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The Gulf War Depleted Uranium Cohort at 20 years
Abstract
During the 1991 GulfWar, U.S. service members were exposed to depleted uranium (DU) through friendly-fire incidents involving DU munitions and vehicles protected by DU armor. Routes of exposure to DU involved inhalation of soluble and insoluble DU oxide particles, wound contamination, and retained embedded DU metal fragments that continue to oxidize in situ and release DU to the systemic circulation. A biennial health surveillance program established for this group of Veterans by the U.S. Department of Veterans Affairs has shown continuously elevated urine DU concentrations in the subset of veterans with embedded fragments for over 20 years. While the 2011 assessment was comprehensive, few clinically significant U-related health effects were observed. This report is focused on health outcomes associated with two primary target organs of concern for long term effects of this combat-related exposure to DU. Renal biomarkers showed minimal DU-related effects on proximal tubule function and cytotoxicity, but significant biomarker results were observed when urine concentrations of multiple metals also found in fragments were examined together. Pulmonary tests and questionnaire results indicate that pulmonary function after 20 y remains within the clinical normal range. Imaging of DU embedded fragment-associated tissue for signs of inflammatory or proliferative reactions possibly associated with foreign body transformation or with local alpha emissions from DU was also conducted using PET-CT and ultrasound. These imaging tools may be helpful in guiding decisions regarding removal of fragments.
... Some metals can induce hypersensitivity reactions [2][3][4][5], while other materials can cause a chronic inflammatory response that may increase the risk of malignant transformation in the surrounding tissue [6][7][8][9]. Regarding the effects of military-relevant metals, clinical studies and animal models revealed evidence of genotoxicity and carcinogenicity [10][11][12][13][14][15][16][17][18], especially for certain metals such as depleted uranium (DU), tungsten (W), nickel (Ni) and cobalt (Co) [16][17][18][19][20][21][22][23][24][25]. ...
... Blast injuries are common on the battlefield, and veterans often return from war zones with retained metal fragments. The health consequences of metal fragments in soft tissue are of significant medical concern and are being actively investigated [11][12][13][15][16][17]35]. Previous study reported that military relevant metals such as Ni, Co, DU and Pb can induce regional transcriptional changes in skeletal muscle indicative of neoplastic transformation, especially Ni and Co, which had the highest incidence and most rapid development of tumors [23]. ...
Aim: Explore the potential of urine microRNAs as biomarkers that may reflect the biological responses to pure metals embedded in skeletal muscle over time. Materials & methods: We tested a panel of military-relevant metals embedded in the gastrocnemius muscles of 3-month-old, male, Sprague–Dawley rats (n = 8/group) for a duration of 1, 3, 6 and 12 months, and performed small RNA-sequencing on the urine samples. Results: Results provide potential tissue targets affected by metal exposure and a list of unique or common urine microRNA biomarkers indicative of exposure to various metals, highlighting a complex systemic response. Conclusion: We have identified a panel of miRNAs as potential urine biomarkers to reflect the complex systemic response to embedded metal exposure.
... To assess U effects, comparisons of clinical parameters were made between those veterans with embedded shrapnel fragments and those without fragments. An enduring finding over more than 20 years of surveillance is that members of the cohort with embedded fragments continue to excrete high levels of urine uranium (uU); the vast majority of these also have a DU isotopic signature [22][23][24][25]. Those without fragments tend to have a lower (near normal) uU versus those with fragments who have a higher uU (above 0.1 μg U/g creatinine). ...
... No consistent differences have been noted between the two exposure groups related to any uranium-related health effects including renal, hematologic, neuro-endocrine, neurocognitive [22][23][24][25], immunologic systems [22,26], and bone metabolism [22] over the more than 20 years of surveillance. ...
Environmental metal exposure, as well as dietary metals, may adversely affect semen quality even as others play an essential role in normal spermatogenesis and fertility. Measures of seminal fluid metals have therefore been of high interest in the last several decades but have shown inconsistent results in correlations with some semen quality parameters. As well, environmental metal measures across various body fluid matrices have not been consistently correlated contrary to what one might hypothesize based on a systemic body burden of metal. This may be due to the body fluid matrices assessed and to other differences in laboratory methods and sample preparation. Measures of uranium, a potentially toxic metal in humans, have not previously been reported in the semen of environmentally metal-exposed populations. We report here uranium seminal fluid results and the high correlation of uranium concentrations across several body fluid matrices in a cohort of military veterans exposed to depleted uranium in combat events during the Iraqi Gulf War. These results inform the risk communication conversation for exposed populations and broaden the public health assessments from various exposure scenarios.
... A further potential exposure of organisms to DU can occur through open wounds, shrapnel or through contact with the skin [24,25]. Fragment sizes of 1 cm and above are indicated for surgical extirpation. ...
... Few clinically significant health effects were observed related to long-term, low-dose DU exposure from embedded shrapnel. Renal biomarkers showed minimal effects on proximal tubular function and cytotoxicity, and pulmonary functions remained within the normal clinical ranges [25]. Further scientific research performed in a population of veterans from the Gulf War (1991) showed that the inhalation of DU exposure did not induce long-term adverse pulmonary effects in the soldiers [53]. ...
The article summarizes contemporary scientific knowledge of depleted uranium effects on human health due to its use in military conflicts. The discussion covers cases of minimal risk due to external irradiation resulting from the storage and handling of depleted uranium ammunition and, in contrast, important toxicological and radio-toxicological risks of late effects resulting from the inhalation and ingestion of dust particles produced by the burning of the core of the anti-tank ammunition.
... A health surveillance program for U.S. Gulf War veterans has shown persistently elevated urinary concentrations of DU in individuals with embedded debris for more than 20 years [90]. No differences were seen between the high and low exposure groups in terms of hematology, clinical chemistry, neuroendocrine parameters, bone metabolism, neurocognitive function, immune function, lung function or nodules. ...
Uranium contamination has become a nonnegligible global health problem. Inhalation of particulate uranium is one of the predominant routes of occupational and environmental exposure. Uranium particle is a complex two-phase flow of matter that is both particulate and flowable. This particular physicochemical property may alter its biological activity. Epidemiological studies from occupationally exposed populations in the uranium industry have concluded that there is a possible association between lung cancer risk and uranium exposure, while the evidence for the risk of other tumors is not sufficient. The toxicological effects of particulate uranium exposure to animals have been shown in laboratory tests to focus on respiratory and central nervous system damage. Fibrosis and tumors can occur in the lung tissue of the respiratory tract. Uranium particles can also induce a concentration-dependent increase in cytotoxicity, targeting mitochondria. The understanding of the health risks and potential toxicological mechanisms of particulate uranium contamination is still at a preliminary stage. The diversity of particle parameters has limited the in-depth exploration. This review summarizes the current evidence on the toxicology of particulate uranium and highlights the knowledge gaps and research prospects.
... This conflict saw the first widespread combat use of depleted uranium (DU) munitions. Unfortunately, as a result of "friendly fire" events, several United States military personnel were wounded by DU shrapnel (McDiarmid et al., 2001(McDiarmid et al., , 2013. Due to the unique chemical and radiological properties of DU, there was apprehension over leaving the embedded metal in place for the life of the wounded individual. ...
Injuries suffered in armed conflicts often result in wounds with embedded metal fragments. Standard surgical guidance has been to leave fragments in place except under certain circumstances; meaning that individuals may carry these retained fragments for their lifetime. Because of advancements in weapon design and the use of improvised explosive devices, the list of metals that could be found in a wound is extensive. In most cases the toxicological properties of these metals when embedded in the body are not known. To assess the potential damage embedded metals may cause to surrounding tissue, we utilized a rodent model to investigate the effect of a variety of military-relevant metals on markers of oxidative damage. The metals tested included tungsten, nickel, cobalt, iron, copper, aluminum, lead, and depleted uranium. Herein we report our findings on creatine kinase activity, lipid and protein oxidation, total antioxidant capacity, and glutathione levels in gastrocnemius homogenates from Sprague-Dawley rats surgically implanted with metal pellets for periods up to 12 months. Not all embedded metals affected the measured markers equally. However, metal-associated effects were seen at various times for muscle and serum creatinine levels, protein oxidation, total antioxidant capacity, and glutathione levels. No metal-induced effects on lipid peroxidation were observed. Taken together, these data suggest that subtle oxidative damage may be occurring in the muscle surrounding an embedded metal and indicates the need for medical surveillance of those individuals wounded by metal shrapnel.
... There was some suggestion that elevation of CTx, a marker for bone resorption (P ¼ 0.05), as well as osteocalcin, an indicator of bone formation (P ¼ 0.19), could be associated with increased uranium exposure (uranium in water and intakes) in males, but no similar relationship was found in females. No clinically significant pathologies have been found in veterans exposed to depleted uranium McDiarmid et al., 2013). ...
... Other studies investigating the testosterone levels in Gulf War veterans compare groups with high or low exposure to depleted uranium. These studies have similarly found no statistically significant differences between these groups in endocrine function (i.e., including serum follicle-stimulating hormone, luteinizing hormone, prolactin, and total testosterone) [70][71][72][73][74][75][76]. This, however, does not rule out the possibility of low testosterone in veterans with Gulf War Illness compared to sedentary Gulf War-era veteran controls. ...
Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI.
... There is significant clinical interest in understanding the local and systemic reactions to metals relevant to medical implants and stents, especially regarding concerns for metal-induced hypersensitivity reactions (16,19,27,39). However, toxicological and carcinogenic effects of military-relevant metals in soft tissue are also being studied clinically and modeled in animals (2,9,14,15,20,23,(28)(29)(30). Evidence of genotoxic and carcinogenic effects of depleted uranium (DU) and tungsten (W) alloys comes from studies in cell culture models (4,17,31,32). ...
As a consequence of military operations, many veterans suffer from penetrating wounds and long-term retention of military grade heavy metal fragments. Fragments vary in size and location, and complete surgical removal may not be feasible or beneficial in all cases. Increasing evidence suggests retention of heavy metal fragments may have serious biological implications, including increased risks for malignant transformation. Previous studies assessed the tumorigenic effects of metal alloys in rats, demonstrating combinations of metals are sufficient to induce tumor formation after prolonged retention in skeletal muscle tissue. In this study, we analyzed transcriptional changes in skeletal muscle tissue in response to eight different military-relevant pure metals over 12 months. We found that most transcriptional changes occur at 1 and 3 months after metal pellets are embedded in skeletal muscle and these effects resolve at 6 and 12 months. We also report significant immunogenic effects of nickel and cobalt and suppressive effects of lead and depleted uranium on gene expression. Overall, skeletal muscle exhibits a remarkable capacity to adapt to and recover from internalized metal fragments; however, the cellular response to chronic exposure may be restricted to the metal-tissue interface. This data suggests that unless affected regions are specifically captured by biopsy, it would be difficult to reliably detect changes in muscle gene expression that would be indicative of long-term adverse health outcomes.
... However, since the study began in 1993, the VA has found minimal effects on proximal tubule function, cytotoxicity, or pulmonary function. 41 ...
History of Army Occupational Health, 1991-2015.
... Mortality and incidence rates of the uranium cohort are preferentially compared with mortality rates of surrounding districts. Over the years 2000-2013, McDiarmid et al. [11][12][13][14][15][16][17] published seven different crosssectional studies of a large cohort of approximately 70 US Gulf War veterans with retained uranium shrapnel fragments. We pooled the results of these seven publications and used it as one clinical study for the biomarker meta-analysis. ...
Purpose:
Uranium is a heavy metal with alpha radioactivity. We state the hypothesis that uranium exposure is harmful to human kidneys and carcinogenic to body tissues. Therefore, we review epidemiological studies from people with known long-lasting uranium exposure.
Materials and methods:
Three meta-analyses are performed using clinical studies published in the PubMed database and applying RevMan 5.3 from the Cochrane Collaboration to calculate the outcome. The first two meta-analyses examine the standardized mortality ratio (SMR) and the standardized incidence ratio for any cancers of uranium workers who were operating in areas ranging from uranium processing to the assembly of final uranium products. The third meta-analysis evaluates the nephrotoxic risk in uranium workers as well as soldiers and of individuals with exposure to drinking water containing uranium.
Results:
Overall and contrasting to our hypothesis, the tumor risk is significantly lower for uranium workers than for control groups (SMR = 0.90 with a 95% confidence interval of 0.84 to 0.96). In addition and also contrasting to our hypothesis, the risk of nephrotoxicity is not increased either. This holds for both the incidence and the mortality due to renal cell carcinoma or due to acute kidney injury or chronic kidney disease. In contrast, a significantly better creatinine clearance is found for the uranium cohort as compared to the control groups (mean difference = 7.66 with a 95% confidence interval of 0.12 to 15.2).
