of 73,330 atomic bomb survivors in Hiroshima and Nagasaki, the slope of an estimated dose response between ionizing radiation and leukemia mortality was found to be steeper (P less than 0.002), by a factor of 2.4, among those who reported epilation within 60 days of the bombings, compared to those who did not experience this sign of acute radiation exposure. The strength of this empirical finding as evidence of biological association in individual radiosensitivity for these two end points is studied here. The major factor complicating the interpretation of this finding as evidence of such an association is the degree of imprecision of the radiation dosimetry system used in assignment of radiation doses to the A-bomb survivors. Using models recently suggested for dealing with dosimetry errors in epidemiological analysis of the A-bomb survivor data, the sensitivity of the apparent association between leukemia mortality and severe epilation to the assumed level of dosimetry error is investigated.     

Comparison of dosimetric characteristics of physical wedge and enhanced dynamic wedge in inhomogeneous medium using Monte Carlo simulations

BackgroundWidely used physical wedges in clinical radiotherapy lead to beam intensity attenuation as well as the beam hardening effect, which must be considered. Dynamic wedges devised to overcome the physical wedges (PWs) problems result in dosimetry complications due to jaw movement while the beam is on. This study was aimed to investigate the usability of physical wedge data instead of enhanced dynamic wedge due to the enhanced dynamic wedge (EDW) dosimetry measurement hardships of Varian 2100CD in inhomogeneous phantom by Monte Carlo code as a reliable method in radiation dosimetry.Materials and methodsA PW and EDW-equipped-linac head was simulated using BEAMnrc code. DOSXYZnrc was used for three-dimensional dosimetry calculation in the CIRS phantom.ResultsBased on the isodose curves, EDW generated a less scattered as well as lower penumbra width compared to the PW. The depth dose variations of PWs and EDWs were more in soft tissue than the lung tissue. Beam profiles of PW and EDW indicated good coincidence in all points, except for the heel area.ConclusionResults demonstrated that it is possible to apply PW data instead of EDW due to the dosimetry and commissioning hardships caused by EDW in inhomogeneous media.     

Comparison of pencil-type ionization chamber calibration results and methods between dosimetry laboratories

A comparison of calibration results and procedures in terms of air kerma length product, P_KL, and air kerma, K, was conducted between eight dosimetry laboratories. A pencil-type ionization chamber (IC), generally used for computed tomography dose measurements, was calibrated according to three calibration methods, while its residual signal and other characteristics (sensitivity profile, active length) were assessed. The results showed that the “partial irradiation method” is the preferred method for the pencil-type IC calibration in terms of P_KL and it could be applied by the calibration laboratories successfully. Most of the participating laboratories achieved high level of agreement (>99%) for both dosimetry quantities (P_KL and K). Estimated relative standard uncertainties of comparison results vary among laboratories from 0.34% to 2.32% depending on the quantity, beam quality and calibration method applied. Detailed analysis of the assigned uncertainties have been presented and discussed.     

Stable and unstable chromosome aberrations in humans and other mammals in relation to the problems of biological dosimetry

Literature data of long-term cytogenetic follow-up of people exposed to radiation as a results of different radiation accidents are considered for the purpose of discussing of some problems of biological dosimetry. The results obtained for mammals are also presented. Of particular interest is a decrease in the level of dicentrics and symmetrical translocations in peripheral blood lymphocytes with the time after acute exposure depending on the dose of irradiation. The frequency of dicentrics decreases in accordance to the exponential law passing the fast and slow phases of elimination. In different radiation situations the values of the parameter which defines the half-life period of lymphocytes characterizing 50% reduction of cells with dicentrics markedly vary. However a general regularity is a decrease in the parameter value as the exposure dose increases. The level of stable translocations estimates by the EISH method remains relatively constant at doses below 1-2 Gy. At higher doses their level in peripheral blood lymphocytes declines with time due to which the retrospective dose appears to be underestimated. The reasons of such regularity, the role of various factors affecting the scoring of translocations, criteria of analysis of the given chromosome aberrations are discussed in the context of common agreements between leading European laboratories on the use of FISH for improving biological dosimetric estimates.     

