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PubMed1979

Aspergillus nidulans as a test organism for assessing radio-induced chromosomal non-disjunction.

A genetically marked heterozygous diploid of Aspergillus nidulans was synthesized and the feasibility of using this system for the simultaneous estimation of radio-induced mitotic crossing-over and non-disjunction has been investigated. In the case of the latter, serious experimental problems have been encountered. Nevertheless, induction curves for non-disjunction with 15-MeV electrons, 50-kVp X-rays, beta-particles and alpha-particles are presented showing an increase in non-disjunction with increasing LET.

Aspergillus nidulans↗

PubMed1996

Formation of two double-strand breaks in the same DNA molecule by a single high-energy photon or ionizing particle.

I calculate the probability that a single high-energy ionizing particle or photon makes two widely spaced double-strand breaks in the same DNA molecule. Deletions (or inversions) between two breaks formed by the same incident particle are linear in radiation dose and occur even at extremely low dose-rates; deletions between breaks induced by separate particles are quadratic in dose and are much fewer at very low dose-rate. The calculations show that for a few grays of sparsely ionizing radiations such as fast electrons, X-rays of gamma-rays, the formation of two double-strand breaks in a DNA molecule 1 megabase in size should be nearly entirely quadratic in dose. For heavily ionizing particles such as alpha particles from radon products, the linear and quadratic terms are comparable in size. These conclusions are robust and insensitive to details of the calculations. The results are essentially the same for DNA in a random coil configuration and for DNA uniformly and randomly distributed within a sphere.

Chromosome Inversion↗

PubMed2000

Measuring the spectrum of mutation induced by nitrogen ions and protons in the human-hamster hybrid cell line A(L)C.

Astronauts can be exposed to charged particles, including protons, alpha particles and heavier ions, during space flights. Therefore, studying the biological effectiveness of these sparsely and densely ionizing radiations is important to understanding the potential health effects for astronauts. We evaluated the mutagenic effectiveness of sparsely ionizing 55 MeV protons and densely ionizing 32 MeV/nucleon nitrogen ions using cells of two human-hamster cell lines, A(L) and A(L)C. We have previously characterized a spectrum of mutations, including megabase deletions, in human chromosome 11, the sole human chromosome in the human-hamster hybrid cell lines A(L)C and A(L). CD59(-) mutants have lost expression of a human cell surface antigen encoded by the CD59 gene located at 11p13. Deletion of genes located on the tip of the short arm of 11 (11p15.5) is lethal to the A(L) hybrid, so that CD59 mutants that lose the entire chromosome 11 die and escape detection. In contrast, deletion of the 11p15.5 region is not lethal in the hybrid A(L)C, allowing for the detection of chromosome loss or other chromosomal mutations involving 11p15.5. The 55 MeV protons and 32 MeV/nucleon nitrogen ions were each about 10 times more mutagenic per unit dose at the CD59 locus in A(L)C cells than in A(L) cells. In the case of nitrogen ions, the mutations observed in A(L)C cells were predominantly due to chromosome loss events or 11p deletions, often containing a breakpoint in the pericentromeric region. The increase in the CD59(-) mutant fraction for A(L)C cells exposed to protons was associated with either translocation of portions of 11q onto a hamster chromosome, or discontinuous or "skipping" mutations. We demonstrate here that A(L)C cells are a powerful tool that will aid in the understanding of the mutagenic effects of different types of ionizing radiation.

Animals↗

PubMed2002

Cancer incidence among Swedish patients exposed to radioactive thorotrast: a forty-year follow-up survey.