Conclusion:
Our hypothesis that a chronic uranium exposure is associated with an increased risk of cancer mortality or of kidney failure is refuted by clinical data. The decreased risk may result from better medical surveillance of uranium workers.
... Ainsi la présence d'uranium dans les urines a été détectée jusqu'à 18 ans après chez des militaires ayant des fragments d'obus implantés dans diverses parties du corps (McDiarmid et al. 2011 ;McDiarmid et al. 2006 ;McDiarmid et al. 2000). Néanmoins les dysfonctionnements tubulaires rénaux attribuables à la contamination par l'uranium ne sont pas significatifs (McDiarmid et al. 2009 ;McDiarmid et al. 2006 ;McDiarmid et al. 2013). ...
Uranium is a radioactive heavy metal found in the environment. Due to its natural presence and to civil and militaries activities, general population can be exposed to U throughout drinking water or contaminated food. The pro/anti-oxidative system is a defense system which is often implicated in case of acute exposure to U. The aim of this thesis is to study the role of the pro/anti-oxidative system after chronic exposure to U in the liver and the kidney. After chronic exposure of rats to different U concentrations, this radionuclide accumulated in the organs in proportion to U intake; until 6 µg.g-1 of kidney tissues. U is localized in nucleus of the proximal tubular cells of the kidney. No nephrotoxicity was described even for the higher U level in drinking water and a reinforcement of the pro/anti-oxidative system with an increase in glutathione is observed. The study of U internal contamination in Nrf2 deficient mice, a cytoprotective transcription factor involved in the anti-oxidative defense has been realized. U accumulate more in Nrf2 -/- mice than in WT mice but the biologic effects of U on the pro/anti-oxidative system did not seem to implicate Nrf2. At the cell level, a correlation between U distribution in HepG2 cells and the biological effects on this system is observed after U exposure at low concentrations. Soluble distribution of U is observed in cell nucleus. The apparition of U precipitates is correlated to the establishment of the adaptive mechanisms overtime which are overwhelmed and lead to a cellular toxicity at higher U level. In conclusion, these results suggest that the reinforcement of pro/anti-oxidative system could be an adaptive mechanism after chronic exposure at low U concentration.
... Urine concentrations of these additional metals, as for U, were determined to be either above or below an upper limit reference value established for each metal from unexposed populations (data not shown). When available, the 2003-2004 NHANES 95th percentile creatinine adjusted value was used as the reference value [USDHHS-CDC, 2012]; otherwise, other reported reference values, such as the upper values reported by clinical laboratories, were used [McDiarmid et al., 2013]. Values reported as mg per 24 hr and mg per L were converted to mg per g creatinine, assuming an average urine volume of 1.2 L per 24 hr and an average creatinine output of 1.2 g creatinine per 24 hr [ACGIH, 1991]. ...
A total of 70 military Veterans have been monitored for HPRT T-cell mutations in five separate studies at two-year intervals over an eight year period. Systemic depleted uranium (DU) levels were measured at the time of each study by determining urinary uranium (uU) excretion. Each HPRT study included 30 to 40 Veterans, several with retained DU-containing shrapnel. Forty-nine Veterans were evaluated in multiple studies, including fourteen who were in all five studies. This permitted a characterization of the HPRT mutation assay over time to assess the effects of age, smoking and non-selected cloning efficiencies, as well as the inter- and intra-individual variability across time points. Molecular analyses identified the HPRT mutation and T-cell receptor (TCR) gene rearrangement in 1377 mutant isolates. An unexpected finding was that in vivo clones of HPRT mutant T-cells were present in some Veterans, and could persist over several years of the study. The calculated HPRT mutant frequencies (MFs) were repeatedly elevated in replicate studies in three outlier Veterans with elevated urinary uranium excretion levels. However, these three outlier Veterans also harbored large and persistent in vivo HPRT mutant T-cell clones, each of which was represented by a single founder mutation. Correction for in vivo clonality allowed calculation of HPRT T-cell mutation frequencies (MutFs). Despite earlier reports of DU associated increases in HPRT MFs in some Veterans, the results presented here demonstrate that HPRT mutations are not increased by systemic DU exposure. Additional battlefield exposures were also evaluated for associations with HPRT mutations and none were found. This article is protected by copyright. All rights reserved.
© 2015 Wiley Periodicals, Inc.
... 4 Extensive medical surveillance of the personnel with the retained DU fragments almost 20 years after being injured has demonstrated no adverse health effects. 5,6 Nonetheless, because of the uncertainty over long-term health effects, many nations, including the United States, have searched for alternatives to DU in armor-penetrating munitions. ...
Continued improvements in the ballistic properties of military munitions have led to metal formulations for which little are known about the long-term health effects. Previously we have shown that a military-grade tungsten alloy comprised of tungsten, nickel, and cobalt, when embedded into the leg muscle of F344 rats to simulate a fragment wound, induces highly aggressive metastatic rhabdomyosarcomas. An important follow-up when assessing a compound's carcinogenic potential is to test it in a second rodent species. In this study, we assessed the health effects of embedded fragments of 2 military-grade tungsten alloys, tungsten/nickel/cobalt and tungsten/nickel/iron, in the B6C3F1 mouse. Implantation of tungsten/nickel/cobalt pellets into the quadriceps muscle resulted in the formation of a rhabdomyosarcoma around the pellet. Conversely, implantation of tungsten/nickel/iron did not result in tumor formation. Unlike what was seen in the rat model, the tumors induced by the tungsten/nickel/cobalt did not exhibit aggressive growth patterns and did not metastasize.
© The Author(s) 2014.
... Th is precludes any conclusion on associations between the diseases of interest and DU exposure. A surveillance program among 80 American veterans of the wars in the Persian Gulf with embedded DU fragments has, however, found some indication of kidney damage, but only at the level of biomarkers (McDiarmid et al. 2013). Th e majority of studies of war veterans used incidence data, important in studies of cancer with high survival rates, such as some of lymphohematopoietic cancers (United States Environmental Protection Agency [US EPA] 2012). ...
Purpose:
Physicochemical properties of uranium, including isotopic composition and solubility, are determinants of its toxicity. We reviewed epidemiological studies in civilian and military workers known to be exposed to uranium with different physicochemical properties to investigate its long-term effects, such as cancerous and circulatory diseases.
Materials and methods:
We systematically searched the Pubmed and the Scopus databases to identify studies of uranium- processing workers (published between 1980 and 2013) and veterans of the wars in the Persian Gulf and the Balkans (published between 1991 and 2013) in which defined outcomes, such as lung, lymphohematopoietic, kidney cancers, and circulatory diseases were examined. RESULTS from these studies in terms of risk of each health outcome (mortality or incidence) and analyses of dose-response relationship were examined to present the impact of uranium physicochemical properties on the observed results.
Results:
Twenty-seven articles were reviewed. There is some evidence for increased lung cancer risk among uranium-processing workers. The evidence is less strong for lymphohematopoietic cancer. We found that most of the studies insufficiently assessed the physicochemical properties of uranium and some of them used proxies for the exposure assessment and risk estimation analyses. Studies of veterans of the wars in the Persian Gulf and the Balkans are uninformative in respect to internal uranium exposure.
Conclusions:
Existing epidemiological data on the physicochemical properties of uranium and associated health outcomes are inconclusive. Further studies among certain groups of uranium-processing workers (uranium-enrichment and fuel-fabrication workers) could contribute to our knowledge of the health effects of uranium with respect to its physicochemical properties.
... Advocates for civilians in Iraq allege that DU is causing increases in birth defects ( Busby et al., 2010), Kaposi sarcoma ( Shelleh, 2012), as well as leukemia, lymphoma, and brain, breast, lung, bladder, skin and stomach cancers ( Aitken, 1999;Fathi et al., 2013). However, authors associated with government agencies contend that exposure levels are too low to cause any significant adverse effects ( Bogers et al., 2013;Brown, 2006;Hines et al., 2013;Marshall, 2008;McDiarmid et al., 2013). Understanding the cellular and molecular mechanisms underlying the genotoxic endpoints of DU exposure will contribute to the evaluation of chemical risks and to identification of biomarkers of DU exposure that may relate to the alleged adverse health effects. ...
Depleted uranium (DU) has a chemical toxicity that is independent of its radioactivity. The purpose of this study was to explore the photoactivation of uranyl ion by ultraviolet (UV) radiation as a chemical mechanism of uranium genotoxicity. The ability of UVB (302 nm) and UVA (368 nm) radiation to photoactivate uranyl ion to produce single strand breaks was measured in pBR322 plasmid DNA, and the presence of adducts and apurinic/apyrimidinic sites that could be converted to single strand breaks by heat and piperidine was analyzed. Results showed that DNA lesions in plasmid DNA exposed to UVB- or UVA-activated DU were only slightly heat reactive, but were piperidine sensitive. The cytotoxicity of UVB-activated uranyl ion was measured in repair-proficient and repair-deficient Chinese hamster ovary cells and human keratinocyte HaCaT cells. The cytotoxicity of co-exposures of uranyl ion and UVB radiation was dependent on the order of exposure and was greater than co-exposures of arsenite and UVB radiation. Uranyl ion and UVB radiation were synergistically cytotoxic in cells, and cells exposed to photoactivated DU required different DNA repair pathways than cells exposed to non-photoactivated DU. This study contributes to our understanding of the DNA lesions formed by DU, as well as their repair. Results suggest that excitation of uranyl ion by UV radiation can provide a pathway for uranyl ion to be chemically genotoxic in populations with dermal exposures to uranium and UV radiation, which would make skin an overlooked target organ for uranium exposures. Copyright © 2014 John Wiley & Sons, Ltd.
Uranium is an element with chemical and radiological properties that make it useful in industry, military, and commerce, but toxic at sufficient levels. Various analytical methods are available to determine the presence, concentration, or quantity of uranium or its isotopes in a range of media. Results confirm that uranium is present in ambient air, water, and soil, so human exposure is assured. At least seven of its more than 100 mineral forms are found at mineable levels in various parts of the world, and the primary producers in 2019 by weight were Australia, Canada, China, Kazakhstan, Namibia, Niger, Russia, and Uzbekistan. Uranium is mined primarily for the ²³⁵U isotope. The process of enrichment adjusts the ratio of the three natural isotopes (²³⁴U, ²³⁵U, and²³⁸U) to produce two fractions. The fraction with increased ²³⁵U compared with natural is called enriched uranium and is the source of energy production for nuclear reactors and weapons. The other fraction is depleted in ²³⁵U and ²³⁴U, termed depleted uranium and is less radioactive than crustal uranium. Uranium is also used in a range of products that include glass tinting agents, ceramic glazes, gyroscope wheels, chemical catalysts, shields for radioactive sources, X-ray tube targets, and military armor and kinetic penetrators. It is no longer used in dental porcelains.
Intakes from water and food are approximately equivalent, at 0.9–1.5 micrograms per day (μg/day) based on the water source (higher in ground water) or diet (higher in beef, beef kidney and liver, onions, parsley, and salt; lower in poultry, fruit juices, fruits and vegetables, and dairy). Air concentrations are normally low. The highest human exposures result from drinking well water high in uranium and working in the uranium milling and production industries, with the greatest environmental challenge coming from mine and mill tailings. Human exposure involves inhalation, ingestion, and, since 1991, military metal fragment wounds. Uranium intestinal absorption is low (0.1%–6%, typically 1%–2.5%), increases with solubility, and is higher for neonates than nonfasting or iron deficient adults. Dermal absorption may not occur across intact skin for insoluble forms, but increases with solubility and extent of skin damage and excoriation, or if a puncture occurs. Severely damaged (e.g., burned) skin has lower absorption. Once in the blood, uranium's distribution and elimination kinetics are functions of its oxidation state. Tetravalent uranium entering the body converts to hexavalent as uranyl ions, which complex with citrate or bicarbonate in blood or plasma proteins. Distribution is broad, with a primary long-term concentration in lung (for heavy occupational exposure to insoluble forms), bone, liver, and kidney. Uranium can cross the placenta and excrete in breast milk based on rat fetus levels following oral exposure of the dam from before mating through lactation. Initial elimination is rapid, with two-or-more phase excretion. Computer programs can estimate timeframe concentrations and radiation doses to organs and tissues. Inhaling 1 μg U/day can result in kidney concentrations of 0.003, 0.00075, and 0.000078 μg U/g for type F (highly soluble), M (moderately soluble), and S (slightly soluble) uranium, respectively. Sv/Bq conversion factors have been developed to estimate radiation doses to the body and selected organs from inhaled or ingested uranium isotopes. The International Commission on Radiological Protection (ICRP) has developed new biokinetics modeling and methodology resulting in revised Sv/Bq (rem/pCi) dose conversion factors. Dose coefficients are being developed with a plan to address exposure via breast milk and cross-placental transfer. Federal Guidance Report No. 13 provides such conversion factors.
