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PubMed1992

Radon and thoron associated dose to the basal layer of the skin.

The radon related alpha-particle annual dose equivalent to the basal layer of the epidermis has been calculated theoretically and is estimated as 2.5 (range 1.7 to 17) mSv y-1, for the exposed, uncovered skin of the face and neck, at the UK average domestic radon exposure of 20 Bq m-3. The thoron-related annual dose equivalent is estimated as 0.3 (range 0 to 1.9) mSv y-1 at the equilibrium equivalent concentration of 0.3 Bq m-3 estimated for UK exposures. Considerably lower dose equivalents are received by regions of the skin which are habitually covered in clothing. The wide range in the dose estimates reflects the wide range in quoted plateout rates for radon and thoron daughters, and uncertainties in the magnitude of the electrostatic charge of the individual. To improve the dose estimates experimental measurements are needed of radon and thoron daughter deposition on the skin surface in situations corresponding to domestic exposure.

Air Pollution, Indoor↗

PubMed1993

Measuring astatine-211 distributions with SPECT.

We have investigated standard SPECT techniques (rotating gamma cameras, multi-hole collimators, and filtered backprojection reconstruction) for imaging astatine-211 distributions. Since 211At emits alpha particles, this nuclide has potential for use in radiotherapy. The capability of imaging this nuclide would allow in vivo evaluation of the distribution and stability of potential 211At-labelled radiotherapeutic agents. 211At decay yields x-rays in the 77-92 keV range in addition to 500-900 keV gamma rays. This study evaluates the feasibility of SPECT imaging using the x-ray emissions of 211At. We have evaluated several collimators, with the determination that the medium-energy collimators we used are suitable, with 7% penetration (uncollimated counts versus collimated counts). Several phantoms were imaged and attenuation coefficients were measured (narrow-beam mu = 0.182 cm-1 for 77-80 keV x-rays in water). Reconstructed images demonstrate qualitative capabilities and a simple quantitative study demonstrates good correction for attenuation and scatter (approximately 10% error), at low count densities, at least for the phantom geometries used in this study.

Astatine↗

PubMed1994

An initiation-promotion model of tumour prevalence from high-charge and energy radiations.

A repair/misrepair kinetic model for multiple radiation-induced lesions (mutation inactivation) is coupled to a two-mutation model of initiation-promotion in tissue to provide a parametric description of tumour prevalence in the mouse Harderian gland from high-energy and charge radiations. Track-structure effects are considered using an action-cross section model. Dose-response curves are described for gamma rays and relativistic ions, and good agreement with experiment is found. The effects of nuclear fragmentation are also considered for high-energy proton and alpha-particle exposures. The model described provides a parametric description of age-dependent cancer induction for a wide range of radiation fields. Radiosensitivity parameters found in the model for an initiation mutation (sigma 0 = 7.6 x 10(-10) cm2 and D0 = 148.0 Gy) are somewhat different than previously observed for neoplastic transformation of C3H10T1/2 cell cultures (sigma 0 = 0.7 x 10(-10) cm2 and D0 = 117.0 Gy). We consider the two hypotheses that radiation acts solely as an initiator or as both initiator and promoter and make model calculations for fractionation exposures from gamma rays and relativistic Fe ions. For fractionated Fe exposures, an inverse-dose-rate effect is provided by a promotion hypothesis with an increase of 30% or more, dependent on the dose level and fractionation schedule, using a mutation rate for promotion similar to that of single-gene mutations.

Animals↗

PubMed1996

Computational methods in radionuclide dosimetry.

The various approaches in radionuclide dosimetry depend on the size and spatial relation of the sources and targets considered in conjunction with the emission range of the radionuclide used. We present some of the frequently reported computational techniques on the basis of the source/target size. For whole organs, or for sources of targets bigger than some centimetres, the acknowledged standard was introduced 30 years ago by the MIRD committee and is still being updated. That approach, based on the absorbed fraction concept, is mainly used for radioprotection purposes but has been updated to take into account the dosimetric challenge raised by therapeutic use of vectored radiopharmaceuticals. At this level, the most important computational effort is in the field of photon dosimetry. On the millimetre scale, photons can often be disregarded, and beta or electron dosimetry is generally reported. Heterogeneities at this level are mainly above the cell level, involving groups of cell or a part of an organ. The dose distribution pattern is often calculated by generalizing a point source dose distribution, but direct calculation by Monte Carlo techniques is also frequently reported because it allows media of inhomogeneous density to be considered. At the cell level, alpha and electron (low-range beta or Auger) are the predominant emissions examined. Heterogeneities in the dose distribution are taken into account, mainly to determine the mean dose at the nucleus. At the DNA level, Auger electrons or alpha-particles are considered from a microdosimetric point of view. These studies are often connected with radiobiological experiments on radionuclide toxicity.