Thorotrast is an alpha-particle-emitting radiological contrast medium that caused chronic exposure to internal alpha-particle radiation when it was administered systemically. Cancer incidence in 432 Swedish patients exposed to Thorotrast was evaluated by computerized linkage of the cohort with the Swedish Cancer Register. Standardized incidence ratios (SIRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population. A total of 170 cancers occurring in 152 individuals were reported, whereas only 57 cases were expected. The SIR was significantly increased for cancer at all sites (3.0), with the largest excesses noted for primary liver and gallbladder cancer (SIR = 39.2). Other significantly elevated risks were observed for liver cancer not specified as primary, small intestine cancer, stomach cancer, leukemia, kidney cancer, CNS tumors, and pancreatic cancer. Among women, there was a significantly increased risk for lung cancer, based on a small number. Our results show that cumulative radiation exposure is directly related to carcinogenesis in the liver and gallbladder, which is consistent with earlier findings. In addition, there may be a relationship between radiation exposure and the development of other solid tumors.

Adolescent↗

PubMed1999

211At- and 131I-labeled bisphosphonates with high in vivo stability and bone accumulation.

UNLABELLED: Bisphosphonates were synthesized for use as carriers for astatine and iodine radioisotopes to target bone neoplasms. METHODS: Radiohalogenated activated esters were coupled to the amino group in the side chain of the bisphosphonate. The bisphosphonate 3-amino-1-hydroxypropylidene bisphosphonate was combined with four different acylation agents: N-succinimidyl 3-[211At]astatobenzoate, N-succinimidyl 3-[131I]iodobenzoate, N-succinimidyl-5-[211At]astato-3-pyridinecarboxylate and N-succinimidyl-5-[131I]iodo-5-pyridinecarboxylate. The products, 3-[131I]iodobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (IBPB), 3-[211At]astato-benzamide-N-3-hydroxypropylidene-3,3-bisphosphonat e (ABPB), 5-[131I]iodopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphospho nate (IPPB) and 5-[211At]astatopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphos phonate (APPB), were injected intravenously into Balb/c mice. MIRD and Monte Carlo methods were used on the basis of cumulated activity calculated from biodistribution data to estimate dose to organs and bone segments. RESULTS: All 131I- and 211At-labeled analogs were strongly incorporated into osseous tissue and retained there at stable levels, while a rapid clearance from blood was observed. The bone uptake was found to be similar for 211At- and 131I-labeled bisphosphonate when compared in paired label experiments. Bone uptake and bone-to-tissue ratios were better for IBPB compared with IPPB, and ABPB compared with APPB. All four compounds appeared to be highly resistant to in vivo dehalogenation as indicated by low uptake of 131I/211At in the thyroid gland and stomach. According to dosimetric estimates, the bone surface-to-bone marrow ratio was three times higher with 211At than with 131I. CONCLUSION: Both the beta-particle- and alpha-particle-emitting compounds showed high in vivo stability and excellent affinity for osseous tissue. Further preclinical evaluation is therefore warranted.

Animals↗

PubMed1990

Fluorine microanalysis in teeth.

Fluorine content in dental tissues has been measured by using nuclear reactions with high energy proton beams and detecting alpha particles and/or gamma rays emitted from fluorine nuclei. The sensitivity of the nuclear analysis reaches 0.1 mg/g and the depth distribution of fluorine atoms can be determined up to 5 mum. The depth resolution is about 0.3 mum with alpha particles and 0.1 mum with gamma rays. Distributions of fluorine both in surface enamel and in cross section of teeth were measured by using a proton probe 500 mum in diameter. A systematic increase in the fluorine concentration has been observed in the healthy incisors dental enamel (1-3 mg/g) with respect to the molar ones (0.5-1 mg/g). A comparison between the fluorine content in healthy teeth and in pathological ones was made.

Alpha Particles↗

PubMed1999

Comparative stochastic effects of inhaled alpha- and beta-particle-emitting radionuclides in beagle dogs.