Overexposure impacting human and animal health depends on pathway, enrichment, and compound. It has been determined that adverse health effects of natural or low-enriched uranium are primarily from its chemical rather than radiological toxicity and this chemical toxicity is independent of its radiation exposure. Lung damage from inhaled uranium involves alveolar injury with potential long-term fibrosis and emphysema. The health effects from inhalation, oral, and dermal exposure are primarily to the kidney, and nonsevere damage can be reversible. Less severe effects are observed for the liver, lung, nervous system, and reproductive system. The mechanism for renal toxicity involves the accumulation of uranium in tubular epithelium progressing to tubulointerstitial nephritis or tubular necrosis based on exposure and duration. This may be from cellular oxidative stress, altered cell signaling-related gene expression, and inhibited sodium-dependent phosphate and glucose transport systems. Impacts on liver enzymes and receptors might affect drug therapy regimens. Uranium can interfere with bone remodeling and liver integrity. Uranium is not classified as a carcinogen, and cancer has not been observed in high-dose human and animal studies, except for a foreign body response at metal implantation sites. If cancer should develop, bone sarcomas are the most likely since uranium, like radium, deposits long term in bone and radium dial painters developed sarcomas. Immunological and genetic assessments could tease out unconfirmed effects or mechanisms.
Implanted metallic medical devices release many of the same metals (e.g., aluminum, nickel, cobalt, chromium) that individuals are exposed to from environmental or occupational sources. At sufficiently high doses, these metals can produce adverse effects at the site of implantation, in target tissues distant to the implant site, or both. As a result, it is necessary to assess the potential local and systemic toxicity of metal ions and metallic wear debris that may be released from implanted medical devices. Adverse health effects associated with metal release from implanted neurological, cardiovascular, reproductive, and orthopedic devices are explored in this chapter. We also examine the unique issues that should be addressed when estimating the risk posed by exposure of patients to metals released from implanted metallic devices, notably, the need to account for the form (particulate vs. ionic) and valence of the compound, the ability to estimate the dose of the compound released using computational models and biomonitoring data, and the need to account for local effects at the implant site as well as systemic effects on target organs distant to the implant. The need for new approaches to assess the toxicity of novel metallic alloys and biodegradable metallic materials is also explored.
Exposure to retained metal fragments from war‐related injuries can result in increased systemic metal concentrations, thereby posing potential health risks to target organs far from the site of injury. Given the large number of veterans who have retained fragments and the lack of clear guidance on how to medically manage these individuals, the Department of Veterans Affairs (VA) convened a meeting of chelation experts and clinicians who care for embedded fragment patients to discuss current practices and provide medical management guidance. Based on this group's clinical expertise and review of published literature, the evidence presented suggests that, at least in the case of lead fragments, short‐term chelation therapy may be beneficial for embedded fragment patients experiencing acute symptoms associated with metal toxicity; however, in the absence of clinical symptoms or significantly elevated blood lead concentrations (greater than 80 µg/dL), chelation therapy may offer little to no benefit for individuals with retained fragments and pose greater risks due to remobilization of metals stored in bone and other soft tissues. The combination of periodic biomonitoring to assess metal body burden, longitudinal fragment imaging, and selective fragment removal when metal concentrations approach critical injury thresholds offers a more conservative management approach to caring for patients with embedded fragments.
A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored in a clinical surveillance program since 1993. During the spring of 2017, 42 members of the cohort were evaluated with a protocol which includes exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes including measures of bone metabolism, and for participants >50 years, bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained DU shrapnel fragments. Only the mean serum estradiol concentration, a marker of bone metabolism, was found to be significantly different for lower-vs- higher urine U (uU) cohort sub-groups. For the first time, a significant deficit in BMD was observed in the over age 50, high uU sub-group. After more than 25 years since first exposure to DU, an aging cohort of military veterans continues to exhibit few U-related adverse health effects in known target organs of U toxicity. The new finding of reduced BMD in older cohort members, while biologically plausible, was not suggested by other measures of bone metabolism in the full (all ages) cohort, as these were predominantly within normal limits over time. Only estradiol was recently found to display a difference as a function of uU grouping. As BMD is further impacted by aging and the U-burden from fragment absorption accrues in this cohort, a U effect may be clarified in future surveillance visits.
Uranium from the environment enters the human body by ingestion with food and drink and by inhalation of respirable airborne uranium-containing dust particles or aerosols. A 70 kg, non-occupationally exposed 'Reference Man' living in Europe or in the United States has an estimated total body uranium content of about 22 micrograms. Uranium is absorbed from the intestine or the lungs, enters the bloodstream, and is rapidly deposited in the tissues, predominantly kidney and bone, or excreted in the urine. In the bloodstream, uranium is associated with red cells, and its clearance is relatively rapid. Renal toxicity is a major adverse effect of uranium, but the metal has toxic effects on the cardiovascular system, liver, muscle, and nervous system as well. Any possible direct risk of cancer or other chemical- or radiation-induced health detriments from uranium deposited in the human body is probably less than 0.005% in contrast to an expected indirect risk of 0.2% to 3% through inhaling the radioactive inert gas radon, which is produced by the decay of environmental uranium-238 in rocks and soil and is present in materials that are used to build dwellings and buildings where people live and work.
Introduction:
A cohort of Gulf War I veterans who sustained exposure to depleted uranium undergoes biennial surveillance for potential uranium-related health effects. We performed impulse oscillometry and hypothesized that veterans with higher uranium body burdens would have more obstructive abnormalities than those with lower burdens.
Methods:
We compared pulmonary function of veterans in high versus low urine uranium groups by evaluating spirometry and oscillometry values.
Results:
Overall mean spirometry and oscillometry resistance values fell within the normal ranges. There were no significant differences between the high and low uranium groups for any parameters. However, more veterans were classified as having obstruction by oscillometry (42%) than spirometry (8%).
Conclusions:
While oscillometry identified more veterans as obstructed, obstruction was not uranium-related. However, the added sensitivity of this method implies a benefit in wider surveillance of exposed cohorts and holds promise in identifying abnormalities in areas of the lung historically described as silent.
The present study aimed to investigate uranium hazardous effects, as well as the ameliorative effects of
cardamom on the cerebellum and midbrain of adult male albino rats at different time intervals. The administration of 40 mg/Kg of uranyl acetate dehydrate (UAD) caused a significant decrease in Pi, K+ ions
contents and GSH level while, a significant increase in Na+ and Ca2+ ions content and MDA level were
observed, which may be due to the decrease in ATP synthesis and the inhibition of Na+/K+ ATPase activity.
Also, UDA has the ability to increase lipid peroxidation and decrease GSH synthesis. On the other
hand, the administration of 250 mg/kg of cardamom extract induced significant increase in Pi, K+ ions
content and GSH level, while it caused a significant decrease in Na+, Ca2+ ions content and MDA level
which may be due to the increase of ATP synthesis and its anticonvulsant and antioxidant effects. It could
be concluded that the pre -and post-treatment with cardamom could ameliorate the hazardous effects of
UAD intoxication.
The uranium concentration in the drinking water of the residents of the Jaipur and Ajmer districts of Rajasthan has been measured for exposure assessment. The daily intake of uranium from the drinking water for the residents of the study area is found to vary from 0.4 to 123.9 μg per day. For the average uranium ingestion rate of 35.2 μg per day for a long term exposure period of 60 years, estimations have been made for the retention of uranium in different body organs and its excretion with time using ICRP's biokinetic model of uranium. Radioactive and chemical toxicity of uranium has been reported and discussed in detail in the present manuscript.
Background:
A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored for health changes in a clinical surveillance program at the Veterans Affairs Medical Center, Baltimore since 1994.
Methods:
During the spring of 2015, an in-patient clinical surveillance protocol was performed on 36 members of the cohort, including exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes.
Results:
On-going mobilization of U from embedded fragments is evidenced by elevated urine U concentrations. The DU isotopic signature is observed principally in participants possessing embedded fragments. Those with only an inhalation exposure have lower urine U concentration and a natural isotopic signature.
Conclusions:
At 25 years since first exposure to DU, an aging cohort of military veterans continues to show no U-related health effects in known target organs of U toxicity. As U body burden continues to accrue from in-situ mobilization from metal fragment depots, and increases with exposure duration, critical tissue-specific U concentration thresholds may be reached, thus recommending on-going surveillance of this veteran cohort.
Studies into the effects from environmental pollution by uranium compounds have been overviewed. Analysis of the impact of uranium oxides resulted from military operations using armor-piercing shells made of depleted uranium shows a predominance of chemical toxicity caused by the strong oxidizing power of uranyl ions. They induce oxidative stress through the generation of reactive oxygen species. As a result, oxidative damage to biomolecules and disruption of metabolic processes occur. Oxidative DNA damage causes long-term genotoxic effects in the form of mutagenesis, carcinogenesis, and other pathologies. The necessity of prohibiting the use of depleted uranium shells as chemical weapons of mass destruction has been substantiated.
The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.
Implanted metallic medical devices release many of the same metals (e.g. aluminum, nickel, cobalt, chromium) that individuals are exposed to from environmental or occupational sources. At sufficiently high doses, these metals can produce adverse effects at the site of implantation, in target tissues distant to the implant site, or both. As a result, it is necessary to assess the potential local and systemic toxicity of metal ions and metallic wear debris that may be released from implanted medical devices. Adverse health effects associated with metal release from implanted neurological, cardiovascular, and orthopedic devices are explored in this chapter. We also examine the unique issues that should be addressed when estimating the risk posed by exposure of patients to metals released from implanted metallic devices, notably the need to account for the form (particulate vs. ionic) and valence of the compound released from the device, the ability to estimate the dose of the compound released from the device using biomonitoring data, and the need to account for local effects at the implant site as well as systemic effects on target organs distant to the implant. The need for new approaches to assess the toxicity of novel metallic alloys and biodegradable metallic materials is also explored.
The brain is a target of environmental toxic pollutants that impair cerebral functions. Uranium is present in the environment as a result of natural deposits and release by human applications. The first part of this review describes the passage of uranium into the brain, and its effects on neurological functions and cognitive abilities. Very few human studies have looked at its cognitive effects. Experimental studies show that after exposure, uranium can reach the brain and lead to neurobehavioral impairments, including increased locomotor activity, perturbation of the sleep-wake cycle, decreased memory, and increased anxiety. The mechanisms underlying these neurobehavioral disturbances are not clearly understood. It is evident that there must be more than one toxic mechanism and that it might include different targets in the brain. In the second part, we therefore review the principal mechanisms that have been investigated in experimental models: imbalance of the anti/pro-oxidant system and neurochemical and neurophysiological pathways. Uranium effects are clearly specific according to brain area-, dose-, and time. Nonetheless, this review demonstrates the paucity of data about its effects on developmental processes and the need for more attention to the consequences of exposure during development.
Copyright © 2015. Published by Elsevier Ireland Ltd.
Depleted uranium (DU)-containing weapons have been used in military operations since 1991. There is interest in following veterans who were occupationally exposed to DU by either inhalation or retention of fragments. A cohort of DU-exposed Gulf War I veterans has been followed longitudinally at the Baltimore Veterans Administration Medical Center since 1993.
The aim was to monitor chronic dermatological findings associated with occupational DU exposure in the 2013 cohort.
Thirty-five veterans were evaluated. This study was reviewed and approved by the institutional review board and the Baltimore Veterans Administration Medical Center research service. Depleted uranium exposure was measured using creatinine-adjusted urine uranium concentrations (micrograms of uranium per gram of creatinine [μgU/gCrea]). Detailed medical histories, physical examinations, and exposure histories were performed.
Using a cutoff level of 0.1 μgU/gCrea, 11 veterans were placed in the high-uranium exposure group, whereas 23 veterans were placed in the low-uranium exposure group. Retained fragments were documented in 91% of the high-exposure group versus that in 13% of the low-exposure group (P < 0.001), and fragment-related scarring was significantly increased in the high-exposure group (P = 0.002). Other dermatological findings such as dermatitis were also assessed.
