Gulf War and Health Updated Literature Review of Depleted Uranium (2008) / Chapter Skim
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3 Toxicology
3 Toxicology
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Some sections of this chapter have been adapted from Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines (IOM, 2000)
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Insoluble uranium compounds may remain in the pulmonary tissues, especially the pulmonary lymph nodes, for a long time and thus pose a localized radiologic hazard. As a general rule, uranium absorption from the intestinal tract is lower than that from the respiratory tract and results in lower doses per unit intake.
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The lungs and the tracheobronchial lymph nodes are the two major sites of accumulation for type S uranium compounds (administered as uranium dioxide) in dogs, monkeys, and rats, accounting for greater than 90% of the total body burden of uranium after inhalation of the compounds (Leach et al., 1970)
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. The absorption of uranium in the gastrointestinal tract generally increases with increasing solubility of the compound, but only a small fraction of even the soluble uranium compounds is absorbed through the gastrointestinal epithelium.
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. The authors reported substantial uptake of a uranyl nitrate solution through intact rat skin within the first 6 hours of exposure.
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(1992) showed that uranium concentrations in rat femurs were 6.3 times higher after 28 days of ingestion of uranyl nitrate in drinking water than after 91 days of ingestion.
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have proposed a median lethal dose for acute oral intake of uranium in humans of 5.0 g and for acute inhalation of soluble uranium compounds of 1.0 g. Carcinogenic Effects Four studies of the carcinogenic effects of uranium were described in Volume 1; two reported positive findings (Leach et al.
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A number of studies have been conducted since Volume 1 on genotoxic effects of depleted uranium in humans. In a 10-year postwar followup assessment, 13 Gulf War veterans with high concentrations of depleted uranium from embedded fragments had a statistically significantly higher incidence of chromosomal aberrations in their peripheral blood lymphocytes than 26 in the low-exposure group (McDiarmid et al., 2004)
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Several in vitro studies of the effects of uranium on lung epithelial cells and macrophages have been published recently; details are presented in Table 3-4. In rat lung epithelial cells, treatment with uranyl (VI)
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. After a 91-day exposure to uranyl nitrate hexahydrate in drinking water at 0.96, 4.8, 24, 120, or 600 mg/L, histopathologic lesions were observed in the kidneys of male and female New Zealand white rabbits in all groups, including the lowest-exposure groups (Gilman et al., 1998b)
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. In vitro studies in rat cortical neuron cultures exposed to uranyl acetate showed little cytotoxicity at concentrations below 100 µM (Jiang et al., 2007)
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Intramuscular injection of uranyl acetate at 0.1 and 1.0 mg/kg for 7 days daily was followed by a 30-day observation period. On cessation of treatment, the sensorimotor functions of the animals were evaluated with a battery of tests that included measurements of postural reflexes, limb placing, orientation to vibrissa touch, grip time, beam walking, and inclined-plane performance.
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Exposure to 4% enriched uranium or depleted uranium in drinking water for 1.5 months resulted in substantial accumulation of uranium in the hippocampus, hypothalamus, and striatum of rats, and the uranium concentrations were consistently 1.5-2 times higher in the hippocampus, hypothalamus, and adrenal of rats exposed to enriched uranium than of rats exposed to depleted uranium or control rats (Houpert et al., 2005)
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in drinking water at 40 mg/L for up to 9 months on dopaminergic and serotoninergic metabolism in rats and found subtle and transient perturbations of monoamine concentrations and AChE activity in discrete brain areas. Biologic Plausibility Collectively, the results of those studies indicate that depleted uranium is a toxicant that can cross the blood-brain barrier and might produce some acute and prolonged behavioral changes.
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addressed the effects of 9 months of exposure to depleted uranium in drinking water on drug-metabolizing enzymes. Hepatic CYP3A1 and CYP3A2 mRNA expression was statistically significantly higher in rats exposed to depleted uranium than in controls, but CYP1A1 mRNA expression was not different.
