Depleted uranium exposure and health effects in Gulf War veterans

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.     

Toxicological assessments of Gulf War veterans

Concerns about unexplained illnesses among veterans of the 1991 Gulf War appeared soon after that conflict ended. Many environmental causes have been suggested, including possible exposure to depleted uranium munitions, vaccines and other drugs used to protect troops, deliberate or accidental exposure to chemical warfare agents and pesticides and smoke from oil-well fires. To help resolve these issues, US and UK governments have sought independent expert scientific advice from prestigious, independent scientific and public health experts, including the US National Academies of Science and the UK Royal Society and Medical Research Council. Their authoritative and independent scientific and medical reviews shed light on a wide range of Gulf War environmental hazards. However, they have added little to our understanding of Gulf War veterans' illnesses, because identified health effects have been previously well characterized, primarily in the occupational health literature. This effort has not identified any new health effects or unique syndromes associated with the evaluated environmental hazards. Nor do their findings provide an explanation for significant amounts of illnesses among veterans of the 1991 Gulf War. Nevertheless, these independent and highly credible scientific reviews have proven to be an effective means for evaluating potential health effects from deployment-related environmental hazards.     

Uranium quantification in semen by inductively coupled plasma mass spectrometry

In this study we report uranium analysis for human semen samples. Uranium quantification was performed by inductively coupled plasma mass spectrometry. No additives, such as chymotrypsin or bovine serum albumin, were used for semen liquefaction, as they showed significant uranium content. For method validation we spiked 2 g aliquots of pooled control semen at three different levels of uranium: low at 5 pg/g, medium at 50 pg/g, and high at 1000 pg/g. The detection limit was determined to be 0.8 pg/g uranium in human semen. The data reproduced within 1.4–7% RSD and spike recoveries were 97–100%. The uranium level of the unspiked, pooled control semen was 2.9 pg/g of semen (n = 10). In addition six semen samples from a cohort of Veterans exposed to depleted uranium (DU) in the 1991 Gulf War were analyzed with no knowledge of their exposure history. Uranium levels in the Veterans’ semen samples ranged from undetectable (<0.8 pg/g) to 3350 pg/g. This wide concentration range for uranium in semen is consistent with known differences in current DU body burdens in these individuals, some of whom have retained embedded DU fragments.     

Depleted uranium is not toxic to rat brain endothelial (RBE4) cells

Studies on Gulf War veterans with depleted uranium (DU) fragments embedded in their soft tissues have led to suggestions of possible DU-induced neurotoxicity. We investigated DU uptake into cultured rat brain endothelial cells (RBE4). Following the determination that DU readily enters RBE4 cells, cytotoxic effects were analyzed using assays for cell volume increase, heat shock protein 90 (Hsp90) expression, 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) reduction, and lactate dehydrogenase (LDH) activity. The results of these studies show that uptake of the U₃O₈ uranyl chloride form of DU into RBE4 cells is efficient, but there are little or no resulting cytotoxic effects on these cells as detected by common biomarkers. Thus, the present experimental paradigm is rather reassuring and provides no indication for overt cytotoxicity in endothelial cells exposed to DU.     

Managing future Gulf War Syndromes: international lessons and new models of care

After the 1991 Gulf War, veterans of the conflict from the United States, United Kingdom, Canada, Australia and other nations described chronic idiopathic symptoms that became popularly known as 'Gulf War Syndrome'. Nearly 15 years later, some 250 million dollars in United States medical research has failed to confirm a novel war-related syndrome and controversy over the existence and causes of idiopathic physical symptoms has persisted. Wartime exposures implicated as possible causes of subsequent symptoms include oil well fire smoke, infectious diseases, vaccines, chemical and biological warfare agents, depleted uranium munitions and post-traumatic stress disorder. Recent historical analyses have identified controversial idiopathic symptom syndromes associated with nearly every modern war, suggesting that war typically sets into motion interrelated physical, emotional and fiscal consequences for veterans and for society. We anticipate future controversial war syndromes and maintain that a population-based approach to care can mitigate their impact. This paper delineates essential features of the model, describes its public health and scientific underpinnings and details how several countries are trying to implement it. With troops returning from combat in Afghanistan, Iraq and elsewhere, the model is already getting put to the test.     

