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PubMed1984

Peroxidation of the dried thin film of lipid by high-energy alpha particles from a cyclotron.

High-energy alpha particles produced a dose-dependent linear increase in different lipid peroxidation products (e.g., malondialdehyde (MDA), conjugated dienes, and hydroperoxides) in the dried thin film state. An inverse dose-rate effect was observed when the dose rate was varied by changing either the alpha-particle fluence rate or the alpha-particle energy. The antioxidants alpha-tocopherol and butylated hydroxytoluene (BHT) suppressed the alpha-particle-induced lipid peroxidation in the dried thin film state, and in this respect alpha-tocopherol was found superior to BHT. It was found that alpha-tocopherol was equally efficient in inhibiting lipid peroxidations by alpha particles and ultraviolet light.

Alpha Particles↗

PubMed2005

A bystander effect in alpha-particle irradiations of human prostate tumor cells.

Alpha-particle exposures were used to determine whether cells of the human prostate carcinoma cell line DU-145 can produce and respond to a bystander effect signal. An apparatus for alpha-particle irradiation of cells growing as a monolayer on a 1.4-microm-thick Mylar membrane directly above an 241Am alpha-particle source was constructed and calibrated. At the cell irradiation position, the alpha-particle fluence was 998 counts/mm2 s(-1), the average alpha-particle energy was 3.14 MeV, and the average linear energy transfer was 128 keV/microm. The average dose rate to the cells growing on the Mylar surface was 1.2 Gy/min. A co-culture system was used to examine bystander effects transmitted through the medium from the directly targeted cells to tumor cells growing on an insert well beyond the range of the alpha particles. Alpha-particle doses from 0.1 to 6.0 Gy to the targeted cells on the Mylar membrane, followed by a 2-h co-incubation of the cells on the insert in the irradiated medium above the irradiated cells, all caused an approximately 50% increase in micronucleus formation in the nontargeted co-cultured cells. Addition of the radical scavenger DMSO to the medium during the irradiation and the 2-h postirradiation incubation period completely blocked the bystander effect, whereas addition of a nitric oxide scavenger had no effect. Irradiation of medium containing serum, followed by a 2-h incubation, caused no bystander effect in the co-cultured cells. When the co-cultured cells on the insert were placed into the irradiated medium above the directly targeted cells immediately (approximately 1 min) after the irradiation and co-incubated for 2 h, there was no bystander effect. These data indicate that the observed bystander effect requires that the co-cultured cells be present in the medium during the irradiation of the directly targeted cells and suggest the involvement of a short-lived radical species.

Alpha Particles↗

PubMed1983

Alpha-particle autoradiography in CR-39: a technique for quantitative assessment of alpha-emitters in biological tissue.

The techniques for alpha-particle autoradiography based on the plastic nuclear track detector CR-39, previously reported, have been developed considerably. The techniques are applied to alpha-autoradiography of human lung tissue in particular but are applicable to any biological tissue. The most important developments are: (i) Improvements in the manufacture and pre-etching of the plastic. These allow activities as low as approximately 10(-15) Ci g-1 to be determined. (ii) High resolution alpha-particle spectroscopy in CR-39 plastic based on the analysis of the structure of the etched track. This enables the energy of individual alpha-particles to be determined to approximately 35 keV. (iii) Calculation of the effective thickness of tissue sampled by the plastic. This relates the tissue activity to the track density on the plastic. (iv) A deconvolution analysis which takes the distributions of track length and dip angle in the plastic and determines the alpha-particle range spectrum and distribution of tissue activity with height above the plastic surface. This enables both the absolute abundance and the microdistribution of alpha-active nuclides present to be determined. (v) The analysis of radon diffusion in tissue to determine the mean radon diffusion distance in tissue and plastic.

Adult↗

PubMed1981

Morphology of cells malignantly transformed by alpha particle irradiation.

