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PubMed2004

Stable intrachromosomal biomarkers of past exposure to densely ionizing radiation in several chromosomes of exposed individuals.

A multicolor banding (mBAND) fluorescence in situ hybridization technique was used to investigate the presence inhuman populations of a stable biomarker-intrachromosomal chromosome aberrations-of past exposure to high-LET radiation. Peripheral blood lymphocytes were taken from healthy Russian nuclear workers occupationally exposed from 1949 onward to either plutonium, gamma rays or both. Metaphase spreads were produced and chromosomes 1 and 2 were hybridized with mBAND FISH probes and scored for intra-chromosomal aberrations. A large yield of intrachromosomal aberrations was observed in both chromosomes of the individuals exposed to high doses of plutonium, whereas there was no significant increase over the (low) background control rate in the population who were exposed to high doses of gamma rays. Interchromosome aberration yields were similar in both the high plutonium and the high gamma-ray groups. These results for chromosome 1 and 2 confirm and extend data published previously for chromosome 5. Intrachromosomal aberrations thus represent a potential biomarker for past exposure to high-LET radiations such as alpha particles and neutrons and could possibly be used as a biodosimeter to estimate both the dose and type of radiation exposure in previously exposed populations.

Aged↗

PubMed2004

Down-regulation of Betaig-h3 gene is involved in the tumorigenesis in human bronchial epithelial cells induced by heavy-ion radiation.

High-energy (HZE) heavy ions, when compared to low-LET radiation, are highly effective in inducing gene mutation, chromosomal aberrations and neoplastic transformation. However, the underlying molecular mechanisms are not clearly understood. We have recently shown that the down-regulation of Betaig-h3 expression is causally linked to the tumorigenic phenotype of papillomavirus-immortalized human bronchial epithelial (BEP2D) cells treated with high-LET alpha-particle radiation. Using the BEP2D cell culture system, a radiation-induced transformation model has been established by a single 60-cGy dose of (56)Fe heavy-ion radiation. To determine whether the Betaig-h3 gene is involved in (56)Fe ion-induced tumorigenesis, the expression levels of the Betaig-h3 gene in tumorigenic cell lines and the ability of in vivo tumor suppression through the reintroduction of the Betaig-h3 gene in tumorigenic cells were determined. We found that the expression level of this gene is markedly decreased in three tumorigenic cell lines ((56)FeT1-T3) compared with parental BEP2D cells. Ectopic expression of its cDNA in the (56)FeT2 tumorigenic cells significantly suppressed their tumorigenicity. Although biologically active TGFB1 is elevated in two of three tumorigenic cell lines, all these cell lines are resistant to the induction of Betaig-h3 expression by incubating the transformed cells with exogenous TGFB1 relative to control cells. Our data strongly suggest that down-regulation of Betaig-h3 expression results from the defect in the TGFB1 signaling pathway and plays a pivotal role in the tumorigenic process induced by (56)Fe heavy-ion radiation.

Bronchi↗

PubMed2005

Lung fibrosis in plutonium workers.

There have been few systematic studies of the non-malignant health effects of alpha-particle radiation in humans. Animal studies and a report on plutonium-exposed workers from Russia suggest an association between high doses to the lung from plutonium exposure and the development of fibrotic lung disease. Prompted by a case of lung fibrosis in a retired plutonium worker, we tested the hypothesis that plutonium inhalation increases the risk for developing chest radiograph abnormalities consistent with pulmonary fibrosis. We conducted a retrospective study of nuclear weapons workers that included estimating absorbed doses to the lung with an internal dosimetry model. Our study population consisted of 326 plutonium-exposed workers with absorbed lung doses from 0 to 28 Sv and 194 unexposed workers. We compared the severity of chest radiograph interstitial abnormalities between the two groups using the International Labour Organization profusion scoring system. There was a significantly higher proportion of abnormal profusion scores among plutonium-exposed workers (17.5%) than among unexposed workers (7.2%), P < 0.01. Lung doses of 10 Sv or greater conferred a 5.3-fold risk (95% CI 1.2-23.4) of having an abnormal chest X ray consistent with pulmonary fibrosis when compared with unexposed individuals after controlling for the effects of age, smoking and asbestos exposure. This study shows that plutonium may cause lung fibrosis in humans at absorbed lung doses above 10 Sv.