Healthcare utilization and mortality among veterans of the Gulf War

The authors conducted an extensive search for published works concerning healthcare utilization and mortality among Gulf War veterans of the Coalition forces who served during the 1990-1991 Gulf War. Reports concerning the health experience of US, UK, Canadian, Saudi and Australian veterans were reviewed. This report summarizes 15 years of observations and research in four categories: Gulf War veteran healthcare registry studies, hospitalization studies, outpatient studies and mortality studies. A total of 149728 (19.8%) of 756373 US, UK, Canadian and Australian Gulf War veterans received health registry evaluations revealing a vast number of symptoms and clinical conditions but no suggestion that a new unique illness was associated with service during the Gulf War. Additionally, no Gulf War exposure was uniquely implicated as a cause for post-war morbidity. Numerous large, controlled studies of US Gulf War veterans' hospitalizations, often involving more than a million veterans, have been conducted. They revealed an increased post-war risk for mental health diagnoses, multi-symptom conditions and musculoskeletal disorders. Again, these data failed to demonstrate that Gulf War veterans suffered from a unique Gulf War-related illness. The sparsely available ambulatory care reports documented that respiratory and gastrointestinal complaints were quite common during deployment. Using perhaps the most reliable data, controlled mortality studies have revealed that Gulf War veterans were at increased risk of injuries, especially those due to vehicular accidents. In general, healthcare utilization data are now exhausted. These findings have now been incorporated into preventive measures in support of current military forces. With a few diagnostic exceptions such as amyotrophic lateral sclerosis, mental disorders and cancer, it now seems time to cease examining Gulf War veteran morbidity and to direct future research efforts to preventing illness among current and future military personnel.     

Neurotoxicity of depleted uranium

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

Brain accumulation of depleted uranium in rats following 3- or 6-month treatment with implanted depleted uranium pellets

Depleted uranium (DU) is used to reinforce armor shielding and increase penetrability of military munitions. Although the data are conflicting, DU has been invoked as a potential etiological factor in Gulf War syndrome. We examined regional brain DU accumulation following surgical implantation of metal pellets in male Sprague-Dawley rats for 3 or 6 mo. Prior to surgery, rats were randomly divided into five groups: Nonsurgical control (NS Control); 0 DU pellets/20 tantalum (Ta) pellets (Sham); 4 DU pellets/16 Ta pellets (Low); 10 DU pellets/10 Ta pellets (Medium); 20 DU pellets/0 Ta pellets (High). Rats were weighed weekly as a measure of general health, with no statistically significant differences observed among groups in either cohort. At the conclusion of the respective studies, animals were perfused with phosphate-buffered saline, pH 7.4, to prevent contamination of brain tissue with DU from blood. Brains were removed and dissected into six regions: cerebellum, brainstem (pons and medulla), midbrain, hippocampus, striatum, and cortex. The uranium content was measured in digested samples as its ²³⁸U isotope by high-resolution inductively coupled plasma-mass spectrometry. After 3 mo postimplantation, DU significantly accumulated in all brain regions except the hippocampus in animals receiving the highest dose of DU (p<0.05). By 6 mo, however, significant accumulation was measured only in the cortex, midbrain, and cerebellum (p<0.01). Our data suggest that DU implanted in peripheral tissues can preferentially accumulate in specific brain regions.     

Multi-symptom illnesses, unexplained illness and Gulf War Syndrome

Explanatory models for the increased prevalence of ill health in Gulf veterans compared to those not deployed to the Gulf War 1990-1991 remain elusive. This article addresses whether multi-symptom reporting in Gulf veterans are types of medically unexplained symptoms and whether the alleged Gulf War Syndrome is best understood as a medically unexplained syndrome. A review of the epidemiological studies, overwhelmingly cross-sectional, describing ill health was conducted including those that used factor analysis to search for underlying or latent clinical constructs. The overwhelming evidence was that symptoms in Gulf veterans were either in keeping with currently defined psychiatric disorders such as depression and anxiety or were medically unexplained. The application of factor analysis methods had varied widely with a risk of over interpretation in some studies and limiting the validity of their findings. We concluded that ill health in Gulf veterans and the alleged Gulf War Syndrome is best understood within the medically unexplained symptoms and syndromes constructs. The cause of increased reporting in Gulf veterans are still not clear and requires further inquiry into the interaction between sociological factors and symptomatic distress.     

