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PubMed1990

The combined effects of alpha-particles and X-rays on cell killing and micronuclei induction in lung epithelial cells.

Understanding how cellular damage produced by high-linear energy transfer (LET) radiation interacts with that produced by low-LET is important both in radiation therapy and in evaluating risk. To study such interactions, rat lung epithelial cells (LEC) were grown on Mylar films and exposed to both X-rays and alpha-particles, separately or simultaneously. Cell killing, and the numbers of binucleated cells and micronuclei, were measured as indicators of damage. X-rays and alpha-particles given separately caused dose-related increases in cell cycle time, with alpha-particles producing greater mitotic delay than X-rays. Damage from alpha-particles and X-rays given simultaneously did not interact to alter further the cell cycle. Cell survival data following exposure to X-rays and alpha-particles, combined or individually, were fitted by linear-quadratic models. Survival curves following exposure to alpha-particles only, or to 1.0 Gy alpha-particles plus graded X-ray doses, were adequately described using only the linear (alpha) term of a linear-quadratic model with alpha coefficients of 0.9 +/- 0.04 and 1.03 +/- 0.18 Gy-1, respectively. Survival following exposure to X-rays only or to 0.06 Gy alpha-particles combined with X-rays was best fitted using both alpha and beta terms of the linear-quadratic model (0.12 +/- 0.03)D + (0.007 +/- 0.002)D2 and (0.57 +/- 0.08)D + (0.3 +/- 0.02)D2, respectively. The numbers of micronuclei produced by exposure to alpha-particles or X-rays alone increased linearly with dose, with slopes of 0.48 +/- 0.07 and 0.19 +/- 0.05 micronuclei/binucleated cell per Gy for alpha and X-rays, respectively. Simultaneous exposure to graded levels of X-rays and a constant alpha dose of either 1.0 or 0.06 Gy increased micronuclei frequency, with a slope of 0.74 +/- 0.05 or 0.58 +/- 0.04 micronuclei/binucleated cell per Gy, respectively. These slopes are similar to that produced by alpha-particles alone. These studies demonstrated that both cell killing and the induction of micronuclei were increased by combined exposures compared with that predicted for separate exposures.

Alpha Particles↗

PubMed1994

Initial damage in human interphase chromosomes from alpha particles with linear energy transfers relevant to radon exposure.

To determine the efficiency at which alpha particles at LETs chosen to simulate exposure to radon progeny break chromosomes, the premature chromosome condensation technique was used to measure breaks soon after irradiation. Noncycling human fibroblasts were irradiated with graded doses of monoenergetic alpha particles accelerated to produce LETs of 90, 120, 150, 180 and 200 keV/microns at the midpoint of the cell nuclei. Premature chromosome condensation was initiated immediately after irradiation and cells were scored for the total number of prematurely condensed chromosomes and fragments per cell. Similar experiments were conducted with 250 kVp X rays for comparison. Irradiation with alpha particles produced 8.6 to 13.1 excess fragments per gray, while X rays produced 5.8 excess fragments, resulting in RBEs around 2. Calculations of the number of breaks produced on average by a single particle traversal of a cell nucleus indicated that at the LETs tested more than one break (1.5-2.8) was produced by each traversal, the maximum being that produced by 180 keV/microns alpha particles. When chromosome aberrations are scored at metaphase after high-LET irradiation, RBEs considerably greater than those recorded here (approximately 2) have been reported. These results showing relatively small differences in initial break levels for alpha particles in the LET range of the radon progeny relative to X rays indicate that the greater aberration frequencies are not due principally to an increase in breakage efficiency, but interactions between breaks along the same particle track are important.

Alpha Particles↗

PubMed2005

mFISH analysis reveals complexity of chromosome aberrations in individuals occupationally exposed to internal plutonium: a pilot study to assess the relevance of complex aberrations as biomarkers of exposure to high-LET alpha particles.