The idea that one alpha particle (with LET approximately 100keV/micrometers) traversing a cell nucleus would kill a cell has been a concept which has been traditionally accepted by most radiation biologists. It was, therefore, difficult to see how alpha radiation could act directly on nuclear DNA to cause cancer. In experiments where mouse embryo cells (C3H 10T1/2) were irradiated with a parallel beam of 5.6 MeV alpha particles from a Tandem Van de Graaff machine, we made the surprising discovery that about 10 to 20 alpha particles through each nucleus were required to kill 2/3 of the cells (Lloyd 1979a). Earlier workers were misled because they failed to make measurements of nuclear areas of the cells as they were irradiated. We have used scanning electron microscopy, both to observe the cells at the time of irradiation and to document the change in unirradiated cellular dimensions as the cells become flattened on conventional tissue culture plates. The present paper also describes the morphological changes observed by SEM between cells which were subsequently transformed to become malignant by alpha irradiation and untransformed control cells.

Alpha Particles↗

PubMed2000

A new alpha-particle irradiator with absolute dosimetric determination.

A new experimental setup for uniform alpha-particle irradiation of cells in vitro is described. The alpha-particle irradiator is based on a radioactive (212)Pb/(212)Bi source. In the experimental setup proposed, cells are grown directly on a polylysine-coated track-etch material that forms the base of custom-made cell dishes. Alpha-particle irradiation is done through the base of the dish. Immediately prior to irradiation, the cell dish is scanned under a microscope, and images of cells with the corresponding coordinates are saved. After irradiation and after the biological end point under study has been determined, the cell dish is etched to develop alpha-particle tracks in the dish base. A microscope image series of alpha-particle track images is obtained by accurately revisiting every original (preirradiation) cell position in the track-etched dish. The number of alpha-particle traversals of each individual cell is scored by mapping images of alpha-particle tracks onto the images of cells recorded prior to irradiation. The uncertainty of the alpha-particle hit determination is 0.9 microm. The procedure described thus presents a method for radiobiological experiments with absolute, rather than statistical, cell dosimetry.

Air↗

PubMed1996

Survival and yields of chromosome aberrations in hamster and human lung cells irradiated by alpha particles.

The effects of alpha-particle irradiation on hamster and human lung cells have been studied. In both cases two end points were taken, cell death and the induction of chromosome aberrations. The hamster cells were common stock V79 cells; the human ones were freshly derived from fetal material. For both types of cells, the survival curves could be described by straight lines in the conventional exponential plot, with values of D(o) of 0.78 and 0.37 Gy for the hamster and human cells, respectively. The rate of induction of chromosome aberrations could also be described by straight lines with slopes of 0.30 and 0.62 aberration per cell per gray. Thus, for this second end point also, it appears that human cells are twice as sensitive to the effects of alpha-particle irradiation as hamster cells.

Alpha Particles↗

PubMed1997

Genetic factors influencing alpha-particle-induced chromosomal instability.

Alpha-particle-induced chromosomal instability in haemopoietic cells obtained from the CBA/H, DBA/2 and C57BL/6 inbred strains of mouse has been demonstrated at frequencies dependent on genotype. The CBA/H and DBA/2 strains may be regarded as 'sensitive' and the C57BL/6 strain as 'resistant'; resistance was dominant in cells from F1 hybrids. Previously, in cultures where we demonstrated radiation-induced chromosomal instability we also demonstrated an enhanced and persisting oxyradical activity. Quantitative differences in superoxide generation have now been correlated with genetically determined differences in the expression of chromosomal instability. Our findings demonstrate an important influence of genetic factors in alpha-particle-induced chromosomal instability.

Alpha Particles↗

PubMed1996

Alterations in the progression of cells through the cell cycle after exposure to alpha particles or gamma rays.

