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PubMed1996

Effect of radon on the immune system: alterations in the cellularity and functions of T cells in lymphoid organs of mouse.

Exposure to radon and its progeny induces significant damage to the cells of the respiratory tract and causes lung cancer. Whether a similar exposure to radon would alter the functions of the immune system has not been previously investigated. In the current study, we investigated the effect of exposure of C57BL/6 mice to 1000 or 2500 working-level months (WLM) of radon and its progeny by inhalation, on the number and function of T lymphocytes in lymphoid organs. The control mice received uranium ore dust carrier aerosol by inhalation. Exposure to radon induced marked decrease in the total cellularity of most lymphoid organs such as thymus, peripheral lymph nodes (PLN), and lung-associated lymph nodes (LALN), when compared to the controls. The percentage of T cells increased, while that of non-T cells decreased, in all peripheral lymphoid organs at both the doses of radon. In the thymus, particularly at 2500 WLM of radon exposure, there was a marked decrease in CD4+CD8+ T cells and an increase in the immature CD4-CD8- T cells. Such alterations in both the numbers and percentages of lymphocytes and macrophages in radon-exposed mice may have resulted from the cell killing by the alpha particles as the immune cells were migrating through the lungs, or it may have been caused by altered migration of cells, inasmuch as expression of CD44, a molecule involved in migration and homing of immune cells, was significantly altered on cells found in different lymphoid organs. In the LALN, where one would predict the largest number of damaged cells to be present, there was a significant decrease in the T-cell responsiveness to mitogens while the B-cell response was not affected. Such alterations may have resulted from the direct effect of alpha-particle exposure on the migrating lymphocytes, altered percentage of lymphocytes as seen in secondary lymphoid organs, or altered expression of adhesion molecules involved in cell activation such as CD44 and CD3. Interestingly, radon exposure caused and increase in the T- and B-cell responsiveness to mitogens in the spleen and PLN. Since there is little evidence of direct radiation dose from radon in lymphoid organs, our studies demonstrating immunological alterations suggest an indirect effect of radon exposure that may have significant repercussions on the development of hypersensitivity and increased susceptibility to infections and cancer in the lung.

Administration, Inhalation↗

PubMed1991

Theoretical response of a ZnS(Ag) scintillation detector to alpha-emitting sources and suggested applications.

The classic problem of alpha absorption is discussed in terms of the quantitative determination of the activity of "weightless" alpha sources and the specific alpha activity of extended sources accounting for absorption in the source medium and the window of a large area ZnS(Ag) scintillation detector. The relationship for the expected counting rate gamma of a monoenergetic source of active area A, specific alpha activity C, and thickness H that exceeds the effective mass density range Rs of the alpha particle in the source medium can be expressed by a quadratic equation in the window thickness x when this source is placed in direct contact with the window of the ZnS(Ag) detector. This expression also gives the expected counting rate of a finite detector of sensitive area A exposed to an infinite homogeneous source medium. Counting rates y obtained for a source separated from a ZnS(Ag) detector by different thicknesses x of window material can be used to estimate parameter values in the quadratic equation, y = a + bx + cx2. The experimental value determined for the coefficient b provides a direct estimation of the specific activity C. This coefficient, which depends on the ratio of the ranges in the source medium and detector window and not the ranges themselves, is essentially independent of the energy of the alpha particle. Although certain experimental precautions must be taken, this method for estimating the specific activity C is essentially an absolute method that does not require the use of standards, special calibrations, or complicated radiochemical procedures. Applications include the quantitative determination of Rn and progeny in air, water, and charcoal, and the measurement of the alpha activity in soil and on air filter samples.

Alpha Particles↗

PubMed1993

Single-cell gel technique supports hit probability calculations.