We recently demonstrated that a significant proportion of apparently stable insertions induced after exposure to a mean of one alpha particle/cell, detected using three-color FISH, were part of larger unstable complexes when visualized by 24-color FISH. Interestingly, regardless of the long-term persistence capability of the cell, the complexity of each alpha-particle-induced complex appeared to be specific to the nuclear traversal of a single alpha particle. To assess whether aberrations of a similar complexity are observed in vivo and also to examine the usefulness of detecting such aberrations as a biomarker of chronic exposure to alpha particles, we have carried out a limited pilot study of Russian workers with large body burdens of alpha-particle-emitting plutonium. We found unstable cells containing non-transmissible complex aberrations in all of the plutonium-exposed subjects analyzed by mFISH. In addition, all of the complexes seen were consistent with those previously observed in vitro. Non-transmissible complex aberrations were more common than transmissible-type complexes, consistent with ongoing/chronic exposure, and insertions were dominant features of both types of complex. Accordingly, this preliminary study supports the proposal that aberration complexity and non-transmissibility are the major cytogenetic features of alpha-particle exposure that could potentially be exploited as a specific indicator of chronic exposures to high-LET alpha particles.

Biomarkers↗

PubMedDate not supplied

Induction of single- and double-strand breaks in plasmid DNA by monoenergetic alpha-particles with energies below the Bragg-maximum.

The yield of single-strand breaks (ssb) and double-strand breaks (dsb) produced by alpha-particles at the end of their track in DNA-films was determined experimentally. Helium nuclei were accelerated to 600 keV in the 400 kV ion accelerator and scattered at a carbon target. The elastically scattered alpha-particles with energies of 344 keV and 485 keV were used to irradiate supercircular plasmid DNA in vacuo. For the dosimetry of the alpha-particles a surface barrier detector was used and the energy distribution of the alpha-particles determined. The energy loss of the particles in the DNA-layer was calculated. DNA samples were separated into the three conformational isomers using agarose gel electrophoresis. After fluorochromation the number of ssb and dsb per plasmid DNA molecule was established from the band intensities assuming the validity of Poisson statistics. Linear dose effect correlations were found for ssb and dsb per plasmid molecule. In the case of 344 keV-alpha-particles the yield of dsb was (8.6 +/- 0.9) x 10(-11) breaks/Gy x dalton. The ratio of ssb/dsb was 0.5 +/- 0.2. This is at least a factor of six larger than the ratio found in experiments with higher energy alpha-particles and from model calculations. Similar experiments with protons yielded a relative biological effectiveness (rbe) value of 2.8 for the induction of double-strand breaks by track end alpha-particles.

Alpha Particles↗

PubMed1996

The severity of alpha-particle-induced DNA damage is revealed by exposure to cell-free extracts.

The rejoining of single-strand breaks induced by alpha-particle and gamma irradiation in plasmid DNA under two scavenging conditions has been compared. At the two scavenger capacities used of 1.5 x 10(7) and 3 x 10(6) s-1 using Tris-HCl as the scavenger, the ratio of single- to double-strand breaks for alpha particles is fivefold less than the corresponding ratios for gamma irradiation. The repair of such radiation-induced single-strand breaks has been examined using a cell-free system derived from human whole-cell extracts. We show that the rejoining of single-strand breaks for both alpha-particle- and gamma-irradiated plasmid is dependent upon the scavenging capacity and that the efficiency of rejoining of alpha-particle-induced single-strand breaks is significantly less than that observed for gamma-ray-induced breaks. In addition, for DNA that had been irradiated under conditions that mimic the cellular environment with respect to the radical scavenging capacity, 50% of alpha-particle-induced single-strand breaks are converted to double-strand breaks, in contrast with only approximately 12% conversion of gamma-ray-induced single-strand breaks, indicating that the initial damage caused by alpha particles is more severe. These studies provide experimental evidence for increased clustering of damage which may have important implications for the induction of cancer by low-level alpha-particle sources such as domestic radon.

Alpha Particles↗

PubMed1994

Chromatid damage induced by 238Pu alpha-particles in G2 and S phase Chinese hamster V79 cells.

