A Monte Carlo t Test to Evaluate Mesothelioma and Radiation in the US Transuranium and Uranium Registries.

A cluster of nine mesothelioma cases was observed among 341 registrants' deaths in the US Transuranium and Uranium Registries. Descriptive analysis showed that mesothelioma cases had the highest average cumulative external radiation dose compared with lung cancer, other cancer, and noncancer deaths. Further analysis indicated that the mesothelioma cluster was very different demographically from lung cancer, other cancer, and noncancer deaths. Therefore, an internally matched case-control approach was applied to evaluate the differences in an average cumulative external radiation dose between mesothelioma deaths and other causes of death. A Monte Carlo t test was used to examine the statistical significance of the differences. The results showed that there were no significant statistical differences in an average cumulative external radiation dose between mesothelioma and lung cancer, other cancers, or noncancers for the internally matched cases and controls.

Medical effects of internal contamination with actinides: further controversy on depleted uranium and radioactive warfare.

The Nuclear Age began in 1945 with testing in New Mexico, USA, and the subsequent bombings of Hiroshima and Nagasaki. Regardless of attempts to limit the development of nuclear weapons, the current world arsenal has reached the staggering dimensions and presents a significant concern for the biosphere and mankind. In an explosion of a nuclear weapon, over 400 radioactive isotopes are released into the biosphere, 40 of which pose potential dangers including iodine, cesium, alkaline earths, and actinides. The immediate health effects of nuclear explosions include thermal, mechanical, and acute radiation syndrome. Long-term effects include radioactive fallout, internal contamination, and long-term genotoxicity. The current controversial concern over depleted uranium's somatic and genetic toxicity is still a subject of worldwide sustained research. The host of data generated in the past decades has demonstrated conflicting findings, with the most recent evidence showing that its genotoxicity is greater than previously considered. Of particular concern are the osteotropic properties of uranium isotopes due to their final retention in the crystals of exchangeable and nonexchangeable bone as well as their proximity to pluripotent stem cells. Depleted uranium remains an unresolved issue in both warfare and the search for alternative energy sources.

Radiological and chemical toxicity due to ingestion of uranium through drinking water in the environment of Bangalore, India.

Groundwater samples collected from 96 bore wells in the study area (city of Bangalore) were analysed for concentration of natural uranium using laser-induced fluorimetry. The risk to the population of the region associated with radiological and chemical toxicity of uranium due to its ingestion through drinking water over a lifetime was estimated. The concentration of uranium was found to be in the range 0.136 to 2027.5 µg L(-1) with an average value of 92.42 µg L(-1). In the present study, about 61% of the samples show concentrations of uranium within the safe limit of 30 µg L(-1) as set by the world health organisation. The radiological risk estimated as lifetime cancer risk is in the range 4.3 × 10(-7) to 6.4 × 10(-3) with an average of 2.9 × 10(-4). The chemical toxicity risk measured as lifetime average daily dose is found to range from 0.005 to 75.42 µg kg(-1) d(-1). The reference dose estimated as 1.12 µg kg(-1) d(-1) was used to assess the chemical toxicity. The results indicate that the chemical toxicity due to ingestion of uranium through drinking water is of more concern than the radiological toxicity. The present study, being the first of its kind in this region, will augment the database of uranium in groundwater.

Zinc protects human kidney cells from depleted uranium-induced apoptosis.