A G1-phase delay after exposure to alpha particles has not been report ed previously, perhaps because immortalized cell lines or cell lines from tumor cells were used in past studies. Therefore, we compared the effects of alpha particles (0.19 or 0.57 Gy) and approximately equitoxic doses of gamma rays (2 or 4 Gy) on progression of cells through the cell cycle in normal human skin fibroblasts. Cell cycle analyses were performed using flow cytometry by measuring incorporation of bromodeoxyuridine (BrdUrd) in each phase of the cell cycle up to 44 h after irradiation. We observed an alpha-particle-induced G1-phase delay in human skin fibroblasts even at the lowest dose, 0.19 Gy. At equitoxic doses, more pronounced and persistent G1-phase delays and arrests were observed in gamma-irradiated cultures in that increased fractions of the G1-phase cells remained BrdUrd- over the course of the study after gamma-ray exposure compared to cells exposed to alpha particles. In addition, G1-phase cells that became BrdUrd+ after gamma irradiation re-arrested in G1 phase, whereas BrdUrd+ G1-phase cells in alpha-particle-irradiated cultures continued cycling. In contrast, comparable percentages of cells were delayed in G2 phase after either alpha-particle or gamma irradiation. Both gamma and alpha-particle irradiation caused increases in cellular p53 and p2lCip1 shortly after the exposures, which suggests that the G1-phase delay that occurs in response to alpha-particle irradiation is dependent on p53 like the initial G1-phase delay induced by gamma rays.

Alpha Particles↗

PubMed1996

Clastogenic effects of defined numbers of 3.2 MeV alpha particles on individual CHO-K1 cells.

Research to determine the effects of defined numbers of alpha particles on individual mammalian cells is helpful in understanding risks associated with exposure to radon. This paper reports the first biological data generated using the single-particle/single-cell irradiation system developed at Pacific Northwest Laboratory. Using this apparatus, CHO-K1 cells were exposed to controlled numbers of 3.2 MeV alpha particles, and biological responses of individual cells to these irradiations were quantified. Chromosomal damage, measured by the induction of micronuclei, was evaluated after no, one, two, three or five particle traversals. Exposures of up to five alpha particles had no influence on the total numbers of cells recovered for scoring. With increased numbers of alpha particles there was a decrease in the ratio of binucleated to mononucleated cells of 3.5%/hit, suggesting that alpha particles induced dose-dependent mitotic delay. A linear hit-response relationship was observed for micronucleus induction: Micronuclei/binucleated cell = 0.013 +/- 0.036 + (0.08 +/- 0.013) x D, where D is the number of particles. When the estimated dose per alpha-particle traversal was related to the frequency of induced micronuclei, the amount of chromosomal damage per unit dose was found to be similar to that resulting from exposures to alpha particles from other types of sources. Approximately 72% of the cells exposed to five alpha particles yield no micronuclei, suggesting the potential for differential sensitivity in the cell population. Additional studies are needed to control biological variables such as stage of the cell cycle and physical parameters to ensure that each cell scored received the same number of nuclear traversals.

Alpha Particles↗

PubMed1998

The minimum Do for cell killing for alpha-particle emitters uniformly distributed in an extended medium.

For cells irradiated by alpha particles in suspension, there is presently no simple test to show that the cell killing can be attributed to alpha-particle passages through the nuclei. In this communication, for a uniform distribution of alpha-particle sources and spherical nuclei, a D0 is calculated such that at least 63% of the cell nuclei have at least one alpha-particle passage. For a uniform distribution of alpha-particle sources and spherical nuclei, it is shown that the average dose for 63% of the cell nuclei to be hit (37% not hit) is equal to the average dose per hit. For this condition an energy deposition of any size would result in cell death and the average dose is the minimum D0 possible. Minimum D0 values are calculated using a Monte Carlo treatment for nuclear diameters from 4 to 10 microm and initial alpha-particle energies between 3.18 and 8.38 MeV.

Alpha Particles↗

PubMed1997

Extracellular factor(s) following exposure to alpha particles can cause sister chromatid exchanges in normal human cells.