We have used the alkaline single-cell gel technique to provide a biological estimate of the percentage of cell nuclei "hit" by alpha particles during in vitro radon exposure. The single-cell gel electrophoretic technique measures DNA strand breaks as increased migration of the DNA out of lysed cells embedded in the middle layer of a three-layer gel formed on a microscope slide. Two of the advantages of this system are that individual cells of an exposed population can be evaluated and that histograms can be constructed to estimate the population response. Chinese hamster ovary and AL cells were each exposed to 0.39 Gy of radon, a dose at which our dosimetry model predicts that 63 and 73%, respectively, of the cell nuclei will be traversed by an alpha particle. The difference in the percentages at similar doses is mainly due to the larger nucleus volume in AL cells. A 1.5-Gy x-ray response was also evaluated as a low-LET control. As expected, the x-ray profile of DNA damage was shifted from the nonirradiated profile in the direction of greater DNA migration and approximated a normal distribution. The profile of the radon-exposed cells was biphasic, with one distribution corresponding to the control (nonirradiated) response and the other profile showing increased DNA migration. We interpret the second profile in the biphasic profile as representing cell nuclei that had received an alpha "hit." The percentages of cell nuclei in the "hit" category (approximately 51 and 45% for CHO and AL, respectively), as judged by the single-cell gel technique, were 81 and 62% of the calculated values.

Alpha Particles↗

PubMed1991

Induction of sperm head abnormalities by incorporated radionuclides: dependence on subcellular distribution, type of radiation, dose rate, and presence of radioprotectors.

In contrast to the biological effects caused by exposure to external beams of radiation, the effects of tissue-incorporated radionuclides are highly dependent on the type of radiation emitted and on their distribution at the macroscopic, microscopic, and subcellular levels, which are in turn determined by the chemical nature of the radionuclides administered. Induction of abnormalities of sperm heads in mice is investigated in this work after the injection of a variety of radiochemicals including alpha emitters. When the initial slopes of the dose-response curves are used to compare the relative biological effectiveness (RBE) of different radiocompounds, the alpha particles emitted in the decay of 210Po are more effective than Auger electrons emitted by 125I incorporated in the DNA of the spermatogonial cells, and both emissions are more effective than X rays. It is also shown that the Auger emitters (125I, 111In) distributed in the cell nucleus are more efficient in producing abnormalities than the same radionuclides localized in the cytoplasm. These findings are consistent with our earlier observations, where spermatogonial cell survival is assayed as a function of the testicular absorbed dose. Further, chronic irradiation of testis with gamma rays from intratesticularly administered 7Be is about three times more effective in causing abnormalities than a single acute exposure to 120-kVp X rays. The resulting RBE values correlate well with our data on sperm head survival with the same radiocompounds. Finally, the radioprotector cysteamine, when administered in small, nontoxic amounts, significantly reduces the incidence of sperm abnormalities from alpha-particle radiation as well as emissions from 125I incorporated into DNA, the dose reduction factors being 10 and 14, respectively.

Alpha Particles↗

PubMed2005

Intracellular sequestration of 223Ra by the iron-storage protein ferritin.

Incorporation of bone-seeking, alpha-particle-emitting, heavy-metal radionuclides dramatically increases the incidence of osteosarcoma in humans and experimental animals. The accumulation of these radionuclides within the mineral phase of the bone matrix is believed to result in local irradiation of only those proliferating cells close to the bone surface. We now present evidence for a more general pathway for the irradiation of target cells, mediated through the sequestration of heavy-metal radionuclides by the intracellular iron-storage protein ferritin. In vitro studies reveal the transfer of radionuclide from a 223Ra-transferrin complex into immunoprecipitable cytosolic ferritin. In vivo studies confirm the co-localization of incorporated 224Ra and cellular iron stores. This pathway would result in the highly localized irradiation of ferritin-containing cells. Since osteoblastic cells express large quantities of a ferritin isoform specialized in long-term metal storage, we suggest that this may represent an unrecognized source of intracellular irradiation by alpha-particle-emitting radionuclides. Such a local concentration within target cells has implications both for cellular dosimetry and for inferences of track length and target cell populations within the skeleton.

