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1.  An iron-dependent and transferrin-mediated cellular uptake pathway for plutonium 
Nature chemical biology  2011;7(8):560-565.
Plutonium is a toxic synthetic element with no natural biological function, but it is strongly retained by humans when ingested. Using small angle X-ray scattering, receptor binding assays, and synchrotron X-ray fluorescence microscopy we find that rat adrenal gland (PC12) cells can acquire plutonium in vitro through the major iron acquisition pathway, receptor-mediated endocytosis of the iron transport protein serum transferrin; however only one form of the plutonium-transferrin complex is active. Low-resolution solution models of plutonium-loaded transferrins derived from small angle scattering demonstrate that only transferrin with plutonium bound in the protein’s C-terminal lobe and iron bound in the N-lobe (PuCFeNTf) adopts the proper conformation for recognition by the transferrin receptor protein. Although the metal binding site in each lobe contains the same donors in the same configuration and both lobes are similar, the differences between transferrin’s two lobes act to restrict, but not eliminate, cellular Pu uptake.
doi:10.1038/nchembio.594
PMCID: PMC3462652  PMID: 21706034
2.  Plutonium Uptake and Distribution in Mammalian Cells: Molecular vs Polymeric Plutonium 
Purpose
To study the cellular responses to molecular and polymeric forms of plutonium using PC12 cells derived from rat adrenal glands.
Materials and methods
Serum starved PC12 cells were exposed to polymeric and molecular forms of plutonium for three hours. Cells were washed with 10 mM EGTA, 100 mM NaCl at pH 7.4 to remove surface sorbed plutonium. Localization of plutonium in individual cell was quantitatively analyzed by synchrotron X-ray fluorescence (XRF) microscopy.
Results
Molecular plutonium complexes introduced to cell growth media in the form of NTA, citrate, or transferrin complexes were taken up by PC12 cells, and mostly co-localized with iron within the cells. Polymeric plutonium prepared separately was not internalized by PC12 cells but it was always found on the cell surface as big agglomerates; however polymeric plutonium formed in situ was mostly found within the cells as agglomerates.
Conclusions
PC12 cells can differentiate molecular and polymeric forms of plutonium. Molecular plutonium is taken up by PC12 cells and mostly co-localized with iron but aged polymeric plutonium is not internalized by the cells.
doi:10.3109/09553002.2011.584941
PMCID: PMC3679905  PMID: 21770702
PC12 Cells; plutonium polymer; molecular plutonium; X-ray fluorescence microscopy
3.  Lung Cancer Risks from Plutonium: An Updated Analysis of Data from the Mayak Worker Cohort 
Radiation research  2013;179(3):332-342.
Workers at the Mayak nuclear facility in the Russian Federation offer a unique opportunity to evaluate health risks from exposure to inhaled plutonium. Risks of mortality from lung cancer, the most serious carcinogenic effect of plutonium, were evaluated in 14,621 Mayak workers who were hired in the period from 1948–1982, followed for at least 5 years, and either monitored for plutonium or never worked with plutonium. Over the follow-up period from 1953–2008, there were 486 deaths from lung cancer, 446 of them in men. In analyses that were adjusted for external radiation dose and smoking, the plutonium excess relative risk (ERR) per Gy declined with attained age and was higher for females than for males. The ERR per Gy for males at age 60 was 7.4 (95% CI: 5.0–11) while that for females was 24 (95% CI: 11–56). When analyses were restricted to plutonium doses <0.2 Gy, the ERR per Gy for males at age 60 was similar: 7.0 (95% CI: 2.5–13). Of the 486 lung cancer deaths, 105 (22%) were attributed to plutonium exposure and 29 (6%) to external exposure. Analyses of the 12,708 workers with information on smoking indicated that the relationship of plutonium exposure and smoking was likely sub-multiplicative (P = 0.011) and strongly indicated that it was super-additive (P < 0.001). Although extensive efforts have been made to improve plutonium dose estimates in this cohort, they are nevertheless subject to large uncertainties. Large bioassay measurement errors alone are likely to have resulted in serious underestimation of risks, whereas other sources of uncertainty may have biased results in ways that are difficult to predict.
doi:10.1667/RR3054.1
PMCID: PMC3661277  PMID: 23391147
4.  Plutonium from Above-Ground Nuclear Tests in Milk Teeth: Investigation of Placental Transfer in Children Born between 1951 and 1995 in Switzerland 
Environmental Health Perspectives  2008;116(12):1731-1734.
Background
Occupational risks, the present nuclear threat, and the potential danger associated with nuclear power have raised concerns regarding the metabolism of plutonium in pregnant women.
