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PubMed1992

Microdosimetric considerations of effects of heavy ions on E. coli K-12 mutants.

The inactivation cross sections of E. coli K-12 recombination-deficient mutants, JC1553 (recA) and AB2470 (recB), for several MeV/u alpha-particles and N ions have been successfully analyzed by Katz's target theory in which radiosensitivity parameter E0 is assumed to be LET independent and equal to D37 for gamma-rays. For E. coli K-12 wild type, AB1157 (rec+, uvr+), however, it is impossible to interpret the inactivation cross section data by an LET-independent E0-value. In the latter case, as in the case of B. subtilis spore, it is necessary to assume that the radiosensitivity of the target for the core of a heavy ion is higher than that for delta-electrons. As well as Waligorski, Hamm and Katz's dose, the dose around the trajectory of an ion based on Tabata and Ito's energy deposition algorithm for electrons has been used in the course of analysis.

Algorithms↗

PubMed1988

Spatial and temporal distribution of energy.

Studies of the spatial and temporal distribution of microscopic radiation doses lead to potentially important questions regarding conventional approaches to radiation protection. The short ranges of alpha-particle and Auger-electron emissions from radionuclides lead to uncertainties in assessing their hazards. The conventional extrapolations from intermediate doses to low doses and dose rates are questioned by observed dose-rate effects in the so-called "initial slope," by the total lack of data for single tracks in cells and by the possibility of multiple-cell effects. At all subcellular levels, even down to DNA, high linear-energy-transfer (LET) radiations can produce unique initial damage, different from that possible with low-LET radiations, and therefore may even, in principle, produce unique final biological effects. This questions simple extrapolations from low- to high-LET radiations and the application of universal quality factors to diverse effects. Further understanding of these questions could lead, in future, to substantial increases or decreases in estimations of risk.

Alpha Particles↗

PubMed1994

Interleukin 7-dependent B lymphocyte precursor cells are ultrasensitive to apoptosis.

We have compared the sensitivity of clonogenic interleukin 7 (IL-7)-dependent murine B cell precursors with that of clonogenic mature B cells and myeloid precursors to alpha-particles from plutonium-238 and X radiation. All three populations are relatively sensitive, but B cell precursors are ultrasensitive. This differential sensitivity is also observed with corticosteroid, etoposide, and cisplatin, all apoptosis-inducing drugs used in the treatment of leukemia and other cancers. Further, we show that x-rays and drugs induce the bulk of the B cell precursor population to undergo rapid apoptosis, despite the continued presence of IL-7. B cell precursors were found to express very low levels of BCL-2 protein compared with mature splenic B cells and their resistance to x-rays and corticosteroid could be enhanced by expression of a BCL-2 transgene. These data have important implications for normal lymphopoiesis and for the behavior of leukemic lymphoid precursor cells.

Alpha Particles↗

PubMed2004

The radiation-induced bystander effect: evidence and significance.

A multitude of biological effects observed over the past two decades in various in vivo and in vitro cell culture experiments have indicated that low dose/low fluence ionizing radiation has significantly different biological responses than high dose radiation. Exposure of cell populations to very low fluences of alpha-particles or incorporated radionuclides results in significant biological effects occurring in both the irradiated and nonirradiated cells in the population. Cells recipient of growth medium from irradiated cultures can also respond to the radiation exposure. This phenomenon, termed the 'bystander response', has been postulated to impact both the estimation of risks of exposure to ionizing radiation and radiotherapy. Amplification of radiation-induced cytotoxic and genotoxic effects by the bystander effect is in contrast to the observations of adaptive responses, which are generally induced following exposure to low dose, low linear energy transfer radiation and which tend to attenuate radiation-induced damage. In this article, the evidence for existence of radiation-induced bystander effects and our current knowledge of the biochemical and molecular events involved in mediating these effects are described. Potential similarities between factors that mediate the radiation-induced bystander and adaptive responses are highlighted.