The stochastic effects of inhaled, insoluble particles of alpha- or beta-particle-emitting radionuclides were compared in dogs. Male and female beagle dogs were exposed briefly by nasal inhalation to relatively insoluble aerosols of (239)PuO(2) or (144)Ce in fused aluminosilicate particles (FAP) and observed for cancer for their lifetimes. The initial lung burden and retention of each radionuclide was determined by whole-body counting of the emissions from (144)Ce-(144)Pr- or (169)Yb-labeled (239)PuO(2). Lung doses were calculated for each dog from these data. The lung doses ranged from 0.21 to 1200 Gy for (144)Ce FAP and 1.6 to 58 Gy for (239)PuO(2). Dogs with doses to the lung of about 60 Gy or greater from (144)Ce or about 2 Gy or greater from (239)PuO(2) had an increased incidence of lung carcinomas. In dogs exposed to (144)Ce FAP, three organs were targets for neoplasia: lung, tracheobronchial lymph nodes, and heart. The insoluble FAP carried to the lymph nodes draining the lung delivered high radiation doses to the nodes and adjacent heart, resulting in hemangiosarcomas of these organs. In the lung, high radiation doses induced hemangiosarcomas and carcinosarcomas. At lower doses, carcinomas of various histological patterns were induced in the lung. In dogs exposed to (239)PuO(2), the lung was the sole target organ for neoplasia. Nearly all of these neoplasms were carcinomas of various histological patterns. These results indicated that relatively low doses of alpha-particle radiation can induce pulmonary cancers, but relatively large doses of beta-particle radiation are required. In addition, inhaled beta-particle emitters can also induce cancers in lung-associated lymph nodes and heart at these larger absorbed radiation doses.

Administration, Inhalation↗

PubMed2004

Changes in micronucleus frequency resulting from preirradiation of cell culture surfaces.

We have initiated a series of experiments to quantify the impact of environmental variables on the observed frequency of micronuclei in monolayer cultures. In this paper the influence of preirradiation of cell culture vessels on micronucleus formation in Chinese hamster ovary cells was examined. Dry cell culture vessels were preirradiated with 2 Gy of either alpha particles or X rays and immediately plated with nonirradiated cells. About 48 h later a group of randomly chosen containers was set aside, and the rest of the containers were exposed to a range of doses of X rays or alpha-particle radiation. Nonirradiated cells plated on previously irradiated cell culture surfaces manifested nearly as many micronuclei as the irradiated cells. In all experiments, preirradiation of the cell substrate (the culture dish) led to a significantly increased micronucleus frequency relative to unirradiated substrate. These results suggest that methods of cell culture vessel sterilization and the composition of cell attachment surfaces could be a confounding factor, particularly in low-dose experiments.

Alpha Particles↗

PubMed2002

Distributions of specific energy in sensitive layers of the human respiratory tract.

The purpose of the present work was to calculate the specific energy distribution in sensitive cells of the human lung. Specific energy distributions were calculated by applying Monte Carlo methods and the ICRP 66 model of the human respiratory tract. Specific energies were calculated at various depths in the epithelium and combined according to the relative cell abundance. Distributions are given for various combinations of sources, alpha-particle energies, targets and regions of the lung. The chord length does not follow the triangular distribution when the particle range is comparable to the diameter of the target. The notion of "effective volume" is introduced and defined, which is needed for estimation of hit frequency in some particular targets. It has been shown that basal cells are subjected to a larger proportion of alpha-particle hits with small energy transfer than secretory cells. Small energy transfer events that lead to minor damage of the DNA are more efficient in cancer induction than are hits with large energy deposition that lead to cell killing.

Alpha Particles↗

PubMed1979

Effect of gamma and alpha irradiation on survival of wild-type and sensitive mutants of yeast.

Survival curves have been obtained for haploid and diploid Saccharomyces cerevisiae of the wild-type strain and the sensitive mutant rad51-1 exposed to gamma-rays and alpha-particles. The difference in radio-sensitivities of the wild-type diploid strain and the homozygous rad51-1 mutant was significantly higher after low-LET radiation than after high-LET radiation. This was not true for haploid strains. The liquid-holding recovery of irradiated cells was greater for gamma-ray-induced damage than for damage inflicted by alpha-particles. The value of the RBE of high-LET radiation was correlated with cell-repair capacity.

Alpha Particles↗

PubMed2003

Involvement of the nonhomologous end joining DNA repair pathway in the bystander effect for chromosomal aberrations.