Alpha Particles↗

PubMed1985

Micronucleus induction in mammalian cell cultures treated with ionizing radiations.

Exponentially growing and plateau phase cultures of Ehrlich ascites tumor cells (suspension strain) were treated with either fast electrons, X-rays, fast neutrons or Am-241-alpha-particles in a dose range from about 0.02 Gy to 1 Gy and for comparison also at higher doses. After the first post-irradiation division, cells were scored for the presence of micronuclei and the micronucleus fraction as well as the number of micronuclei/cell was determined. Micronuclei were counted using the DNA specific stain H 33258 in a fluorescence microscope. A comparison with cytofluorometric measurements established that microscopic detection accounted for up to 90% of all micronuclei present within a sample, the rest probably being hidden in direct observation by the main nucleus. Dose response curves based on the micronucleus fraction as well as on the number of micronuclei/cell were found to be linear in the whole dose range tested at low and at high ionization density. Linearity was maintained also when repair of primary lesions was promoted or suppressed. The RBE of alpha-particles compared with X-rays was dependent on the time of fixation and was at a maximum immediately after the first division (RBE = 4.8 +/- 0.5). Micronucleus distribution showed overdispersion relative to Poissonian statistics with every radiation quality used, in accordance with earlier observations on the distribution of acentric fragments in irradiated cultures.

Alpha Particles↗

PubMed2004

DNA fragmentation in V79 cells irradiated with light ions as measured by pulsed-field gel electrophoresis. II. Simulation with a generalized broken stick model.

PURPOSE: To characterize the differences among the experimental DNA fragmentation spectra induced in Chinese hamster V79 cells by gamma-rays, low-energy protons and alpha-particles through the use of a phenomenological model. MATERIALS AND METHODS: A model of DNA fragmentation was developed as a generalization of the broken-stick model, in which the double-strand breaks induced by radiation were considered randomly placed, but in which the manifestly non-random fragmentation of the control sample was fully taken into account and considered as the initial fragment distribution. Further, an analytical method was introduced that allowed an evaluation of the deviation from randomness of the fragmentation induced by radiation. RESULTS: The analysis of the experimental distribution of DNA fragments showed that there was a progressive departure from randomness in radiation-induced fragmentation going from gamma-rays to protons and then to alpha-particles. This deviation was characterized by an enhanced induction of fragments, and therefore by a larger correlation of double-strand breaks, in the experimental range of lower molecular weights. CONCLUSION: The analysis shows that low-energy light ions induce DNA fragmentation, at the loop level of the chromatin organization, that can be significantly non-random. The same analysis can readily be applied at different length scales, and thus it could offer a basis for the study of the link between DNA damage, correlated at various spatial scales and biological end-points.

Alpha Particles↗

PubMed1995

Distribution of 210Pb at endosteal surfaces of bone from Canadian Arctic caribou.

Alpha particle energy spectra were measured at femoral endosteal surfaces of Canadian Arctic caribou (Rangifer tarandus) to assess the profile of concentration with depth of 210Po supported by 210Pb. Femur samples from five caribou all showed a pronounced superficial concentration of 210Po, in a layer 1.9 - 6.4 microns thick. Within this layer 210Po was concentrated 1.5 - 10 times with respect to diffuse volume-distributed 210Po. This result is consistent with an earlier study of 210Po at human cranial bone surfaces, which showed 210Po to be concentrated about four times in a surface layer <3 microns thick. However, the present results have higher precision than the human bone data due to the much greater concentration of 210Pb and 210Po in caribou bone. The validity of using 210Po as a marker of 210Pb, and the in vivo 210Po/210Pb ratio are discussed. As a result of the measured endosteal superficial concentration of 210Po in caribou, the alpha particle dose was calculated to be enhanced by a factor of 1.06 - 1.96 (mean 1.48) for bone lining cells, and of 1.08 - 2.39 (mean 1.69) for soft tissue above the bone surface, assuming equilibrium between 210Pb and 210Po. It is suggested that an additional longer-lived compartment for bone surface lead could be incorporated into bio-kinetic models for lead.