Beta Particles↗

PubMed1997

Monte Carlo calculated stopping-power ratios, water/air, for clinical proton dosimetry (50-250 MeV).

Calculations of stopping power ratios, water to air, for the determination of absorbed dose to water in clinical proton beams using ionization chamber measurements have been undertaken using the Monte Carlo method. A computer code to simulate the transport of protons in water (PETRA) has been used to calculate sw.air-data under different degrees of complexity, ranging from values based on primary protons only to data including secondary electrons and high-energy secondary protons produced in nonelastic nuclear collisions. All numerical data are based on ICRU 49 proton stopping powers. Calculations using primary protons have been compared to the simple continuous slowing-down approximation (c.s.d.a.) analytical technique used in proton dosimetry protocols, not finding significant differences that justify elaborate Monte Carlo simulations except beyond the mean range of the protons (the far side of the Bragg peak). The influence of nuclear nonelastic processes, through the detailed generation and transport of secondary protons, on the calculated stopping-power ratios has been found to be negligible. The effect of alpha particles has also been analysed, finding differences smaller than 0.1% from the results excluding them. Discrepancies of up to 0.6% in the plateau region have been found, however, when the production and transport of secondary electrons are taken into account. The large influence of nonelastic nuclear interactions on proton depth-dose distributions shows that the removal of primary protons from the incident beam decreases the peak-to-plateau ratio by a large factor, up to 40% at 250 MeV. It is therefore emphasized that nonelastic nuclear reactions should be included in Monte Carlo simulations of proton beam depth-dose distributions.

Air↗

PubMed2002

Computer modelling of radiation-induced bystander effect.

Radiation-induced genomic instability and bystander effects are now well established consequences of exposure of living cells to ionising radiation. It has been observed that cells not directly hit by radiation tracks may still exhibit radiation effects. We present a quantitative modelling of the radiation-induced bystander effect based on a diffusion model of spreading the bystander signal. The model assumes the bystander factor to be aprotein of low molecular weight, given out by the hit cell, diffusing in the medium and reacting with non-hit cells. The model calculations successfully predict the results of cell survival in an irradiated conditioned medium. The model predicts the shape of dose-effect relationship for cell survival and oncogenic transformation induced by broad-beam and micro-beam irradiation by alpha-particles.

Bystander Effect↗

PubMed2002

Modelling carcinogenic effects of low doses of inhaled radon progenies.

In this study, cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or in support of the linear no-threshold dose-effect hypothesis. In this work, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions which are characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors, that is, local per average deposition densities, were simulated, and the effects of the inhomogeneity of deposition on hit probabilities were characterised. Our results suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high even at low doses.

Administration, Inhalation↗

PubMed2004

The bystander effect model of Brenner and Sachs fitted to lung cancer data in 11 cohorts of underground miners, and equivalence of fit of a linear relative risk model with adjustment for attained age and age at exposure.

Bystander effects following exposure to alpha-particles have been observed in many experimental systems, and imply that linearly extrapolating low dose risks from high dose data might materially underestimate risk. Brenner and Sachs (2002 Int. J. Radiat. Biol. 78 593-604; 2003 Health Phys. 85 103-8) have recently proposed a model of the bystander effect which they use to explain the inverse dose rate effect observed for lung cancer in underground miners exposed to radon daughters. In this paper we fit the model of the bystander effect proposed by Brenner and Sachs to 11 cohorts of underground miners, taking account of the covariance structure of the data and the period of latency between the development of the first pre-malignant cell and clinically overt cancer. We also fitted a simple linear relative risk model, with adjustment for age at exposure and attained age. The methods that we use for fitting both models are different from those used by Brenner and Sachs, in particular taking account of the covariance structure, which they did not, and omitting certain unjustifiable adjustments to the miner data. The fit of the original model of Brenner and Sachs (with 0 y period of latency) is generally poor, although it is much improved by assuming a 5 or 6 y period of latency from the first appearance of a pre-malignant cell to cancer. The fit of this latter model is equivalent to that of a linear relative risk model with adjustment for age at exposure and attained age. In particular, both models are capable of describing the observed inverse dose rate effect in this data set.