Depleted uranium (DU) is a weak radioactive heavy metal, and zinc (Zn) is an effective antidote to heavy metal poisoning. However, the effect of Zn on DU-induced cytotoxicity and apoptosis is not completely understood. The purpose of this study was to evaluate the effect of Zn on DU-induced cell apoptosis in human kidney cells (HK-2) and explore its molecular mechanism. Pre-treatment with Zn significantly inhibited DU-induced apoptosis. It reduced the formation of reactive oxygen species in the cells, increased the catalase (CAT) and glutathione (GSH) concentrations, suppressed the DU-induced soluble Fas receptor (sFasR) and soluble Fas ligand (sFasL) overexpression, suppressed the release of cytochrome c and apoptosis inhibitor factor (AIF) from mitochondria to cytoplasm, inhibited the activation of caspase-9, caspase-8 and caspase-3, and induced metallothionein (MT) expression. Furthermore, exogenous MT effectively inhibited DU-induced cell apoptosis. In conclusion, mitochondrial and FasR-mediated apoptosis pathways contribute to DU-induced apoptosis in HK-2 cells. Through independent mechanisms, such as indirect antioxidant effects, inhibition of the activation of caspase-9, caspase-8 and caspase-3, and induction of MT expression, Zn inhibits DU-induced apoptosis.

Impact of chemical exposure on cancer mortality in a French cohort of uranium processing workers.

BACKGROUND: Nuclear workers may be exposed to a variety of chemical hazards, in addition to radiation. We examined the effect of chemical exposures on cancer mortality among French uranium processing workers at the AREVA NC Pierrelatte facility. METHODS: A cohort of 2,897 uranium processing workers employed for at least 6 months was followed from 1968 through 2006. Exposure to uranium and potentially carcinogenic chemicals was assessed with a plant-specific job-exposure matrix. Mortality hazard ratios (HRs) for cancers of the lung, lymphohematopoietic system, kidney and bladder, brain and central nervous system (BCNS), and prostate were estimated for each specific chemical exposure, with Cox regression models stratified for sex and calendar period and adjusted for socioeconomic status. Additional adjustments enabled us to examine the effect of co-exposure to uranium and other chemicals. RESULTS: Exposure to aromatic solvents was associated with increased risk of BCNS malignancies after adjustment for other chemicals (HR=6.53, 95% CI=1.14-37.41; n=6) and for other chemicals and uranium (HR=7.26, 95% CI=0.90-58.19) in the annual exposure status model. Selected groups of lymphohematopoietic cancers were found associated with solvent exposure. Inconclusive results were found regarding chromium (VI) exposure, since only 2 workers died from lung cancer among 109 exposed. CONCLUSION: Based on our pilot study, it seemed important to take into account chemical exposures in the analyses of cancer mortality among French uranium processing workers.

Lung cancer mortality among uranium gaseous diffusion plant workers: a cohort study 1952-2004.

BACKGROUND: 9%-15% of all lung cancers are attributable to occupational exposures. Reports are disparate regarding elevated lung cancer mortality risk among workers employed at uranium gaseous diffusion plants. OBJECTIVE: To investigate whether external radiation exposure is associated with lung cancer mortality risk among uranium gaseous diffusion workers. METHODS: A cohort of 6820 nuclear industry workers employed from 1952 to 2003 at the Paducah uranium gaseous diffusion plant (PGDP) was assembled. A job-specific exposure matrix (JEM) was used to determine likely toxic metal exposure categories. In addition, radiation film badge dosimeters were used to monitor cumulative external ionizing radiation exposure. International Classification for Disease (ICD) codes 9 and 10 were used to identify 147 lung cancer deaths. Logistic and proportional hazards regression were used to estimate lung cancer mortality risk. RESULTS: Lung cancer mortality risk was elevated among workers who experienced external radiation >3.5 mrem and employment duration >12 years. CONCLUSION: Employees of uranium gaseous diffusion plants carry a higher risk of lung cancer mortality; the mortality is associated with increased radiation exposure and duration of employment.

Cancer incidence in Dutch Balkan veterans.