Fine scale measurement and mapping of uranium in soil solution in soil and plant-soil microcosms, with special reference to depleted uranium

Background and aims

Residues from use of depleted uranium (DU) munitions pose a lasting environmental impact through persistent contamination of soils. Consequently, an understanding of the factors determining the fate of DU in soil is necessary. An understudied factor is the interaction of root exudates with DU. This study describes the use of ‘Single-Cell-Sampling-and-Analysis’ (SiCSA) for the first time in soil and investigates the effects of root exudates on DU dissolution.

Methods

Soil solutions from soil and plant-soil microcosms containing DU fragments were sampled and analysed using SiCSA and capillary electrophoresis/ICP-MS for organic acids and uranium.

Results

Nanolitre volumes of soil solution were sampled and analysed. Soils with DU fragments but no citrate addition showed low uranium concentrations in contrast to those with added citrate. Lupin root exudation gave concentrations up to 8 mM citrate and 4.4 mM malate in soil solution which solubilised DU fragments yielding transient solution concentrations of up to 30 mM.

Conclusions

Root exudates solubilise DU giving high localised soil solution concentrations. This should be considered when assessing the environmental risk of DU munitions. The SiCSA method was used successfully in soil for the first time and enables investigations with high spatial and temporal resolution in the rhizosphere.

Leaching of depleted uranium in soil as determined by column experiments

The basic features of the leachability of depleted uranium (DU) projectiles in soil was investigated by using 12 projectiles (145–294 g DU) and 16 columns installed in an air-conditioned laboratory. Two soils widely distributed in Europe, a sandy-loamy cambisol and a silty-loamy luvisol, were filled into the columns (3.3 kg dry soil each). The effluents of all columns were collected weekly during the observation period of 1 year. In 648 samples, ²³⁵U and ²³⁸U were determined by inductively coupled plasma mass spectrometry. The leaching rates of ²³⁸U from natural uranium were in general about 0.01 μg week^-1 or smaller, while those of ²³⁸U from the DU munitions varied considerably and reached values of up to 100 μg week^-1, for the different columns. In total, about 0.3 μg natural uranium corresponding to 20 ppm of its inventory in the soil was leached during the observation period. From the projectiles, an average of about 50 μg DU were leached corresponding to 18 ppm of the corroded DU mass (about 1.6% of the mean initial DU mass of the projectiles). Assuming that corrosion and leaching continue as observed, the mobilisation of ²³⁸U from DU munitions will last, on an average, for thousands of years in the soils investigated, while the munitions themselves will have been corroded after a much shorter time. It is proposed to use, for the investigated soil types, the mean leaching rates of the six columns with projectiles for transport calculations of ²³⁸U to the groundwater and, thus, for a better risk assessment of the water-dependent uptake pathways of DU.     

Stress and stressors of the early phases of the Persian Gulf War

Soldiers who deployed to Saudi Arabia in support of Operation Desert Shield were exposed to a wide variety of stressors. These stressors from the pre-combat phase of the deployment undoubtedly affect the current health of Gulf War veterans, but the exact mechanisms and linkages are not known. This article examines the nature of those stressors and possible effects on later health of veterans.     

Gulf War illness: a view from Australia

Australia sent a small, mostly naval, deployment to the 1991 Gulf War. When papers and media concerns arose about unexplained Gulf War illnesses in Gulf War troops from other countries, Australia decided to undertake its own study of Australian veterans. Undertaking a later study, more than 10 years after the Gulf War, allowed us to incorporate some methodological improvements on previous research, such as the inclusion of a face-to-face health assessment where more objective health data could be collected in addition to using a postal questionnaire. Despite the different Gulf War experience for the mostly naval Australian group, there were remarkable consistencies in the patterns of multiple symptom reporting found in overseas studies, including the fact that no unique symptom clusters were identified. In general, this excess symptom reporting was not found to occur with excesses in more objective measures of physical health. These objective physical measures included a wide range of haematological, biochemical and serological markers, a physical examination, spirometry and a step test of fatigability. In contrast, several psychological disorders, including anxiety, post-traumatic stress disorder, depression and substance abuse, were found to occur in excess in the Australian Gulf War group and were associated with Gulf War psychological stressors. These findings have helped raise awareness in Australia of psychological health problems in deployed military personnel.     