Adult↗

PubMed2006

FISH chromosome analysis of plutonium workers from the Sellafield nuclear facility.

Chromosome analysis using a single-color FISH technique to paint three pairs of chromosomes was undertaken on a group of 46 retired plutonium workers with assessed bone marrow doses >60 mSv, 34 of whom were categorized as having robust dosimetry and 12 for whom internal doses were considered less reliable. Comparisons were made with a group of 34 workers with negligible radiation exposure and a group of 34 workers with similar recorded external gamma-ray doses but negligible internal dose. The simple translocation frequency of 17.65 +/- 1.96 x 10(-3) per genome equivalent for the 34 plutonium workers with robust dosimetry was significantly increased in comparison with that of 10.06 +/- 1.16 x 10(-3) per genome equivalent for the unirradiated control group (P = <0.001) and that of 13.55 +/- 1.43 x 10(-3) per genome equivalent for the group with similar external gamma-ray exposure (P = 0.012). Thus, although in vitro studies have indicated that the majority of alpha-particle-irradiated cells suffer complex non-transmissible chromosome damage, in vivo a significant proportion survive with simple exchanges that can be passed on to descendant cells. In contrast, the three groups demonstrated no significant differences in stable complex aberrations. No evidence of an increase in dicentrics or unstable complex aberrations associated with plutonium exposure was observed, and it can therefore be assumed that there is little, if any, ongoing irradiation of mature lymphocytes. The translocation frequency of 12.08 +/- 1.92 x 10(-3) per genome equivalent for the group of 12 plutonium workers with less reliable internal dosimetry could adequately be accounted for by age and external dose and indicates that the internal bone marrow doses are likely to have been overestimated. Cytogenetic analysis can therefore make a valuable contribution to the validation of internal doses from plutonium deposition.

Aged↗

PubMed1981

An electron microscopic study of the kitten liver with special reference to fat-storing cells.

In a 67-day -old female kitten, the morphological differentiation of the hepatic parenchyma has been electron microscopically examined. 1)In spite of the advanced ultrastructural differentiation of the hepatocyte, the usual location of the Golgi complex to the apical cytoplasm around the bile canaliculus has not yet been established. Numerous mitochondria are mingled with round microbodies characterized by a marginal plate and a crystalloid core. Tubular cisternae of the SER occur only around the microbodies and lack within the accumulation of glycogen alpha-particles. 2)The sinusoidal lining has been fully differentiated and is composed of the "cytoplasmic processes" and the "sieve plates" whose fenestrae average 13300 A in diameter. 3) Kupffer cell shows an active phagocytosis to blood cells. The fuzzy coat is unsatisfactorily preserved. The cytoplasm occasionally shows short segments of a worm-like body. 4) The fat-storing cell (FSC) contains a small amount of lipid droplets which mostly appear within the dense accumulation of glycogen beta-particles. Also empty FSCs devoid of lipid droplets mostly possess glycogen accumulations. The glycogen accumulations enclosing lipid droplets are closely juxtaposed by cisternae of the RER and mitochondria, suggesting the possible involvement of these organelles as well as glycogen in the lipid synthesis in the FSC. In most FSCs, abundant cisternae of the RER are dilated and filled up with a finely flocculent material, suggesting an active production of collagen precursor. The FSCs possess abundant microfilaments and microtubules. A single cilium is issued into the Disse's space from one of the paired centrioles located in the Golgi area. 5) The Disse's space of the kitten contains, besides FSCs, plasma cells and macrophages. The latter agree in ultrastructure with the Kupffer cells and are assumed to be transformed into them by being incorporated in the endothelial lining of the sinusoid.

Animals↗

PubMed1999

Residential radon exposure and risk of lung cancer in Missouri.

