Depleted uranium: all the questions about DU and Gulf War syndrome are not yet answered.
Bertell R.
[email protected]

For 15 years, the debate about depleted uranium (DU) and its detrimental effects on the health of veterans of the Gulf War of 1991, on the Iraqi people and military (and subsequently on the people of Kosovo, Afghanistan, and Iraq during the second war) has remained unresolved. Meanwhile, the number of Gulf War veterans who have developed the so-called Gulf War syndrome has risen to about one-third of the 800,000 U.S. forces deployed, and unknown proportions of those involved in the subsequent wars. Uncounted civilians and personnel of other nations that fought in Iraq and other wars since 1991 have also been afflicted. The veterans have suffered from multiple serious physiological disorders and have received little or no official recognition, medical relief, or compensation. We need to take another look at this issue, using a holistic and interactive model for the toxic matrix of exposures, identifying the major roadblocks to resolving the scientific questions, and finding appropriate medical and political responses. This commentary is such an attempt.

PMID: 16981628 [PubMed - in process]

 

1: Biol Trace Elem Res. 2006 Summer;111(1-3):185-97. Links
Brain accumulation of depleted uranium in rats following 3- or 6-month treatment with implanted depleted uranium pellets.
Fitsanakis VA,
Erikson KM,
Garcia SJ,
Evje L,
Syversen T,
Aschner M.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.

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.

PMID: 16943605 [PubMed - indexed for MEDLINE]

1: Inhal Toxicol. 2006 Oct;18(11):885-94. Links
Distribution and genotoxic effects after successive exposure to different uranium oxide particles inhaled by rats.
Monleau M,
De Meo M,
Frelon S,
Paquet F,
Donnadieu-Claraz M,
Dumenil G,
Chazel V.
IRSN/DRPH/SRBE, Laboratoire de Radiotoxicologie Experimentale, Pierrelatte Cedex, France.

In nuclear fuel cycle facilities, workers may inhale airborne uranium compounds that lead to internal contamination, with various exposure scenarios depending on the workplace. These exposures can be chronic, repeated, or acute, and can involve many different compounds. The effect of uranium after multiple scenarios of exposure is unknown. The aim of this study, therefore, was to investigate the genotoxic and biokinetics consequences of exposure to depleted insoluble uranium dioxide (UO2) by repeated or acute inhalation on subsequent acute inhalation of moderately soluble uranium peroxide (UO4) in rats. The results show that UO2 repeated preexposure by inhalation increases the genotoxic effects of UO4 inhalation, assessed by comet assay, in different cell types, when UO4 exposure alone has no effect. At the same time, the study of UO4 bioaccumulation showed that the UO4 biokinetics in the kidneys, gastrointestinal tract, and excreta, but not in the lungs, were slightly modified by previous UO2 exposures. All these results show that both genotoxic and biokinetics effects of uranium may depend on preexposure and that repeated exposure induces a potentiation effect compared with acute exposure.

PMID: 16864406 [PubMed - indexed for MEDLINE]

1: J Toxicol Environ Health A. 2006 Sep;69(17):1613-28. Links
Short-term effects of depleted uranium on immune status in rat intestine.
Dublineau I,
Grison S,
Linard C,
Baudelin C,
Dudoignon N,
Souidi M,
Marquette C,
Paquet F,
Aigueperse J,
Gourmelon P.
Institut de Radioprotection et de Surete Nucleaire, Direction de la RadioProtection de l'Homme, Service de Radiobiologie et d'Epidemiologie, Laboratoire de Radiotoxicologie Experimentale IRSN, Fontenay-aux-Roses Cedex, France. [email protected]

In the event of ingestion, the digestive tract is the first biological system exposed to depleted uranium (DU) intake via the intestinal lumen. However, little research has addressed the biological consequences of a contamination with depleted uranium on intestinal properties such as the barrier function and/or the immune status of this tissue. The aim of this study was to determine if the ingestion of depleted uranium led to changes in the gut immune system of the intestine. The experiments were performed at 1 and 3 d following a per os administration of DU to rats at sublethal dose (204 mg/kg). Several parameters referring to the immune status, such as gene and protein expressions of cytokines and chemokines, and localization and density of immune cell populations, were assessed in the intestine. In addition, the overall toxicity of DU on the small intestine was estimated in this study, with histological appearance, proliferation rate, differentiation pattern, and apoptosis process. Firstly, the results of this study indicated that DU was not toxic for the intestine, as measured by the proliferation, differentiation, and apoptosis processes. Concerning the immune properties of the intestine, the ingestion of depleted uranium induced some changes in the production of chemokines and in the expression of cytokines. A diminished production of monocyte chemoattractant protein-1 (MCP-1) was noted at 1 day post exposure. At 3 d, the increased gene expression of interferon gamma (IFNgamma) was associated with an enhanced mRNA level of Fas ligand, suggesting an activation of the apoptosis pathway. However, no increased apoptotic cells were observed at 3 d in the contaminated animals. There were no changes in the localization and density of neutrophils, helper T lymphocytes, and cytotoxic T lymphocytes after DU administration. In conclusion, these results suggest that depleted uranium is not toxic for the intestine after acute exposure. Nevertheless, DU seems to modulate the expression and/or production of cytokines (IFNgamma) and chemokines (MCP-1) in the intestine. Further experiments need to be performed to determine if a chronic contamination at low dose leads in the long term to modifications of cytokines/chemokines patterns, and to subsequent changes in immune response of the intestine.