The impact of the 1991 Gulf War on the mind and brain: findings from neuropsychological and neuroimaging research

Many veterans of the 1991 Gulf War (GW) have complained of somatic and cognitive symptoms that may be neurological in nature. However, whether or not changes in brain function are associated with GW service continues to be debated. Studies of GW veterans using objective, performance-based neuropsychological measures have yielded inconsistent findings, with those indicating deficits among GW veterans typically revealing only relatively mild levels of neuropsychological impairment. Further, performances on objective neuropsychological tasks show little correspondence to subjective perceptions of cognitive functioning. Although preliminary magnetic resonance spectroscopy (MRS) studies demonstrate reduced N-acetylaspartate-to-creatine (NAA/Cr) ratio in select brain regions among GW veterans who report health concerns, this work requires further replication with larger, more representative samples. There is no evidence from neuroimaging studies of a non-specific effect of GW service or of changes in brain structure or function related to health status when conventional radiological methods are used. Owing to the paucity of objective exposure, baseline health data, and the now significant time elapsed since the GW, aetiological issues may never be fully resolved. Therefore, research addressing clinical management of GW veterans with neuropsychological dysfunction and neuroimaging abnormalities may prove more fruitful than exclusive focus on aetiology.     

贫铀经口慢性染毒对小鼠肠道菌群多样性的影响

目的观察贫铀经口慢性染毒对小鼠肠道菌群多样性的影响。方法通过将不同剂量的贫铀混入饲料中饲养小鼠,以小鼠肝脏和肾脏铀含量作为判断贫铀在动物体内蓄积的指标,建立贫铀经121慢性染毒小鼠模型,观察各组小鼠之间的体重变化,对各组小鼠进行基于细菌16SrRNAV6－V8区的PCR－DGGE分析。结果食入贫铀的各组小鼠肝脏和肾脏铀含量显著高于对照组（P〈0．05）,各组小鼠体重差异无统计学意义（P〉0．05）,各组小鼠V6－V8IXDGGE图谱的丰富度和多样性指数差异均无统计学意义（P〉0．05）。结论贫铀经日慢性染毒对小鼠肠道菌群多样性无显著影响。     

Micronuclei assay: A potential biomonitoring protocol in occupational exposure studies

As micronuclei (MN) derive from chromosomal fragments and whole chromosomes lagging behind in anaphase, the MN assay can be used to show both clastogenic and aneugenic effects. This particularly concerns the use of MN as a biomarker of genotoxic exposure and effects, where differences in MN frequencies between exposed subjects and referents are expected to be small. The present paper reviews the use of the MN assay in biomonitoring of occupational exposure studies.     

The challenges of exposure assessment in health studies of Gulf War veterans

A variety of exposures have been investigated in Gulf War veterans' health studies. These have most commonly been by self-report in a postal questionnaire but modelling and bio-monitoring have also been employed. Exposure assessment is difficult to do well in studies of any workplace environment. It is made more difficult in Gulf War studies where there are a number and variety of possible exposures, no agreed metrics for individual exposures and few contemporary records associating the exposure with an individual. In some studies, the exposure assessment was carried out some years after the war and in the context of media interest. Several studies have examined different ways to test the accuracy of exposure reporting in Gulf War cohorts. There is some evidence from Gulf War studies that self-reported exposures were subject to recall bias but it is difficult to assess the extent. Occupational exposure-assessment methodology can provide insights into the exposure-assessment process and how to do it well. This is discussed in the context of the Gulf War studies. Alternative exposure-assessment methodologies are presented, although these may not be suitable for widespread use in veteran studies. Due to the poor quality of and accessibility of objective military exposure records, self-assessed exposure questionnaires are likely to remain the main instrument for assessing the exposure for a large number of veterans. If this is to be the case, then validation methods with more objective methods need to be included in future study designs.     