Fragment retainment and related scarring was significantly increased in veterans exposed to high levels of DU. Continuous monitoring of this cohort will yield interesting dermatological findings related to DU exposure.
Molecular studies that involved cDNA and genomic DNA sequencing as well as multiplex PCR, of the HPRT gene were performed to determine the molecular mutational spectrum for 1377 HPRT mutant isolates obtained from 61 Veterans of the 1991 Gulf War, most of whom were exposed to depleted uranium (DU). Mutant colonies were isolated from one to four times from each Veteran (in 2003, 2005, 2007 and/or 2009). The relative frequencies of the various types of mutations (point mutations, deletions, insertions etc.) were compared between high versus low DU exposed groups, (based on their urine U concentration levels), with HPRT mutant frequency (as determined in the companion paper) and with a database of historic controls. The mutational spectrum includes all classes of gene mutations with no significant differences observed in Veterans related to their DU exposures. This article is protected by copyright. All rights reserved.
© 2015 Wiley Periodicals, Inc.
A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly fire incidents have been monitored in a clinical surveillance program at the Veterans Affairs Medical Center, Baltimore since 1994.
An in-patient clinical surveillance protocol was performed on 35 members of the cohort, including exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes.
Although urine U concentrations continue to be elevated in this group, illustrating on-going in situ mobilization of U from embedded fragments, no consistent U-related health effects have been observed.
Now more than 20 years since first exposure to DU, an aging cohort of military veterans continues to show no U-related health effects in known target organs of U toxicity. As tissue concentrations continue to accrue with exposure duration, critical tissue-specific U concentration thresholds may be reached, thus recommending on-going surveillance of this veteran cohort. Am. J. Ind. Med. © 2015 Wiley Periodicals, Inc.
© 2015 Wiley Periodicals, Inc.
Natural uranium is comprised of three radioactive isotopes: 238U, 235U, and 234U. Depleted uranium (DU) is a byproduct of the processes for the enrichment of the naturally occurring 235U isotope. The world wide stock pile contains some 1½ million tons of depleted uranium. Some of it has been used to dilute weapons grade uranium (~90% 235U) down to reactor grade uranium (~5% 235U), and some of it has been used for heavy tank armor and for the fabrication of armor-piercing bullets and missiles. Such weapons were used by the military in the Persian Gulf, the Balkans and elsewhere. The testing of depleted uranium weapons and their use in combat has resulted in environmental contamination and human exposure. Although the chemical and the toxicological behaviors of depleted uranium are essentially the same as those of natural uranium, the respective chemical forms and isotopic compositions in which they usually occur are different. The chemical and radiological toxicity of depleted uranium can injure biological systems. Normal functioning of the kidney, liver, lung, and heart can be adversely affected by depleted uranium intoxication. The focus of this review is on the chemical and toxicological properties of depleted and natural uranium and some of the possible consequences from long term, low dose exposure to depleted uranium in the environment.
Radiation is in the public eye because of Fukushima, computed tomography examinations, airport screenings, and possible terrorist attacks. What if the Boston Marathon pressure cooker had also contained a radioactive source? Nuclear power may be on the resurgence. Because of the increasing uses of radiation, the increases in population exposures, and the increasing knowledge of radiation effects, constant vigilance is needed to keep up with the changing times. Psychosocial disorders associated with the inappropriate (but real) fear of radiation need to be recognized as radiation detriments. Radiation risk communication, radiation education, and communication must improve at all levels: to members of the public, to the media, to other scientists, and to radiation professionals. Stakeholders must continue to be involved in all radiation protection initiatives. Finally, we are at a crisis as the number of war babies (me) and baby boomers (you?) who are also radiation professionals continues its rapid decline, and there are few in the pipeline to fill the current and looming substantial need: "The old road is rapidly agin'" (Dylan). NCRP has begun the WARP initiative-Where Are the Radiation Professionals?-an attempt to rejuvenate the pipeline of future professionals before the trickle becomes tiny drops. A Workshop was held in July 2013 with government agencies, military, private sector, universities, White House representatives, and societies to develop a coordinated and national action plan. A "Manhattan Project" is needed to get us "Back to the Future" in terms of the funding levels that existed in years past that provided the necessary resources to train, engage, and retain (a.k.a., jobs) the radiation professionals needed for the nation. If we don't keep swimmin' (Disney's Nemo) we'll "sink like a stone" (Dylan).Introduction of Implications of Radiation Dose and Exposed Populations (Video 2:06, http://links.lww.com/HP/A25).
The U.S. military consists of five armed services: the Army, Navy, Marine Corps, Air Force, and Coast Guard. It directly employs 1.4 million active duty military, 1.3 million National Guard and reserve military, and 700,000 civilian individuals. This paper describes the military guidance used to preserve and maintain the health of military personnel while they accomplish necessary and purposeful work in areas where they are exposed to radiation. It also discusses military exposure cohorts and associated radiogenic disease compensation programs administered by the U.S. Department of Veterans Affairs, the U.S. Department of Justice, and the U.S. Department of Labor. With a few exceptions, the U.S. military has effectively employed ionizing radiation since it was first introduced during the Spanish-American War in 1898. The U.S military annually monitors 70,000 individuals for occupational radiation exposure: ∼2% of its workforce. In recent years, the Departments of the Navy (including the Marine Corps), the Army, and the Air Force all have a low collective dose that remains close to 1 person-Sv annually. Only a few Coast Guard individuals are now routinely monitored for radiation exposure. As with the nuclear industry as a whole, the Naval Reactors program has a higher collective dose than the remainder of the U.S. military. The U.S. military maintains occupational radiation exposure records on over two million individuals from 1945 through the present. These records are controlled in accordance with the Privacy Act of 1974 but are available to affected individuals or their designees and other groups performing sanctioned epidemiology studies.Introduction of Radiation Exposure of U.S. Military Individuals (Video 2:19, http://links.lww.com/HP/A30).
Depleted uranium (DU) is a high-density heavy metal that has been used in munitions since the 1991 Gulf War. DU is weakly radioactive and chemically toxic, and long-term exposure may cause adverse health effects. This study evaluates genotoxic effects of exposure to DU by measuring chromosome damage in peripheral blood lymphocytes with fluorescence in situ hybridization whole-chromosome painting. Study participants are Gulf War-I Veterans with embedded DU fragments and/or inhalation exposure due to involvement in friendly-fire incidents; they are enrolled in a long-term health surveillance program at the Baltimore Veterans Administration Medical Center. Blood was drawn from 35 exposed male veterans aged 39 to 62 years. Chromosomes 1, 2, and 4 were painted red and chromosomes 3, 5, and 6 were simultaneously labeled green. At least 1800 metaphase cells per subject were scored. Univariate regression analyses were performed to evaluate the effects of log(urine uranium), age at time of blood draw, log(lifetime X-rays), pack-years smoked and alcohol use, against frequencies of cells with translocated chromosomes, dicentrics, acentric fragments, color junctions and abnormal cells. No significant relationships were observed between any cytogenetic endpoint and log(urine uranium) levels, smoking, or log(lifetime X-rays). Age at the time of blood draw showed significant relationships with all endpoints except for cells with acentric fragments. Translocation frequencies in these Veterans were all well within the normal range of published values for healthy control subjects from around the world. These results indicate that chronic exposure to DU does not induce significant levels of chromosome damage in these Veterans.
In response to a Congressional request, the Office of the Assistant Secretary of the Army (OASA) Installations, Logistics & Environment (I,L&E) tasked the Army Environmental Policy Institute to study the health and environmental consequences of using depleted uranium (DU) on the battlefield. The study also examined the potential for remediating DU contamination, ways to reduce DU toxicity, and methods to protect the environment from the long-term consequences of DU use. Results from the study were initially presented in a Summary Report to Congress. Documentation and detail about the findings and conclusions of the summary report are presented in this technical report.
In this descriptive case series, 80 soldiers from Fort Campbell, Kentucky, with inhalational exposures during service in Iraq and Afghanistan were evaluated for dyspnea on exertion that prevented them from meeting the U.S. Army's standards for physical fitness.
The soldiers underwent extensive evaluation of their medical and exposure history, physical examination, pulmonary-function testing, and high-resolution computed tomography (CT). A total of 49 soldiers underwent thoracoscopic lung biopsy after noninvasive evaluation did not provide an explanation for their symptoms. Data on cardiopulmonary-exercise and pulmonary-function testing were compared with data obtained from historical military control subjects.
Among the soldiers who were referred for evaluation, a history of inhalational exposure to a 2003 sulfur-mine fire in Iraq was common but not universal. Of the 49 soldiers who underwent lung biopsy, all biopsy samples were abnormal, with 38 soldiers having changes that were diagnostic of constrictive bronchiolitis. In the remaining 11 soldiers, diagnoses other than constrictive bronchiolitis that could explain the presenting dyspnea were established. All soldiers with constrictive bronchiolitis had normal results on chest radiography, but about one quarter were found to have mosaic air trapping or centrilobular nodules on chest CT. The results of pulmonary-function and cardiopulmonary-exercise testing were generally within normal population limits but were inferior to those of the military control subjects.
In 49 previously healthy soldiers with unexplained exertional dyspnea and diminished exercise tolerance after deployment, an analysis of biopsy samples showed diffuse constrictive bronchiolitis, which was possibly associated with inhalational exposure, in 38 soldiers.
As part of a longitudinal surveillance program, 35 members of a larger dynamic cohort of 79 Gulf War I veterans exposed to depleted uranium (DU) during combat underwent clinical evaluation at the Baltimore Veterans Administration Medical Center. Health outcomes and biomonitoring results were obtained to assess effects of DU exposure and determine the need for additional medical intervention. Clinical evaluation included medical and exposure histories, physical examination, and laboratory studies including biomarkers of uranium (U) exposure. Urine collections were obtained for U analysis and to measure renal function parameters. Other laboratory measures included basic hematology and chemistry parameters, blood and plasma U concentrations, and markers of bone metabolism. Urine U (uU) excretion remained above normal in participants with embedded DU fragments, with urine U concentrations ranging from 0.006 to 1.88 μg U/g creatinine. Biomarkers of renal effects showed no apparent evidence of renal functional changes or cellular toxicity related to U body burden. No marked differences in markers of bone formation or bone resorption were observed; however, a statistically significant decrease in levels of serum intact parathyroid hormone and significant increases in urinary calcium and sodium excretion were seen in the high versus the low uU groups. Eighteen years after first exposure, members of this cohort with DU fragments continue to excrete elevated concentrations of uU. No significant evidence of clinically important changes was observed in kidney or bone, the two principal target organs of U. Continued surveillance is prudent, however, due to the ongoing mobilization of uranium from fragment depots.
The authors conducted a study of an aboriginal community to determine if kidney func-tion had been affected by the chronic ingestion of uranium in drinking water from the community's drilled wells. Uranium concentrations in drinking water varied from < 1 to 845 ppb. This nonin-vasive study relied on the measurement of a combination of urinary indicators of kidney function and markers for cell toxicity. In all, 54 individuals (12-73 years old) participated in the study. Correlation of uranium excreted in urine with bio-indicators at p <or=.05 indicated interference with the kidney's reabsorptive function. Because of the community's concerns regarding cancer incidence, the authors also calculated cumulative radiation doses using uranium intake in drinking water over the preceding 15-year period. The highest total uranium intake over this period was 1,761 mg. The risk of cancer from the highest dose, 2.1 mSv, is 13 in 100,000, which would be difficult to detect in the community studied (population size = 1,480). This study indicates that at the observed levels of uranium intake, chemical toxicity would be a greater health concern than would radiation dose.
Chronic kidney disease (CKD) has recently assumed epidemic proportion, becoming a troubling emerging cause of morbidity, especially if it progresses to terminal stage (ESRD). The authors aimed to evaluate whether neutrophil gelatinase-associated lipocalin (NGAL), a novel specific biomarker of acute kidney injury, could predict the progression of CKD.
Serum and urinary NGAL levels, together with a series of putative progression factors, were evaluated in a cohort of 96 patients (mean age: 57 +/- 16 years) affected by nonterminal CKD (eGFR > or =15 ml/min/1.73 m(2)) of various etiology. Progression of CKD, assessed as doubling of baseline serum creatinine and/or onset of ESRD, was evaluated during follow-up.
