Chromosome aberration frequency and radiation dose to lymphocytes by alpha-particles from internal deposit of Thorotrast

Summary Frequencies of chromosome aberrations in peripheral blood lymphocytes from 63 Thorotrast patients were analysed basing on the age distribution of lymphocytes. The frequency and distribution of chromosome aberrations among lymphocytes are best explained if we assume that the lymphocytes are renewed as an exponential function of time and spend most of their lifetime in the distributive pool where, while exchange of lymphocytes is taking place, the lymphocytes are hit by-particles from Thorotrast aggregates resulting in the formation of chromosome aberrations and killing at specific rates per hit. The model predicts that the aberration frequency is rather insensitive to the fluence rate because of modulation by cell killing by hit. Fitting the observed data to the model showed that approximately 0.8 dicentrics and rings were produced by a single path of-particle and average fluence rate to lymphocytes in a group of patients with the highest aberration frequency was estimated to be about 1.5 hits or 87 rad/lymphocyte/year.     

Effect of low dose rate radiation on cell growth kinetics.

Experimental determinations were made of cell number as a function of time for two strains of L5178Y mammalian cells maintained continuously in various environments of radiation. One strain possessed a shoulder in its dose response curve whereas the other did not. Neither strain showed any significant difference in growth rate for interdivision doses on the order of the median lethal dose or less delivered continuously at a low dose rate or pulsed every 4 h at a high instantaneous dose rate. It was also shown that large numbers of dead cells have little effect on growth rate and that these dead cells last as discrete entities for many days. A simple theory of growth rate in the presence of radiation is presented, and the agreement with the observations implies that there is no effect of any sublethal low dose rate radiation received in one generation on the growth rate or radiation sensitivity of the succeeding generation. Further analysis of the data also showed that for the no-shoulder cells at 37 degrees C, tritiated water had a relative biological effect close to unity for cell sterilization.     

Cell kinetics and radiation biology

The cell cycle, the growth fraction and cell loss influence the response of cells to radiation in many ways. The variation in radiosensitivity around the cell cycle, and the extent of radiation-induced delay in cell cycle progression have both been clearly demonstrated in vitro. This translates into a variable time of expression of radiation injury in different normal tissues, ranging from a few days in intestine to weeks, months or even years in slowly proliferating tissues like lung, kidney, bladder and spinal cord. The radiosensitivity of tumours, to single doses, is dominated by hypoxic cells which arise from the imbalance between tumour cell production and the proliferation and branching of the blood vessels needed to bring oxygen and other nutrients to each cell. The response to fractionated radiation schedules is also influenced by the cell kinetic parameters of the cells comprising each tissue or tumour. This is described in terms of repair, redistribution, reoxygenation and repopulation. Slowly cycling cells show much more curved underlying cell survival curves, leading to more dramatic changes with fractionation, dose rate or l.e.t. Rapidly cycling cells redistribute around the cell cycle when the cells in sensitive phases have been killed, and experience less mitotic delay than slowly proliferating cells. Reoxygenation seems more effective in tumours with rapidly cycling cells and high natural cell loss rates. Compensatory repopulation within a treatment schedule may spare skin and mucosa but does not spare slowly proliferating tissues. Furthermore, tumour cell proliferation during fractionated radiotherapy may be an important factor limiting the overall success of treatment.     

Biodosimetry and assessment of radiation dose

Aim

When investigating radiation accidents, it is very important to determine the exposition dose to the individuals. In the case of exposures over 1 Gy, clinicians may expect deterministic effects arising the following weeks and months, in these cases dose estimation will help physicians in the planning of therapy. Nevertheless, for doses below 1 Gy, biodosimetry data are important due to the risk of developing late stochastic effects. Finally, some accidental overexposures are lack of physical measurements and the only way of quantifying dose is by biological dosimetry.

Background

The analysis of chromosomal aberrations by different techniques is the most developed method of quantifying dose to individuals exposed to ionising radiations.^1,2 Furthermore, the analysis of dicentric chromosomes observed in metaphases from peripheral lymphocytes is the routine technique used in case of acute exposures to assess radiation doses.