Objective
We measured plutonium levels in the milk teeth of children born between 1951 and 1995 to assess the potential risk that plutonium incorporated by pregnant women might pose to the radiosensitive tissues of the fetus through placenta transfer.
Methods
We used milk teeth, whose enamel is formed during pregnancy, to investigate the transfer of plutonium from the mother’s blood plasma to the fetus. We measured plutonium using sensitive sector field inductively coupled plasma mass spectrometry techniques. We compared our results with those of a previous study on strontium-90 (90Sr) released into the atmosphere after nuclear bomb tests.
Results
Results show that plutonium activity peaks in the milk teeth of children born about 10 years before the highest recorded levels of plutonium fallout. By contrast, 90Sr, which is known to cross the placenta barrier, manifests differently in milk teeth, in accordance with 90Sr fallout deposition as a function of time.
Conclusions
These findings demonstrate that plutonium found in milk teeth is caused by fallout that was inhaled around the time the milk teeth were shed and not from any accumulation during pregnancy through placenta transfer. Thus, plutonium may not represent a radiologic risk for the radiosensitive tissues of the fetus.
doi:10.1289/ehp.11358
PMCID: PMC2599771  PMID: 19079728
fetus exposure; milk teeth; nuclear bomb test fallout; placenta transfer; plutonium; plutonium metabolism
5.  Lung, liver and bone cancer mortality in Mayak workers 
Workers at the Mayak nuclear facility in the Russian Federation offer the only adequate human data for evaluating cancer risks from exposure to plutonium. Risks of mortality from cancers of the lung, liver and bone, the organs receiving the largest doses from plutonium, were evaluated in a cohort of 17,740 workers initially hired 1948–1972 using, for the first time, recently improved individual organ dose estimates. Excess relative risk (ERR) models were used to evaluate risks as functions of internal (plutonium) dose, external (primarily gamma) dose, gender, attained age and smoking. By December 31, 2003, 681 lung cancer deaths, 75 liver cancer deaths and 30 bone cancer deaths had occurred. Of these 786 deaths, 239 (30%) were attributed to plutonium exposure. Significant plutonium dose-response relationships (p < 0.001) were observed for all 3 endpoints, with lung and liver cancer risks reasonably described by linear functions. At attained age 60, the ERRs per Gy for lung cancer were 7.1 for males and 15 for females; the averaged-attained age ERRs for liver cancer were 2.6 and 29 for males and females, respectively; those for bone cancer were 0.76 and 3.4. This study is the first to present and compare dose-response analyses for cancers of all 3 organs. The unique Mayak cohort with its high exposures and well characterized doses has allowed quantification of the plutonium dose-response for lung, liver and bone cancer risks based on direct human data. These results will play an important role in plutonium risk assessment.
doi:10.1002/ijc.23581
PMCID: PMC4020282  PMID: 18528867
lung cancer; liver cancer; bone cancer; plutonium; ionizing radiation; nuclear workers
6.  A Proteomic Approach to Identification of Plutonium Binding Proteins in Mammalian Cells 
Journal of proteomics  2011;75(5):1505-1514.
Plutonium can enter the body through different routes and remains there for decades; however its specific biochemical interactions are poorly defined. We, for the first time, have studied plutonium-binding proteins using a metalloproteomic approach with rat PC12 cells. A combination of immobilized metal ion chromatography, 2D gel electrophoresis, and mass spectrometry were employed to analyze potential plutonium-binding proteins. Our results show that several proteins from PC12 cells show affinity towards Pu4+-NTA (plutonium bound to nitrilotriacetic acid). Proteins from seven different spots in the 2D gel were identified. In contrast to the previously known plutonium-binding proteins transferrin and ferritin, which bind ferric ions, most identified proteins in our experiment are known to bind calcium, magnesium, or divalent transition metal ions. The identified plutonium interacting proteins also have functional roles in downregulation of apoptosis and other pro-proliferative processes. MetaCore analysis based on this group of proteins produced a pathway with a statistically significant association with development of neoplastic diseases.
doi:10.1016/j.jprot.2011.11.023
PMCID: PMC3688465  PMID: 22146473
PC12 cells; 2-D gel electrophoresis; proteomics; plutonium-binding proteins; IMAC; anti-apoptotic; GO process
7.  Plutonium release from Fukushima Daiichi fosters the need for more detailed investigations 
Scientific Reports  2013;3:2988.