Alpha Particles↗

PubMed1984

Comparison of the carcinogenicity of radium and bone-seeking actinides.

The relative effectiveness of nine bone-seeking radionuclides with their progeny for the production of malignant skeletal tumors (mostly osteogenic sarcoma), principally by chronic alpha-particle irradiation, is examined with available data obtained from lifetime studies at three laboratories of pure-bred beagles exposed to graded dosages in controlled experiments. The lifetime tumor dose-rate/time-response relationships observed in beagles injected with 226Ra at the University of California at Davis, in which 123 cases of bone cancer (98% osteosarcoma) have been observed for dose rates between 0.05 and 20 rad/day, provide the basis for comparing the induction of bone cancer by the other radionuclides. All nine radionuclide studies were found to demonstrate with high precision (sigma g less than 1.2) a three-dimensional lognormal response relationship represented in two dimensions by the equation of the time to death from bone cancer t = KD-s, where t is the elapsed time to death, D is the average skeletal dose rate, K is a parameter characteristic of the radionuclide, risk level and exposure details, and S observed to be 0.29 (0.01 SE) and suggested to be exactly one-third for all the nine radionuclides. The results show the relative biological effectiveness (RBE) for bone-cancer induction potency with respect to radiation exposure from 226Ra to be 3.0 for 228Ra , 6.4 for 241Am, 6.6 for 249Cf , 252Cf and 253Es , 9.0 for 239Pu, 10.7 for 228Th , and 15.5 for 238Pu. The observed RBE values are interpreted in terms of the relative exposure of sensitive cells of the skeleton since they all involve primarily alpha irradiation. Scaling to people is accomplished using a response ratio (RR) of 3.6 with respect to beagles.

Actinoid Series Elements↗

PubMed1989

Determining the charged fractions of 218Po and 214Pb using an environmental gamma-ray and Rn detector.

The rate of 218Po and 214Pb atoms collected electrostatically inside an environmental gamma-ray and 222Rn detector (EGARD) was measured. These measurements were used to directly infer the charged fraction of 218Po and to calculate the charged fraction of 214Pb. Thirty-two percent of the 218Po was collected electrostatically using approximately -1500 V on a 2.54 cm diameter Mylar covered disc inside a vented A1 EGARD of 1 L volume. About 91% of the 214Pb is collected electrostatically under the same conditions. The measurements were performed in a calibrated 222Rn test chamber at the Environmental Measurements Laboratory (EML) using the Thomas alpha-counting method with 222Rn concentrations averaging about 4300 Bq m-3. The atomic collection rates were used with other measured quantities to calculate the thermoluminescent dosimeter (TLD) signal acquired from EGARD for exposure to 1 Bq m-3 of 222Rn. The calculations account for 222Rn progeny collection using a Teflon electret and alpha and beta detection using TLDs inside EGARD. The measured quantities include the energies of 218Po and 214Po alpha-particles degraded by passage through the 25 microns thick electret. The TLD responses to these alpha- and beta-particles with an average energy approaching that obtained from the combined spectra of 214Pb and 214Bi were also measured. The calculated calibration factor is within 30% of the value obtained by exposing EGARD to a known concentration of 222Rn. This result supports our charged fraction estimates for 218Po and 214Pb.

Air Pollutants↗

PubMed2002

Heavy ion-induced DNA double-strand breaks in yeast.