Suspicion has been raised about an increased cancer risk among Balkan veterans because of alleged exposure to depleted uranium. The authors conducted a historical cohort study to examine cancer incidence among Dutch Balkan veterans. Male military personnel (n=18,175, median follow-up 11 years) of the Army and Military Police who had been deployed to the Balkan region (1993-2001) was compared with their peers not deployed to the Balkans (n=135,355, median follow-up 15 years) and with the general Dutch population of comparable age and sex. The incidence of all cancers and 4 main cancer subgroups was studied in the period 1993-2008. The cancer incidence rate among Balkan deployed military men was 17% lower than among non-Balkan deployed military men (hazard ratio 0.83 (95% confidence interval 0.69, 1.00)). For the 4 main cancer subgroups, hazard ratios were statistically non-significantly below 1. Also compared to the general population cancer rates were lower in Balkan deployed personnel (standardised incidence rate ratio (SIR) 0.85 (0.73, 0.99). The SIR for leukaemia was 0.63 (0.20, 1.46). The authors conclude that earlier suggestions of increased cancer risks among veterans are not supported by empirical data. The lower risk of cancer might be explained by the 'healthy warrior effect'.

Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau.

Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2 × 10(-5)) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.

The performance of functional methods for correcting non-Gaussian measurement error within Poisson regression: corrected excess risk of lung cancer mortality in relation to radon exposure among French uranium miners.

A broad variety of methods for measurement error (ME) correction have been developed, but these methods have rarely been applied possibly because their ability to correct ME is poorly understood. We carried out a simulation study to assess the performance of three error-correction methods: two variants of regression calibration (the substitution method and the estimation calibration method) and the simulation extrapolation (SIMEX) method. Features of the simulated cohorts were borrowed from the French Uranium Miners' Cohort in which exposure to radon had been documented from 1946 to 1999. In the absence of ME correction, we observed a severe attenuation of the true effect of radon exposure, with a negative relative bias of the order of 60% on the excess relative risk of lung cancer death. In the main scenario considered, that is, when ME characteristics previously determined as most plausible from the French Uranium Miners' Cohort were used both to generate exposure data and to correct for ME at the analysis stage, all three error-correction methods showed a noticeable but partial reduction of the attenuation bias, with a slight advantage for the SIMEX method. However, the performance of the three correction methods highly depended on the accurate determination of the characteristics of ME. In particular, we encountered severe overestimation in some scenarios with the SIMEX method, and we observed lack of correction with the three methods in some other scenarios. For illustration, we also applied and compared the proposed methods on the real data set from the French Uranium Miners' Cohort study.

Quantitative relationship between silica exposure and lung cancer mortality in German uranium miners, 1946-2003.

BACKGROUND: In 1996 and 2009, the International Agency for Research on Cancer classified silica as carcinogenic to humans. The exposure-response relationship between silica and lung cancer risk, however, is still debated. Data from the German uranium miner cohort study were used to further investigate this relationship. METHODS: The cohort includes 58677 workers with individual information on occupational exposure to crystalline silica in mg m(-3)-years and the potential confounders radon and arsenic based on a detailed job-exposure matrix. In the follow-up period 1946-2003, 2995 miners died from lung cancer. Internal Poisson regression with stratification by age and calendar year was used to estimate the excess relative risk (ERR) per dust-year. Several models including linear, linear quadratic and spline functions were applied. Detailed adjustment for cumulative radon and arsenic exposure was performed. RESULTS: A piecewise linear spline function with a knot at 10 mg m(-3)-years provided the best model fit. After full adjustment for radon and arsenic no increase in risk <10 mg m(-3)-years was observed. Fixing the parameter estimate of the ERR in this range at 0 provided the best model fit with an ERR of 0.061 (95% confidence interval: 0.039, 0.083) >10 mg m(-3)-years. CONCLUSION: The study confirms a positive exposure-response relationship between silica and lung cancer, particularly for high exposures.

Dosimetric calculations for uranium miners for epidemiological studies.

Epidemiological studies on uranium miners are being carried out to quantify the risk of cancer based on organ dose calculations. Mathematical models have been applied to calculate the annual absorbed doses to regions of the lung, red bone marrow, liver, kidney and stomach for each individual miner arising from exposure to radon gas, radon progeny and long-lived radionuclides (LLR) present in the uranium ore dust and to external gamma radiation. The methodology and dosimetric models used to calculate these organ doses are described and the resulting doses for unit exposure to each source (radon gas, radon progeny and LLR) are presented. The results of dosimetric calculations for a typical German miner are also given. For this miner, the absorbed dose to the central regions of the lung is dominated by the dose arising from exposure to radon progeny, whereas the absorbed dose to the red bone marrow is dominated by the external gamma dose. The uncertainties in the absorbed dose to regions of the lung arising from unit exposure to radon progeny are also discussed. These dose estimates are being used in epidemiological studies of cancer in uranium miners.