OBJECTIVES: This study investigated residential radon exposure and lung cancer risk, using both standard radon dosimetry and a new radon monitoring technology that, evidence suggests, is a better measure of cumulative radon exposure. METHODS: Missouri women (aged 30 to 84 years) newly diagnosed with primary lung cancer during the period January 1, 1993, to January 31, 1994, were invited to participate in this population-based case-control study. Both indoor air radon detectors and CR-39 alpha-particle detectors (surface monitors) were used. RESULTS: When surface monitors were used, a significant trend in lung cancer odds ratios was observed for 20-year time-weighted-average radon concentrations. CONCLUSIONS: When surface monitors were used, but not when standard radon dosimetry was used, a significant lung cancer risk was found for radon concentrations at and above the action level for mitigation of houses currently used in the United States (148 Bqm-3). The risk was below the action level used in Canada (750 Bqm-3) and many European countries (200-400 Bqm-3).

Adult↗

PubMed1996

Targeting disseminated melanoma with radiolabelled methylene blue: Comparative bio-distribution studies in man and animals.

Targeted radiotherapy for pigmented melanoma with 3,7-(dimethylamino) phenazathionium chloride [methylene blue (MTB)] labelled with Astatine-211 (211At; alpha-particle emitter) proved to be very effective in animal model systems. Since the results justified an introduction of the treatment to the clinic, the aim of the bio-distribution studies using [123I]-MTB and [131I]-MTB in patients was to confirm selectiveness of radiolabelled MTB uptake in melanoma lesions. The investigations were carried out using planar and SPECT (single photon emission computed tomography) gamma-cameras. A stable uptake of radioiodinated MTB was found in pigmented melanomas in man, with tumour/surrounding tissue and tumour/blood ratios amounting to 9 at 19 h after a single i.v. injection. A time-dependent kinetics of radioiodinated MTB distribution was similar to that observed in human melanoma-bearing athymic mice. Blood radioactivity decreased by about 90% during the first 2.5 min after i.v. injection of the compound (T1/2biol = 0.58 min). Its retention time in various organs was either the same or very similar to that characteristic of the blood. A rapid uptake of radioiodinated MTB in the liver and kidneys confirmed the importance of these organs in excreting the compound: 25-30% of the radioactivity administered was expelled with urine over the first 24 h after the injection. There was no obvious retention of radioiodinated MTB in the brain over the observation period and in the eyes for at least the first 14 h.

Adult↗

PubMed1996

Auger-electron spectra of radionuclides for therapy and diagnostics.

The present paper documents the calculation of radiation spectra and of radial dose distribution around a point source for 24 selected radionuclides. The radionuclides were ordered into three groups: Nuclides potentially useful for therapy by emission of Auger electrons: 51Cr, 64Cu, 67Ga, 73Se, 75Se, 77Br, 80mBr, 94Tc, 99mTc, 114mIn, 115mIn, 123I, 124I, 125I, 167Tm, 193mPt, and 195mPt, nuclides potentially useful for therapy by alpha-particles with additional emission of Auger electrons: 212Bi, 211At and 255Fm, and nuclides potentially useful for electron Auger-therapy with simultaneous PET diagnosis: 73Se, 94Tc and 124I. The calculations imply strongly the development of labelled DNA-seeking compounds useful as carrier for the Auger- and Coster-Kronig electron-emitting radionuclides.

Half-Life↗

PubMed1996

Radioprotection by DMSO against the biological effects of incorporated radionuclides in vivo--Comparison with other radioprotectors and evidence for indirect action of Auger electrons.

Dimethyl sulfoxide (DMSO) was studied for its capacity to protect against the biological effects of chronic irradiation by incorporated radionuclides. Spermatogenesis in mice was used as experimental model and spermatogonial cell survival was the biological endpoint. DMSO was injected intratesticularly 4 h prior to a similar injection of the radiochemical and the spermhead survival determined. Iodine-125 was localized in either the cytoplasm (H125IPDM) or in the DNA (125IUdR) of the testicular cells. Protection was observed against the high-LET type effects of DNA-bound 125I as well as the low-LET effects of cytoplasmically localized 125I with dose modification factors (DMF) of 3.1+/-1.0 and 4.4+/-1.0 respectively. No protection (DMF = 1.1+/-0.1) was observed against the effects of high-LET 5.3 MeV alpha particles of 210Po. The present findings provide supporting evidence that the mechanism responsible for the extreme biological damage caused by DNA-bound Auger emitters is largely radical mediated and therefore indirect in nature.