The mechanism(s) by which alpha particles like those emitted from inhaled radon and radon progeny cause their mutagenic and carcinogenic effects remains unclear. Although direct nuclear traversals by alpha particles may be involved in mediating these outcomes, increasing evidence indicates that alpha particles can cause alterations in DNA in the absence of direct "hits" to cell nuclei. Using the occurrence of excessive sister chromatid exchanges (SCEs) as an index of DNA damage in human lung fibroblasts, we investigated the hypothesis that alpha particles may induce DNA damage via the generation of extracellular factors. We have found that a relatively low dose of alpha particles indeed results in the generation of extracellular factors, which, upon transfer to unexposed normal human cells, can cause excessive SCEs to an extent equivalent to that observed when the cells are directly irradiated with the same irradiation dose. A short-lived, SCE-inducing factor(s) was generated in alpha-irradiated culture medium containing serum in the absence of cells; it was found that the activity of this factor can be promptly inhibited by superoxide dismutase. A more persistent SCE-inducing factor(s), which can survive freeze-thawing, is heat labile and also can be inhibited by superoxide dismutase, was produced by fibroblasts after exposure to alpha particles. These results indicate that the initiating target for alpha-particle-induced genetic changes can be larger than the nuclear compartment alone and even larger than the cytoplasmic compartment. How transmissible factors like those observed here in vitro may extend to the in vivo condition in the context of alpha-particle-induced carcinogenesis in the respiratory tract and elsewhere remains to be determined.

Alpha Particles↗

PubMed1997

Radiotoxicity of gadolinium-148 and radium-223 in mouse testes: relative biological effectiveness of alpha-particle emitters in vivo.

The biological effects of radionuclides that emit alpha particles are of considerable interest in view of their potential for therapy and their presence in the environment. The present work is a continuation of our ongoing effort to study the radiotoxicity of alpha-particle emitters in vivo using the survival of murine testicular sperm heads as the biological end point. Specifically, the relative biological effectiveness (RBE) of very low-energy alpha particles (3.2 MeV) emitted by 148Gd is investigated and determined to be 7.4 +/- 2.4 when compared to the effects of acute external 120 kVp X rays. This datum, in conjunction with our earlier results for 210Po and 212Pb in equilibrium with its daughters, is used to revise and extend the range of validity of our previous RBE-energy relationship for alpha particles emitted by tissue-incorporated radionuclides. The new empirical relationship is given by RBE alpha = 9.14 - 0.510 E alpha where 3 < E alpha < 9 MeV. The validity of this empirical relationship is tested by determining the RBE of the prolific alpha-particle emitter 223Ra (in equilibrium with its daughters) experimentally in the same biological model and comparing the value obtained experimentally with the predicted value. The resulting RBE values are 5.4 +/- 0.9 and 5.6, respectively. This close agreement strongly supports the adequacy of the empirical RBE-E alpha relationship to predict the biological effects of alpha-particle emitters in vivo.

Alpha Particles↗

PubMed2006

A 244Cm irradiator for protracted exposure of cultured Mammalian cells with alpha particles.

A 244Cm alpha-particle irradiator was designed and constructed for radiobiological studies where protracted exposure at a low dose rate of cultured mammalian cells is required. It allows irradiation of a cell monolayer attached to the Mylar bottom of a specially designed Petri dish of 56 mm diameter (approximately 25 cm(2) area). The irradiator is based on a 20-mm-diameter stainless steel chamber containing a 148 kBq 244Cm source. The chamber, flushed with helium gas at a pressure kept slightly above the external pressure, is inserted into a cell incubator where temperature and CO2 concentration are controlled. Spectrometric and dosimetric characterization of the irradiator was carried out by means of an ion-implanted-silicon charged-particle detector, CR39 detectors, and Monte Carlo simulations with the TRIM code. Average LET of particles incident on the cells at the center of the Petri dish was evaluated to be 120 keV microm(-1) at 59 mm from the source, and the average dose rate was 5.69 x 10 Gy s(-1), with +12% and -8% variations at the center and the edge, respectively. The irradiator has been successfully tested and used for several experiments involving 16-d exposure of human fibroblasts monolayers.