The toxicity of depleted uranium.

Depleted uranium (DU) is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a clear and defined set of symptoms. Chronic low-dose, or subacute, exposure to depleted uranium alters the appearance of milestones in developing organisms. Adult animals that were exposed to depleted uranium during development display persistent alterations in behavior, even after cessation of depleted uranium exposure. Adult animals exposed to depleted uranium demonstrate altered behaviors and a variety of alterations to brain chemistry. Despite its reduced level of radioactivity evidence continues to accumulate that depleted uranium, if ingested, may pose a radiologic hazard. The current state of knowledge concerning DU is discussed.

Are nested case-control studies biased?

It has been recently asserted that the nested case-control study design, in which case-control sets are sampled from cohort risk sets, can introduce bias ("study design bias") when there are lagged exposures. The bases for this claim include a theoretical and an "empirical evaluation" argument. We examined both of these arguments and found them to be incorrect. We describe an appropriate empirical evaluation method to explore the performance of nested case-control study designs and analysis methods from an existing cohort. This empirical evaluation approach relies on simulating case-control outcomes from risk sets in the cohort from which the case-control study is to be performed. Because it is based on the underlying cohort structure, the empirical evaluation can provide an assessment that is tailored to the specific characteristics of the study under consideration. The methods are illustrated using samples from the Colorado Plateau uranium miners cohort.

Surveillance results of depleted uranium-exposed Gulf War I veterans: sixteen years of follow-up.

As part of a longitudinal surveillance program, 35 members of a larger cohort of 77 Gulf War I veterans who were victims of depleted uranium (DU) "friendly fire" during combat underwent a 3-day clinical assessment at the Baltimore Veterans Administration Medical Center (VAMC). The assessment included a detailed medical history, exposure history, physical examination, and laboratory studies. Spot and 24-h urine collections were obtained for renal function parameters and for urine uranium (U) measures. Blood U measures were also performed. Urine U excretion was significantly associated with DU retained shrapnel burden (8.821 mug U/g creatinine [creat.] vs. 0.005 mug U/g creat., p = .04). Blood as a U sampling matrix revealed satisfactory results for measures of total U with a high correlation with urine U results (r = .84) when urine U concentrations were >/=0.1 mug/g creatinine. However, isotopic results in blood detected DU in only half of the subcohort who had isotopic signatures for DU detectable in urine. After stratifying the cohort based on urine U concentration, the high-U group showed a trend toward higher concentrations of urine beta(2) microglobulin compared to the low-U group (81.7 v. 69.0 mug/g creat.; p = .11 respectively) and retinol binding protein (48.1 vs. 31.0 mug/g creat.; p = .07 respectively). Bone metabolism parameters showed only subtle differences between groups. Sixteen years after first exposure, this cohort continues to excrete elevated concentrations of urine U as a function of DU shrapnel burden. Although subtle trends emerge in renal proximal tubular function and bone formation, the cohort exhibits few clinically significant U-related health effects.

Inositol hexaphosphate: a potential chelating agent for uranium.

Chelation therapy is an optimal method to reduce the radionuclide-related risks. In the case of uranium incorporation, the treatment of choice is so far i.v infusion of a 1.4% sodium bicarbonate solution, but the efficacy has been proved to be not very high. In this study, we examine the efficacy of some substances: bicarbonate, citrate, diethylenetriamine pentaacetic acid (DTPA), ethidronate (EHBP) and inositol hexaphosphate (phytic acid) to chelate uranium using a test developed by Braun et al. Different concentrations of phytic acid, an abundant component of plant seeds that is widely distributed in animal cells and tissues in substantial levels, were tested and compared to the same concentrations of sodium citrate, bicarbonate, EHBP and DTPA. The results showed a strong affinity of inositol hexaphosphate for uranium, suggesting that it could be an effective chelating agent for uranium in vivo.

