A quantitative comparison of the chemo- and radiotoxicity of uranium at different enrichment grades.

OBJECTIVE: The radiotoxic effects of uranium are often in the focus of the public fears but the chemical toxic effects of uranium are reported to surpass radiation effects. As there is no uranium isotope that is not radioactive, it is not possible to study chemical effects fully independently from radiation effects. In order to quantitate and compare radio- and chemotoxicity, we determined the median lethal doses of uranium due to its chemical toxicity and calculated the absorbed radiological doses resulting from the ingestion or inhalation of corresponding amounts depending on the isotopic enrichment grade. Committed effective doses over 50 years are related to the stochastic health effects like cancer occurrence and can be converted to a loss of statistical life time (mean loss 0.4 day / mSv). The equivalent doses absorbed within a short time frame permits conclusion on the induction of deterministic effects (e.g. acute radiation sickness). METHOD: Simulations were based on the biokinetic models of the International Commission for Radioprotection and performed using Integrated Modules for Bioassay Analysis software. Results were compared with the doses given by the calculator of the WISE uranium project. The fractions of the total doses absorbed within different time periods were derived from the respective areas under the activity-time curves in the whole body. RESULTS: The distribution of the total dose on the organs and tissues depends on the invasion pathway and the solubility of the compound. In the case of inhalation, the absorption of the total dose is more protracted than after ingestion. The incorporation of depleted or natural uranium in lethal amounts due to nephrotoxicity does not lead to deterministic radiation effects and is associated with committed effective doses reaching at most about 200 mSv (proposed possible threshold for therapeutic interventions after accidental radionuclide incorporation). The inhalation of low enriched uranium leads to higher effective doses up to 690 mSv, but they are still insufficient to cause acute deterministic effects. Even highly enriched uranium seems not to induce radiation nephropathy, but deterministic effects on the hematopoetic system cannot be excluded in particularly sensitive patients. But the equivalent doses to the lungs associated with the inhalation of poorly soluble compounds of highly enriched uranium are in a range that may induce radiation pneumonitis. CONCLUSION: Our findings give clear evidence that for depleted and natural uranium chemical toxicity is much more marked than radiotoxicity. However, this conclusion must not be drawn for enriched and in particular highly enriched compounds that besides stochastic effects may even cause deterministic radiation effects.

Mortality (1968-2008) in a French cohort of uranium enrichment workers potentially exposed to rapidly soluble uranium compounds.

OBJECTIVES: Until recently, enrichment of uranium for civil and military purposes in France was carried out by gaseous diffusion using rapidly soluble uranium compounds. We analysed the relationship between exposure to soluble uranium compounds and exposure to external γ-radiation and mortality in a cohort of 4688 French uranium enrichment workers who were employed between 1964 and 2006. METHODS: Data on individual annual exposure to radiological and non-radiological hazards were collected for workers of the AREVA NC, CEA and Eurodif uranium enrichment plants from job-exposure matrixes and external dosimetry records, differentiating between natural, enriched and depleted uranium. Cause-specific mortality was compared with the French general population via standardised mortality ratios (SMR), and was analysed via Poisson regression using log-linear and linear excess relative risk models. RESULTS: Over the period of follow-up, 131 161 person-years at risk were accrued and 21% of the subjects had died. A strong healthy worker effect was observed: all causes SMR=0.69, 95% CI 0.65 to 0.74. SMR for pleural cancer was significantly increased (2.3, 95% CI 1.06 to 4.4), but was only based on nine cases. Internal uranium and external γ-radiation exposures were not significantly associated with any cause of mortality. CONCLUSIONS: This is the first study of French uranium enrichment workers. Although limited in statistical power, further follow-up of this cohort, estimation of internal uranium doses and pooling with similar cohorts should elucidate potential risks associated with exposure to soluble uranium compounds.

Renal cell carcinoma: Review of etiology, pathophysiology and risk factors.

BACKGROUND AND AIMS: The global incidence of renal cell cancer is increasing annually and the causes are multifactorial. Early diagnosis and successful urological procedures with partial or total nephrectomy can be life-saving. However, only up to 10% of RCC patients present with characteristic clinical symptoms. Over 60% are detected incidentally in routine ultrasound examination. The question of screening and preventive measures greatly depends on the cause of the tumor development. For the latter reason, this review focuses on etiology, pathophysiology and risk factors for renal neoplasm. METHODS: A literature search using the databases Medscape, Pubmed, UpToDate and EBSCO from 1945 to 2015. RESULTS AND CONCLUSIONS: Genetic predisposition/hereditary disorders, obesity, smoking, various nephrotoxic industrial chemicals, drugs and natural/manmade radioactivity all contribute and enviromental risks are a serious concern in terms of prevention and the need to screen populations at risk. Apropos treatment, current oncological research is directed to blocking cancer cell division and inhibiting angiogenesis based on a knowledge of molecular pathways.

A model study on the absorbed dose of radiation following respiratory intake of 238U3O8 aerosols.