Animals↗

PubMed1999

Mortality after long-term exposure to radioactive Thorotrast: a forty-year follow-up survey in Sweden.

To evaluate temporal patterns of cause-specific mortality after long-term exposure to the alpha-particle-emitting contrast medium Thorotrast, we investigated a cohort consisting of 693 Swedish patients with neurological disorders who received Thorotrast during cerebral angiography, with follow-up ending in 1993. Standardized mortality ratios (SMRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population. Persons exposed to Thorotrast had significant excesses of all causes of death (SMR = 2.8; 95% CI 2.5-3.0), with similar increases noted for men and women. The largest risks were observed for deaths from hematological causes (SMR = 16.4; n = 8), cerebrovascular diseases (SMR = 10.1; n = 18), gastrointestinal disorders including liver cirrhosis (SMR = 5.2; n = 36), and tumors (SMR = 4.7; n = 187). There was a significant decrease in SMR with time since injection for cerebrovascular and circulatory diseases, indicative of the impact of underlying neurological disorders. In contrast, the SMR increased significantly with time for tumors and gastrointestinal diseases, suggestive of a detrimental effect of cumulative radiation dose. A significant dose-response relationship was found for all causes of death and malignant tumors among all age groups, and since SMR increased with time for the latter category, this is consistent with an effect of cumulative radiation exposure on cancer development. However, the findings should be treated with caution, since selection bias may have influenced some of the results.

Aged↗

PubMed1999

Effects of radiation on incidence of primary liver cancer among atomic bomb survivors.

We describe the radiation risk for primary liver cancers between 1958 and 1987 in a cohort of atomic bomb survivors in Hiroshima and Nagasaki, Japan. The analysis is based on a comprehensive pathology review of known or suspected liver neoplasms that generated 518 incident, first primary cases, mostly hepatocellular carcinoma. Excess relative risk from atomic bomb radiation was linear: 0.81 per sievert weighted liver dose (95% CI [0.32, 1.43]; P < 0.001). Males and females had similar relative risk so that, given a threefold higher background incidence in males, the radiation-related excess incidence was substantially higher in males. Excess risk peaked for those with age at exposure in the early 20s; there was essentially no excess risk in those exposed before age 10 or after age 45. Whether this was due to a difference in sensitivity or possible confounding by other factors could not be addressed retrospectively in the full cohort. A paucity of cholangiocarcinoma and hemangiosarcoma cases suggested that they are not significantly associated with whole-body radiation exposure, as they are with the internal alpha-particle-emitting radiological contrast medium Thorotrast. Because most of the radiation-related excess cases occurred among males, it is important to ascertain what factors put men at greater risk of radiation-related liver cancer.

Cohort Studies↗

PubMed1999

Radon testing in households with a residential smoker--United States, 1993-1994.

Epidemiologic investigations of underground miners and studies of alpha particle carcinogenesis among laboratory animals suggest that exposure to the radioactive decay products (progeny) of radon is an important risk factor for lung cancer. Persons who smoke cigarettes and are exposed to these radon progeny have a substantially greater risk for developing malignancy than nonsmokers. Residential radon concentrations above the U.S. Environmental Protection Agency's (EPA) action level of 4 pCi/L are the primary sources of exposure among the general population. EPA and the Public Health Service promote home testing for radon, especially in households with a person who smokes. However, it is unknown whether households that contain smokers are more likely than those without smokers to test for radon. To characterize radon testing practices of households that contain a person who smokes within the dwelling (i.e., residential smoker), CDC analyzed survey data from the National Health Interview Survey (NHIS). This report summarizes the results of this analysis, which indicates that households with a residential smoker are significantly less likely to test for radon than those without smokers.

Air Pollutants, Radioactive↗

PubMed1999

Malignancies in patients treated with high doses of radium-224.