Neurotoxicity of depleted uranium: reasons for increased concern.

Depleted uranium (DU) is a byproduct of the enrichment process of uranium for its more radioactive isotopes to be used in nuclear energy. Because DU is pyrophoric and a dense metal with unique features when combined in alloys, it is used by the military in armor and ammunitions. There has been significant public concern regarding the use of DU by such armed forces, and it has been hypothesized to play a role in Gulf War syndrome. In light of experimental evidence from cell cultures, rats, and humans, there is justification for such concern. However, there are limited data on the neurotoxicity of DU. This review reports on uranium uses and its published health effects, with a major focus on in vitro and in vivo studies that escalate concerns that exposure to DU might be associated with neurotoxic health sequelae.

Biological monitoring and surveillance results of Gulf War I veterans exposed to depleted uranium.

OBJECTIVE: To relate medical surveillance outcomes to uranium biomonitoring results in a group of depleted uranium (DU)-exposed, Gulf War I veterans. METHODS: Thirty-two veterans of Gulf War I who were victims of 'friendly fire' involving DU weapons, in whom exposure assessment can accurately be measured, had urine uranium concentrations determined using ICP-MS technology. Clinical laboratory parameters were measured and related to urine uranium concentrations. Data were examined by stratifying the cohort into a low U group, <0.10 mug/g creatinine versus a high U group, >/=0.10 mug/g creatinine and assessing differences between groups. RESULTS: Over a decade after first exposure, soldiers possessing embedded DU fragments continue to excrete elevated concentrations of uranium in urine. No clinically significant uranium related health effects were observed in blood count, blood chemistries including renal markers, neuropsychological measures, and semen quality or genotoxicity measures. Markers of early changes in renal glomerular and tubular function were not statistically different between groups; however, genotoxicity measures continue to show subtle, mixed results. CONCLUSION: Persistent urine uranium elevations continue to be observed more than 12 years since first exposure. Despite this, renal and other clinical abnormalities were not observed, likely due to the 'relatively' low uranium burden in this cohort compared to historical uranium-exposed occupational groups. Continuing surveillance is indicated, however, due to the on-going nature of the exposure. These results are an important finding in light of the on-going controversy regarding health effects observed in soldiers of the Gulf War and other conflicts, whose uranium exposure assessment is unable to be accurately determined.

Exposure pathways and health effects associated with chemical and radiological toxicity of natural uranium: a review.

Natural uranium exposure derives from the mining, milling, and processing of uranium ore, as well as from ingestion of groundwater that is naturally contaminated with uranium. Ingestion and inhalation are the primary routes of entry into the body. Absorption of uranium from the lungs or digestive track is typically low but can vary depending on compound specific solubility. From the blood, two-thirds of the uranium is excreted in urine over the first 24 hours and up to 80% to 90% of uranium deposited in the bone leaves the body within 1.5 years. The primary health outcomes of concern documented with respect to uranium are renal, developmental, reproductive, diminished bone growth, and DNA damage. The reported health effects derive from experimental animal studies and human epidemiology. The Lowest Observed Adverse Effect Level (LOAEL) derived from animal studies is 50 microg/m3 for inhalation and 60 ug/kg body weight/day for ingestion. The current respiratory standard of the Occupational Safety and Health Administration (OSHA), 50 microg/m3, affords no margin of safety. Considering the safety factors for species and individual variation, the ingestion LOAEL corresponds to the daily consumption set by the World Health Organization Drinking Water Standard at 2 microg/L. Based on economic considerations, the United States Environmental Protection Agency maximum contaminant level is 30 microg/L. Further research is needed, with particular attention on the impact of uranium on indigenous populations, on routes of exposure in communities near uranium sites, on the combined exposures present at many uranium sites, on human developmental defects, and on health effects at or below established exposure standards.