Cells of mouse knockout cell lines for Ku80 (now known as Xrcc5), Ku70 (now known as G22p1), DNA-PKcs (now known as Prkdc) and PARP (now known as Adprt) were synchronized in G1 phase and exposed to very low fluences of alpha particles. The frequency of gross chromosomal aberrations was scored at the first postirradiation metaphase. At the two lowest doses examined, aberrations were induced in 4-9% of wild-type cells and 36-55% of Xrcc5-/- cells, whereas only 2-3% of the nuclei were traversed by an alpha particle and thus received any radiation exposure. G22p1-/- cells responded similarly to Xrcc5-/- cells, whereas Prkdc-/- and Adprt-/- cells showed an intermediate effect. The frequency of aberrations per nuclear traversal increased approximately 30-fold for Xrcc5-/- and G22p1-/- cells at the lowest mean dose examined (0.17 cGy), compared with 10-fold in Prkdc-/- cells and 3-fold in wild-type cells. Based on these and other findings, we hypothesize that the marked sensitization of repair-deficient bystander cells to the induction of chromosomal aberrations is a consequence of unrejoined DNA double-strand breaks occurring as a result of clustered damage arising from opposed oxidative lesions and single-strand breaks.

Alpha Particles↗

PubMed1995

Fission fragment relative biological effectiveness for liver tumor induction.

The risk coefficients for liver tumors as derived from 60 beagles with body burdens of 249Cf or 252Cf were used to determine the relative biological effectiveness of fission fragments relative to alpha particles. For liver malignancies the relative biological effectiveness was calculated to be about 2 +/- 3. The estimate based on the combined benign and malignant liver tumors was about 7, with a proportionately larger standard deviation of about +/- 14. Although the confidence intervals were wide, it is possible that the relative biological effectiveness of fission fragments relative to alpha particles, using liver neoplasia as the endpoint, is greater than 1.0 as compared to a value only slightly above zero when bone cancer was the lesion of interest.

Alpha Particles↗

PubMed1999

Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry.

UNLABELLED: The alpha-particle-emitting radionuclides have several physical characteristics that make them attractive candidates for radioimmunotherapy: (a) high linear energy transfer; (b) short path lengths (50-80 microm); and (c) limited ability of cells to repair damage to DNA. This article describes the pharmacokinetic, bioactivity, toxicity and chemical characteristics of alpha-particle-emitting, 213Bi and 212Bi radiometal conjugated HuM195 (anti-CD33) constructs. Conjugation of HuM195 to SCN-CHX-A-DTPA resulted in the attachment of up to 10 chelating ligand molecules per antibody. RESULTS: Radiolabeling efficiency of the CHX-A-DTPA-HuM195 construct with 213Bi was 78%+/-10% (n = 46) after 10 min at specific activities of up to 1110 MBq/mg. The immunoreactivity of the 213Bi-labeled CHX-A-DTPA-HuM195 construct was 84%+/-10% (n = 28) and was independent of the specific activity. The bismuth-labeled CHX-A-DTPA-HuM195 construct was rapidly internalized into the cell in a time-dependent manner ranging from 50% at 1 h to 65% at 24 h. 205Bi/206Bi-labeled constructs were stable for at least 2 d in vitro in the presence of human serum at 37 degrees C. After injection into mice, there was no uptake or loss of bismuth to mouse tissues, which do not express CD33, or to the kidney, which has avidity for free bismuth. Mice injected intraperitoneally with doses of (213Bi)CHX-A-DTPA-HuM1 95 ranging from 18.5 to 740 MBq/kg showed no toxicity, but at 2590 MBq/kg, two of the three mice died within 2 wk and a third mouse showed significant reductions in white blood cell counts. Mice injected intravenously with doses of (213Bi)CHX-A-DTPA-HuM195 up to 370 MBq/kg exhibited little toxicity, but 666 MBq/kg was above the MTD for mice. Leukemia cell killing in vitro with bismuth-labeled HuM1 95 showed dose- and specific activity-dependent killing of CD33+ HL60 cells; approximately 50% killing was observed when two bismuth atoms (50 fM radiolabeled antibody) were initially bound onto the target cell surface. CONCLUSION: Alpha-emitting antibodies are among the most potent cytotoxic agents known, yet are specific and appear safe in vivo. The physical and biochemical characteristics of the 213Bi isotope and its generation, as well as the biochemistry of the 213Bi-labeled CHX-A-DTPA-HuM195 construct, make it possible to use the constructs safely and feasibly in humans at therapeutic levels.