At baseline, both serum and urinary NGAL were inversely, independently, and closely related to eGFR. After a median follow-up of 18.5 mo (range 1.01 to 20), 31 patients (32%) reached the composite endpoint. At baseline, these patients were significantly older and showed increased serum creatinine, calcium-phosphate product, C-reactive protein, fibrinogen, daily proteinuria, and NGAL levels, whereas eGFR values were significantly lower. Univariate followed by multivariate Cox proportional hazard regression analysis showed that urinary NGAL and sNGAL predicted CKD progression independently of other potential confounders, including eGFR and age.
In patients with CKD, NGAL closely reflects the entity of renal impairment and represents a strong and independent risk marker for progression of CKD.
Urinary kidney injury molecule (KIM-1) is a sensitive quantitative biomarker for early detection of kidney tubular injury. The objective of the present work was to analytically validate this urinary renal injury biomarker. Duo-set reagents from R&D were used to develop the ELISA and validate the assay's linearity, intra-run precision, inter-run precision, lower limit of quantification, recovery, dilutional verification, reference range, stability, and length of run. The reference range data suggests that the healthy population falls within the assay range (59 - 2146 pg/mL) and upper limit of quantitation for this assay is 17168 pg/mL for the patient population. This is a robust assay to detect urinary levels of KIM-1, which serves as a non-invasive sensitive, reproducible, and potentially high-throughput method to detect early kidney injury in drug development studies.
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.
A study was conducted of the chemical effects on the human kidney induced by the chronic ingestion of uranium in drinking water. Subjects were divided into two groups: The low-exposure group, whose drinking water was obtained from a municipal water system and contained < 1 microgram uranium/L, and the high-exposure group, whose drinking water was obtained from private drilled wells and contained uranium levels that varied from 2 to 781 micrograms/L. Years of residence varied from 1 to 33 years in the low-exposure group and from 3 to 59 years in the high-exposure group. The indicators of kidney function measured in this study included glucose, creatinine, protein, and beta 2-microglobulin (BMG). The markers for cell toxicity studied were alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), and N-acetyl-beta-D-glucosaminidase (NAG). Urinary glucose was found to be significantly different and positively correlated with uranium intake for males, females, and pooled data. Increases in ALP and BMG were also observed to be correlated with uranium intake for pooled data. In contrast, the indicators for glomerular injury, creatinine and protein, were not significantly different between the two groups nor was their urinary excretion correlated to uranium intake. These results suggest that at the intakes observed in this study (0.004 microgram/kg to 9 micrograms/kg body wt), the chronic ingestion of uranium in drinking water affects kidney function and that the proximal tubule, rather than the glomerulus, is the site for this interference.
To determine clinical health effects in a small group of US Gulf War veterans (n = 50) who were victims of depleted uranium (DU) "friendly fire," we performed periodic medical surveillance examinations. We obtained urine uranium determinations, clinical laboratory values, reproductive health measures, neurocognitive assessments, and genotoxicity measures. DU-exposed Gulf War veterans with retained metal shrapnel fragments were excreting elevated levels of urine uranium 8 years after their first exposure (range, 0.018 to 39.1 micrograms/g creatinine for DU-exposed Gulf War veterans with retained fragments vs 0.002 to 0.231 microgram/g creatinine in DU exposed but without fragments). The persistence of the elevated urine uranium suggests ongoing mobilization from the DU fragments and results in chronic systemic exposure. Clinical laboratory outcomes, including renal functioning, were essentially normal. Neurocognitive measures showing subtle differences between high and low uranium exposure groups, seen previously, have since diminished. Sister chromatid exchange frequency, a measure of mutation in peripheral lymphocytes, was related to urine uranium level (6.35 sister chromatid exchanges/cell in the high uranium exposure group vs 5.52 sister chromatid exchanges/cell in the low uranium exposure group; P = 0.03). Observed health effects were related to subtle but biologically plausible perturbations in central nervous system function and a general measure of mutagen exposure. The findings related to uranium's chemical rather than radiologic toxicity. Observations in this group of veterans prompt speculation about the health effects of DU in other exposure scenarios.
In this study, we determined the carcinogenicity of depleted uranium (DU) metal fragments containing 0.75% titanium in muscle tissues of rats. The results have important implications for the medical management of Gulf War veterans who were wounded with DU fragments and who retain fragments in their soft tissues. We compared the tissue reactions in rats to the carcinogenicity of a tantalum metal (Ta), as a negative foreign-body control, and to a colloidal suspension of radioactive thorium dioxide ((232)Th), Thorotrast, as a positive radioactive control. DU was surgically implanted in the thigh muscles of male Wistar rats as four squares (2.5 x 2.5 x 1.5 mm or 5.0 x 5.0 x 1.5 mm) or four pellets (2.0 x 1.0 mm diameter) per rat. Ta was similarly implanted as four squares (5.0 x 5.0 x 1.1 mm) per rat. Thorotrast was injected at two sites in the thigh muscles of each rat. Control rats had only a surgical implantation procedure. Each treatment group included 50 rats. A connective tissue capsule formed around the metal implants, but not around the Thorotrast. Radiographs demonstrated corrosion of the DU implants shortly after implantation. At later times, rarifactions in the radiographic profiles correlated with proliferative tissue responses. After lifetime observation, the incidence of soft tissue sarcomas increased significantly around the 5.0 x 5.0 mm squares of DU and the positive control, Thorotrast. A slightly increased incidence occurred in rats implanted with the 2.5 x 2.5 mm DU squares and with 5.0 x 5.0 mm squares of Ta. No tumors were seen in rats with 2.0 x 1.0 mm diameter DU pellets or in the surgical controls. These results indicate that DU fragments of sufficient size cause localized proliferative reactions and soft tissue sarcomas that can be detected with radiography in the muscles of rats.
Animal studies and small studies in humans have shown that uranium is nephrotoxic. However, more information about its renal effects in humans following chronic exposure through drinking water is required. We measured uranium concentrations in drinking water and urine in 325 persons who had used drilled wells for drinking water. We measured urine and serum concentrations of calcium, phosphate, glucose, albumin, creatinine, and beta-2-microglobulin to evaluate possible renal effects. The median uranium concentration in drinking water was 28 microg/L (interquartile range 6-135, max. 1,920 microg/L) and in urine 13 ng/mmol creatinine (2-75), resulting in the median daily uranium intake of 39 microg (7-224). Uranium concentration in urine was statistically significantly associated with increased fractional excretion of calcium and phosphate. Increase of uranium in urine by 1 microg/mmol creatinine increased fractional excretion of calcium by 1.5% [95% confidence interval (CI), 0.6-2.3], phosphate by 13% (1.4-25), and glucose excretion by 0.7 micromol/min (-0.4-1.8). Uranium concentrations in drinking water and daily intake of uranium were statistically significantly associated with calcium fractional excretion, but not with phosphate or glucose excretion. Uranium exposure was not associated with creatinine clearance or urinary albumin, which reflect glomerular function. In conclusion, uranium exposure is weakly associated with altered proximal tubulus function without a clear threshold, which suggests that even low uranium concentrations in drinking water can cause nephrotoxic effects. Despite chronic intake of water with high uranium concentration, we observed no effect on glomerular function. The clinical and public health relevance of the findings are not easily established, but our results suggest that the safe concentration of uranium in drinking water may be within the range of the proposed guideline values of 2-30 microg/L.
Medical surveillance of a group of U.S. Gulf War veterans who were victims of depleted uranium (DU) "friendly fire" has been carried out since the early 1990s. Findings to date reveal a persistent elevation of urine uranium, more than 10 yr after exposure, in those veterans with retained shrapnel fragments. The excretion is presumably from ongoing mobilization of DU from fragments oxidizing in situ. Other clinical outcomes related to urine uranium measures have revealed few abnormalities. Renal function is normal despite the kidney's expected involvement as the "critical" target organ of uranium toxicity. Subtle perturbations in some proximal tubular parameters may suggest early although not clinically significant effects of uranium exposure. A mixed picture of genotoxic outcomes is also observed, including an association of hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutation frequency with high urine uranium levels. Findings observed in this chronically exposed cohort offer guidance for predicting future health effects in other potentially exposed populations and provide helpful data for hazard communication for future deployed personnel.
The attack on the World Trade Center (WTC) created an acute environmental disaster of enormous magnitude. This study characterizes the environmental exposures resulting from destruction of the WTC and assesses their effects on health. Methods include ambient air sampling; analyses of outdoor and indoor settled dust; high-altitude imaging and modeling of the atmospheric plume; inhalation studies of WTC dust in mice; and clinical examinations, community surveys, and prospective epidemiologic studies of exposed populations. WTC dust was found to consist predominantly (95%) of coarse particles and contained pulverized cement, glass fibers, asbestos, lead, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and polychlorinated furans and dioxins. Airborne particulate levels were highest immediately after the attack and declined thereafter. Particulate levels decreased sharply with distance from the WTC. Dust pH was highly alkaline (pH 9.0–11.0). Mice exposed to WTC dust showed only moderate pulmonary inflammation but marked bronchial hyperreactivity. Evaluation of 10,116 firefighters showed exposure-related increases in cough and bronchial hyperreactivity. Evaluation of 183 cleanup workers showed newonset cough (33%), wheeze (18%), and phlegm production (24%). Increased frequency of newonset
To relate medical surveillance outcomes to uranium biomonitoring results in a group of depleted uranium (DU)-exposed, Gulf War I veterans.
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.
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.
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.
Serum creatinine is not an ideal marker of renal function in patients with acute kidney injury (AKI). Previous studies demonstrated that urinary IL-18 is increased in human AKI. Thus, whether urine IL-18 is an early diagnostic marker of AKI was investigated. A nested case-control study was performed within the Acute Respiratory Distress Syndrome (ARDS) Network trial. AKI was defined as an increase in serum creatinine by at least 50% within the first 6 d of ARDS study enrollment. A total of 400 urine specimens that were collected on study days 0, 1, and 3 of the ARDS trial were available from 52 case patients and 86 control patients. The data were analyzed in a cross-sectional manner and according to the time before development of AKI. The median urine IL-18 levels were significantly different at 24 and 48 h before AKI in case patients as compared with control patients. On multivariable analysis, urine IL-18 values predicted development of AKI 24 and 48 h later after adjustment for demographics, sepsis, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) III score, serum creatinine, and urine output. Urine IL-18 levels of >100 pg/ml are associated with increased odds of AKI of 6.5 (95% confidence interval 2.1 to 20.4) in the next 24 h. On diagnostic performance testing, urine IL-18 demonstrates an area under the receiver operating characteristic curve of 73% to predict AKI in the next 24 h. The urine IL-18 values were also significantly different between survivors and nonsurvivors (P < 0.05), and on multivariable analysis, the urine IL-18 value on day 0 is an independent predictor of mortality. Urinary IL-18 levels can be used for the early diagnosis of AKI. Urine IL-18 levels also predict the mortality of patients who have ARDS and are in the intensive care unit.
Health effects stemming from depleted uranium (DU) exposure in a cohort of Gulf War veterans who were in or on US Army vehicles hit by friendly fire involving DU munitions are being carefully monitored through the Baltimore Veterans Affairs (VA) DU Follow-Up Program initiated in 1993. DU exposure in this cohort has been directly measured using inductively coupled plasma-mass spectrometer (ICP-MS) isotopic analysis for DU in urine specimens. Soldiers with embedded DU fragments continue to excrete elevated concentrations of U in their urine, documenting ongoing systemic exposure to U released from their fragments. Biennial surveillance visits provide a detailed health assessment that includes basic clinical measures and surveillance for early changes in kidney function, an expected target organ for U. Tests also include measurements of genotoxicity and neuroendocrine, neurocognitive and reproductive function. With the exception of the elevated urine U excretion, no clinically significant expected U-related health effects have been identified to date. Subtle changes in renal function and genotoxicity markers in veterans with urine U concentrations greater than 0.1 microg(-1) creatinine, however, indicate the need for continued surveillance of these DU-exposed veterans.
The long-term effects of metal-on-metal arthroplasty are currently under scrutiny because of the potential biological effects of metal wear debris. This review summarises data describing the release, dissemination, uptake, biological activity, and potential toxicity of metal wear debris released from alloys currently used in modern orthopaedics. The introduction of risk assessment for the evaluation of metal alloys and their use in arthroplasty patients is discussed and this should include potential harmful effects on immunity, reproduction, the kidney, developmental toxicity, the nervous system and carcinogenesis.