Alpha Particles↗

PubMed1988

Interaction between X-ray and alpha-particle damage in V79 cells.

V79 cells have been exposed to X-rays or 238Pu alpha-particles or to X-rays following priming alpha-particle doses of 0.5, 2 or 2.5 Gy. The survival curve for exposure to alpha-particles was exponential with a D0 of 0.89 Gy. Following exposure to priming alpha-particle doses the resulting X-ray survival curves had the same slope as the single dose X-ray curve, but a reduced shoulder. For alpha-particle priming doses of 0.5 and 2 Gy this reduction was the same as for the same X-ray doses. 2.5 Gy alpha-particles reduced the subsequent X-ray curve Dq to almost zero. alpha-particles do cause damage capable of interacting with X-ray damage.

Alpha Particles↗

PubMed2004

Remote optical detection of alpha particle sources.

Spectral investigations of the phenomenon of alpha-radioluminescence in the atmosphere have been carried out in the UV-V region. It was found that: (1) more than 95% of the intensity of the alpha radiation induced luminescence (alpha-radioluminescence) falls in the narrow range between 310 and 400 nm, (2) the alpha-radioluminescence spectrum consists of a small number of bands typically 2-3 nm wide and belonging to the 2+ system of nitrogen molecule transitions, (3) each alpha particle emitted from the surface causes creation of approximately 30 UV photons in ambient air, (4) alpha particles emitted from the source surface have an angular distribution proportional approximately to cos8 (theta). By determining the main features of the alpha-radioluminescence spectrum, it should be possible to design optical methods and techniques for the indirect remote detection of alpha particle sources even in the presence of a high background of beta or gamma radiation. With the aim of proving this possibility, a laboratory model of an optical receiving system was designed and tested. From a distance of 30 m, the optical image of a clean alpha source (239Pu, 3.7 x 10(7) Bq) placed close to a high activity gamma ray source (60Co, 18.5 x 10(7) Bq) was captured photographically by the model system. The possibility of the practical indoor implementation of such a passive optical method for the remote (hundreds of metres) detection of alpha particle sources even in intense beta/gamma radiation fields is discussed. The potential for an active version of the method is also considered.

Air Pollution, Radioactive↗

PubMed1999

Alpha particles induce the production of interleukin-8 by human cells.

The pulmonary microenvironment is a primary target for alpha particles like those emitted by inhaled radon and its progeny. While exposure to alpha particles has recently been associated with the generation of extracellular and intracellular reactive oxygen species (ROS; Cancer Res. 57, 3963-3971, 1997), little is known about how exposure to alpha particles may affect the generation of oxidative stress-related mediators in the respiratory tract. Interleukin-8 (IL8) is a cytokine recognized for its potent role as a chemoattractant and activator of polymorphonuclear leukocytes. Oxidative stress can up-regulate expression of the gene that encodes IL8 (IL8) in a variety of cell types. In this study, we set out to investigate a potential linkage between the generation of ROS and production of IL8 in alpha-particle-irradiated normal human lung fibroblasts. ELISA revealed that exposure of the fibroblasts to low doses of alpha particles (3.6-19 cGy) caused significant increases in generation of the IL8 protein as early as 30 min after irradiation. Northern blot analyses revealed that such increases were associated with increased IL8 mRNA levels. Cells exposed to alpha particles in the presence of antioxidants, i.e. superoxide dismutase and dimethyl sulfoxide, resulted in significant decreases in extracellular IL8 protein levels. Similar results were obtained with cells treated with dexamethasone, an inhibitor of transcription. Our results indicate that alpha-particle-induced increases in production of IL8 occur temporally in parallel with elevated production of ROS. Conceivably, such production of IL8 induced by alpha particles may contribute to an inflammatory response in the lower respiratory tract. Additionally, the promitogenic effects of IL8 may be a factor in hyperplastic responses in the airway epithelial cells to inhaled radon and radon progeny and perhaps other stresses associated with ROS.