The contamination of Japan after the Fukushima accident has been investigated mainly for volatile fission products, but only sparsely for actinides such as plutonium. Only small releases of actinides were estimated in Fukushima. Plutonium is still omnipresent in the environment from previous atmospheric nuclear weapons tests. We investigated soil and plants sampled at different hot spots in Japan, searching for reactor-borne plutonium using its isotopic ratio 240Pu/239Pu. By using accelerator mass spectrometry, we clearly demonstrated the release of Pu from the Fukushima Daiichi power plant: While most samples contained only the radionuclide signature of fallout plutonium, there is at least one vegetation sample whose isotope ratio (0.381 ± 0.046) evidences that the Pu originates from a nuclear reactor (239+240Pu activity concentration 0.49 Bq/kg). Plutonium content and isotope ratios differ considerably even for very close sampling locations, e.g. the soil and the plants growing on it. This strong localization indicates a particulate Pu release, which is of high radiological risk if incorporated.
doi:10.1038/srep02988
PMCID: PMC3798882  PMID: 24136192
8.  Sub-micron Hard X-ray Fluorescence Imaging of Synthetic Elements 
Analytica chimica acta  2012;722:21-28.
Synchrotron-based X-ray fluorescence microscopy (SXFM) using hard X-rays focused into sub-micron spots is a powerful technique for elemental quantification and mapping, as well as microspectroscopic measurement such as μ-XANES (X-ray absorption near edge structure). We have used SXFM to image and simultaneously quantify the transuranic element plutonium at the L3 or L2 edge as well as lighter biologically essential elements in individual rat pheochromocytoma (PC12) cells after exposure to the long-lived plutonium isotope 242Pu. Elemental maps reveal that plutonium localizes principally in the cytoplasm of the cells and avoids the cell nucleus, which is marked by the highest concentrations of phosphorus and zinc, under the conditions of our experiments. The minimum detection limit under typical acquisition conditions for an average 202 μm2 cell is 1.4 fg Pu/cell or 2.9 × 10−20 moles Pu/μm2, which is similar to the detection limit of K-edge SXFM of transition metals at 10 keV. Copper electron microscopy grids were used to avoid interference from gold X-ray emissions, but traces of strontium present in naturally occurring calcium can still interfere with plutonium detection using its Lα X-ray emission.
doi:10.1016/j.aca.2012.01.064
PMCID: PMC3688452  PMID: 22444530
9.  AMS of the Minor Plutonium Isotopes 
VERA, the Vienna Environmental Research Accelerator, is especially equipped for the measurement of actinides, and performs a growing number of measurements on environmental samples. While AMS is not the optimum method for each particular plutonium isotope, the possibility to measure 239Pu, 240Pu, 241Pu, 242Pu and 244Pu on the same AMS sputter target is a great simplification. We have obtained a first result on the global fallout value of 244Pu/239Pu = (5.7 ± 1.0) × 10−5 based on soil samples from Salzburg prefecture, Austria. Furthermore, we suggest using the 242Pu/240Pu ratio as an estimate of the initial 241Pu/239Pu ratio, which allows dating of the time of irradiation based solely on Pu isotopes. We have checked the validity of this estimate using literature data, simulations, and environmental samples from soil from the Salzburg prefecture (Austria), from the shut down Garigliano Nuclear Power Plant (Sessa Aurunca, Italy) and from the Irish Sea near the Sellafield nuclear facility. The maximum deviation of the estimated dates from the expected ages is 6 years, while relative dating of material from the same source seems to be possible with a precision of less than 2 years. Additional information carried by the minor plutonium isotopes may allow further improvements of the precision of the method.
doi:10.1016/j.nimb.2012.06.017
PMCID: PMC3617651  PMID: 23565016
Minor plutonium isotopes; Plutonium dating; Environmental plutonium; AMS
10.  The Russian radiation legacy: its integrated impact and lessons. 
Environmental Health Perspectives  1997;105(Suppl 6):1385-1391.
Information about the consequences of human exposure to radiation in the former Soviet Union has recently become available. These data add new insights and provide possible answers to several important questions regarding radiation and its impact on occupational and public health. The 1986 Chernobyl accident initiated a major and early increase in childhood thyroid cancer that resulted from ingestion of iodine-131 (131I) by young children living in the most heavily contaminated areas of Belarus, Ukraine, and Russia. No significant additional cancer or other adverse medical effects have yet been reported in the affected populations and among clean-up workers. Major psychological stress independent of radiation dose has been observed in those people thought to be exposed. During the early days of the atomic energy program in the former Soviet Union, some unfortunate events occurred. The country's first atomic test in Semipalatinsk in 1949 exposed over 25,000 people downwind from the blast to significant doses of fission products, especially 131I. During the late 1940s and the early 1950s nuclear material production facilities were developed near Chelyabinsk in the South Ural Mountains, which resulted in major releases into the environment and significant overexposures for thousands of workers and nearby populations. Chronic radiation sickness was observed early in exposed workers, and increases in leukemia and other cancers were also reported. The series of plutonium inhalation-related lung cancers and fatalities among workers exposed in that first decade appears to be unique. Long-term consequences of chronic radiation sickness and four decades of follow-up are being described for the first time. Villagers downstream from the plant consumed high levels of 137Cs and 90Sr and, it is reported, manifested increases in leukemia from internal and external exposures. Although the 40-year databases for retrospective dosimetry epidemiology studies are just beginning to be integrated and evaluated, preliminary evaluations suggest that there may be graded, significant dose-rate amelioration factors for cancer and leukemia risks in workers and the general population relative to the risk data on the Japanese atomic bomb survivors. Even for plutonium-induced lung cancers in workers, such a dose-rate effect may be evident. These experiences give us insight into the consequences of protracted radiation at high and low doses and rates. If these findings are validated and confirmed, they can provide information that reduces some of the uncertainties in retrospective radiation dosimetry and radiation risk estimates (especially for low-level, chronic exposures) for activities related to medicine as well as the handling of nuclear materials and nuclear facility decommissioning, decontamination, and demilitarization.