Aim: Beyond inflicting acute traumatic injury, contact with improvised explosive devices, the leading cause of injury for soldiers serving in Iraq and Afghanistan, may result in wound contamination with embedded fragments permitting chronic exposure to toxic materials. Because health effects associated with embedded fragments are not well-delineated, the U.S. Department of Veterans Affairs (VA) is establishing an exposure registry and surveillance center to identify, track and monitor the health of veterans who have embedded fragments. Methods: U.S. Veterans wounded with embedded fragments are identified when making contact for healthcare using a screening process incorporated into the Veterans Administration's national electronic medical record system. A data review results in recommended follow-up which may include fragment analysis, urine biological monitoring, and/or clinical consultation. The registry will link to the individual's electronic medical record and other data sources to capture injury and exposure data, urine biological monitoring data, health outcomes, and fragment content results, when available. Results: Preliminary data suggest that approximately 3% of veterans have embedded fragments and are eligible for inclusion in the registry. Most fragments are metallic; therefore, a suite of 13 metals frequently found in fragments will be included in the biological monitoring protocol. Conclusions: Using a public health exposure registry, the surveillance center team will employ population level surveillance to better characterize exposure and identify potential health outcomes associated with retained fragments. The registry also provides an avenue for ongoing contact with exposed veterans as knowledge evolves affecting medical and surgical management guidelines for veterans with embedded fragments.
Isotopic ratios of urinary uranium (U) provide a decisive tool in diagnosing a patient's potential exposure to depleted uranium (DU). This study investigated the measurement of urinary 236U/238U and 235U/238U ratios of ultra trace concentrations using a sector field inductively coupled plasma mass spectrometer (ICP-MS). Uranium was separated from the urinary matrix and pre-concentrated by co-precipitation with calcium and magnesium after addition of ammonium hydroxide. The precipitates were collected, dissolved and analyzed by ICP-MS. 235U/238U and 236U/238U ratios were measured using a desolvating sample introduction system and a sector field ICP-MS. These ratios were accurately measured in samples containing as low as 5 ng L− 1 U. 236U measurement was hindered by abundance sensitivity limitations and uranium hydride (235UH) formation. Measured 235U/238U and 236U/238U ratios were about 7 × 10− 3 and < 5 × 10− 6, respectively, in urine samples from patients not exposed to DU. The 235U/238U ratio was consistently about 2 × 10− 3 in 12 urine samples from patients with embedded fragments of DU, while the corresponding ratio of 236U/238U ranged from 9 × 10− 6 to 33 × 10− 6. This wide range in 236U/238U ratios might suggest different sources of depleted uranium in those DU-urine samples. It is proposed that 235U/238U and 236U/238U ratios are 7 × 10− 3 and < 5 × 10− 6, respectively, in urine samples from individuals not exposed to DU, and 2 × 10− 3 and > 7 × 10− 6, respectively, in urine samples from DU-exposed individuals.
Whether bullets remaining in tissues can give rise to lead poisoning has long been a subject of discussion. The great body of opinion, first expressed by Paré, holds that bullets in tissues will not cause intoxication, but there have also been proponents of the opposite point of view, and cases of plumbism from retained bullets have been reported from time to time, the earliest record being that of Bronvin1 in 1867. Among the more than fifty publications on this subject there are reports of forty cases in which the clinical diagnosis of plumbism resulting from retained bullets has been made.2The entire assumption of the occurrence of plumbism from retained bullets being dependent on the occurrence of clinically identifiable lead poisoning, it would seem desirable at the outset to state the criteria on which my associates and I base such a diagnosis. They are the existence of (1)
To ensure that all veterans with retained embedded fragments are properly monitored for potential health effects of embedded materials.
Urine biomonitoring and health surveillance programs were developed to gather information about health risks associated with chemicals released from embedded fragments.
Elevated systemic exposure to depleted uranium (DU) that continues to occur in veterans with DU fragments remains a concern, although no clinically significant DU-related health effects have been observed to date. Other metals and local tissue reactions to embedded fragments are also of concern.
Knowledge gained from these programs will help to develop guidelines for surgical removal of tissue-embedded fragments.
Cadmium (Cd) is a nephrotoxic industrial and environmental pollutant that causes a generalized dysfunction of the proximal tubule. Kim-1 is a transmembrane glycoprotein that is normally not detectable in non-injured kidney, but is up-regulated and shed into the urine during the early stages of Cd-induced proximal tubule injury. The objective of the present study was to examine the relationship between the Cd-induced increase in Kim-1 expression and the onset of necrotic and apoptotic cell death in the proximal tubule. Adult male Sprague-Dawley rats were treated with 0.6 mg (5.36 μmol) Cd/kg, subcutaneously, 5 days per week for up to 12 weeks. Urine samples were analyzed for levels of Kim-1 and the enzymatic markers of cell death, lactate dehydrogenase (LDH) and alpha-glutathione-S-transferase (α-GST). In addition, necrotic cells were specifically labeled by perfusing the kidneys in situ with ethidium homodimer using a procedure that has been recently developed and validated in the Prozialeck laboratory. Cryosections of the kidneys were also processed for the immunofluorescent visualization of Kim-1 and the identification of apoptotic cells by TUNEL labeling. Results showed that significant levels of Kim-1 began to appear in the urine after 6 weeks of Cd treatment, whereas the levels of total protein, α-GST and LDH were not increased until 8–12 weeks. Results of immunofluorescence labeling studies showed that after 6 weeks and 12 weeks, Kim-1 was expressed in the epithelial cells of the proximal tubule, but that there was no increase in the number of necrotic cells, and only a modest increase in the number of apoptotic cells at 12 weeks. These results indicate that the Cd-induced increase in Kim-1 expression occurs before the onset of necrosis and at a point where there is only a modest level of apoptosis in the proximal tubule.
New-onset asthma rates are higher among US soldiers deployed to Iraq/Afghanistan than stateside, but overall respiratory symptom and spirometry rates among soldiers returning from Iraq/Afghanistan have not yet been addressed. We determined these rates in soldiers deployed to Iraq/Afghanistan versus troops stationed elsewhere.
Retrospective review of active-duty soldiers (2004 to 2010) registered at Veterans Affairs Medical Center, Northport, New York, with Long Island/New York City zip codes. Subjects were examined by physicians or physicians' assistants. We counted number of spirometries, which required respiratory symptoms, and the provider was required to submit a diagnosis as part of the request process.
Twenty-five percent of 7151 troops went to Iraq/Afghanistan (n = 1816) and 75% went elsewhere (n = 5335), with more smokers in the Iraq/Afghanistan group (16.1% vs 3.3%). Rates of symptoms and spirometry were 14.5% and 1.8%, for Iraq/Afghanistan, versus troops deployed elsewhere, respectively (P < 0.001). Both groups had similar forced expired volume in 1 second/forced vital capacity ratios (78%).
New-onset Iraq/Afghanistan war lung injury is common and rates of symptoms leading to a diagnosis requiring spirometry are high.
The Depleted Uranium Follow-Up Program is a clinical surveillance program run by the Baltimore Veterans Affairs Medical Center since 1993 for veterans of the Gulf and Iraqi wars who were exposed to depleted uranium (DU) as a result of "friendly-fire" incidents.
In 2009, 40 veterans from this cohort were screened for skin reactivity to metals by patch-testing with extended metal series and uranyl acetate (0.25%, 2.5%, and 25%). A control arm comprised 46 patients without any known occupational exposures to DU who were seen at the University of Maryland Dermatology Clinic for evaluation of allergic contact dermatitis.
Excluding irritant reactions, no patch-test reactions to uranyl acetate were observed in the participants. Irritant reactions to DU were more common in the clinic cohort, likely reflective of the demographic differences between the two arms of the study. Biologic monitoring of urine uranium concentrations in the DU program participants with 24-hour urine samples showed evidence of percutaneous uranium absorption from the skin patches.
We conclude that dermatitis observed in a subset of the veterans was unrelated to their military DU exposure. Our data suggest that future studies of skin testing with uranyl acetate should utilize 0.25%, the least irritating concentration.
Concerns about respiratory conditions have surfaced among persons deployed to Iraq and Afghanistan. Data on 46,077 Millennium Cohort Study participants who completed baseline (July 2001-June 2003) and follow-up (June 2004-February 2006) questionnaires were used to investigate 1) respiratory symptoms (persistent or recurring cough or shortness of breath), 2) chronic bronchitis or emphysema, and 3) asthma. Deployers had a higher rate of newly reported respiratory symptoms than nondeployers (14% vs. 10%), while similar rates of chronic bronchitis or emphysema (1% vs. 1%) and asthma (1% vs. 1%) were observed. Deployment was associated with respiratory symptoms in both Army (adjusted odds ratio = 1.73, 95% confidence interval: 1.57, 1.91) and Marine Corps (adjusted odds ratio = 1.49, 95% confidence interval: 1.06, 2.08) personnel, independently of smoking status. Deployment length was linearly associated with increased symptom reporting in Army personnel (P < 0.0001). Among deployers, elevated odds of symptoms were associated with land-based deployment as compared with sea-based deployment. Although respiratory symptoms were associated with deployment, inconsistency in risk with cumulative exposure time suggests that specific exposures rather than deployment in general are determinants of postdeployment respiratory illness. Significant associations seen with land-based deployment also imply that exposures related to ground combat may be important.
Biologic response to orthopedic implants debris is central to clinical performance. Eventual implant loosening due to aseptic osteolysis has been attributed to local inflammatory responses to wear and corrosion products that are produced by articulating implant interfaces. The response to implant debris is dominated by local immune activation, e.g. macrophages. Immune reactivity has been shown to depend on the number of particles produced or the dose (i.e., the concentration of phagocytosable particles per tissue volume, which can be characterized by knowing the size distribution and amount of debris). Elongated particles (fbers) are generally more pro-inflammatory than round particles, and there is a growing consensus that metals particles are more proinflammatory than polymers in vivo. Generally, to produce an in vitro inflammatory response, particles need to be less than 10 mum, i.e. phagocytosable. However, both soluble and particulate debris derived from Co-Cr-Mo alloy implants can induce monocyte/macrophage activation and secretion of pro-inflammatory cytokines such as IL-1beta, TNFalpha, IL-6 and IL-8 via up-regulation of transcription factor NFkappabeta, and activation of inflammasome danger signaling in human macrophages. Not only does activation of local (and systemic) inflammation result in decreased osteoblast function but osteoclast activity increases. Some people are more predisposed to implant debris induced inflammation and metal "allergy" testing services are becoming available. New pathways of implant debris-induced inflammatory reactions continue to be discovered, such as the "danger signaling" inflammasome pathway, which provides new targets for pharmaceutical intervention and improved implant performance.
A man was hospitalized on three occasions for symptoms of lead intoxication 20 to 25 years after a gunshot wound that resulted in retention of a lead bullet in his hip joint. The potential for lead toxicity as a complication of a lead missile injury appears to be related to (1) the surface area of lead exposed for dissolution, (2) the location of the lead projectile, and (3) the length of time during which body tissues are exposed to absorbable lead. Cases of lead poisoning of immediate onset resulting from lead shot have been reported in Europe, but all documented cases of ammunition-related plumbism reported in the United States have involved synovial fluid dissolution of a single lead bullet over many years. The solvent characteristics of synovial fluid and associated local arthritis are apparently important factors in the dissolution and absorption of lead from projectiles located in joints. Awareness that lead intoxication can be a complication of retained lead projectiles should allow rapid institution of appropriate diagnostic and therapeutic modalities when such a clinical situation arises.
Attempts were made to analyze the process of foreign body (FB) tumorigenesis and to identify etiologically significant factors by correlating information in the literature and recent experimental data from our labroatory. It appears that the process of FB tumorigenesis is dependent on sequence of specific conditions as expressed by the following criteria: (a) cellular proliferation and tissue infiltration during acute FB reaction; (b) fibrosis of the tissue capsule surrounding the FB; (c) quiescence of the tissue reaction, i. e., dormancy and phagocytic inactivity of FB-attached macrophages; and (d) availability of a FB surface for direct contact with clonal preneoplastic cells. There is no indication that the initial acquisition of neoplastic potential and the determination of specific tumor characteristics are based on direct physical or chemical reaction between cells and the FB. These etiological key events occur presumably in mesenchymal stem cells associated with the microvasculature no later than during the acute stage of FB reaction and certainly long before clonal descendants of these cells are first found in contact with the FB surface. In fact, there is no reason to assume that cells with neoplastic determination may be present in normal tissue prior to the introduction of a FB and that the FB would only create the conditions required for stepwise preneoplastic maturation.