Alpha Particles↗

PubMed1996

Microdosimetric approach to the problem of lung cancer induced by radon progeny.

The increased risk of lung cancer arising from chronic exposure to radon progeny in Czech uranium mines was analyzed on the basis of specific energy distributions for basal and secretory cell nuclei. The distributions were calculated from published results of lung microdosimetry. Whereas classical concepts consider that cell nuclei are hit one or more times by alpha particle tracks, the microdosimetry is able to distinguish glancing (non-lethal, possibly carcinogenic) hits from alpha particle traversals near to nucleus center (which probably inactivate the cell). The simple microdosimetric model differentiates both cases by the quantity termed boundary specific energy. The importance of some confounding factors is examined. Particularly the continuous replacement of bronchial epithelium cells by the new ones is worth considering. Still, the lung cancer frequency seems to be related to the number of sensitive cells with glancing hits. This might be a relevant argument to the toxicity of radon progeny. The central idea of the model, the boundary specific energy, was tested on the basis of radiobiological experiments with isolated cell lines.

Humans↗

PubMed2001

Radon progeny dose conversion coefficients for Chinese males and females.

The airway dimensions for Caucasian males have been scaled by multiplying by factors 0.95 and 0.88 to give those for Chinese males and females, respectively. Employing the most recent data on physical and biological parameters, the radiation doses to the basal and secretory cells due to alpha particles from 218Po and 214Po, homogeneously distributed in the mucous layer, have been calculated. The emission of alpha particles has been simulated by a Monte Carlo method. For both basal and secretory cells, the dose conversion coefficients (DCCs) for physical conditions of sleep, rest, light and heavy exercise, have been obtained for Chinese males and females for unattached progeny, and for attached progeny of diameters 0.02, 0.15, 0.25, 0.30 and 0.50 micron. For basal cells, the coefficients lie in the range 0.69-6.82 mGy/(Js/m3) or 8.7-86 mGy/WLM for unattached progeny and in the range 0.045-1.98 mGy/(Js/m3) or 0.57-25 mGy/WLM for attached progeny. The corresponding ranges for Caucasian males are 1.27-8.81 mGy/(Js/m3) or 16-111 mGy/WLM-1 and 0.05-2.30 mGy/(Js/m3) or 0.64-29 mGy/WLM. For secretory cells, the coefficients lie in the range 0.095-16.82 mGy/(Js/m3) (1.2-212 mGy/WLM) for unattached progeny and in the range 0.095-6.67 mGy/(Js/m3) (1.2-84 mGy/WLM) for attached progeny. The corresponding ranges for Caucasian males are 0.34-21.51 mGy/(Js/m3) (4.3-271 mGy/WLM) and 0.1-7.78 mGy/(Js/m3) (1.3-98 mGy/WLM). The overall DCCs calculated for a typical home environment are 0.59 and 0.52 mSv/(Js/m3) (7.4 and 6.5 mSv/WLM) for Chinese males and females, respectively, which are 80 and 70% of the value, 0.73 mSv/(Js/m3) (9.2 mSv/WLM), for Caucasian males.

Activities of Daily Living↗

PubMedDate not supplied

[The microlocalization of natural uranium in bone tissue].

The author experimentally confirms the presence of a large share of uranium within the organic matrix of bone tissue and its uniform distribution within the bone mineral. It was shown in the powder-typed stratum bone cuts that the bone uranium is uniformly distributed within the bone mineral. The same is with the organic fraction of bone where uranium is uniformly distributed as well. This conclusion simplifies the calculation of the dose rate of irradiation of bone cells and red bone marrow cells with alpha-particles from the incorporated uranium, the event that these cells are plunged into a "cloud" of alpha-particles being proposed.

Animals↗

PubMed2001

Radiation dosimetry using three-dimensional optical random access memories.