PMCID: PMC1469939  PMID: 9467049
11.  Alterations in the K-ras and p53 genes in rat lung tumors. 
Environmental Health Perspectives  1997;105(Suppl 4):901-906.
Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. Only two agents, TNM and plutonium, led to mutation frequencies of > 10%. In both cases, the transition mutations formed could have been derived from deamination of cytosine. The identification of non-ras transforming genes in rat lung tumors induced by mutagenic and nonmutagenic exposures such as NNK and beryllium would help define some of the mechanisms underlying cancer induction by different types of DNA damage. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarcinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 to 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors.
Images
PMCID: PMC1470039  PMID: 9255578
12.  Mortality of employees of the Atomic Weapons Establishment, 1951-82. 
BMJ : British Medical Journal  1988;297(6651):757-770.
A total of 22,552 workers employed by the Atomic Weapons Establishment between 1951 and 1982 were followed up for an average of 18.6 years. Of the 3115 who died, 865 (28%) died of cancer. Mortality was 23% lower than the national average for all causes of death and 18% lower for cancer. These low rates were consistent with the findings in other workforces in the nuclear industry and reflect, at least in part, the selection of healthy people to work in the industry and the disproportionate recruitment of people from the higher social classes. At some time during their employment 9389 (42%) of the workers were monitored for exposure to radiation, the average cumulative whole body exposure to external radiation being 7.8 mSv. Their mortality was generally similar to that of other employees, even when exposures were lagged by 10 years. The rate ratio after a 10 year lag in workers with a radiation record compared with other workers was 1.01 (95% confidence interval 0.92 to 1.10) for all causes of death and 1.06 (0.89 to 1.27) for all malignant neoplasms. The only significant differences were for prostatic cancer (rate ratio 2.23; 95% confidence interval 1.13 to 4.40) and for cancers of ill defined and secondary sites (rate ratio 2.37; 1.23 to 4.56). Cancers of lymphatic and haemopoietic tissues were notable for their low occurrence in the study population, with only four deaths from leukaemia and two from multiple myeloma in workers with a radiation record, 9.16 and 3.55 deaths respectively being expected on the basis of national rates. Among workers who had a radiation record 3742 (40%) were also monitored for possible internal exposure to plutonium, 3044 (32%) to uranium, 1562 (17%) to tritium, 638 (7%) to polonium, and 281 (3%) to actinium. In these workers mortality from malignant neoplasms as a whole was not increased, but after a 10 year lag death rates from prostatic and renal cancers were generally more than twice the national average, these excesses arising in a small group of workers monitored for exposure to multiple radionuclides. Though mortality from lung cancer in workers monitored for exposure to plutonium was below the national average, it was some two thirds higher than in other radiation workers, the excess being of borderline statistical significance. Mortality from malignant neoplasms as a whole showed a weak and non-significant increasing trend with increasing level of cumulative whole body exposure to external radiation. When the exposures were lagged by 10 years the trend became stronger and significant, the estimated increase in relative risk per 10 mSv being 7.6% (95% confidence interval 0.4% to 15.3%). This trend was confined almost entirely to workers who were also monitored for exposure to radionuclides (p<0.001), the main contributions coming from lung cancer and prostatic cancer. Exposures of the lung and prostate from internal sources of radiation were not quantified, except for the contribution from tritium. It was therefore not possible to assess the extent to which the associations were due to internally deposited radionuclides rather than external exposure. The finding for prostatic cancer taken in conjunction with the results of other studies suggest a specific occupational hazard in a small group of workers in the nuclear industry who had comparatively high exposures to external radiation and who were also monitored for internal exposure to multiple radionuclides. Research is needed to discover whether any of the radionuclides and other substances concerned are concentrated in the prostate. The occurrence of lung cancer in this workforce requires further investigation taking into account smoking habits and tissue doses from inhaled radionuclides.