Co, Cr, and Ni concentrations were determined by electrothermal atomic absorption spectrophotometry in serum and urine specimens collected from a group of 28 patients at intervals of from 1 day to 2.5 years after total knee or hip arthroplasty with porous-coated prostheses fabricated of Co-Cr alloy (ASTM F-75-82). Two control groups were also tested: (a) 42 healthy adults and (b) 16 orthopaedic patients after total knee or hip arthroplasty with porous-coated prostheses fabricated predominantly of Ti-Al-V alloy (ASTM F-136-84). All prostheses contained polyethylene components to avoid metal-to-metal contact. Mean Co concentrations in serum and urine were slightly increased in patients with Co-Cr knee implants at 6-120 weeks after surgery, compared with (a) preoperative values, (b) corresponding values in patients with Co-Cr hip implants, and (c) corresponding values in control patients with Ti-Al-V knee and hip prostheses. Substantially increased Co levels were observed in serum and urine of two patients at 7 weeks and 22 months postarthroplasty, associated with loosening of the prostheses; one of the patients also had elevated Cr levels in serum and urine. Although ASTM F-75-82 and F-136-84 alloys contain very little Ni (less than 1.0 and less than 0.2% Ni, respectively, by wt), mean Ni concentrations in serum and urine were greatly increased at 1-2 days after implantation of Ti-Al-V and Co-Cr prostheses, diminishing by 2 weeks. The postoperative hypernickelemia and nickeluresis may reflect contamination of the operative field with Ni-containing particles from the drills, cutting jigs, and drilling jigs, or it may represent a previously unrecognized pathophysiological response to surgery.
By the late 1950s, the views had evolved that 1) U does not enter cells but damages the kidneys by binding to the luminal membranes of renal tubular cells, interfering with reabsorption of glucose, sodium, amino acids, protein, water, and other substances, and causing slow cell death by suppression of respiration; and 2) U does not cause significant damage to the kidneys at concentrations below 3 micrograms U g-1 kidney. Although there has not been a major unified effort in the past three decades to update the toxicology of U as a nephrotoxin, there have been numerous isolated studies that may be useful in reevaluating these longstanding views on the behavior and action of U in the kidneys and the renal U concentration at which toxic effects may become evident. This paper is a brief review and synthesis of current information on U nephrotoxicity. Much more experimental research and reevaluation of existing data are needed concerning U nephrotoxicity, particularly for the case of chronic exposure.
Although the kidney is the critical organ limiting occupational exposure to soluble uranium compounds, there have been no adequate studies evaluating renal tubular dysfunction in chronically exposed workers. The present investigation evaluated kidney function among 39 uranium mill workers and 36 local cement plant workers of equivalent age, sex, and race. The uranium workers showed a significantly higher excretion of beta-2-microglobulin and five amino acids than the reference group. Although the levels of tubular proteinuria were mild, a dose-effect relation existed between the clearance of beta-2-microglobulin, relative to that of creatinine, and the length of time that the uranium workers had spent in the yellowcake drying and packaging area, the work area with the highest exposures to soluble uranium. Age did not account for this relationship. Glomerular function was significantly better among the uranium workers than among the referents, though this may have been the result of differences in the physical activity of the groups during the collection period. The data presented suggest reduced renal proximal tubular reabsorbtion of amino acids and of low molecular weight proteins, consistent with uranium nephrotoxicity.
Uranium mining on the Colorado Plateau started as an aggressive industry in 1950. At that time, little was known about the carcinogenic hazards of uranium mining except for the high incidence of cancer in the Old World uranium mining industry of Schneeberg in Germany and Joachimsthal in Czechoslovakia during the 19th century. Suspicions were voiced and predictions made that there could be a high incidence of lung cancer in our uranium mining population.
The purpose of this study was to determine whether human fibroblasts express CD40, a 50-kDa member of the tumor necrosis factor-alpha-receptor superfamily. CD40 is an important mitogenic receptor on B lymphocytes which regulates B lymphocyte proliferation and differentiation. Interestingly, CD40 mRNA was detected in human lung, gingival, synovial, dermal (foreskin), and spleen fibroblasts using the reverse-transcriptase polymerase chain reaction. Moreover, the CD40 protein was detected on cultured human fibroblasts using anti-CD40 mAbs (G28-5, EA-5) and flow cytometry and on fibroblasts in dermal tissue sections via in situ staining. In contrast to B lymphocytes, where CD40 expression is unregulated both by interleukin-4 and interferon (IFN-gamma), CD40 expression on cultured human fibroblasts could only be upregulated by IFN-gamma. IFN-gamma induced a 10-fold increase in CD40 mRNA and protein levels. Furthermore, via a two-color staining technique for CD40 expression and DNA content, IFN-gamma not only upregulated CD40 expression on cultured human fibroblasts, but also shifted fibroblasts into the G0/G1 phase of the cell cycle. This observation suggested that nonproliferating fibroblasts might display elevated levels of CD40. To test this hypothesis, CD40 expression was analyzed on fibroblasts in log phase growth vs fibroblasts which had reached confluency and were nonproliferating. Interestingly, confluent fibroblasts expressed higher levels of CD40 than fibroblasts in log phase growth. These data suggest that CD40 expression by human fibroblasts is related to cell growth. In summary, this report is the first to demonstrate that human fibroblasts from a variety of tissues display CD40. While the function of CD40 on fibroblasts is not yet known, it may facilitate fibroblast proliferation, an event important for tissue repair, and may facilitate inflammation via interaction with T lymphocytes and mast cells, which display the CD40 ligand.
Because keratinocytes are tolerogenic antigen-presenting cells (APC), we investigated the role of B7/BB-1 in reconstituting defective accessory cell (AC) and APC functions by such nonlymphoid cells. KC were induced to stably express B7/BB-1 by DNA-mediated gene transfection. This single-transformed B7/BB-1+ A431 cell line (but not control A431) functioned as AC for lectin-induced T-cell proliferation, as well as oxidative mitogenesis. This costimulation was dependent on B7/BB-1 expression since the monoclonal antibody BB-1 blocked costimulation of PHA mitogenesis by 75%. After the induction of class II MHC antigen expression by interferon-gamma, B7/BB-1+ KC but not control KC presented alloantigens to resting T-cells in the primary mixed lymphocyte reaction. These data indicate that the stable expression of B7/BB-1 antigen by KC reconstitutes defective AC and alloantigen-presenting activity. The lack of expression of such second signal by normal KC may be responsible for their ability to induce clonal anergy in vitro and in vivo.
Although the expression and function of CD40 on B lymphocytes has been well studied, the significance of CD40 on non-lymphoid cells such as keratinocytes (KC) is not as well characterized. We demonstrate in this report that CD40 is expressed by virtually all human KC, and that it functions as an important signaling molecule. Flow cytometry of undifferentiated and terminally differentiated KC indicated that both cell types expressed CD40, as determined by binding to monoclonal antibodies and a recombinant CD40 ligand fusion protein; interferon-gamma (IFN-gamma) treatment of KC increased CD40 expression. Cultured KC also expressed 1.5-kb CD40 transcripts. Activation of KC cell surface CD40 using the monoclonal antibody G28.5 resulted in the rapid generation of a 50-kDa tyrosine phosphorylated polypeptide, as well as a dose-dependent increase in the secretion of interleukin-6, a cytokine that has been linked to KC proliferation. KC also co-stimulated a significant T lymphocyte proliferative response to the mitogen phytohemagglutinin that was CD40 dependent. These data indicate that KC constitutively express a low level of functional CD40 and regulate their expression in response to IFN-gamma. These data support the concept that KC, via their expression of CD40, have the capacity to amplify inflammation in the skin by interacting with CD40 ligand-bearing T cells.
"Spot samples" of urine are routinely used to monitor occupational exposure to uranium and other toxic heavy metals, such as mercury, lead, and cadmium. In the present work, it was shown that diurnal variations in the uranium concentration in different urine samples from the same individual could be quite large. However, these variations were in correlation to the creatinine level of the same samples, with values of R = 0.72-0.99, for the five subjects studied here. Thus, it is proposed here that uranium concentrations in "spot" urine samples be expressed in terms of ng uranium g(-1) creatinine rather than ng uranium L(-1). Once the 24-h creatinine level is estimated for the individual based on weight, height and age, the adjusted values can be used for determination of the internal dose of uranium.
Unlabelled:
There is an increasing recognition that, in the long term, total joint replacement may be associated with adverse local and remote tissue responses that are mediated by the degradation products of prosthetic materials. Particular interest has centered on the metal-degradation products of total joint replacements because of the known toxicities of the metal elements that make up the alloys used in the implants. We measured the concentrations of titanium, aluminum, cobalt, and chromium in the serum and the concentration of chromium in the urine of seventy-five patients during a three-year prospective, longitudinal study. Twenty patients had had a so-called hybrid total hip replacement (insertion of a modular cobalt-alloy femoral stem and head with cement and a titanium acetabular cup without cement), fifteen had had insertion of an extensively porous-coated cobalt-alloy stem with a cobalt-alloy head and a titanium-alloy socket without cement, and twenty had had insertion of a proximally porous-coated titanium-alloy stem with a cobalt-alloy head and a titanium socket without cement. The remaining twenty patients did not have an implant and served as controls. The results of our study showed that, thirty-six months postoperatively, patients who have a well functioning prosthesis with components containing titanium have as much as a threefold increase in the concentration of titanium in the serum and those who have a well functioning prosthesis with cobalt-alloy components have as much as a fivefold and an eightfold increase in the concentrations of chromium in the serum and urine, respectively. The predominant source of the disseminated chromium-degradation products is probably the modular head-neck junction and may be a function of the geometry of the coupling. Passive dissolution of extensively porous-coated cobalt-alloy stems was not found to be a dominant mode of metal release.
Clinical relevance:
Increased concentrations of circulating metal-degradation products derived from orthopaedic implants may have deleterious biological effects over the long term that warrant investigation. This is a particularly timely concern because of recent clinical trends, including the reintroduction of metal-on-metal bearing surfaces and the increasing popularity of extensively porous-coated devices with large surface areas of exposed metal. Accurate monitoring of the concentrations of metal in the serum and urine after total hip replacement also can provide insights into the mechanisms of metal release. Our findings suggest that fretting corrosion at the head-neck coupling is an important source of metal release that can lead to increased concentrations of chromium in the serum. Determinations of the concentrations of metal in the serum and urine may be useful in the diagnosis of patients who are symptomatic after a total joint replacement as increased levels are indicative of at least one mode of mechanical dysfunction (for example, fretting corrosion) of the device.
The use of depleted uranium in munitions has given rise to a new exposure route for this chemically and radioactively hazardous metal. A cohort of U.S. soldiers wounded while on or in vehicles struck by depleted uranium penetrators during the Persian Gulf War was identified. Thirty-three members of this cohort were clinically evaluated, with particular attention to renal abnormalities, approximately 3 y after their injury. The presence of retained shrapnel was identified by x ray, and urine uranium concentrations were measured on two occasions. The absorption of uranium from embedded shrapnel was strongly suggested by measurements of urine uranium excretion at two time intervals: one in 1993/1994 and one in 1995. Mean urine uranium excretion was significantly higher in soldiers with retained shrapnel compared to those without shrapnel at both time points (4.47 vs. 0.03 microg g(-1) creatinine in 1993/1994 and 6.40 vs. 0.01 microg g(-1) creatinine in 1995, respectively). Urine uranium concentrations measured in 1995 were consistent with those measured in 1994/1993, with a correlation coefficient of 0.9. Spot urine measurements of uranium excretion were also well correlated with 24-h urine collections (r = 0.95), indicating that spot urine samples can be reliably used to monitor depleted uranium excretion in the surveillance program for this cohort of soldiers. The presence of uranium in the urine can be used to determine the rate at which embedded depleted uranium fragments are releasing biologically active uranium ions. No evidence of a relationship between urine uranium excretion and renal function could be demonstrated. Evaluation of this cohort continues.