Alpha Particles↗

PubMed2002

Vascular-targeted radioimmunotherapy with the alpha-particle emitter 211At.

Astatine-211, an alpha-particle emitter, was employed in a model system for vascular-targeted radioimmunotherapy of small tumors in mouse lung to compare its performance relative to other radioisotopes in the same system. Astatine-211 was coupled to the lung blood vessel-targeting monoclonal antibody 201B with N-succinimidyl N-(4-[211At]astatophenethyl) succinamate linker. Biodistribution data showed that the conjugate delivered 211At to the lung (260-418% ID/g), where it remained with a biological half-time of about 30 h. BALB/c mice bearing about 100 lung tumor colonies of EMT-6 cells, each about 2000 cells in size, were treated with 211At-labeled monoclonal antibody 201B. The administered activity of 185 kBq per animal extended the life span of treated mice over untreated controls. Injections of 370 kBq, corresponding to an absorbed dose of 25-40 Gy, were necessary to eradicate all of the lung tumors. Mice receiving 740 kBq of 211At-labeled monoclonal antibody 201B developed pulmonary fibrosis 3-4 months after treatment, as did mice treated with 3700 kBq of the alpha-particle emitter 213Bi-labeled monoclonal antibody 201B in previous work. Animals that were injected with 211At bound to untargeted IgG or to glycine, as control agents, also demonstrated therapeutic effects relative to untreated controls. Control groups that received untargeted 211At required about twice as much administered activity for effective therapy as did groups with lung-targeted radioisotope. These results were not consistent with radioisotope biodistribution and dosimetry calculations that indicated that lung-targeted 211At should be at least 10-fold more efficient for lung colony therapy than 211At bound to nontargeting controls. The data showed that 211At is useful for vascular-targeted radioimmunotherapy because lung tumor colonies were eradicated in the mice. Work in this model system demonstrates that vascular targeting of alpha-particle emitters is an efficient therapy for small perivascular tumors and may be applicable to human disease when specific targeting agents are identified.

Alpha Particles↗

PubMed1991

Response of X-ray-sensitive CHO mutant cells (xrs-6c) to radiation. II. Relationship between cell survival and the induction of chromosomal damage with low doses of alpha particles.

The induction of cytotoxicity, chromosomal aberrations, and sister chromatid exchanges (SCEs) was measured in CHO K-1c cells and in isogenic X-ray-sensitive mutant xrs-6c cells that had been irradiated with X rays and alpha particles in isoleucine-deficient alpha-minimal essential medium in G1 phase of the cell cycle. There was a noticeable shoulder region on the survival curve for CHO K-1c cells irradiated with very low doses of alpha particles, whereas this feature was absent for xrs-6c cells with alpha-particle doses as low as 0.5 cGy. Higher frequencies of chromatid-type aberrations were induced in G1-phase xrs-6c cells than in G1-phase CHO K-1c cells by both gamma- and alpha-particle irradiation. Induction of nonlethal chromosomal aberrations was observed following exposure to 2-6 cGy of alpha particles, doses yielding 97-100% cell survival. Irradiation with 0.5 cGy of alpha particles induced SCE; nearly 60% of irradiated cells contained significantly increased levels of SCE. However, only 3% of the nuclei of cells exposed to 0.5 cGy of alpha-particle radiation were actually traversed by an alpha particle. The observation that a large fraction of cells apparently survive exposure to very low doses of alpha-particle radiation with persistent genetic damage manifested by both chromosomal aberrations and SCEs may have important implications for the carcinogenic hazards of high-LET radiation.

Alpha Particles↗