PMID: 16854789 [PubMed - indexed for MEDLINE]

Environ Toxicol. 2006 Aug;21(4):349-54. Links

A search for cellular and molecular mechanisms involved in depleted uranium (DU) toxicity.
Pourahmad J,
Ghashang M,
Ettehadi HA,
Ghalandari R.
Faculty of Pharmacy and Pharmaceutical Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran. [email protected]

Addition of U(VI) (uranyl acetate) to isolated rat hepatocytes results in rapid glutathione oxidation, reactive oxygen species (ROS) formation, lipid peroxidation, decreased mitochondrial membrane potential, and lysosomal membrane rupture before hepatocyte lysis occurred. Cytotoxicity was prevented by ROS scavengers, antioxidants, and glutamine (ATP generator). Hepatocyte dichlorofluorescein oxidation was inhibited by mannitol (a hydroxyl radical scavenger) or butylated hydroxyanisole and butylated hydroxytoluene (antioxidants). Glutathione depleted hepatocytes were resistant to U(VI) toxicity and much less dichlorofluorescein oxidation occurred. Reduction of U(VI) by glutathione or cysteine in vitro was also accompanied by oxygen uptake and was inhibited by Ca(II) (a U(IV) or U(VI) reduction inhibitor). U(VI)-induced cytotoxicity and ROS formation was also inhibited by Ca(II), which suggests that U(IV) and U(IV) GSH mediate ROS formation in isolated hepatocytes. The U(VI) reductive mechanism required for toxicity has not been investigated. Cytotoxicity was also prevented by cytochrome P450 inhibitors, particularly CYP 2E1 inhibitors, but not inhibitors of DT diaphorase or glutathione reductase. This suggests that P450 reductase and reduced cytochrome P450 contributes to U(VI) reduction to U(IV). In conclusion, U(VI) cytotoxicity is associated with mitochondrial/lysosomal toxicity by the reduced biological metabolites and ROS. Copyright 2006 Wiley Periodicals, Inc.

PMID: 16841314 [PubMed - in process]

1: Int J Environ Res Public Health. 2006 Jun;3(2):129-35. Links

The evolution of depleted uranium as an environmental risk factor: lessons from other metals.
Briner WE.
Department of Psychology, University of Nebraska at Kearney, Kearney, NE 68849, USA Email: [email protected].

Depleted uranium (DU) is used in both civilian and military applications. Civilian uses are primarily limited to ballast and counterweights in ships and aircraft with limited risk of environmental release. The very nature of the military use of DU releases DU into the environment. DU released into the environment from military use takes the form of large fragments that are chemically unchanged and dust in the form of oxides. DU dust is nearly insoluble, respirable and shows little mobility in the soil. Exposure to DU occurs primarily from inhalation of dust and possible hand to mouth activity. Toxicity of DU is believed to be primarily chemical in nature with radiological activity being a lesser problem. DU has been shown to have a variety of behavioral and neurological effects in experimental animals. DU has been used the Balkans, Afghanistan, and both Iraq wars and there is a high probability of its use in future conflicts. Further, other nations are developing DU weaponry; some of these nations may use DU with a greater radiological risk than those currently in use. The toxicity of DU has been studied mostly as an issue of the health of military personnel. However, many tons of DU have been left in the former theater of war and indigenous populations continue to be exposed to DU, primarily in the form of dust. Little epidemiological data exists concerning the impact of DU on these groups. It may be possible to extrapolate what the effects of DU may be on indigenous groups by examining the data on similar metals. DU has many similarities to lead in its route of exposure, chemistry, metabolic fate, target organs, and effect of experimental animals. Studies should be conducted on indigenous groups using lead as a model when ascertaining if DU has an adverse effect.

PMID: 16823086 [PubMed - in process]