PMCID: PMC1834407  PMID: 3142540
13.  Plutonium(IV) Reduction by the Metal-Reducing Bacteria Geobacter metallireducens GS15 and Shewanella oneidensis MR1▿  
Applied and Environmental Microbiology  2007;73(18):5897-5903.
The bacterial reduction of actinides has been suggested as a possible remedial strategy for actinide-contaminated environments, and the bacterial reduction of Pu(VI/V) has the potential to produce highly insoluble Pu(IV) solid phases. However, the behavior of plutonium with regard to bacterial reduction is more complex than for other actinides because it is possible for Pu(IV) to be further reduced to Pu(III), which is relatively more soluble than Pu(IV). This work investigates the ability of the metal-reducing bacteria Geobacter metallireducens GS15 and Shewanella oneidensis MR1 to enzymatically reduce freshly precipitated amorphous Pu(IV) (OH)4 [Pu(IV)(OH)4(am)] and soluble Pu(IV)(EDTA). In cell suspensions without added complexing ligands, minor Pu(III) production was observed in cultures containing S. oneidensis, but little or no Pu(III) production was observed in cultures containing G. metallireducens. In the presence of EDTA, most of the Pu(IV)(OH)4(am) present was reduced to Pu(III) and remained soluble in cell suspensions of both S. oneidensis and G. metallireducens. When soluble Pu(IV)(EDTA) was provided as the terminal electron acceptor, cell suspensions of both S. oneidensis and G. metallireducens rapidly reduced Pu(IV)(EDTA) to Pu(III)(EDTA) with nearly complete reduction within 20 to 40 min, depending on the initial concentration. Neither bacterium was able to use Pu(IV) (in any of the forms used) as a terminal electron acceptor to support growth. These results have significant implications for the potential remediation of plutonium and suggest that strongly reducing environments where complexing ligands are present may produce soluble forms of reduced Pu species.
doi:10.1128/AEM.00747-07
PMCID: PMC2074912  PMID: 17644643
14.  Cancer mortality and morbidity in employees of the United Kingdom Atomic Energy Authority, 1946-86. 
British Journal of Cancer  1993;67(3):615-624.
In further analyses of a cohort of 39,718 United Kingdom Atomic Energy Authority employees after 7 more years follow-up, cancer mortality, based on 1,506 deaths in 1946-86, was 20% below the national average. Prostatic cancer mortality showed a statistically significant association with external radiation exposure, largely confined to men who were also monitored for internal contamination by radionuclides other than plutonium. Prostatic cancer mortality was highest in radiation workers at Winfrith. In women monitored for radiation exposure, mortality from cancer of the uterus (including the cervix uteri) was increased relative to other employees, and, showed a statistically significant association with external radiation exposure. While there were some other statistically significant results, as would be expected by chance alone when multiple comparisons are made, there were no other cancer sites with consistently exceptional findings. Point estimates for risk associated with increasing exposure to radiation suggest a decrease of four deaths per 10(4) person-years per Sv for leukaemia and an increase of 20 deaths for all cancers except leukaemia, but confidence intervals indicate that a wide range of values are compatible with the data. Cancer morbidity based on 1,699 registrations in 1971-84 was 12% below the national average. Findings from site-specific analyses largely replicated those of the mortality analyses.
PMCID: PMC1968277  PMID: 8439513
15.  Multiplicative effect of inhaled plutonium oxide and benzo (a) pyrene on lung carcinogenesis in rats. 
British Journal of Cancer  1984;50(2):215-221.
This study describes the effect of intratracheal instillations (2 X 5 mg) of benzo(a)pyrene (B(a)P) on lung carcinogenesis in rats which had previously inhaled different levels of 239 plutonium oxide (220, 630, 6300 Bq, initial lung burden). Survival decreased with increasing PuO2 exposure and additional B(a)P exposure. The incidence of malignant lung tumours, adjusted for differences in survival, increased in a dose-related fashion with PuO2 dose and was elevated in the presence of additional B(a)P exposure. A multiplicative relative risk model was found to describe reasonably well the observed joint effect. The practical implications of these findings are discussed.
PMCID: PMC1976869  PMID: 6087866
16.  Histochemical Phosphatases and Metachromasia in Murine Tumours Induced by Bone Seeking Radionuclides 
British Journal of Cancer  1974;29(3):206-222.
Tumours induced in mice, either CBA normal and chimaerical, or C3H, by 90Sr or 226Ra or plutonium have been examined histochemically with (1) diazotate fast red violet LB salt in naphthol AS-MX phosphate buffer at pH 8·6 and 5·2, (2) 1: 9 dimethyl methylene blue (Taylor).