Correlates of breastfeeding frequency among nomadic pastoralists of Turkana,Kenya: A retrospective study

Recent research has shown that significant variation in breast-feeding behavior exists among natural fertility populations, all of whom have been characterized as practicing “on-demand” breastfeeding. A number of recent prospective studies have contributed to a better understanding of breastfeeding structure and of its consequences for population differences in fertility. Currently, there is a growing interest in quantifying the complex environmental and biocultural interactions which influence that structure; in other words, in establishing an ecology of breastfeeding. In this paper, a carefully structured retrospective study of breastfeeding behavior among nomadic Turkana is used to identify environmental, biobehavioral, and socioeconomic factors associated with variation in breastfeeding frequency among Turkana women. In agreement with the results of a prospective study conducted as part of the same research, the age (growth) and physical development of nurslings show significant correlations with breastfeeding frequency. Maternal physical status, the depth of the maternal social network, and, to a lesser degree, rainfall patterns are also significant. All of these factors appear to influence breastfeeding through their effects on maternal participation in herding activities and related absences from camp. Finally, the study also presents new strategies for collecting and utilizing retrospective data, which are notoriously unreliable and difficult to classify according to operational definitions recently developed for prospective studies. Results of the present study suggest methods by which the quality and reliability of recall data may be enhanced. © 1995 Wiley-Liss, Inc.     

A critical survey of fish measurements in populations of the southern Urals

A critical survey of all published measurements made so far aimed at retrospective biological dosimetry using fluorescence in situ hybridisation (FISH) techniques on some workers at the Mayak reprocessing plant and on members of the Techa River cohort is given. Each individual has a recorded dose derived from personal monitoring measurements, usually external gamma-rays for Mayak workers or from reconstruction techniques, usually internally derived for the Techa River cohort. From the person's age, which affects the control level, and the stated dose, an expected number of translocations is calculated for each individual and comparisons made to the observed numbers of translocations. From this, an assessment of how well FISH studies can help to validate existing estimates of dose is made. This varies from study to study. Good agreement is generally obtained for the Techa River cohort and lower doses of the Mayak cohort. Rather poorer agreement applies to the more highly exposed Mayak workers. Some of the discrepancy could be because the FISH painting technique was new and was applied to populations before a proper investigation on how to use it for retrospective biological dosimetry had taken place. In addition, too few cells were generally scored per individual so that statistical uncertainties were large.     

Bayesian model selection validates a biokinetic model for zirconium processing in humans

ABSTRACT: BACKGROUND: In radiation protection, biokinetic models for zirconium processing are of crucial importance in dose estimation and further risk analysis for humans exposed to this radioactive substance. They provide limiting values of detrimental effects and build the basis for applications in internal dosimetry, the prediction for radioactive zirconium retention in various organs as well as retrospective dosimetry. Multi-compartmental models are the tool of choice for simulating the processing of zirconium. Although easily interpretable, determining the exact compartment structure and interaction mechanisms is generally daunting. In the context of observing the dynamics of multiple compartments, Bayesian methods provide efficient tools for model inference and selection. RESULTS: We are the first to apply a Markov chain Monte Carlo approach to compute Bayes factors for the evaluation of two competing models for zirconium processing in the human body after ingestion. Based on in vivo measurements of human plasma and urine levels we were able to show that a recently published model is superior to the standard model of the International Commission on Radiological Protection. The Bayes factors were estimated by means of the numerically stable thermodynamic integration in combination with a recently developed copula based Metropolis-Hastings sampler. CONCLUSIONS: In contrast to the standard model the novel model predicts lower accretion of zirconium in bones. This results in lower levels of noxious doses for exposed individuals. Moreover, the Bayesian approach allows for retrospective dose assessment, including credible intervals for the initially ingested zirconium, in a significantly more reliable fashion than previously possible. All methods presented here are readily applicable to many modeling tasks in systems biology.