Materials and methods

Solid stain of chromosomes is used to determine dicentric yields for dose estimation. Fluorescence in situ hybridization (FISH) for translocations analysis is used when delayed sampling or suspected chronically irradiation dose assessment. Recommendations in technical considerations are based mainly in the IAEA Technical Report No. 405.²

Results

Experience in biological dosimetry at Gregorio Marañón General Hospital is described, including own calibration curves used for dose estimation, background studies and real cases of overexposition.

Conclusion

Dose assessment by biological dosimeters requires a large previous standardization work and a continuous update. Individual dose assessment involves high qualification professionals and its long time consuming, therefore requires specific Centres. For large mass casualties cooperation among specialized Institutions is needed.     

The influence of radiation dose on the magnitude and kinetics of reoxygenation in a C3H mammary carcinoma

The variation in hypoxic fraction as a function of time after various priming doses of radiation has been investigated in a C3H mouse mammary carcinoma in situ. The hypoxic fraction was calculated from data for local tumor control. Untreated tumors were found to contain 4.8% radiobiologically hypoxic cells. Within minutes after a priming dose of 20 Gy given in air, the hypoxic fraction increased to a value not significantly different from 100%. After 4 h, reoxygenation was complete (hypoxic fraction 1.3%), and the hypoxic fraction stabilized at a level significantly below the untreated value. Following a priming dose of 40 Gy the reoxygenation pattern was different: The hypoxic fraction stayed above the pretreatment value for 4 h, and pronounced reoxygenation occurred after 12 h (hypoxic fraction 0.4%). At longer time intervals the hypoxic fraction again increased to--and slightly above--the oxygenation level of untreated tumors. The present findings show that reoxygenation in solid tumors is a function of radiation dose, and the data suggest that mechanisms other than a decrease in tumor cell O2 consumption are involved in tumor reoxygenation.     

Undulating kinetics factors in radiation mutagenesis]

Air-dry Crepis capillaris seeds, soaked for 14 and 20 hours, were dried to the moisture content of 1,1% with the following gamma-irradiation at a dose of 1500 r. Irradiated seeds were stored in the state of identical moisture for 38 days. The drying of three groups of seeds to moisture content of 1,1% provided their identical initial radiosensitivity. In the course of the storage mutability of treated seeds significantly increased as compared with the yield of mutations in non-stored seeds, and revealed undulating kinetics that involved all types of arising chromosome and chromatid rearrangements. The character of undulating kinetics is due to a correlation between functional state of nucleus (early G1, late G1, S) and water content in seeds.     

Wound trauma alters ionizing radiation dose assessment

ABSTRACT: BACKGROUND: Wounding following whole-body gamma-irradiation (radiation combined injury, RCI) increases mortality. Wounding-induced increases in radiation mortality are triggered by sustained activation of inducible nitric oxide synthase pathways, persistent alteration of cytokine homeostasis, and increased susceptibility to bacterial infection. Among these factors, cytokines along with other biomarkers have been adopted for biodosimetric evaluation and assessment of radiation dose and injury. Therefore, wounding could complicate biodosimetric assessments. RESULTS: In this report, such confounding effects were addressed. Mice were given 60Co gamma-photon radiation followed by skin wounding. Wound trauma exacerbated radiation-induced mortality, body-weight loss, and wound healing. Analyses of DNA damage in bone-marrow cells and peripheral blood mononuclear cells (PBMCs), changes in hematology and cytokine profiles, and fundamental clinical signs were evaluated. Early biomarkers (1 d after RCI) vs. irradiation alone included significant decreases in survivin expression in bone marrow cells, enhanced increases in gamma-H2AX formation in Lin+ bone marrow cells, enhanced increases in IL-1beta, IL-6, IL-8, and G-CSF concentrations in blood, and concomitant decreases in gamma-H2AX formation in PBMCs and decreases in numbers of splenocytes, lymphocytes, and neutrophils. Intermediate biomarkers (7 - 10 d after RCI) included continuously decreased gamma-H2AX formation in PBMC and enhanced increases in IL-1beta, IL-6, IL-8, and G-CSF concentrations in blood. The clinical signs evaluated after RCI were increased water consumption, decreased body weight, and decreased wound healing rate and survival rate. Late clinical signs (30 d after RCI) included poor survival and wound healing. CONCLUSION: Results suggest that confounding factors such as wounding alters ionizing radiation dose assessment and agents inhibiting these responses may prove therapeutic for radiation combined injury and reduce related mortality.     