Induction of DSBs in the diploid yeast, Saccharomyces cerevisiae, was measured by pulsed-field gel electrophoresis (PFGE) after the cells had been exposed on membrane filters to a variety of energetic heavy ions with values of linear energy transfer (LET) ranging from about 2 to 11,500 keV/microm, (241)Am alpha particles, and 80 keV X rays. After irradiation, the cells were lysed, and the chromosomes were separated by PFGE. The gels were stained with ethidium bromide, placed on a UV transilluminator, and analyzed using a computer-coupled camera. The fluorescence intensities of the larger bands were found to decrease exponentially with dose or particle fluence. The slope of this line corresponds to the cross section for at least one double-strand break (DSB), but closely spaced multiple breaks cannot be discriminated. Based on the known size of the native DNA molecules, breakage cross sections per base pair were calculated. They increased with LET until they reached a transient plateau value of about 6 x 10(-7) microm(2) at about 300-2000 keV/microm; they then rose for the higher LETs, probably reflecting the influence of delta electrons. The relative biological effectiveness for DNA breakage displays a maximum of about 2.5 around 100-200 keV/microm and falls below unity for LET values above 10(3) keV/microm. For these yeast cells, comparison of the derived breakage cross sections with the corresponding cross section for inactivation derived from the terminal slope of the survival curves shows a strong linear relationship between these cross sections, extending over several orders of magnitude.

Alpha Particles↗

PubMed2005

Liquid holding recovery kinetics in wild-type and radiosensitive mutants of the yeast Saccharomyces exposed to low- and high-LET radiations.

Three wild-type diploid yeast strains Saccharomyces ellipsoideus and Saccharomyces cerevisiae and five radiosensitive mutants of S. cerevisiae in the diploid state were irradiated with gamma-rays from 60Co and alpha-particles from 239Pu in the stationary phase of growth. Survival curves and the kinetics of the liquid holding recovery were measured. It was shown that the irreversible component was enhanced for the densely ionizing radiation in comparison to the low-LET radiation while the probability of the recovery was identical for both the low- and high-LET radiations for all the strains investigated. It means that the recovery process itself is not damaged after densely ionizing radiation and the enhanced RBE of the high-LET radiation may be caused by the increased yield of the irreversible damage. A parent diploid strain and all its radiosensitive mutants showed the same probability for recovery from radiation damage. Thus, the mechanism of the enhanced radiosensitivity of the mutant cells might not be related to the damage of the repair systems themselves but with the production of some kind of radiation damage from which cells are incapable to recover.

Adenosine Triphosphatases↗

PubMed1999

p53 mutations in tumors derived from irradiated human thyroid epithelial cells.

A non-tumorigenic human thyroid epithelial cell line (HTori-3) has been transformed into tumorigenic cells by exposure in vitro to alpha particles or gamma-radiation. These transformants were tumorigenic in athymic nude mice and tumors were transplantable into other nude mice. To further characterize processes involved in neoplastic progression, the tumor cell lines derived from these radiation-induced primary tumors were screened for mutations in the p53 tumor suppressor gene. p53 mutation was detected by single-strand conformation polymorphism (SSCP) analysis of exons 5 to 8 inclusive. Mutations detected by SSCP analysis were confirmed by sequencing. Mutations were detected in all four exons analysed, although there was no correlation between dose, LET or mutation position or frequency. Mutations in p53 exons 6 and 7 have been reported in the childhood papillary thyroid carcinomas in Belarus presumably as a result of radioiodine fall-out. Similarly here, p53 mutations are induced experimentally during the development of human thyroid tumors generated by irradiation of a human thyroid epithelial cell line in vitro.

Alpha Particles↗

PubMed2001

The bystander effect in C3H 10T cells and radon-induced lung cancer.

Little, M. P. and Wakeford, R. The Bystander Effect in C3H 10T(1/2) Cells and Radon-Induced Lung Cancer. Radiat. Res. 156, 695-699 (2001).Bystander effects, whereby cells that are not directly exposed to radiation exhibit adverse biological effects, have been observed in a number of experimental systems, including C3H 10T(1/2) cells exposed to alpha-particle radiation. The bystander effect implies that risks from exposure to low doses of radiation obtained by linear extrapolation from data for high-dose exposures might be substantial underestimates. The best estimate of the ratio of the lung cancer risk among persons exposed to low (residential) doses of radon daughters to that among persons (underground miners) exposed to high doses of radon daughters is in the range of 2.4-4.0, with an upper 95% confidence limit of about 14. Assuming that the bystander effect observed in the in vitro C3H 10T(1/2) cell system applies to human lung cells in vivo, these epidemiological data imply that the central estimate of the number of neighboring cells that can contribute to the bystander effect is between 0 and 1, with an upper 95% confidence limit of about 7. As a consequence, the bystander effect observed in the experimental C3H 10T(1/2) cell system probably does not play a large part in the process of radon-induced lung carcinogenesis in humans.