Predominantly from 1945 to 1955, a group of patients in Germany was treated with multiple injections of the short-lived alpha-particle emitter (224)Ra. The patients suffered from ankylosing spondylitis, tuberculosis and in a few cases from other diseases. The "Spiess study" (study I) follows up the health of 899 of these patients; it includes most of the patients who were treated with high doses (mean bone surface dose: 30 Gy, mean specific activity: 0.66 MBq/kg), and nearly all of those treated under the age of 21 years. The most striking consequence of the (224)Ra injections was the occurrence of 56 malignant bone tumors. They appeared in a temporal wave that peaked around 8 years after exposure. A new analysis was recently performed, because a reassessment of the dosimetry resulted in changed bone surface doses, especially for the patients treated at younger ages. Averaged over all ages at exposure, the estimated risk coefficient is in general agreement with earlier analyses. However, there is now an increase in bone tumor risk that is significantly greater for younger ages at exposure. The earlier finding of an inverse protraction factor is confirmed. During the most recent years of follow-up, a significant excess of nonskeletal solid malignancies has become manifest. In 1998, a significant increase of breast cancer incidence, of soft tissue malignancies, of thyroid carcinomas, and of liver, kidney and bladder cancer was found. An eightfold increased risk of mammary cancers in those treated at a young age is particularly striking. Equally notable are two cases of breast cancer in male patients. To identify potential confounders, a control group of tuberculosis patients not treated with (224)Ra was established. The comparison confirms that the (224)Ra treatment is responsible for most of the excess of mammary cancer.

Adolescent↗

PubMed1999

Late effects in ankylosing spondylitis patients treated with 224Ra.

This study is comprised of 1577 ankylosing spondylitis patients from 9 German hospitals who have been treated with multiple injections of (224)Ra. The majority of the patients, most of them treated in the years 1948-1975, received one series of 10 weekly intravenous injections of about 1 MBq of (224)Ra each. This dose leads to a mean absorbed dose due to alpha-particle radiation of 0.56 Gy to the marrow-free skeleton of a 70- kg man (mean bone surface dose of about 5 Gy). To provide comparative information on causes of death and on health effects possibly related to the basic disease itself, a control group of 1462 ankylosing spondylitis patients with roughly the same age distribution has been established. By the end of 1998, 649 patients in the exposed group and 762 control patients had died. Among other observations, it is of particular interest that 13 cases of leukemia in the exposed group have been observed. This is a highly significant excess (P < 0.001) compared to a standard population, but only a marginally significant excess in comparison to the seven cases observed in the control group. Subclassification of the leukemias shows a clear preponderance of the myeloid leukemias in the exposed group (8 cases observed compared to 1.7 cases expected, P < 0.001), whereas in the control group the observed cases are within the expected range for myeloid leukemia (3 cases observed compared to 2.2 cases expected, P = 0.3). The (224)Ra cohort of the earlier study (higher-dose group) has provided a risk coefficient that predicts about 8 excess malignant bone tumors for the irradiated cohort in this study. In actuality, 4 cases of malignant tumors in the skeleton have been observed so far. However, excess of breast cancer has not been observed in either the irradiated or the control group, which is in contrast to the findings in the earlier (224)Ra cohort of Study I.

Adult↗

PubMed1999

Pathology of radium-induced bone tumors: new aspects of histopathology and histogenesis.

A revision of bone tumor pathology in patients treated with multiple injections of the short-lived alpha-particle emitter radium-224, predominantly for tuberculosis and ankylosing spondylitis, revealed an unexpectedly high proportion of bone sarcomas of the fibrous connective tissue type. This included the first case of malignant fibrous histiocytoma of bone described after internal irradiation. A comparison of bone tumor types in the radium-224 patients and bone sarcoma after incorporation of radium-226 and radium-228 and external irradiation and in tumors arising at sites of pre-existing bone lesions showed the same spectrum of tumors. The high incidence of bone tumors of the fibroblastic and fibrohistiocytic type was observed in all these "secondary" bone sarcomas. These results suggest that a close histogenetic relationship exists between disorder of the local milieu caused by deterministic radiation damage accompanied by disturbances of the remodeling process. The reactive proliferation of the predominantly fibroblastic tissue could be the presumptive origin of these special types of radiation-induced bone sarcomas.