Aerosols of depleted uranium oxides, formed upon high-energy impact of shells on hard targets during military operations, are able to disperse, reach the alveolar region of the lungs and be absorbed and distributed throughout various parts of the body. The absorbed particles are subjected to clearance in the upper respiratory tract, distribution to other body districts, dissolution and excretion. While the soluble forms of uranium are known to deliver a small dose of radiation to the body due to their homogeneous distribution and the low specific activity of (238)U, ceramic particles exhibit a low dissolution rate and irradiate a limited volume of tissue for a long time with alpha particles with an energy of 4.267 MeV. The extent of the irradiated tissues depends on the radius of the particles and the total intake of uranium oxides. For the measured intake of U3O8 of a war veteran (15.51 µg) the number of particles ranges from 5.56×10(4) to 6.95×10(6) for sizes of 0.4-2.0 µm. Modelling the distribution of the particles between two compartments of the body, the averaged dose absorbed in 20 y by tissues surrounding the particles and within the range of the alpha particles varies from 6.8 mGy to 0.85 Gy for lungs and 8.1 mGy to 1.0 Gy for the lymph nodes, respectively. Correspondingly, due to the clearance and redistribution, the mass irradiated by 2.0-µm particles falls in 20 y from 6.06 mg to 0.94 µg in the lungs and grows from 0 to 1.0 mg in the lymph nodes. The estimated rate of formation of hydroxyl radicals upon radiolysis of water in the lungs and lymph nodes is 5.17×10(4) d(-1) per cell after 1 y.

Actinide handling after wound entry with local or systemic decorporation therapy in the rat.

BACKGROUND: Treatment of actinide-contaminated wounds may be problematic because of contaminant physicochemical properties, dissemination and anatomical localization. This study investigates different chelation/resection protocols after contamination of rats with americium (Am) or plutonium (Pu) nitrate or mixed oxide (MOX; uranium (U), Pu oxide). METHODS: Anesthetized rats were contaminated with Am or Pu nitrate (moderately soluble) or MOX (insoluble) following wounding of hind leg muscle. DTPA (diethylene triamine pentaacetic acid) treatment (30 µmol/kg) was immediate or delayed, systemic or local and combined or not with wound resection. Actinide urinary and tissue levels were measured. RESULTS: Comparison of Pu nitrate and MOX dissemination at the wound site indicated a more heterogeneous localization of MOX particles. In all cases DTPA treatment reduced target tissue (bone, liver) activity levels even if DTPA treatment was started 7 days after contamination. Surgery alone increased urinary excretion suggesting release from the wound site but no subsequent increases in organ retention (bone, liver) were observed. The combination of surgery and DTPA increased Pu excretion and reduced tissue levels markedly. CONCLUSION: This rodent model of actinide wound contamination has been used to test different treatments. It provides evidence of activity release as a result of surgery that seems not to lead to increased organ retention.

Pulmonary health effects in Gulf War I service members exposed to depleted uranium.

OBJECTIVE: In a population of Gulf War I veterans who sustained inhalational exposure to depleted uranium during friendly fire incidents in 1991, we evaluated whether those with high body burdens of uranium were more likely to have pulmonary health abnormalities than those with low body burdens. METHODS: We compared self-reported respiratory symptoms, mean pulmonary function values, and prevalence of low-dose chest computed tomography abnormalities between high and low urine uranium groups. RESULTS: We found no significant differences in respiratory symptoms, abnormal pulmonary function values, or prevalence of chest computed tomography abnormalities between high and low urine uranium groups. Overall, the cohort's pulmonary function values fell within the expected clinical range. CONCLUSIONS: Our results support previous estimates that the depleted uranium levels inhaled during the 1991 friendly fire incidents likely do not cause long-term adverse pulmonary health effects.

Does uranium induce circulatory diseases? First results from a French cohort of uranium workers.

OBJECTIVES: Increased risk of circulatory system diseases (CSDs) was observed in nuclear workers handling uranium and plutonium in Russia and the UK. This work examines the CSD mortality after chronic intake of uranium among 2897 workers (79,892 person-years) at a uranium processing plant (1960-2006) in France. METHODS: Cumulative exposure to different uranium compounds, classified by their isotopic composition and solubility type, was quantified on the basis of a plant-specific job-exposure matrix and individual job histories. HRs and associated 95% CI for CSD (n = 111) and specific CSD categories were estimated using Cox regression models, stratified on sex and birth cohort and adjusted for potential confounders. The effect of smoking was analysed among 260 smokers (42 CSD deaths). RESULTS: Compared to unexposed workers, CSD mortality was increased among workers exposed to slowly soluble reprocessed uranium (RPU) (HR = 2.13, 95% CI = 0.96 to 4.70) and natural uranium (HR = 1.73, 95% CI = 1.11 to 2.69). The risk increased with cumulative exposure and exposure duration. In the subgroup of smokers, the risk estimates were higher but with larger CIs: HR=1.91 (95% CI = 0.92 to 3.98) for natural uranium and HR = 4.78 (95% CI = 1.38 to 16.50) for RPU. CONCLUSIONS: The authors observed that exposure to slowly soluble uranium, namely RPU, may increase the risk of CSD mortality. However, these results are preliminary since the study is lacking statistical power and many other biological and lifestyle-related factors may cause CSD. More detailed investigations are necessary to confirm these findings and analyse in depth the effects of internal radiation exposure on the circulatory system.