Alpha Particles↗

PubMed1983

Sites of incidence of osteosarcoma in the long bones of man and the beagle.

Information has been assembled on the frequency of occurrence of osteosarcomas in the long bones of groups of beagles irradiated by alpha particles from bone-seeking radionuclides. These data are compared with measured trabecular surface areas in the long bones of a beagle, determined at the Bone Dosimetry Research Laboratory, Cookridge Hospital, Leeds. It is shown that, as in the human case, the percentage tumour occurrence in a long bone (or in separate thirds of a long bone) was linearly related to the corresponding trabecular surface area with a high value of the correlation coefficient. For single injections of 226Ra the low percentage tumour occurrence in the mid-thirds of the beagle bones was close to that found in man. For the surface-seeking radionuclides (239Pu, 228Th) and for 228Ra much higher percentages of tumours were found in the mid-thirds of the dog bones than for 226Ra injection. When, however, 226Ra was given in eight fractions with 14 days between each injection, a very high tumour incidence was found in the mid-thirds of the beagle long bones. These results are discussed in the light of dosimetric and other relevant factors.

Alpha Particles↗

PubMed1991

[Boron neutron capture therapy of human gastric cancer by boron-containing immunoliposomes under thermal neutron irradiation].

Boron neutron capture therapy (BNCT) is based on the nuclear reaction yielding high LET Li-7 and alpha particles when boron-10 is irradiated with thermal neutrons. (Et4N)2(10)B10H10 was entrapped in 40 nm liposomes coating the monoclonal antibody, MGb 2, against human gastric cancer. There were 1.4 x 10(4) 10B atoms encapsulated and 20 molecules of MGb 2 incorporated per liposomes ELISA indicated that the immunoreactivity of antibodies on liposomes retained 80%. Preferred binding to human gastric cancer cell line SGC-7901 was observed as many as 15.1 x 10(9) 10B atoms/tumor cell, 38-fold more than that to normal human embryonic lung cell line SL 7. The fluorescent immunoliposome-stained tumor cells showed membrane-fluorescence while SL 7 cells showed no obvious fluorescence. Irradiated with thermal neutrons (0.025 eV, 3.12 x 10(11)n/cm2, gamma-ray 0.84 Gy), 10B-containing immunoliposomes pretreated SGC-7901 cells survived 27%, significantly lower than non-irradiated cells or non-pretreated cells with irradiation (P less than 0.001). The results demonstrated that boron-containing immunoliposomes could bind selectively and deliver sufficient amount of boron-10 to the target tumor cells.

Alpha Particles↗

PubMed1985

Lethal, potentially lethal, and nonlethal damage induction by heavy ions in cultured human cells.

In the fields of high-LET radiotherapy and space radiation safety it is important to know the relative probabilities with which a cell whose nucleus is struck by a heavy ion will be damaged or killed. Experiments were performed in which synchronous cultured human T-1 cells (presumptive HeLa) were irradiated with natural alpha particles of energy approximately 3.5 MeV at various times after mitotic selection up to the middle of S phase. Nuclear-area histograms were determined as a function of time after mitosis under conditions identical to those used for irradiation. The efficiency with which one particle passing through the nucleus killed a cell was found to be 0.14-0.20. This value was extrapolated to experimental cell survival data obtained when asynchronous cultured human cells were irradiated with He, Li, B, C, N, O, Ne, Ar ions of energy 6.58 or 5.5 MeV/amu, and the cell killing efficiency was found to be in the broad range of 0.5-1.0 under single-hit conditions. Similarly irradiated cells were examined for colony-size distribution by an image analysis technique, and it was found that the loss of large colonies was dose and LET-dependent in a systematic way. Dose-response data suggest two predominant subpopulations, resistant and sensitive cells, and it appears that the sensitive population is affected by single-hit kinetics. The single-hit coefficient for the induction of inherited slow growth varied with LET in a similar way to that for survival. The action cross section for this form of heritable damage appears to be comparable to the geometric cross section of the cell nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha Particles↗

PubMed1995

Measurements of 220Rn emanation from rocks.