The comparative induction of chromatid aberrations by 238Pu alpha-particles, or by 250 kVp X-rays was investigated in V79 Chinese hamster cells. Metaphases were sampled at hourly intervals postirradiation up to 8 h and BrdU/FPG staining methods were used to distinguish G2, S and G1 phase cells. Two experiments were performed. In the first, an alpha-particle dose of 0.41 Gy was compared with an X-ray dose of 1.5 Gy used in a previously published study. In the second, an X-ray dose of 1.2 Gy was used in parallel with 0.41 Gy of alpha-particles to produce a similar overall frequency of interchanges, and allow comparative ratios to be derived for other aberration types. At these isoexchange doses, alpha-particles produce relatively less gaps and breaks, particularly in late G2, and significantly more isochromatid deletions. A very high proportion of the isochromatid deletions were incomplete after alpha-particles compared with X-rays, but no difference in incompleteness was found for interchanges. With X-rays, about 6% of interchanges are complex intra-interchange forms. At similar exchange frequencies this increases to 26.7% for alpha-irradiation, suggesting increased multiple lesion interaction. Differences in dose distribution between alpha-particles and X-rays are discussed and mitotic delay is examined after separation of the analysed cells into damaged and undamaged classes.

Alpha Particles↗

PubMed1994

Biological effect of lead-212 localized in the nucleus of mammalian cells: role of recoil energy in the radiotoxicity of internal alpha-particle emitters.

The radiochemical dipyrrolidinedithiocarbamato-212Pb(II) [212Pb(PDC)2] is synthesized and its effects on colony formation in cultured Chinese hamster V79 cells are investigated. The cellular uptake, biological retention, subcellular distribution and cytotoxicity of the radiocompound are determined. The 212Pb is taken up quickly by the cells, reaching saturation levels in 1.25 h. When the cells are washed, the intracellular activity is retained with a biological half-life of 11.6 h. Gamma-ray spectroscopy indicates that the 212Pb daughters (212Bi, 212Po and 208Tl) are in secular equilibrium within the cell. About 72% of the cellular activity localizes in the cell nucleus, of which 35% is bound specifically to nuclear DNA. The mean cellular uptake required to achieve 37% survival is 0.35 mBq of 212Pb per cell, which delivers a dose of 1.0 Gy to the cell nucleus when the recoil energy of 212Bi and 212Po decays is ignored and 1.7 Gy when recoil is included. The corresponding RBE values compared to acute external 137Cs gamma rays at 37% survival are 4.0 and 2.3, respectively. The chemical Pb(PDC)2 is not chemotoxic at the concentrations used in this study. Because the beta-particle emitter 212Pb decays to the alpha-particle-emitting daughters 212Bi and 212Po, these studies provide information on the biological effects of alpha-particle decays that occur in the cell nucleus. Our earlier studies with cells of the same cell line using 210Po (emits 5.3 MeV alpha particle) localized predominantly in the cytoplasm resulted in an RBE of 6. These earlier results for 210Po, along with the present results for 212Pb, suggest that the recoil energy associated with the 212Bi and 212Po daughter nuclei plays little or no role in imparting biological damage to critical targets in the cell nucleus.

Alpha Particles↗

PubMed1988

Induction of sister chromatid exchanges (SCE) in G0 lymphocytes by plutonium-238 alpha-particles.

Irradiation of human G0 lymphocytes with plutonium-238 alpha-particles and X-rays was performed to investigate the production of sister chromatid exchanges (SCE). Alpha-particles produce a significant increase in SCE and this elevation is more significant when separated lymphocytes are irradiated. X-ray irradiation did not induce any significant increase in SCE. Therefore the relative biological effectiveness (RBE) for the induction of SCE by alpha-particles in this system is undefined and effectively infinite.

Alpha Particles↗

PubMed1992

Inactivation of C3H 10T1/2 cells by monoenergetic high LET alpha-particles.