Ultrasound-detected thyroid nodule prevalence and radiation dose from fallout

Settlements near the Semipalatinsk Test Site (SNTS) in northeastern Kazakhstan were exposed to radioactive fallout during 1949-1962. Thyroid disease prevalence among 2994 residents of eight villages was ascertained by ultrasound screening. Malignancy was determined by cytopathology. Individual thyroid doses from external and internal radiation sources were reconstructed from fallout deposition patterns, residential histories and diet, including childhood milk consumption. Point estimates of individual external and internal dose averaged 0.04 Gy (range 0-0.65) and 0.31 Gy (0-9.6), respectively, with a Pearson correlation coefficient of 0.46. Ultrasound-detected thyroid nodule prevalence was 18% and 39% among males and females, respectively. It was significantly and independently associated with both external and internal dose, the main study finding. The estimated relative biological effectiveness of internal compared to external radiation dose was 0.33, with 95% confidence bounds of 0.09-3.11. Prevalence of papillary cancer was 0.9% and was not significantly associated with radiation dose. In terms of excess relative risk per unit dose, our dose-response findings for nodule prevalence are comparable to those from populations exposed to medical X rays and to acute radiation from the Hiroshima and Nagasaki atomic bombings.     

Measurement of three-dimensional radiation dose distributions using MRI

Recent investigations have shown that nuclear magnetic resonance (NMR) can be used in conjunction with a suitable chemical dosimeter to estimate the dose from ionizing radiation (Gore et al., Phys Med. Biol. 29, 1189-1197, 1984). Based on this fact it was proposed that spatial dose distributions can be measured in gels infused with the chemical dosimeter using NMR imaging. There have been few such attempts and they provided only qualitative results. In this paper, we report results demonstrating the feasibility of obtaining quantitative dose distribution measurements by this technique. It is shown that quantitative dose distribution measurements necessitate the calculation of relaxation rate maps. We have determined that the spin-spin relaxation rate is a more sensitive parameter than the spin-lattice relaxation rate. It is also demonstrated that the addition of chemical sensitizers could improve the dose sensitivity of the measured NMR parameters. The two features characterizing a photon beam, depth-dose relationship, and beam profile as measured by this technique are in good agreement with the measurements using conventional methods, ionization chambers, and film dosimetry.     

Topografia delle cellule di Kupffer e Thorotrast

Zusammenfassung Verf. erläutert einen noch nicht geschilderten morphologischen Befund. Während der bei Kaninchen mit Thorotrast ausgeführten Speicherungsuntersuchungen des retikulär-endothelialen Systems hat er beobachten können, daß die Kupffer-Sternzellen bei seit langer Zeit behandelten Tieren aus ihrem normalen Sitz im hepatischen Acinus gegen seine zentrale Ader gewandert sind, indem sie um dieselbe einen Umkreis von mit Thorotrast belasteten Kupffer- Sternzellen bildeten und indem sie auch in das Leberaderblut eindrangen. Dagegen findet man bei seit kurzer Zeit behandelten Tieren die mit Thorotrast belasteten Zellen im Acinus, wie gewöhnlich, diffus verteilt. Verf. erörtert diese Befunde im Zusammenhang mit der Bedeutung und dem Wesen der KupfferSternzellen.     

Hepatoma Induced by Thorium Dioxide (Thorotrast)

A case of hepatoma induced by thorium dioxide (Thorotrast) is reported. The literature concerning neoplasia associated with this agent is reviewed, with emphasis on the long latent period before the development of these tumours and the equally long latent period which preceded the recognition of their iatrogenic nature.In particular, this report is intended to illustrate the diagnosis of such tumours on radiological and histological findings, provided that one is aware of their existence and familiar with the distribution and appearance of thorium dioxide deposits in the tissues. Such a diagnosis can be made without a history of thorium dioxide administration, which often may not be available.