Microbial Community Composition Near Depleted Uranium Impact Points

Military training activities can result in the deposition of depleted uranium (DU) into surface soils. Mechanisms of introduction include the generation of dust from firing and impact as well as the eventual corrosion of projectile fragments and unexploded ordnance. Microorganisms in surface soils have the potential to affect the transport of DU by direct binding of the metal to the cell surface, by altering near field soil chemistry that affects metal solubility, and by microbially influenced corrosion. We investigated the response (in terms of community composition) of a native soil microbiota to the presence of DU in an arid environment. Bacteria in soils outside of the test area were challenged in dilute media with “yellow cake” or U ₃ O ₈ . At concentrations of 200 to 20,000 mg L^{? 1} only species of Bacillus were identified. In situ characterizations (by PLFA analysis) of exposed site soils showed an enrichment in sulfate reducing bacterial (i17:1w7c up 39%) and Bacillus species (a15:0 up 35%) biomarkers. Three types of microbial communities were defined (as PLFA profiles) using exploratory statistics and related to three different levels of DU exposure. The community types were then statistically corresponded to site soil chemistry. Observed differences in site soil chemistry were attributed to munitions firing since enrichments (unexposed to exposed) were observed in the minerals magnesium (increase of ～ 18 mg kg^?1 ), potassium (increase of ～ 46 mg kg^?1 ) and sulfur (increase of ～ 12 mg kg^?1 ), all constituents of munitions residues. Increased concentrations of these minerals corresponded with a community type that was associated with an area of extensive DU round use.     

Premature Mortality in the Kingdom of Saudi Arabia Associated with Particulate Matter Air Pollution from the 1991 Gulf War

The State of Kuwait oil fires and military operations associated with the 1991 Gulf War resulted in substantially increased levels of airborne particulate matter (PM) in the Kingdom of Saudi Arabia (KSA) during 1991 and 1992. Using quantitative risk assessment methodology, this article estimates the increase in premature deaths in citizens of the KSA associated with the Gulf War–related increase in PM air pollution levels. Meta-analysis of daily time-series studies of non-accidental mortality associated with increased PM₁₀ levels using two alternative methodologies yielded exposure-response relative risk functions of 2.7% and 3.5% per 50 μ g/m³ increase in PM₁₀ concentration. Combining these exposure-response functions with estimates of the magnitude and duration of the increased PM₁₀ exposure, the size of the exposed population and baseline mortality rates provided an estimate of approximately 1,080 to 1,370 excess non-accidental deaths of Saudi citizens during 1991–1992 associated with the Gulf War–related increase in PM levels.     

Low paraoxonase in Persian Gulf War Veterans self-reporting Gulf War Syndrome

Exposure to organophosphate (OP's) insecticides and nerve gases during the Persian Gulf War has been implicated in the development of Gulf War Syndrome. Paraoxonase (PON1) present in human serum detoxifies OP's. We determined the levels of PON1 in the serum of Gulf War Veterans and compared these to those found in a control population. One hundred fifty-two Gulf War Veterans from the UK who self-reported the presence of Gulf War Syndrome via a questionnaire and 152 age and gender matched controls were studied. PON1 activity, concentration, and genotype were determined. In the Gulf War Veterans, paraoxon hydrolysis was less than 50% of that found in the controls (100.3 (14.8-233.8) vs 214.6 (50.3-516.2) nmol/min/ml, P < 0.001). This low activity was independent of the effect of PON1 genotype. The serum PON1 concentration was also lower in the Gulf War Veterans (75.7 (18.1-351.3) vs 88.2 (34.5-527.4) microg/ml, P < 0.00025), which was again independent of PON1 genotype. There was no difference in the rate of diazoxon hydrolysis between the groups (10. 2 +/- 4.1 micromol/min/ml vs 9.86 +/- 4.4, P = NS). A decreased capacity to detoxify OP insecticides resulting from low serum PON1 activity may have contributed to the development of Gulf War Syndrome.