Reprocessed uranium exposure and lung cancer risk.

This study investigated the risk of lung cancer in regards to protracted occupational exposure to reprocessed uranium compounds. Two thousand seven hundred and nine male workers employed at the AREVA NC uranium processing plant between 1960 and 2005 in France were included in the cohort. Historical exposure to reprocessed uranium compounds classified by their solubility type was assessed on the basis of the plant's specific job-exposure matrix. Cox proportional hazard models adjusted for attained age, calendar period, and socioeconomic status were used to estimate relative risks in regards of each type of uranium compound. The relative risk of lung cancer tended to increase with decreasing solubility of reprocessed uranium compounds. The highest-though not statistically significant-relative risk was observed among workers exposed to slowly soluble reprocessed uranium dioxide. This study is the first suggesting an increasing risk of lung cancer associated with exposure to reprocessed uranium. Our results are consistent with data from experimental studies of biokinetics and the action mechanism of slowly soluble uranium compounds, but need to be confirmed in larger studies with more detailed dose-response analyses.

[Theoretic evaluation of allowable time for evacuation from occupational zone of accidentally released uranium hexafluoride].

Transdermal intake of uranium hexafluoride hydrolysis products is analysed. The authors present calculations of uranium and fluor amounts entering human body, in accordance with duration of stay in hazardous circumstances.

Exposure to subcutaneously implanted uranium dioxide impairs bone formation.

The introduction of uranium particles into subcutaneous tissue is a risk that affects workers engaged in the extraction, purification, and manufacture of uranium, as well as soldiers who are wounded with uranium shrapnel. The authors evaluated the effect of an internal source of an insoluble form of uranium on bone. Uranium dioxide powder (0.125 gm/kg body weight) was implanted subcutaneously in rats. After 30 days, animals exposed to uranium weighed less than controls. Bone formation activity in endochondral ossification and bone growth were also lower in the experimental animals, as evidenced by histomorphometric and morphometric methods. This is the first study to report bone damage resulting from continuous, nonlethal exposure to an insoluble compound of uranium dioxide over a period of 30 days.

Evaluating the risk from depleted uranium after the Boeing 747-258F crash in Amsterdam, 1992.

On 4 October 1992, a large cargo plane crashed into an apartment building in the Bijlmermeer quarter of Amsterdam. In the years following the accident, an increasing number of people started reporting health complaints, which they attributed to exposure to dangerous substances after the crash. Since the aircraft had been carrying depleted uranium as counterbalance weights and about 150 kg uranium had been found missing after clearance of the crash site, exposure to uranium oxide particles was pointed out as the possible cause of their health complaints. Six years after the accident, a risk analysis was therefore carried out to investigate whether the health complaints could be attributed to exposure to uranium oxide set free during the accident. The scientific challenge was to come up with reliable results, knowing that - considering the late date - virtually no data were available to validate any calculated result. The source term of uranium was estimated using both generic and specific data. Various dispersion models were applied in combination with the local setting and the meteorological conditions at the time of the accident to estimate the exposure of bystanders during the fire caused by the crash. Emphasis was given to analysing the input parameters, inter-comparing the various models and comparing model results with the scarce information available. Uranium oxide formed in the fire has a low solubility, making the chemical toxicity to humans less important than the radiotoxicity. Best-estimate results indicated that bystanders may have been exposed to a radiation dose of less than 1 microSv, whereas a worst-case approach indicated an upper limit of less than 1 mSv. This value is considerably less than the radiation dose for which acute effects are to be expected. It is therefore considered to be improbable that the missing uranium had indeed led to the health complaints reported.

Association of p53, K-ras and proliferating cell nuclear antigen with rat lung lesions following exposure to simulated nuclear fuel particles.

Expression of p53, K-ras, and proliferating cell nuclear antigen (PCNA) and mutations of p53 and K-ras genes in lung lesions of Han/Wistar rats were investigated by immunohistochemistry and direct DNA sequencing following a long-term exposure of animals to neutron-activated UO2 particles. The p53 protein was overexpressed in all five malignant tumors, in 62% of benign tumors, and in 42% of hyperplastic lesions examined. K-ras protein and PCNA levels were only slightly elevated in all types of lung lesions. In three malignant tumors a C-->T transition was detected in codon 288 (human 290) of the p53 gene, but this mutation was not present in seven other tumors analyzed. No mutations were detected in codons 12/13 and 61 of the K-ras gene in any of the five tumors analyzed. Our findings suggest that K-ras overexpression is a rare alteration, whereas p53 protein overexpression (sometimes associated with mutated p53 gene), as assessed with the CM5 antibody, is a relatively common phenomenon in hot particle-induced preneoplastic and neoplastic rat lung lesions.