Bone Neoplasms↗

PubMed1999

Accelerator mass spectrometry for the detection of ultra-low levels of plutonium in urine, including that excreted after the ingestion of Irish sea sediments.

Currently, most methods for the quantitative assessment of (239)Pu have minimum detection levels (25 microBq for alpha-particle spectrometry) that are much higher than the levels of this isotope in many human bioassay and environmental samples. Accordingly, a priority has existed to develop methods that are more sensitive. Fission-track and ICP-MS methods have been used, but these can suffer either from an uncertain level of removal and/or recovery of uranium or from isobaric mass interferences. Accelerator mass spectrometry (AMS) has no such disadvantages, and its demonstrated detection limits for plutonium isotopes approach levels of attograms, equivalent to about 500 nBq for (239)Pu. This paper describes the application of AMS to the measurement of (239)Pu in urine produced by youths living in London (3.5 microBq day(-1)) and by adults (approximately 2-260 microBq day(-1)), some of whom were exposed occupationally. In addition, an experiment was undertaken to measure the fasted absorbed fraction of ingested plutonium after the ingestion of 15 g of Irish Sea sediment by a volunteer. The measured absorbed fraction was 4.5 x 10(-5). It is concluded that accelerator mass spectrometry is a suitable method for the ultra-trace detection of plutonium.

Adult↗

PubMed1999

The reticuloendothelial system and macrophage-monocyte system in thorotrast patients.

To evaluate the function of the reticuloendothelial system and macrophage-monocyte system, blood samples from Thorotrast patients and age-matched healthy controls were used to determine the titer of plasma antibodies to lipid A and the numbers of several lymphocyte subclasses in peripheral blood and for an autoradiographic study of peripheral blood monocytes. The titer of plasma IgM class antibodies to lipid A was significantly elevated in the Thorotrast patients. Counts of CD 11-positive lymphocytes and CD 57-positive lymphocytes, which correspond to monocytes and natural killer cells, respectively, were significantly increased in the Thorotrast patients. Autoradiography showed that alpha-particle tracks were emitted from the monocytes isolated from the peripheral blood of Thorotrast patients. Thus the depressed function of the reticuloendothelial system resulted in the activation of the macrophage-monocyte system in the Thorotrast patients.

Aged↗

PubMed1999

Influence of exposure rate on lung cancer induction in rats exposed to radon progeny.

Animal studies were used in addition to epidemiological studies to investigate the effects of exposure, exposure rate and other factors in predicting risks resulting from exposures to radon progeny. A trend toward increasing tumor risk with decreasing exposure rate was observed in rats exposed at a cumulative exposure varying from about 0.72 J h m(-3) (200 WLM) up to 10.8 J h m(-3) (3,000 WLM) and high exposure rates varying from 25 WLM per week to 500 WLM per week. In contrast, at low cumulative exposure, comparable to lifetime domestic indoor exposures or lifetime occupational exposure in uranium mines, no evidence of an inverse exposure-rate effect was found. Chronic radon exposure at 0.09 J h m(-3) (25 WLM), protracted over 18 months, at a potential alpha-particle energy concentration (PAEC) of 0.042 mJ m(-3) (2 WL), resulted in fewer lung carcinomas in rats than a similar cumulative exposure protracted over 4 to 6 months at a PAEC of 2.1 mJ m(-3) (100 WL). The preliminary results of a new series of experiments carried out at relatively low cumulative exposures of 0.36 J h m(-3) (100 WLM) and PAEC varying from 0.21 mJ m(-3) (10 WL) to 3.15 mJ m(-3) (150 WL) indicate that at cumulative exposures comparable to lifetime indoor or occupational exposures, the risk of lung cancer in rats decreases with decreasing PAEC, i.e. exposure rate. These data suggest that the risk of radon-induced lung cancer results from a complex interplay between cumulative exposure and exposure rate at a given exposure level.

Animals↗