It is concluded:
(a) The diagnosis of osteosarcoma is facilitated with Taylor's Blue which stains osteoid metachromatically. Cells of osteosarcoma, like normal osteoblasts, contain alkaline phosphatase but this may be lost by mutation either in the original tumour or subsequently on passage of the tumour serially to compatible hosts.
(b) Osteosarcomata may contain giant-cells of two forms, bizarre tumour cells and osteoclasts; the latter contain acid phosphatase. Osteosarcomata which retain their osteoid on serial passage have few cells containing acid phosphatases.
(c) Primitive mesenchymal cell tumours of angiomatous form may occur, if the bone marrow is irradiated, e.g. by 90Sr-90Y and Pu. These tumours lack osteoid and cells interpretable as osteoblasts or osteoclasts (though they destroy bone).
(d) Tumours classifiable as fibrosarcomata occur rarely, and may be truly of fibroblastic origin or be mutated osteosarcomata.
(e) Lymphomata also occur when the marrow is irradiated (90Sr-90Y and Pu). They may be generalized, when their cells may contain alkaline phosphatase or lack it. They may be localized to abdominal viscera, the reticulo-sarcomatous form, in which case the cells lack alkaline phosphatase.
Images
PMCID: PMC2009098  PMID: 4133784
17.  Safety regulations of food and water implemented in the first year following the Fukushima nuclear accident 
Journal of Radiation Research  2012;53(5):641-671.
An earthquake and tsunami of historic proportions caused massive damage across the northeastern coast of Japan on the afternoon of 11 March 2011, and the release of radionuclides from the stricken reactors of the Fukushima nuclear power plant 1 was detected early on the next morning. High levels of radioiodines and radiocesiums were detected in the topsoil and plants on 15 March 2011, so sampling of food and water for monitoring surveys began on 16 March 2011. On 17 March 2011, provisional regulation values for radioiodine, radiocesiums, uranium, plutonium and other transuranic α emitters were set to regulate the safety of radioactively contaminated food and water. On 21 March 2011, the first restrictions on distribution and consumption of contaminated items were ordered. So far, tap water, raw milk, vegetables, mushrooms, fruit, nut, seaweeds, marine invertebrates, coastal fish, freshwater fish, beef, wild animal meat, brown rice, wheat, tea leaves and other foodstuffs had been contaminated above the provisional regulation values. The provisional regulation values for radioiodine were exceeded in samples taken from 16 March 2011 to 21 May 2011, and those for radiocesiums from 18 March 2011 to date. All restrictions were imposed within 318 days after the provisional regulation values were first exceeded for each item. This paper summarizes the policy for the execution of monitoring surveys and restrictions, and the outlines of the monitoring results of 220 411 samples and the enforced restrictions predicated on the information available as of 31 March 2012.
doi:10.1093/jrr/rrs032
PMCID: PMC3430419  PMID: 22843368
food safety regulation; Fukushima nuclear accident; provisional regulation value; provisional tolerance value; internal radiation exposure
18.  Direct Determination of the Intracellular Oxidation State of Plutonium 
Inorganic chemistry  2011;50(16):7591-7597.
Microprobe X-ray absorption near edge structure (μ-XANES) measurements were used to determine directly, for the first time, the oxidation state of intracellular plutonium in individual 0.1 μm2 areas within single rat pheochromocytoma cells (PC12). The living cells were incubated in vitro for 3 hours in the presence of Pu added to the media in different oxidation states (Pu(III), Pu(IV), and Pu(VI)) and in different chemical forms. Regardless of the initial oxidation state or chemical form of Pu presented to the cells, the XANES spectra of the intracellular Pu deposits was always consistent with tetravalent Pu even though the intracellular milieu is generally reducing.
doi:10.1021/ic200588p
PMCID: PMC3688463  PMID: 21755934
19.  Trench ‘Bathtubbing’ and Surface Plutonium Contamination at a Legacy Radioactive Waste Site 
Environmental Science & Technology  2013;47(23):13284-13293.