Air Pollutants, Radioactive↗

PubMed2002

Selective uptake of p-borophenylalanine by undifferentiated thyroid carcinoma for boron neutron capture therapy.

Undifferentiated thyroid carcinoma (UTC) lacks an effective treatment. Boron neutron capture therapy (BNCT) is based on the selective uptake of 10B-boronated compounds by some tumors, followed by irradiation with an appropriate neutron beam. The radioactive boron originated (11B) decays releasing 7Li, gamma rays and alpha particles, and these latter will destroy the tumor. In order to explore the possibility of applying BNCT to UTC we have studied the biodistribution of BPA. In in vitro studies, the uptake of p-10borophenylalanine (BPA) by the UTC cell line ARO, primary cultures of normal bovine thyroid cells (BT), and human follicular adenoma (FA) thyroid was studied. No difference in BPA uptake was observed between proliferating and quiescent ARO cells. The uptake by quiescent ARO, BT, and FA showed that the ARO/BT and ARO/FA ratios were 4 and 5, respectively (p < 0.001). In in vivo studies, ARO cells were transplanted into the scapular region of NIH nude mice, and after 2 weeks BPA (350 or 600 mg/kg body weight) was injected intraperitoneally. The animals were sacrificed between 30 and 150 minutes after the injection. With 350 mg, tumor uptake was highest after 60 minutes and the tumor/normal thyroid and tumor/blood ratios were 3 and 5, respectively. When 600 mg/kg body weight BPA were administered, after 90 minutes the tumor/blood, tumor/normal thyroid, and tumor/distal skin ratios for 10B concentrations per gram of tissue were approximately 3, showing a selective uptake by the tumor. The present experimental results open the possibility of applying BNCT for the treatment of UTC.

Adenoma↗

PubMed1999

Targeting melanoma with 211At/131I-methylene blue: preclinical and clinical experience.

The increasing incidence of melanoma and a lack of effective therapy have stimulated a search for new methods of early detection and treatment of the disease. Melanin synthesized in melanoma cells presents a unique target to which the treatment can be selectively addressed, provided the pigment is recognized by a suitable drug. Methylene blue possesses a high affinity for melanin and, therefore, accumulates preferentially in melanoma cells. Since not directly toxic to the tumor, methylene blue serves as a carrier for radioisotopes and, once taken up by melanoma cells, acts as a selectively localized source of radiation. Hence, radioderivatives of the compound can be used for diagnosis and therapy of disseminated melanoma. 131I-methylene blue in conjunction with gamma camera imaging has already proved in clinical studies to be a useful tool for the detection of early melanoma dissemination. 211At-methylene blue exceptional efficacy in treating melanoma and preventing its metastatic spread without damaging normal structures when administered systemically to human melanoma-bearing mice led to the approval of this alpha-particle emitting methylene blue derivative for the Phase I clinical trial.

Animals↗

PubMed1999

Alterations of p53 in tumorigenic human bronchial epithelial cells correlate with metastatic potential.

The cellular and molecular mechanisms of radiation-induced lung cancer are not known. In the present study, alterations of p53 in tumorigenic human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells induced by a single low dose of either alpha-particles or 1 GeV/nucleon (56)Fe were analyzed by PCR-single-stranded conformation polymorphism (SSCP) coupled with sequencing analysis and immunoprecipitation assay. A total of nine primary and four secondary tumor cell lines, three of which were metastatic, together with the parental BEP2D and primary human bronchial epithelial (NHBE) cells were studied. The immunoprecipitation assay showed overexpression of mutant p53 proteins in all the tumor lines but not in NHBE and BEP2D cells. PCR-SSCP and sequencing analysis found band shifts and gene mutations in all four of the secondary tumors. A G-->T transversion in codon 139 in exon 5 that replaced Lys with Asn was detected in two tumor lines. One mutation each, involving a G-->T transversion in codon 215 in exon 6 (Ser-->lle) and a G-->A transition in codon 373 in exon 8 (Arg-->His), was identified in the remaining two secondary tumors. These results suggest that p53 alterations correlate with tumorigenesis in the BEP2D cell model and that mutations in the p53 gene may be indicative of metastatic potential.

Animals↗

PubMed2004

Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma.