Inactivation of mouse C3H 10T1/2 cells in plateau-phase (7.8 x 10(4) cells/cm2) was studied by using alpha-particles from the irradiation facility installed for radiobiological experiments at the 3 MV Tandem accelerator, University of Naples. Silicon detectors and CR39 plastic track detectors were employed for dosimetric purposes. The cells were exposed to high LET monoenergetic alpha-particles (energy of 1.8 MeV at the centre of the cell nucleus, track-averaged LET of 177 keV/micron and dose-rate of 1.1 Gy/min) and low-LET 80 kVp X-rays. The X-ray survival curve showed a significant shoulder (alpha/beta = 9 Gy) while the survival curve for alpha-particles was close to exponential. The mean lethal dose of alpha-particles was 0.77 +/- 0.02 Gy and the RBE was 5.2 at 80% survival and 3.0 at 5% survival. Survival of exponentially growing cells (2 x 10(4) cells/cm2) following irradiation with the alpha-particle beam is also reported. The nuclear areas of 10T1/2 cells were measured as 299 +/- 9 micron 2 and 250 +/- 8 micron 2 for cells in log phase and plateau phase, respectively. The inactivation cross-section, obtained from the mean lethal dose, was 34 micron 2 and 37 micron 2 for cells in log phase and plateau phase, respectively. These values appear to be the maximum measured values for the inactivation cross-section of 10T1/2 cells as a function of the alpha-particle LET. This saturation cross-section is very similar to the saturation values reported in the literature for other mammalian cell lines.

Alpha Particles↗

PubMed1984

Experimental examination of cavity ionisation theory applied to alpha-particle fields.

The form of a general theory of cavity ionisation is outlined and its applications to alpha-particle fields considered. The attenuation of the alpha particles within the cavity, which gives rise to the weighting factor in general cavity theory, is considered in detail and an appropriate treatment for alpha-particle fields developed. Apparatus, consisting of an ionisation chamber composed of electrodes emitting alpha rays, was constructed in order to impose a rigorous test on the theory in the most critical region of cavity size. The general theory of cavity ionisation as applied to alpha-particle fields is shown to be in close agreement with the experimental results. As in the case of photon and electron fields, it is possible to characterise a cavity by a single chord length (path length) but the charged particle energy spectrum and the variation of stopping power with energy must be considered in detail.

Alpha Particles↗

PubMed2000

The role of higher-order chromatin structure in the yield and distribution of DNA double-strand breaks in cells irradiated with X-rays or alpha-particles.

PURPOSE: To determine whether the non-random distributions of DNA double-strand breaks in cells observed after alpha-particle irradiation are related to the higher-order structure of the chromatin within the nucleus. MATERIALS AND METHODS: Chinese hamster V79 cells were irradiated as either cellular monolayers, nuclear monolayers with condensed chromatin or nuclear monolayers with relaxed chromatin, and the yields and distribution of DSB measured using two pulsed-field gel electrophoresis protocols capable of separating fragments of 10kbp to 5.7 Mbp. RESULTS: Using conventional FAR analysis, the effect of isolating nuclear monolayers and changing the chromatin condensation state was less for alpha-particle irradiated substrates than for X-irradiated ones. When the total number of breaks was measured by separating and quantifying all the fragments produced in the 10kbp to 5.7Mbp region, the difference between the observed yields of breaks in X-irradiated cells (7.3 x 10(-9) DSB/Gy/bp) relative to alpha-particles (12.1 x 10(-9) DSB/Gy/bp) was largely removed when nuclear monolayers with decondensed chromatin were exposed. The yields, although similar, increased to 44.4 x 10(-9) DSB/Gy/bp for X-irradiated decondensed nuclear monolayers and 46.6 x 10(-9) DSB/Gy/bp for alpha-particle irradiated monolayers. However, the alpha-particle DSB distributions remained non-random. CONCLUSIONS: Our results suggest that the non-random distribution of breaks observed in cells with alpha-particle irradiation, which leads to a high probability for the production of regionally multiply damaged sites, is not related to the underlying chromatin condensation state present in the nucleus.

Alpha Particles↗

PubMed1998

Partition of thorium between organs of monkeys injected with thorotrast: implications for alpha-particle dosimetry.