Three-dimensional optical random access memories (3D ORAMs) are a new generation of high-density data storage devices. Binary information is stored and retrieved via a light induced reversible transformation of an ensemble of bistable photochromic molecules embedded in a polymer matrix. This paper describes the application of 3D ORAM materials to radiation dosimetry. It is shown both theoretically and experimentally, that ionizing radiation in the form of heavy charged particles is capable of changing the information originally stored on the ORAM material. The magnitude and spatial distribution of these changes are used as a measure of the absorbed dose, particle type and energy. The effects of exposure on 3D ORAM materials have been investigated for a variety of particle types and energies, including protons, alpha particles and 12C ions. The exposed materials are observed to fluoresce when exposed to laser light. The intensity and the depth of the fluorescence is dependent on the type and energy of the particle to which the materials were exposed. It is shown that these effects can be modeled using Monte Carlo calculations. The model provides a better understanding of the properties of these materials. which should prove useful for developing systems for charged particle and neutron dosimetry/detector applications.

Alpha Particles↗

PubMed1990

The radiotoxicology of Radithor. Analysis of an early case of iatrogenic poisoning by a radioactive patent medicine.

Radithor was a radioactive patent medicine that was touted as a metabolic stimulant and aphrodisiac. We have obtained several original samples of Radithor and have used these historical specimens and a computer-based calculation model to perform a retrospective analysis of a famous case of Radithor-related radium poisoning. Our data suggest that the victim's cumulative skeletal radiation dose may have exceeded 350 Sv by the time he died. This figure far exceeds most current estimates of what radiation exposure level would constitute a rapidly lethal dose if given acutely. The physiological response to longterm internal radiation exposure and the highly localized nature of alpha particle irradiation may require the development of new models for the assessment of risk in cases of internal alpha particle irradiation.

Bone and Bones↗

PubMed1985

Responses of 4 X-ray-sensitive CHO cell mutants to different radiations and to irradiation conditions promoting cellular recovery.

Four X-ray-sensitive mutants of CHO cells, described previously by Jeggo and Kemp (1983), showed enhanced sensitivity to both 60Co gamma-rays and 238Pu alpha-particles relative to the responses of the parent line. The enhanced response to a densely ionising radiation (alpha-particles) was less than that to X- or gamma-rays, suggesting that these mutants are deficient mainly in the repair of damage from relatively sparsely ionising radiation tracks. Plateau-phase cultures of the parental CHO cells showed considerable recovery upon irradiation with low-dose-rate gamma-rays, compared to irradiation at 'high' dose rates, but little or no recovery was seen for the mutants. Similarly, preliminary data on recovery during post-irradiation holding of plateau-phase cultures show that this process is also absent in the mutants. These responses have several similarities to those of cells from patients with the radiosensitive disorder ataxia telangiectasia (AT), and are discussed with reference to AT cells and other radiosensitive mutants.

Animals↗

PubMed1998

Heavy-ion radiobiology: new approaches to delineate mechanisms underlying enhanced biological effectiveness.

Shortly after the discovery of polonium and radium by Marie Curie and her husband and colleague, Pierre Curie, it was learned that exposure to these alpha-particle emitters produced deleterious biological effects. The mechanisms underlying the increased biological effectiveness of densely ionizing radiations, including alpha particles, neutrons and highly energetic heavy charged particles, remain an active area of investigation. In this paper, we review recent advances in several areas of the radiobiology of these densely ionizing radiations, also known as heavy ions. Advances are described in the areas of DNA damage and repair, chromosome aberrations, mutagenesis, neoplastic transformation in vitro, genomic instability, normal tissue radiobiology and carcinogenesis in vivo. We focus on technical innovations, including novel applications of pulsed-field gel electrophoresis, fluorescence in situ hybridization (FISH), linkage analysis, and studies of gene expression and protein expression. We also highlight the use of new cellular and animal systems, including those with defined DNA repair deficiencies, as well as epithelial cell model systems to assess neoplastic transformation both in vitro and in vivo. The studies reviewed herein have had a substantial impact on our understanding of the genotoxic effects of heavy ions as well as their distinct effects on tissue homeostasis. The use of these radiations in cancer therapy is also discussed. The use of both heavy-ion and proton therapy is on the upswing in several centers around the world, due to their unique energy deposition characteristics that enhance the therapeutic effect and help reduce damage to normal tissue.