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reported that offspring of female mice exposed to uranium acetate at up to 75 mg/L in drinking water for 2 weeks before mating and during gestation and lactation showed more rapid development on some behavioral tests whereas their ratio of brain weight to body weight was statistically significantly lower than in controls. However, the quickened development of uranium-exposed offspring may adversely affect the development of neural systems (Briner, 2007)
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. In contrast, chronic exposure to depleted uranium in drinking water at 40 mg/L for 3, 6, or 9 months was associated with decreased intestinal mast-cell number, increased IL-1beta and IL-10 concentrations, decreased mRNA CCL-2 concentrations, decreased intestinal macrophage density, and increased numbers of neutrophils (Dublineau et al., 2007)
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. There were no histopathologic findings in rat or rabbit muscles after exposure to orally administered uranyl nitrate in drinking water at uranium concentrations up to 40 mg/kg per day for 28 day or up to 53 mg/kg per day for 91 days in Sprague-Dawley rats or up to 53 mg/kg per day for 91 days in rabbits (Gilman et al., 1998a,b)
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Application of the Toxicologic Data As discussed in this chapter, animal toxicity studies have been conducted primarily in rats, mice, and dogs and to a smaller extent in monkeys. The studies exposed groups of laboratory-bred animals to different concentrations of uranium compounds for various portions of the animals' life span by different routes (for example, inhalation, ingestion via drinking water, and surgical implantation)
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Uranyl nitrate hexahydrate [UO2(NO3)
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or hexavalent (uranium, 0.55- and kidney carcinoma, lung 5.32 mg U/kg of body weight) U reticulolymphosarcoma, leukemia in treated animals compared with controls Intratracheal injection Rat, male Natural uranium-ore dust aerosol, 50 4.2 hours/day, 5 days/ Frequency of primary malignant lung Mitchel et al., 1999 Sprague mg/m3 or 19 mg/m3 week for 65 weeks tumors 0.016, 0.175, and 0.328 and Dawley frequency of primary nonmalignant Nose-only inhalation lung tumors 0.016, 0.135, and 0.131 in control, low-exposure, and high-exposure groups, respectively Rat, male DU pellets: 2.0 mm × 1.0 mm in Observed for lifetime Significant increase in incidence of soft- Hahn et al., 2002 Wistar diameter, 6.0 Bqa tissue sarcoma in 5.0 × 5.0 × 1.5-mm group; slight increase in 2.5 × 2.5 × 1.5 DU fragments: 2.5 × 2.5 × 1.5 mm, 20 mm group; no increase in 2.0 × 1.0-mm Bqa; 5.0 × 5.0 × 1.5 mm, 59 Bqa group 4 implants/rat, intramuscular Continued 43
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NOTE: DU = depleted uranium.
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, >0.1 SCE assay: no association between µg/g creatinine; low-DU group SCE and urinary DU concentration (n = 26) , <0.1 µg/g creatinine HPRT mutation frequency: statistically significant positive association between HPRT mutation frequency and urinary DU concentration 50 Gulf War veterans Urinalysis results: 0.002-31.8 8-year postwar followup CA assay: no association between CA McDiarmid et al., (BVAMC DU Followup µg/g creatinine and urinary DU concentration 2001 Program)
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) Whole animal exposure Sprague Dawley, male Inhalation exposure: UO4: 30 minutes Comet assay: UO4 exposure alone Monleau et al., 2006b had no effect on DNA damage; UO4: 116 ± 60 mg/m3 UO2 + UO4: 3 hours + 30 repeated UO2 pre-exposure followed minutes by UO4 exposure increased DNA UO2 + UO4: 375 ± 70 mg/m3 + damage compared with controls 116 ± 60 mg/m3 UO2 + UO4: 3 hours 4 days/week for 3 weeks + UO2 + UO4: 190 ± 41 mg/m3 + 30 minutes 116 ± 60 mg/m3