Risk estimates for alpha-particle-induced malignancies have been based mainly on studies of Thorotrast patients, but certain aspects of its deposition in the body have been at issue: the partition between the liver, spleen and red bone marrow, and the deposition at lower concentrations in other organs, such as muscle and fat, which may contribute to the risk. To supplement the existing data for humans, thorium concentrations were measured in the organs of two female monkeys 3-4 years after injection with Thorotrast. Relative deposits (liver:spleen:red bone marrow) were 54:6:41 and 75:4:21, in better agreement with the most recent observations in Thorotrast patients than with previous reports. Whereas the human testis had ranked among intermediate-level organs such as the adrenal glands and pancreas, the ovary of the monkey was among the organs with the lowest concentrations. The data suggest that risk factors for induction of malignancies by alpha-particle irradiation should be re-examined.

Animals↗

PubMed1996

Gross alpha-particle activities in the ground waters in Western Anatolia.

The purpose of this study is to present data on gross alpha-particle activity, pH and conductivity in the ground waters in Western Anatolia. The gross alpha-particle activities in 27 ground water samples were determined by radiochemical carrier-precipitation methods. The gross alpha-particle activities of water samples were measured by using a ZnS (Ag) detector system. Measurable alpha-particle activity is present in all ground water samples, with one ground water sample having a gross alpha-particle activity > 0.55 Bq/L.

Alpha Particles↗

PubMed2000

Complex chromosome aberrations in peripheral blood lymphocytes as a potential biomarker of exposure to high-LET alpha-particles.

PURPOSE: To determine the induction and transmission, to second and third division cells, of complex chromosome aberrations in peripheral blood lymphocytes after exposure to high-LET alpha-particles in vitro. MATERIALS AND METHODS: Separated peripheral blood lymphocytes collected from four healthy donors were irradiated in vitro with either high-LET alpha-particles (121 keV/microm; 0.5 Gy) or low-LET X-rays (250kV constant potential; 3 Gy). Cells were harvested in first, second and third division post-irradiation and chromosome aberrations observed at each cell division were analysed by combining the techniques of FISH and DAPI/Hoechst 33258 harlequin staining. Whole chromosome probes were used for chromosomes 1, 2 and 5, together with a pan-centromeric probe and the resulting chromosome 'painting' patterns were classified according to the Savage and Simpson (S & S) scheme (Savage and Simpson 1994a, Savage and Tucker 1996). RESULTS: A greater proportion of complex chromosome aberrations was observed, defined as involving three or more breaks in two or more chromosomes, relative to total exchanges, after exposure to 0.5 Gy alpha-particles (mean 1 track/cell) than after the high reference dose of 3 Gy X-rays (49-56% and 20-22%, respectively). Qualitatively, alpha-particles induced chromosome aberrations of far greater complexity than those observed after X-rays. This was reflected by both the rapid reduction in the percentage of damaged cells between first and second division indicative of cell death, and the spectrum of aberration types observed in second and third division cells post-irradiation. Regardless of this complexity, 15% of the complexes induced by alpha-particles at first division were potentially transmissible and by third division, transmissible-type complexes, specifically insertions, represented the predominant complex type (65%). CONCLUSION: Transmissible-type complexes were observed, specifically insertions, in both second and third division cells after exposure to high-LET alpha-particles (0.5 Gy) in vitro. The authors predict these cells to be stable and to be capable of persisting through many cell generations. Considering that the induction of complex chromosome aberrations by low-LET radiation is strongly dependent on dose, so that they are expected to be undetectable at environmental exposures, insertions are much more likely to be a characteristic feature of high-LET radiation at all doses. From this the usefulness of insertions as biomarkers of past exposure to environmentally relevant doses of high-LET alpha-particles is supported.

Alpha Particles↗

PubMed1996

Oncogenic transformation of Syrian hamster embryo cells by 5.3-MeV alpha particles and a tumor promoter phorbol ester.

The primary Syrian hamster embryo (SHE) cells were used to study the oncogenic transformation by 238pu alpha particles or X-rays alone or in combination with a chemical promoter phorbol ester. Survival curves of SHE cells following exposure to alpha-particles or X-rays were fitted to single-or multi-target models, respectively. Model parameters were: Do = 0.55 Gy, n = 1 for alpha particles; Do = 1.44 Gy, Dq = 3.0 Gy, n = 7.7 for X-rays. Incidence of alpha particles or X-rays induced cell transformation was dose-dependent. alpha particles were more efficient in inducing cell transformation than that of X-rays. The enhancement of SHE cell transformation by phorbol 12-myristate 13-acetate (PMA) following exposure to alpha particles of 0.25-1.00 Gy was observed.