Alpha-particle and gamma-ray measurements are employed to determine the individual emanation and production rates associated with the thorium radioactive series for thirty-seven rock specimens of approximately 200 cm3 individual volume representing igneous, sedimentary, and metamorphic types. These results are combined to establish 220Rn emanating powers for each of these specimens, and a wide range of values is observed. The generally large 220Rn emanation observed for these specimens strongly indicates that non-tortuous diffusion paths are commonly present in the associated structures, which gives more evidence for the existence of well-connected pore networks at the nanometer level in many of the specimens studied. While the results are qualitatively explainable, they are not predictable in terms of the current macroscopic observables. Since 220Rn and 222Rn emanation rates from rock specimens have previously been found to be comparable in magnitude, the relatively fast determination of 220Rn emanation rates described herein (measurements involving 1-h duration) is in reasonable probability indicative of a comparable 222Rn emanation rate: The employment of 220Rn as a convenient screening tool for potentially high 222Rn emanation sources is indicated.

Alpha Particles↗

PubMed2000

Delivery of the alpha-emitting radioisotope bismuth-213 to solid tumors via single-chain Fv and diabody molecules.

Intravenously administered anti-tumor single-chain Fv (scFv) and diabody molecules exhibit rapid clearance kinetics and accumulation in tumors that express their cognate antigen. In an attempt to fit the rate of isotope decay to the timing of delivery and duration of tumor retention, anti-HER2/neu CHX-A" DTPA-C6.5K-A scFv and diabody conjugates were labeled with the alpha-particle emitter (213)Bi (t(1/2) = 47 min). Radioimmunotherapy studies employing 0.64, 0.35, or 0.15 microCi of (213)Bi-labeled C6.5K-A diabody or 1.1, 0.6, or 0. 3 microCi of (213)Bi-labeled C6.5K-A scFv were performed in nude mice bearing early, established SK-OV-3 tumors. Only the 0.3 microCi dose of (213)Bi-labeled C6.5K-A scFv resulted in both acceptable toxicity and a reduction in tumor growth rate. The specificity of the anti-tumor effects was determined by comparing the efficacy of treatment with 0.3 and 0.15 microCi doses of (213)Bi-labeled C6.5K-A scFv and (213)Bi-labeled NM3E2 (an irrelevant scFv) in nude mice bearing large established tumors. The 0.3 microCi dose of (213)Bi on both the C6.5K-A and NM3E2 scFvs resulted in similar anti-tumor effects (p = 0.46) indicating that antigen-specific targeting was not a factor. This suggests that the physical half-life of (213)Bi may be too brief to be effectively paired with systemically-administered diabody or scFv molecules.

Alpha Particles↗

PubMed2000

Localization of tumor suppressor gene candidates by cytogenetic and short tandem repeat analyses in tumorigenic human bronchial epithelial cells.