Radioactive waste containing a few grams of plutonium (Pu) was disposed between 1960 and 1968 in trenches at the Little Forest Burial Ground (LFBG), near Sydney, Australia. A water sampling point installed in a former trench has enabled the radionuclide content of trench water and the response of the water level to rainfall to be studied. The trench water contains readily measurable Pu activity (∼12 Bq/L of 239+240Pu in 0.45 μm-filtered water), and there is an associated contamination of Pu in surface soils. The highest 239+240Pu soil activity was 829 Bq/kg in a shallow sample (0–1 cm depth) near the trench sampling point. Away from the trenches, the elevated concentrations of Pu in surface soils extend for tens of meters down-slope. The broader contamination may be partly attributable to dispersion events in the first decade after disposal, after which a layer of soil was added above the trenched area. Since this time, further Pu contamination has occurred near the trench-sampler within this added layer. The water level in the trench-sampler responds quickly to rainfall and intermittently reaches the surface, hence the Pu dispersion is attributed to saturation and overflow of the trenches during extreme rainfall events, referred to as the ‘bathtub’ effect.
doi:10.1021/es403278r
PMCID: PMC3854837  PMID: 24256473
20.  Ischemic Heart Disease in Workers at Mayak PA: Latency of Incidence Risk after Radiation Exposure 
PLoS ONE  2014;9(5):e96309.
We present an updated analysis of incidence and mortality from atherosclerotic induced ischemic heart diseases in the cohort of workers at the Mayak Production Association (PA). This cohort constitutes one of the most important sources for the assessment of radiation risk. It is exceptional because it comprises information on several other risk factors. While most of the workers have been exposed to external gamma radiation, a large proportion has additionally been exposed to internal radiation from inhaled plutonium. Compared to a previous study by Azizova et al. 2012, the updated dosimetry system MWDS-2008 has been applied and methods of analysis have been revised. We extend the analysis of the significant incidence risk and observe that main detrimental effects of external radiation exposure occur after more than about 30 years. For mortality, significant risk was found in males with an excess relative risk per dose of 0.09 (95% CI: 0.02; 0.16) while risk was insignificant for females. With respect to internal radiation exposure no association to risk could be established.
doi:10.1371/journal.pone.0096309
PMCID: PMC4020749  PMID: 24828606
21.  Alveolar macrophage kinetics after inhalation of 239PuO2 by CBA/Ca mice: changes in synthesis of DNA. 
For workers in the nuclear industry, the primary route for the entry of radioactive materials into the body is by inhalation, and the rate of clearance of particles from the pulmonary region of the lung is an important factor in determining radiation dose. It is the function of alveolar macrophages (AM) to maintain the sterility of the lung and to remove insoluble particles from the respiratory surfaces and airways. The AM population is not static, and under normal conditions the loss of macrophages from the alveoli via the conducting airways is balanced by renewal. Studies of the effects of external irradiation on the kinetics of AM are numerous, but to date little is known about the effects of inhaled radioactive particles. In this investigation the effects of inhaled 239PuO2 (plutonium dioxide) particles on the synthesis of DNA by AM were studied at times up to 77 days after exposure. We also measured the number of cells recovered by bronchoalveolar lavage and the incidence of AM with nuclear aberrations. The latter provides a sensitive indicator of the effects of radiation. One of the earliest effects observed after exposure to 239PuO2 is a reduction in the number of AM recovered by lavage. This reduction is associated with a 3-fold reduction in the proportion of AM undergoing DNA synthesis at early times after exposure. The overall mean pulse labeling index of AM recovered from sham-exposed mice is 1.68%, and no trend is observed with time.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1519532  PMID: 1396470
22.  Environmental radiation and the lung 
Environmental sources of radioactive materials and their relation to lung doses and lung burdens are described. The approaches used and the problems encountered in estimating lung doses are illustrated. Exposure to radon daughter products is contrasted to exposure to plutonium as particular examples of the hazards associated with radioactive materials of different chemical and physical characteristics.
PMCID: PMC1475392  PMID: 4620334
23.  To Recycle or Not to Recycle? An Intergenerational Approach to Nuclear Fuel Cycles 
Science and Engineering Ethics  2007;14(2):177-200.
This paper approaches the choice between the open and closed nuclear fuel cycles as a matter of intergenerational justice, by revealing the value conflicts in the production of nuclear energy. The closed fuel cycle improve sustainability in terms of the supply certainty of uranium and involves less long-term radiological risks and proliferation concerns. However, it compromises short-term public health and safety and security, due to the separation of plutonium. The trade-offs in nuclear energy are reducible to a chief trade-off between the present and the future. To what extent should we take care of our produced nuclear waste and to what extent should we accept additional risks to the present generation, in order to diminish the exposure of future generation to those risks? The advocates of the open fuel cycle should explain why they are willing to transfer all the risks for a very long period of time (200,000 years) to future generations. In addition, supporters of the closed fuel cycle should underpin their acceptance of additional risks to the present generation and make the actual reduction of risk to the future plausible.