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; or 3 hours (375 repeated 190-mg/m3 dose; no DNA mg/m3) damage in other groups UO4: 116 ± 60 mg/m3 UO4: 30 minutes Sprague Dawley, male Pellets 1 mm in diameter × 2 mm Urine, serum samples Ames Salmonella reversion assay: Miller et al., 1998b long; implanted in gastrocnemius collected 6, 12, 18 months increased urinary uranium content led muscle; low-, medium-, and high- after pellet implantation to increased mutagenicity dose groups In vitro studies Human bronchial Uranyl acetate: 100, 200, 400, Cells incubated for 24, 48, Both compounds led to time- and Wise et al., 2007 fibroblast cell line that 800 µM 72 hours concentration-dependent cytotoxicity; ectopically expresses uranium trioxide led to increased human telomerase, Uranium trioxide: 0.5, 1, 5, 10 chromosomal damage, but uranyl WTHBF-6 µg/cm3 acetate did not Human liver carcinoma DU-UO2 at 0-50 µg/mL Cells incubated for 48 DU exposure led to dose-dependent Miller et al., 2004 cells (HepG2)
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hours at 10 mg/mL led to 25.5-fold increase in transformation frequency compared with untreated HOS cells Genotoxicity assays (micronuclei induction, SCE concentration, DNA single-strand breaks, dicentric formation) : DU exposure at 5 mg/mL led to significant increases compared with untreated cells Human osteoblast cells DU-UO2Cl2 at 10 µg/mL DU-UO2 Cells incubated for 24 DU exposure led to increase in Miller et al., 2001 (HOS)
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, 48 hours (measurement of Mutagenicity assay: UA exposure led uranium-DNA-P binding) to higher induced mutant frequency (about 5-fold)
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50 TABLE 3-3 Continued Frequency and/or System Studied Route of Exposure/Dose Duration Outcome(s) Reference Normal rat renal proximal Up to 700 µM uranium Cells incubated for 24 DNA damage occurred in time- and Thiébault et al., 2007 cells biocarbonate hours concentration-dependent manner; exposure at 300 µM or higher led to genotoxicity; DNA damage may be reversible at low concentrations and irreversible at higher concentrations pBluescript SK DNA+ 0.1-1.0 mM UA 30 minutes at 37°C UA + ascorbic acid exposure led to Yazzie et al., 2003 plasmid DNA single-strand breaks, demonstrating chemical genotoxicity Calf thymus DNA 1-1,000 µM DU-uranyl nitrate 30 minutes at 37°C DU exposure led to oxidative DNA Miller et al., 2002a damage without significant alpha particle decay NOTE: BVAMC = Baltimore Veterans Affairs Medical Center, CA = chromosomal aberration, DU = depleted uranium, hprt = hypoxanthine-guanine phosphoribosyl transferase, SCE = sister chromatid exchange, UA = uranyl acetate, UO 2 = uranium dioxide, UO2Cl2 = uranyl chloride, UO4 = uranium peroxide.
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TABLE 3-4 Respiratory Effects Cell Line Dose Duration Outcomes Reference Human type II epithelial 0.5 mM uranyl acetate 48-hour incubation Exposure triggered differential Malard et al., 2005 cell line expression of 18 spots, of which 14 corresponded to fragments of cytokeratin 8 (CK8) and cytokeratin 18 and one to peroxiredoxin 1; CK cleavage did not result from caspase or calpain activity Rat lung epithelial cell 0.25, 0.5, 1 mM uranyl 3-hour incubation Induction of oxidative stress at 0.5 Periyakaruppan et al., line acetate and 1 mM; response correlated with 2007 dose and time Rat pulmonary alveolar 10-300 µM uranyl acetate 24-hour incubation Dose-dependent increase in TNFa Gazin et al., 2004 macrophage cell line, production; no secretion on IL-1β, NR8383 IL-10 detected NOTE: IL = interleukin, TNF = tumor necrosis factor.
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Dogs and monkeys Inhalation 5.4 hours/day, 5 days/ Injury to kidneys not observed as Leach et al., 1970 week, up to 5 years result of exposure Uranium dioxide at 5.8 mg/m3 NOTE: BBMV = brush border membrane vesicles, DU = depleted uranium, NAG = N-acetyl-β-D-glucosaminidase.