Radon exposure is associated with increased risk for bronchogenic carcinoma. Mutagenesis analyses have revealed that radon induces mostly multi-locus chromosome deletions. Based on these findings, it was hypothesized that deletion analysis of multiple radon-induced malignant transformants would reveal common mutations in chromosomal regions containing tumor suppressor genes responsible for malignant transformation. This hypothesis was supported by a previous study in which tumorigenic derivatives of the human papillomavirus 18-immortalized human bronchial epithelial cell line BEP2D were established following irradiation with 30 cGy of high linear energy transfer radon-simulated alpha-particles. Herein, we describe the analyses of 10 additional tumorigenic derivative cell lines resulting from the irradiation of five additional independent BEP2D populations. The new transformants have common cytogenetic changes, including the loss of chromosome (ch)Y, one of three copies of ch8, one of two copies of ch11p15-pter and one of three copies of ch14. These changes are the same as those reported previously. Analysis of PCR-amplified short tandem repeats of informative loci confirmed the loss of heterozygosity (LOH) at 12 loci spanning the length of ch8 in cell lines from four of the total of eight irradiation treatments to date and the loss of chY in all cell lines (8 of 8). LOH analysis with a total of 17 informative loci confirmed loss on ch14 in transformants from seven of eight irradiation treatments and indicated a 0.5-1.7 cM region of common involvement centered around locus D14S306. No LOH was detected at any of the informative loci on ch11. The overall results support our stated hypothesis. Further studies are currently in progress to determine whether the ch8 and ch14 regions contain genes with tumor suppressor function in bronchial epithelial cells.

Alpha Particles↗

PubMed1986

Mutational alterations induced in yeast by ionizing radiation.

The cycl-9 ochre (UAA) mutant and the cycl-179 amber (UAG) mutant of the yeast Saccharomyces cerevisiae were reverted with X-rays and alpha-particles. The amino acid sequence changes of iso-1-cytochromes c from 36 of the intragenic revertants were determined by amino acid analysis and peptide mapping, aided by partial amino acid sequencing of 4 revertants. In addition, the DNA segments encompassing 3 unusual mutations with complex changes were cloned and sequenced. This study and previous studies of 16 other revertants of cycl-9 and cycl-179 revealed that ionizing radiation primarily induces single base-pair substitutions; 47 of the 52 revertants arose by transversions and transitions without any apparent preference. However, the A X T----T X A substitution at the first base pair for the cycl-179 UAG codon, leading to the normal protein, was not detected, nor was it found previously in 32 revertants of cycl-179 obtained spontaneously or induced with various other mutagens; apparently, there is a prohibition of certain base-pair substitutions at certain sites in DNA. In addition, 5 of the 52 revertants arose by multiple changes within a short region of 11 base pairs. These consisted of the deletion of 6 base pairs, the substitution of 3 base pairs, and 3 different kinds of substitutions of two base pairs. Compared to other mutagens previously tested with the cycl system, ionizing radiation produces the most random types of base-pair substitutions.

Alpha Particles↗

PubMed1991

Neoplastic diseases induced by chronic alpha-irradiation--epidemiological, biophysical and clinical results of the German Thorotrast Study.

The intravascular injection of the formerly used contrast medium Thorotrast--a colloidal suspension of thorium-dioxide--causes a chronic exposure to alpha-particles especially in the organs of the reticuloendothelial system. The German Thorotrast Study comprises 2326 Thorotrast patients and 1890 contemporary matched patients in the control group to be evaluated. 899 Thorotrast patients and 662 controls had clinical and biophysical follow-up examinations every two years since 1969. The recent most important results of the study are: A high excess rate of primary liver cancer (410/2) was observed beginning after the 15th year of exposure. 31% of the tumors are combined with cirrhosis and 6% with other neoplastic diseases. A clear (mean) dose rate effect relationship exists. The tumor frequency depends on the time of exposure or the cumulative dose to the liver respectively and not primarily on the age at injection. The lowest cumulative doses at 10 years before diagnosis of liver cancer were about 2 Gy. Risk estimates for liver cancer after 40 years of exposure are 500 malignant tumors per 10(4) person-Gy for men and 300 for women. A high excess rate exists also for leukaemias (excluding CLL) starting already 5 years after Thorotrast injection (39/4). The lowest cumulative doses to the red bone marrow at time of death were about 0.5 Gy. According to the present result, an excess rate can be expected for carcinomas of the extrahepatic bile ducts, pancreas, oesophagus, larynx, as well as Non-Hodgkin's lymphomas, bone sarcomas, plasmacytomas and mesotheliomas.

Adolescent↗