Alpha Particles↗

PubMed2001

In utero haemopoietic sensitivity to alpha, beta or X-irradiation in CBA/H mice.

PURPOSE: To assess in utero sensitivity to x-rays, alpha-emissions from plutonium-239 and beta-emissions from tritium in terms of induction of chromosomal aberrations in bone marrow cells. MATERIALS AND METHODS: CBA/H mice were exposed to a single dose of X-rays (0.5Gy) on either day 7 or day 14 of pregnancy or given (239)Pu (100 kBq kg(-1)) by intraperitoneal injection on either day 6 or day 13. Tritium was administered to mice throughout pregnancy as either tritiated water, ad libitum in drinking water (total intake averaged 130 MBq), or as homogenized tritiated cress, administered by gastric intubation (total 60 MBq). Irradiated and unexposed control mice and their offspring were sacrificed at 2-8 weeks after birth. Direct metaphase preparations from femoral bone marrow cells from mothers and offspring were used for G-band analysis. RESULTS: The incidence of stable aberrations was significantly and similarly increased in neonatal and maternal marrow samples after exposure to X-rays, (239)Pu or (3)H. The estimated average bone absorbed doses from (239)Pu in pregnant females were similar to the X-ray dose of 0.5 Gy, suggesting a low RBE for alpha-irradiation in adults. The similar levels of damage observed in neonates after X-irradiation and 239Pu exposure are indicative of greater in utero sensitivity to alpha-irradiation since the overall estimated in utero alpha-particle doses to haemopoietic tissue were much lower. In utero doses from (3)H and corresponding maternal doses were around 0.5Gy, showing no evidence of greater in utero sensitivity, no significant difference between the effects of the two forms of tritium, and were consistent with an RBE value of 1-2. CONCLUSIONS: Comparison of stable aberration yields in haemopoietic cells suggests a greater sensitivity to alpha-particles from (239)Pu than X-rays or beta-particles from (3)H for irradiation in utero but a low RBE value in adults.

Age Factors↗

PubMed1985

Calculation of heavy-ion tracks in liquid water.

Detailed Monte Carlo calculations are presented of proton and alpha-particle tracks in liquid water. The computations treat the interactions of the primary particle and all secondary electrons on a statistical, event-by-event basis to simulate the initial physical changes that accompany the passage of an ion through water. Our methods for obtaining the cross sections needed for such calculations are described. Inelastic scattering probabilities (inverse mean free paths) are derived from a complex dielectric response function constructed for liquid water, based on experimental and theoretical data. Examples of partial cross sections for ionization and excitation by protons are shown. The computation of electron transport and energy loss includes exchange, elastic scattering, and a scheme for the delocalization of energy shared collectively by a large number of electrons in the condensed medium. Several examples of calculated proton and alpha-particle tracks are presented and discussed. The meaning and significance of the concept of a track core are briefly addressed in the light of this work. The present paper treats only the initial, physical changes produced by radiation in water (in approximately 10(-15) s in local regions of a track). The work described here is used in calculations that we have reported in other publications on the later chemical development of charged-particle tracks.

Alpha Particles↗

PubMed1997

Delayed appearance of radiation-induced mutations at the Hprt locus in murine hemopoietic cells.

Earlier work in this laboratory identified high levels of non-clonal chromatid aberrations in the clonal descendants of murine hemopoietic stem cells after many cell divisions postirradiation with densely-ionizing, high linear energy transfer (LET) alpha-particles, but not with sparsely ionizing low LET X-rays. Using the Hprt locus as a marker, we have now demonstrated genomic instability in murine hemopoietic stem cells for greater than 20 cell divisions following both high and low LET irradiation. The increase in Hprt-deficient variants demonstrated following X- as well as alpha-particle and neutron irradiation indicates that there is a difference in the LET-dependence of delayed gene mutations and higher-order cytogenetic effects. Over 90% of the mutations identified arose in the expanding colonies after more than 12 cell divisions postirradiation and therefore cannot be attributed to the initial DNA damage. Such a high frequency of delayed mutations has important implications for mechanistic studies of radiation mutagenesis and for risk estimation.