Animals↗

PubMed2000

Alpha-particle-induced changes in the stability and size of DNA.

The effect of alpha-particle radiation on the thermal stability and size of calf thymus DNA molecules in deoxygenated aqueous solutions was investigated by thermal transition spectrophotometry, pulsed-field gel electrophoresis, and standard agarose gel electrophoresis. The thermal transition of DNA from helix to coil was studied through analysis of the UV A(260) absorbance. The results obtained for alpha particles of mean LET of 128 keV microm(-1) reveal a dual dose response: a tendency for thermal stability of the DNA helix at "low" doses, followed by an increasing instability at higher doses. The same phenomenon was observed for the mean molecular weight of DNA molecules exposed to alpha particles. The results reported here for alpha particles in the low-dose region of 0-16 Gy are consistent with our previous hypothesis of inter- and intramolecular interactions of a covalent character in gamma-irradiated DNA molecules in the dose region of 0-4 Gy.

Alpha Particles↗

PubMed1999

Treatment of lung tumor colonies with 90Y targeted to blood vessels: comparison with the alpha-particle emitter 213Bi.

An in vivo lung tumor model system for radioimmunotherapy of lung metastases was used to test the relative effectiveness of the vascular- targeted beta-particle emitter 90Y, and alpha-particle emitter, 213Bi. Yttrium-90 was shown to be stably bound by CHXa" DTPA-MAb 201B conjugates and delivered efficiently to lung tumor blood vessels. Dosimetry calculations indicated that the lung received 16.2 Gy/MBq from treatment with 90Y MAb 201B, which was a sevenfold greater absorbed dose than any other organ examined. Therapy was optimal for 90Y with 3 MBq injected. Bismuth-213 MAb 201B also delivered a similar absorbed dose (15Gy/MBq) to the lung. Yttrium-90 was found to be slightly more effective against larger tumors than 213Bi, consistent with the larger range of 2 MeV beta particles from 90Y than the 8 MeV alpha particles from 213Bi. Treatment of EMT-6 tumors growing in immunodeficient SCID mice with 90Y or 213Bi MAb 201 resulted in significant destruction of tumor colonies; however, 90Y MAb 201B was toxic for the SCID mice, inflicting acute lung damage. In another tumor model, IC-12 rat tracheal carcinoma growing in SCID mouse lungs, 90Y therapy was more effective than 213Bi at destroying lung tumors. However, 90Y MAb 201B toxicity for the lung limited any therapeutic effect. We conclude that, although vascular-targeted 90Y MAb can be an effective therapeutic agent, particularly for larger tumors, in this model system, acute damage to the lung may limit its application.

Animals↗

PubMed2001

Monte Carlo modeling of the effects of injected short-, medium- and longer-range alpha-particle emitters on human marrow at various ages.

The effects of injected short-, medium- and longer-range alpha-particle emitters ((149)Tb, (211)At/(211)Po and (213)Bi/(213)Po, respectively) on the total hemopoietic stem cell population of active normal bone marrow in humans of various ages has been estimated using Monte Carlo modeling. The fraction of the normal hemopoietic stem cells that are hit and survive has been calculated as a first step toward estimating the risk of development of therapy-induced leukemia. The fraction was lowest for the shorter-range alpha-particle emitter ((149)Tb) and highest for the longer-range alpha-particle emitter ((213)Bi/(213)Po), with the value for the medium-range alpha-particle emitter (211)At/(211)Po being intermediate between these. There was little variation in the data with the age of the subject within each alpha-particle emitter. This lack of age dependence provides reassurance that the fraction of cells hit in any subject of any age with normal marrow can be estimated by modeling newborn marrow (which requires little computing time) despite age-related differences in microarchitecture.

Adult↗