Lung cancer from radon or (239)plutonium exposure has been linked to alpha-particles that damage DNA through large deletions and point mutations. We investigated the involvement of an epigenetic mechanism, gene inactivation by promoter hypermethylation in adenocarcinomas from plutonium-exposed workers at MAYAK, the first Russian nuclear enterprise established to manufacture weapons plutonium. Adenocarcinomas were collected retrospectively from 71 workers and 69 non-worker controls. Lung adenocarcinomas were examined from workers and non-worker controls for methylation of the CDKN2A (p16), O(6)-methylguanine-DNA methyltransferase (MGMT), death associated protein kinase (DAP-K), and Ras effector homolog 1 genes (RASSF1A). The prevalence for methylation of the MGMT or DAP-K genes did not differ between workers and controls, while a higher prevalence for methylation of the RASSF1A gene was seen in tumors from controls. In marked contrast, the prevalence for methylation of p16, a key regulator of the cell cycle, was increased significantly (P = 0.03) in tumors from workers compared with non-worker controls. Stratification of plutonium exposure into tertiles also revealed a striking dose response for methylation of the p16 gene (P = 0.008). Workers in the plutonium plant where exposure to internal radiation was highest had a 3.5 times (C.I. 1.5, 8.5; P = 0.001) greater risk for p16 methylation in their tumors than controls. This increased probability for methylation approximated the 4-fold increase in relative risk for adenocarcinoma in this group of workers exposed to plutonium. In addition, a trend (P = 0.08) was seen for an increase in the number of genes methylated (> or =2 genes) with plutonium dose. Here we demonstrate that exposure to plutonium may elevate the risk for adenocarcinoma through specifically targeting the p16 gene for inactivation by promoter methylation.

Adenocarcinoma↗

PubMed2001

Biomarkers specific to densely-ionising (high LET) radiations.

There have been several suggestions of biomarkers that are specific to high LET radiation. Such a biomarker could significantly increase the power of epidemiological studies of individuals exposed to densely-ionising radiations such as alpha particles (e.g. radon, plutonium workers, individuals exposed to depleted uranium) or neutrons (e.g. radiation workers, airline personnel. We discuss here a potentially powerful high LET biomarker (the H value) which is the ratio of induced inter-chromosomal aberrations to intra-arm aberrations. Both theoretical and experimental studies have suggested that this ratio should differ by a factor of about three between high LET radiation and any other likely clastogen, and will yield more discrimination than the previously suggested F value (ratio of inter-chromosomal aberrations to intra-chromosomal inter-arm aberrations). Evidence of the long-term stability of such chromosomal biomarkers has also been generated. Because these stable intra-arm anld inter-chromosomal aberrations are (1) frequent and (2) measurable at long times after exposure, this H value appears to be a practical biomarker of high LET exposure, and several in vitro studies have confirmed the approach for unstable aberrations. The approach is currently being tested in a population of Russian radiation workers exposed several decades ago to high- or low LET radiation.

Biomarkers↗

PubMed2002

Bystander effects: intercellular transmission of radiation damage signals.

Biological effects were examined in confluent cultures of fibroblasts and epithelial cells exposed to very low mean doses of alpha radiation, doses by which only 1-2% of the cells were actually traversed by an alpha particle. Enhanced frequencies of sister chromatid exchanges and HPRT mutations occurred in the non-irradiated, 'bystander' cells associated with a similar increase in the frequency of micronuclei, indicating the induction of DNA damage in these cells. In order to gain information concerning molecular pathways, changes in gene expression were examined in bystander cells by western analysis and in situ immunofluorescence staining. The expression levels of p53, p21 and MDM2 were significantly modulated in bystander cells; the damage signals leading to these changes were transmitted from irradiated to bystander cells by gap junction mediated intercellular communication. The bystander response was suppressed by incubation with superoxide dismutase as well as an inhibitor of NADPH oxidase, suggesting the effect may be mediated by oxidative stress. To examine other signalling pathways responsive to oxidative stress, the activation of stress-related kinases and their downstream transcription factors were analysed in bystander cells by western blotting and electrophoretic mobility shift assays; a 2-4-fold increase in the phosphorylation levels of JNK, ERK1/2, p90RSK, Elk-1 and ATF2 was observed. These changes were detected by 15 min after irradiation and persisted for at least 1 h. These findings indicate the activation of multiple signal transduction pathways in bystander cells, involving signals arising from the plasma membrane as well as from DNA damage.

Animals↗

PubMed2002

The genetics of radiation-induced osteosarcoma.