Alpha Particles↗

PubMed1998

Track structure in radiation biology: theory and applications.

PURPOSE: A brief review is presented of the basic concepts in track structure and the relative merit of various theoretical approaches adopted in Monte-Carlo track-structure codes are examined. In the second part of the paper, a formal cluster analysis is introduced to calculate cluster-distance distributions. METHOD: Total experimental ionization cross-sections were least-square fitted and compared with the calculation by various theoretical methods. Monte-Carlo track-structure code Kurbuc was used to examine and compare the spectrum of the secondary electrons generated by using functions given by Born-Bethe, Jain-Khare, Gryzinsky, Kim-Rudd, Mott and Vriens' theories. The cluster analysis in track structure was carried out using the k-means method and Hartigan algorithm. RESULTS: Data are presented on experimental and calculated total ionization cross-sections: inverse mean free path (IMFP) as a function of electron energy used in Monte-Carlo track-structure codes; the spectrum of secondary electrons generated by different functions for 500 eV primary electrons; cluster analysis for 4 MeV and 20 MeV alpha-particles in terms of the frequency of total cluster energy to the root-mean-square (rms) radius of the cluster and differential distance distributions for a pair of clusters; and finally relative frequency distribution for energy deposited in DNA, single-strand break and double-strand breaks for 10MeV/u protons, alpha-particles and carbon ions. CONCLUSIONS: There are a number of Monte-Carlo track-structure codes that have been developed independently and the bench-marking presented in this paper allows a better choice of the theoretical method adopted in a track-structure code to be made. A systematic bench-marking of cross-sections and spectra of the secondary electrons shows differences between the codes at atomic level, but such differences are not significant in biophysical modelling at the macromolecular level. Clustered-damage evaluation shows: that a substantial proportion of dose ( 30%) is deposited by low-energy electrons; the majority of DNA damage lesions are of simple type; the complexity of damage increases with increased LET, while the total yield of strand breaks remains constant; and at high LET values nearly 70% of all double-strand breaks are of complex type.

Alpha Particles↗

PubMed2000

Strain differences in carcinogenic and hematopoietic responses of mice after injection of plutonium citrate.

The carcinogenicity of injected (239)Pu citrate was compared in female mice of the C3H, C57BL/6 and BC3F(1) hybrid strains with different spectra of spontaneous or radiation-induced tumors. A significant reduction in survival due to early death caused particularly by the induction of osteosarcomas was noted in each strain after injection of 500 Bq or more. The dose response of osteosarcomas appeared to have a similar pattern in each strain except for the differences in the skeletal dose ranges for the maximum induction. While the incidence of lymphoid tumors decreased as that of osteosarcomas increased sharply to the maximum at higher doses, their histological phenotypes were predominantly non-thymic, pre-B-cell leukemic lymphomas compared to the controls in each strain. Myeloid leukemias were not highly induced in any of the control and (239)Pu-injected mice, and solid tumors involving the other organs were reduced in each strain after injection of 500 Bq or more. To follow up the hematological kinetics related to alpha-particle irradiation of bone marrow stem cells, sequential examinations were done in mice of each strain within 1 year after injection of 5000 Bq. The numbers of peripheral white blood cells and bone marrow cells were consistently reduced in each strain from 90 days on, while spleen cells increased from 180 days on. Granulocyte-macrophage and macrophage colony-forming cells were also consistently reduced in the bone marrow, with a compensatory increase in the spleen from 90 days on. These findings indicate that the carcinogenic and hematopoietic responses were specific to alpha-particle irradiation and were independent of mouse strain after injection with (239)Pu citrate.

Alpha Particles↗