doi:10.1007/s11948-007-9049-y
PMCID: PMC2413106  PMID: 18075732
Intergenerational justice; Nuclear waste management; Reprocessing; Recycling; Future generations; Value conflicts; Sustainability
24.  Health implications of radiological terrorism: Perspectives from Israel 
September 11th events taught us, members of the medical community, that we need to prepared for the worst. Nuclear terror is no longer science fiction. Radiological weapons of mass terror come in three flavors: The first one is nuclear. Since 1992, there have been six known cases of highly enriched uranium or plutonium being intercepted by authorities as it passed in or out of the former Soviet Union. Constructing a nuclear fission weapon requires high-level expertise, substantial facilities, and lots of money. All three of which would be difficult, although not impossible, for a terrorist group to pull off without state support. However, terrorists could carry out potential mass destruction without sophisticated weaponry by targeting nuclear facilities using conventional bombs or hijacked aircrafts. Terror attacks could also carry out mass panic and radioactive contamination of people and environment by dispersal of radioactive materials with or without the use of conventional explosive devices. Most medical and para-medical personnel are not familiar with CBRN terror and radiation casualties. To lessen the impact of those potential attacks and provide care for the greatest number of potential survivors, the community as a whole – and the medical community in particular – must acquire the knowledge of the various signs and symptoms of exposure to irradiation and radioactive contamination as well as have a planned response once such an attack has occurred. Based on knowledge of radiation hazards, medical emergency planers should analyze the risks of each scenario, offer feasible solutions and translate them into internationally accepted plans that would be simple to carry out once such an attack took place. The planned response should be questioned and tested by drills. Those drills should check the triage, evacuation routes, decontamination posts, evacuation centers and receiving hospitals. It is crucial that the drill will consist of simulated casualties that will follow the evacuation route from point zero to the ED. Knowledge and exercise will reduce terror (fear) from radiation and help the community as a whole better cope with such an event. This article will review the general information of radiation types, their biological damage, clinical appearance and general concepts of nuclear event planning, focusing on medical response and focus on the Israeli perspective.
doi:10.4103/0974-2700.50747
PMCID: PMC2700597  PMID: 19561972
Multiple imputation; national trauma data bank; physiological variables
25.  Industrial Health—Meeting the Challenge* 
The modern industrial system had its origin in England just over 200 years ago. This period historically is referred to as the Industrial Revolution. It was marked by mechanical inventions in textile machinery, by advances in the manufacture of iron, and by the introduction of steam power. These, in turn, were the foundations of the factory system.
In 1784 at a cotton mill at Radcliffe, near Manchester, an epidemic of malignant fever affected the operatives and spread to the surrounding population. The situation became serious and the local justices invited Dr. Thomas Percival, a leading local physician, to investigate the nature and circumstances of the outbreak. With his colleagues and leading citizens he formed the Manchester Board of Health. The Board, through authoritative reports, made recommendations for the control of such epidemics by the establishment of isolation hospitals. They also urged the need for the improvement of environmental conditions in mills and factories and for the diminution of working hours, especially for children and women. In pursuance of these objects the Government in 1802 passed the Health and Morals of Apprentices Act. This was the first Factory Act. Since then factory legislation has been greatly extended and is the basis of statutory supervision of factories and factory workers under the inspector of factories. The development of this supervision is traced with special reference to the work of the certifying surgeons, now the appointed factory doctors, and the medical inspectors. Concurrently, public health education and workmen's compensation were advanced through legislation. Since 1935 voluntary medical services have been developed in industry. These services have not been restricted to the observance of the minimum standards prescribed by statute and so have been able to pioneer advances directed to the promotion of safety, health, and welfare in factories and other places of employment.
Radcliffe, Percival, and steam power are recognized as the growing points of the challenge to health by the Industrial Revolution. The means whereby the challenge was met are discussed.
Towards the end of the nineteenth century scientists increasingly concentrated their studies on the elements. This culminated in the isolation of the atom. During the last 10 years atomic power has become a reality and the foundation of the second Industrial Revolution. While the potential hazards of ionizing radiations had long been known and proved at Hiroshima, the inherent dangers for the general population only became impressed on the public mind by a breakdown at the Windscale No. 1 plutonium pile on October 10, 1957. Radio-active iodine escaped, contaminating the atmosphere as far afield as western Europe. A committee under the chairmanship of Sir Alexander Fleck was appointed to investigate the cause of the accident and its consequences and to make recommendations. The report, which laid special emphasis on safety and health, was published early in 1958. So by analogy, Windscale, Fleck, and atomic power are identified as the growing points of the challenge of the Second Industrial Revolution. How this challenge is to be met by doctors is discussed. It is submitted that the urgent need is to formulate now a basic philosophy for future development of industrial medicine. Continuation of the old order will not suffice: ideas must again become revolutionary. The responsibility for leadership rests on the Industrial Health Advisory Committee established in 1955 under the chairmanship of the Minister of Labour and National Service.
PMCID: PMC1037855  PMID: 13618514

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