Individual genetic variation can influence susceptibility to the carcinogenic effects of many environmental carcinogens. In radiation-exposed populations those individuals with a greater genetically determined susceptibility would be at greater risk of developing cancer. To include this modification of risk into radiation protection schemes it is necessary to identify the genes responsible for determining individual sensitivity. Alpha-particle-induced osteosarcoma in the mouse has been adopted as a model of human radiation carcinogenesis, and genome-wide screens have been conducted for allelic imbalance and genetic linkage. These studies have revealed a series of genes involved in determining the sensitivity to radiogenic osteosarcoma formation.

Bone Neoplasms↗

PubMed2002

Observation of radiation-specific damage in human cells exposed to depleted uranium: dicentric frequency and neoplastic transformation as endpoints.

Depleted uranium (DU) is a dense heavy metal used primarily in military applications. Published data from our laboratory have demonstrated that DU exposure in vitro to immortalised human osteoblast cells (HOS) is both neoplastically transforming and genotoxic. DU possesses both a radiological (alpha-particle) and chemical (metal) component. Since DU has a low specific activity in comparison to natural uranium, it is not considered to be a significant radiological hazard. The potential contribution of radiation to DU-induced biological effects is unknown and the involvement of radiation in DU-induced biological effects could have significant implications for current risk estimates for internalised DU exposure. Two approaches were used to address this question. The frequency of dicentrics was measured in HOS cells following DU exposure in vitro. Data demonstrated that DU exposure (50 microM, 24 h) induced a significant elevation in dicentric frequency in vitro in contrast to incubation with the heavy metals, nickel and tungsten which did not increase dicentric frequency above background levels. Using the same concentration (50 microM) of three uranyl nitrate compounds that have different uranium isotopic concentrations and therefore, different specific activities, the effect on neoplastic transformation in vitro was examined. HOS cells were exposed to one of three-uranyl nitrate compounds (238U-uranyl nitrate, specific activity 0.33 microCi.g-1; DU-uranyl nitrate, specific activity 0.44 microCi.g-1; and 235U-uranyl nitrate, specific activity 2.2 microCi.g-1) delivered at a concentration of 50 microM for 24 h. Results showed, at equal uranium concentration, there was a specific activity dependent increase in neoplastic transformation frequency. Taken together these data suggest that radiation can play a role in DU-induced biological effects in vitro.

Cell Transformation, Neoplastic↗

PubMed2002

Microdosimetric one hit detector model for calculation of dose and energy response of some solid state detectors.

A microdosimetric one hit detector model has been applied to calculate dose response, energy response and relative efficiency of thermoluminescent LiF:Mg,Cu,P (MCP-N), CaF2:Tm (TLD-300) and ESR alanine detectors on radiation of different qualities. For each detector type two model parameters, the target size and the saturation parameter, alpha, have been derived. Using those parameters and the microdosimetric distributions in nanometre size targets calculated using Monte Carlo track structure codes TRION and MOCA-14 it was possible to predict a great variety of experimental data for photons, X rays, beta electrons, protons, alpha particles and heavy ions. Due to a good reproducibility of experimental data some solid state detectors might be useful to test biophysical models of radiation action. Furthermore, these models can give some insight into the physics of radiation action in solid state detectors such as the range of charge interaction, energy levels etc.

Luminescent Measurements↗

PubMed2002

Microbeams, microdosimetry and specific dose.

Dose and its usefulness as a single parameter to describe the amount of radiation absorbed are well established for most situations. The conditions where the concept of dose starts to break down are well known, mostly from the study of microdosimetry. For low doses of high LET radiation it is noted that the process of taking the limiting value of the energy absorbed within a test volume divided by the mass within that volume yields either zero or a relatively large value. The problem is further exacerbated with microbeam irradiations where the uniformity of the energy deposition is experimentally manipulated on the spatial scale of cells being irradiated. Booz introduced a quantity to deal with these problems: the unfortunately named 'mean specific energy in affected volumes'. This quantity multiplied by the probability that a test volume has received an energy deposit is equal to dose (in situations where dose can be defined). I propose that Booz's quantity be renamed 'specific dose', that is the mean energy deposited divided by the mass within a specified volume. If we believe for instance that the nucleus of a cell is the critical volume for biological effects, we can refer to the nuclear specific dose. A microbeam experiment wherein 10 per cent of the cell nuclei were targeted with 10 alpha particles would be described as delivering a nuclear specific dose of 1.6 Gy to 10 per cent of the population.

Humans↗