Animals↗

PubMed1994

The development of a [211At]-astatinated endoradiotherapeutic drug: Part II. Therapeutic results for transplanted adenocarcinoma of the rectum in mice and associated studies.

PURPOSE: 6-[211At]-astato-MNDP is of a class of a high linear energy transfer endoradiotherapeutic drug, which selectively targets to an onco-APase isoenzyme expressed by certain epithelial and germ cell tumors. The therapeutic efficacy and acute toxicity of its endogenous alpha-particle emissions have been studied in a murine tumor model. METHODS AND MATERIALS: 211At was produced by the 207Bi(alpha,2n)211 At cyclotron-based nuclear reaction. High specific activity 6-[211At]-astato-MNDP was rapidly synthesized by in vacuo thermal heterogeneous isotopic exchange. The therapeutic potential of 6-[211At]-astato-MNDP and 211At- was determined in mice bearing a transplanted CMT-93 rectal carcinoma which exhibited onco-APase activity. RESULTS: Significant therapeutic effects due to targeted alpha-particle emissions have been confirmed for the activity dose range, 10-750 kBq 6-[211At]-astato-MNDP. A therapeutic window has been identified, whereby cure rates of approximately 45-65% were achieved following administration of 55-300 kBq 6-[211At]-astato-MNDP. Estimated tumor absorbed radiation doses were not inconsistent with clinical response. Irreversible hematoxicity or stigmata of acute radiation damage in other critical normal tissues were not encountered. Nonspecifically internalized 211At- exerted no therapeutic effect. CONCLUSION: Therapeutic results for 6-[211At]-astato-MNDP have confirmed the profound in vivo cytotoxicity of its targeted alpha-radiations in the CMT-93 tumor. Acute normal tissue toxicity was acceptable. A rationale for optimal fractionation of targeted 6-[211At]-astato-MNDP endoradiotherapy is discussed, and its putative role in the possible individualized management of certain human tumors has been proposed.

Adenocarcinoma↗

PubMed1978

The three dose components of negative pion beam and their role in pion radiotherapy.

A new method has been developed for analyzing therapeutic negative pion beams into three LET (linear energy transfer) dose components inherent in such a beam. The technique utilizes thin silicon detectors to obtain pulse height spectra produced by the various particles in the beam traversing the detectors. It is shown that a low LET group is correlated with the incoming pions, muons and electrons; a medium LET group corresponds to protons, deuterons, tritons, and high energy alpha particles; and a high LET group is due to low energy alpha particles, 3He and recoil particles. Several beams used clinically have been studied.

Energy Transfer↗

PubMed2001

Long-term genomic instability in human lymphocytes induced by single-particle irradiation.

Recent evidence suggests that genomic instability, which is an important step in carcinogenesis, may be important in the effectiveness of radiation as a carcinogen, particularly for high-LET radiations. Understanding the biological effects underpinning the risks associated with low doses of densely ionizing radiations is complicated in experimental systems by the Poisson distribution of particles that can be delivered. In this study, we report an approach to determine the effect of the lowest possible cellular radiation dose of densely ionizing alpha particles, that of a single particle traversal. Using microbeam technology and an approach for immobilizing human T-lymphocytes, we have measured the effects of single alpha-particle traversals on the surviving progeny of cells. A significant increase in the proportion of aberrant cells is observed 12-13 population doublings after exposure, with a high level of chromatid-type aberrations, indicative of an instability phenotype. These data suggest that instability may be important in situations where even a single particle traverses human cells.

Cations, Divalent↗