A small group of Gulf War veterans possess retained fragments of depleted uranium (DU) shrapnel, the long-term health consequences of which are undetermined. We evaluated the clinical health effects of DU exposure in Gulf War veterans compared with nonexposed Gulf War veterans. History and follow-up medical examination were performed on 29 exposed veterans and 38 nonexposed veterans. Outcome measures employed were urinary uranium determinations, clinical laboratory values, and psychiatric and neurocognitive assessment. DU-exposed Gulf War veterans with retained metal shrapnel fragments are excreting elevated levels of urinary uranium 7 years after first exposure (range 0.01-30.7 microg/g creatinine vs 0.01- 0.05 microg/g creatinine in the nonexposed). The persistence of the elevated urine uranium suggests on-going mobilization from a storage depot which results in a chronic systemic exposure. Adverse effects in the kidney, a presumed target organ, are not present at this time, though other effects are observed. Neurocognitive examinations demonstrated a statistical relationship between urine uranium levels and lowered performance on computerized tests assessing performance efficiency. Elevated urinary uranium was statistically related to a high prolactin level (>1.6 ng/ml; P=0.04). More than 7 years after first exposure, DU-exposed Gulf War veterans with retained metal fragments continue to excrete elevated concentrations of urinary uranium. Effects related to this are subtle perturbations in the reproductive and central nervous systems.
Manufactures of orthopaedic fracture implants have turned to titanium in a pure form and an alloy during the past ten to fifteen years. Although primarily because of the biomechanical properties of this metal, concern for allergy to nickel and chromium ions in stainless steel was a factor in these decisions.
To document the incidence of baseline sensitivity to metal ions and the incidence of conversion to sensitivity to one of three ions in stainless steel in a population of trauma patients at a Level I trauma center.
Prospective, consecutive patient series.
Level I trauma center.
Patients eighteen years of age and older with no history of metallic implants were recruited for this study between October 1995 and July 1997. Four hundred ninety-three patients had a Finn chamber device with chromium, nickel, and cobalt ions, which were read using a photographic scale on day three. Two hundred forty-two of these patients had placement of a second patch, at a mean interval of 187 days (range 45 to 589 days).
Internal fixation of fracture or osteotomy with metal implant. MAIN OUTCOME MANAGEMENT: Cutaneous reactivity to metal ions.
Prevalence of sensitivity to chromium was 0.2 percent, to nickel 1.3 percent, and to cobalt 1.8 percent. Rates for conversion from a negative to positive status were 2.7 percent for chromium, 3.8 percent for nickel, and 3.8 percent for cobalt. Rates for desensitization (i.e., converting from a positive to negative status) were 2.1 percent for nickel and 3.8 percent for cobalt.
The prevalence of sensitivity to nickel, cobalt, and chromium is apparently low. Similarly, internal fixation devices composed of stainless steel appear to result in an equal incidence of conversion to metal ionic sensitivity and desensitization to metal ions. It is conceivable that cutaneous sensitivity is not representative of deep immune response.
Workers from the Fire Department of New York City were exposed to a variety of inhaled materials during and after the collapse of the World Trade Center. We evaluated clinical features in a series of 332 firefighters in whom severe cough developed after exposure and the prevalence and severity of bronchial hyperreactivity in firefighters without severe cough classified according to the level of exposure.
"World Trade Center cough" was defined as a persistent cough that developed after exposure to the site and was accompanied by respiratory symptoms severe enough to require medical leave for at least four weeks. Evaluation of exposed firefighters included completion of a standard questionnaire, spirometry, airway-responsiveness testing, and chest imaging.
In the first six months after September 11, 2001, World Trade Center cough occurred in 128 of 1636 firefighters with a high level of exposure (8 percent), 187 of 6958 with a moderate level of exposure (3 percent), and 17 of 1320 with a low level of exposure (1 percent). In addition, 95 percent had symptoms of dyspnea, 87 percent had gastroesophageal reflux disease, and 54 percent had nasal congestion. Of those tested before treatment of World Trade Center cough, 63 percent of firefighters (149 of 237) had a response to a bronchodilator and 24 percent (9 of 37) had bronchial hyperreactivity. Chest radiographs were unchanged from precollapse findings in 319 of the 332 with World Trade Center cough. Among the cohort without severe cough, bronchial hyperreactivity was present in 77 firefighters with a high level of exposure (23 percent) and 26 with a moderate level of exposure (8 percent).
Intense, short-term exposure to materials generated during the collapse of the World Trade Center was associated with bronchial responsiveness and the development of cough. Clinical and physiological severity was related to the intensity of exposure.
Hypersensitivity to metallic implants has been documented in case reports and cohort studies. However, this phenomenon remains unpredictable and poorly understood. There is continuing concern about the extrapolation of dermal patch testing to the periimplant environment. The utility of lymphocyte transformation testing (LTT) for predicting implant-related sensitivity in orthopedic patients was evaluated by contrasting LTT and patch-testing protocols and examining original cohort LTT data of subjects with and without implants. LTT of peripheral blood lymphocytes was performed, using four groups: (1) age-matched controls; (2) patients with osteoarthritis (preimplant), with and without dermal metal sensitivity; and (3) patients with total hip arthroplasty. A stimulation index of greater than 2 ( p < .05) indicated metal sensitivity. Patients with osteoarthritis and a history of metal sensitivity were more reactive to nickel than were those of any other group, as expected (ie, 66% incidence and average stimulation index of > 20). However, subjects with implants (group 3) were threefold more reactive to chromium (p < .04) than were controls (group 1) or subjects with osteoarthritis (group 2). Quantifiable lymphocyte reactivity as exemplified by increased incidence and average reactivity levels was metal implant specific (characteristic of adaptive immune responses) and suggests that LTT may be useful in the determination of implant-specific sensitivity. Advantages of LTT include quantitative results and the facilitation of multichallenge agent and dose testing. Thus, LTT (provided by laboratories fully disclosing testing methods) may be an additional tool in the armamentarium of physicians.
Urine uranium concentrations are the best biological indicator for identifying exposure to depleted uranium (DU). Internal exposure to DU causes an increased amount of urine uranium and a decreased ratio of 235U/238U in urine samples, resulting in measurements that vary between 0.00725 and 0.002 (i.e., natural and depleted uranium's 235U/238U ratios, respectively). A method based on inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS) was utilized to identify DU in urine by measuring the quantity of total U and the 235U/238U ratio. The quantitative analysis was achieved using 233U as an internal standard. The analysis was performed both with and without the reaction gas oxygen. The reaction gas converted ionized 235U+ and 238U+ into 235UO2+ (m/z = 267) and 238UO2+ (m/z = 270). This conversion was determined to be over 90% efficient. A polyatomic interference at m/z 234.8 was successfully removed from the 235U signal under either DRC operating conditions (with or without oxygen as a reaction gas). The method was validated with 15 urine samples of known uranium compositions. The method detection limit for quantification was determined to be 0.1 pg U mL(-1) urine and an average coefficient of variation (CV) of 1-2% within the sample measurements. The method detection limit for determining 235U/238U ratio was 3.0 pg U mL(-1) urine. An additional 21 patient samples were analyzed with no information about medical history. The measured 235U/238U ratio within the urine samples correctly identified the presence or absence of internal DU exposure in all 21 patients.
Mobilization of uranium (U) from embedded depleted uranium (DU) metal fragments in Gulf War veterans presents a unique exposure scenario for this radioactive and nephrotoxic metal. In a cohort of exposed veterans, urine U concentrations measured every two years since 1993 persistently range from 10 to over 500 times normal levels, indicating that embedded DU fragments give rise to chronic, systemic exposure to U. Health effects of this exposure are not fully known, but clinical surveillance of these soldiers continues in light of animal studies showing that U released from implanted DU pellets results in tissue accumulation of U. The biokinetic model for uranium recommended by the International Commission on Radiological Protection was used to predict kidney U concentrations and tissue radiation doses in veterans with DU shrapnel based on their urine U excretion. Results suggest that kidney U concentrations in some individuals reached their peak within six years after the war, while in others, concentrations continue to increase and are approaching 1 ppm after 10 y. These results are consistent with urine biomarker tests of renal proximal tubular cell function and cytotoxicity which have shown elevated mean urinary protein excretion indicative of functional effects in veterans with high urine U concentrations (> or =0.10 microg g(-1) creatinine). Predicted lifetime effective radiation dose from DU released to the blood for the highest exposed individual in this cohort was substantially less than the National Council on Radiation Protection (NCRP) limit for occupational exposure. These results provide further support for current health protection guidelines for DU, which are based on the metal's chemical rather than its radiological toxicity. In light of the potential for continued accumulation of U in the kidney to concentrations approaching the traditional guidance level of 3 ppm U, these results indicate the need for continued surveillance of this population for evidence of developing renal dysfunction.
In experimental settings, uranium is toxic to kidneys, but effects on humans are unclear. Ingestion of water from drilled wells is a source of high uranium exposure in some populations.
Uranium exposure was measured in 95 men and 98 women aged 18 to 81 years who had used drinking water from drilled wells for an average of 16 years. Urinary N-acetyl-gamma-d-glucosaminidase, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyltransferase, and glutathione-S-transferase; serum cystatin C; and urinary and serum calcium, phosphate, glucose, and creatinine were measured to evaluate possible toxic effects of uranium on kidney cells and renal function. In addition, supine blood pressure was measured. Associations between uranium exposure and the outcome variables were modeled by using linear regression with adjustment for age, sex, body mass index, smoking, and analgesic use.
Median uranium concentration in drinking water was 25 microg/L (interquartile range, 5 to 148 microg/L; maximum, 1,500 microg/L). Indicators of cytotoxicity and kidney function did not show evidence of renal damage. No statistically significant associations with uranium in urine, water, hair, or toenails was found for 10 kidney toxicity indicators. Uranium exposure was associated with greater diastolic and systolic blood pressures, and cumulative uranium intake was associated with increased glucose excretion in urine.
Continuous uranium intake from drinking water, even at relatively high exposures, was not found to have cytotoxic effects on kidneys in humans.
To appraise the literature on the value of urinary biomarkers in septic acute kidney injury (AKI).
Systematic review.
Academic medical centre.
Human studies of urinary biomarkers.
None.
Fourteen articles fulfilled inclusion criteria. Most studies were small, single-centre, and included mixed medical/surgical adult populations. Few focused solely on septic AKI and all had notable limitations. Retrieved articles included data on low-molecular-weight proteins (beta2-microglobulin, alpha1-microglobulin, adenosine deaminase binding protein, retinol binding protein, cystatin C, renal tubular epithelial antigen-1), enzymes (N-acetyl-beta-glucosaminidase, alanine-aminopeptidase, alkaline phosphatase; lactate dehydrogenase, alpha/pi-glutathione-S-transferase, gamma-glutamyl transpeptidase), cytokines [platelet activating factor (PAF), interleukin-18 (IL-18)] and other biomarkers [kidney injury molecule-1, Na/H exchanger isoform-3 (NHE3)]. Increased PAF, IL-18, and NHE3 were detected early in septic AKI and preceded overt kidney failure. Several additional biomarkers were evident early in AKI; however, their diagnostic value in sepsis remains unknown. In one study, IL-18 excretion was higher in septic than in non-septic AKI. IL-18 also predicted deterioration in kidney function, with increased values preceding clinically significant kidney failure by 24-48 h. Detection of cystatin C, alpha1-microglobulin, and IL-18 predicted need for renal replacement therapy (RRT).
Few clinical studies of urinary biomarkers in AKI have included septic patients. However, there is promising evidence that selected biomarkers may aid in the early detection of AKI in sepsis and may have value for predicting subsequent deterioration in kidney function. Additional prospective studies are needed to accurately describe their diagnostic and prognostic value in septic AKI.
A cohort of seventy-four 1991 Gulf War soldiers with known exposure to depleted uranium (DU) resulting from their involvement in friendly-fire incidents with DU munitions is being followed by the Baltimore Veterans Affairs Medical Center. Biennial medical surveillance visits designed to identify uranium-related changes in health have been conducted since 1993. On-going systemic exposure to DU in veterans with embedded metal fragments is indicated by elevated urine uranium (U) excretion at concentrations up to 1,000-fold higher than that seen in the normal population. Health outcome results from the subcohort of this group of veterans attending the 2005 surveillance visit were examined based on two measures of U exposure. As in previous years, current U exposure is measured by determining urine U concentration at the time of their surveillance visit. A cumulative measure of U exposure was also calculated based on each veteran's past urine U concentrations since first exposure in 1991. Using either exposure metric, results continued to show no evidence of clinically significant DU-related health effects. Urine concentrations of retinol binding protein (RBP), a biomarker of renal proximal tubule function, were not significantly different between the low vs. high U groups based on either the current or cumulative exposure metric. Continued evidence of a weak genotoxic effect from the on-going DU exposure as measured at the HPRT (hypoxanthine-guanine phosphoribosyl transferase) locus and suggested by the fluorescent in-situ hybridization (FISH) results in peripheral blood recommends the need for continued surveillance of this population.