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+ 233U (50 Bq) highest uranium concentration; high accumulation found in hippocampus by each route of exposure Sprague Dawley, male Ingestion (drinking water)
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-2,5 diphenyltetrazolium bromide reduction, lactate dehydrogenase activity Sprague Dawley, male Implanted in gastrocnemius muscle 3, 6 months At 3 months, DU accumulated in all Fitsanakis et brain regions except the hippocampus of al., 2006 DU pellets: 1 mm in diameter × 2 highest-dose animals; at 6 months, DU mm long accumulation found in cortex, midbrain, cerebellum Sprague Dawley, male Intraperitoneal injection Uranyl acetate administered Stress increased clearance of uranium Barber et al., after forced swimming in the brain compared with clearance of 2005 Uranyl acetate dehydrate at 1mg/kg to induce stress; animals brain uranium in unstressed rats euthanized 8 hours, 24 hours, 7 days, 30 days after exposure
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1.5 months Exposure to enriched uranium led to Houpert et al., not specified increases in amount of paradoxical sleep 2005 Enriched or depleted uranium and anxiety and reduction in spatial incorporated as nitrate: 1 mg/day working-memory capacities compared per rat with controls; exposure to DU did not lead to these effects Sprague Dawley, male Intraperitoneal injection Animals euthanized 3 days Exposure at higher concentration led to Lestaevel et after exposure shorter paradoxical sleep compared with al., 2005b Uranyl nitrate at 70, 144 µg/kg controls; no effect at lower concentration Sprague Dawley, male Ingestion (drinking water) 3 months By 30 days, exposure to uranium led to Lestaevel, increase in rapid-eye-movement sleep 2005a Uranyl nitrate at 40 mg/L and theta-band power during light period Sprague Dawley, male Nose-only inhalation 30 minutes/day, 4 days/week Exposure led to behavioral changes Monleau et for 3 weeks (spontaneous locomotion activity, al., 2005 Uranium dioxide at 197 mg/m3 spatial working memory)
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Up to 91 days No signs of neurotoxicity related to Gilman et al., and female exposure 1998c Uranyl nitrate hexahydrate at up to 600 mg/L (37, 54 mg U/kg body weight per day for male, female rats, respectively)
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Sprague Dawley, male Intragastric Single dose Acute cholinergic toxicity observed in Domingo et treated rats al., 1987 Uranyl acetate dehydrate at 11-717 mg U/kg body weight Mouse Phrenic nerve 0.2-0.8 mM uranyl nitrate More than 4-hour incubation Treatment facilitated release of Lin et al., diaphragm from acetylcholine from nerve terminals, 1988 ICR strain, male and potentiated muscle contraction female Other species Caenorhabditis 1, 10, 100 mM uranyl acetate 24-hour incubation period Exposure did not lead to significant Jiang et al., elegans (nematode) neurodegeneration 2007 Dog Inhalation 30 days Muscle weakness and instability of gait Dygert et al., beginning on day 13 at 18 mg U/m3 1949 Uranium hexafluoride gas at 0.5-18 mg U/m3 Dog Inhalation 30 days Exposure associated with anorexia Roberts, 1949 Uranyl nitrate hexahydrate at 9.5 mg U/m3 Cat Inhalation 30 days Muscle weakness and instability of gait Dygert et al., beginning on day 7 at 18 mg U/m3 1949 Uranium hexafluoride gas at 0.5-18 mg U/m3 NOTE: 5HIAA = 5-hydroxyindoleacetic acid, 5HTergic = serotoninergic, AChE = cholinergic acetylcholinesterase, DAergic = dopaminergic, DOPAC = 3,4 dihydroxyphenylacetic acid, DU = depleted uranium.
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9 months mRNA concentrations of CYP3A1, Souidi et al., 2005 male CYP3A2, PXR significantly higher Uranyl nitrate: 1 mg/day per in the DU-exposed group compared animal with controls; mRNA concentrations of CYP1A1, CYP2B1, RXR, CAR unchanged; hepatic activity of CYP2A, CYP2B, CYP2C, CYP3A did not change significantly in treated vs control groups Other species Danio rerio DU: 1.5 Bq/L 3, 10, 20 days Decreased superoxide dismutase, Barillet et al., (zebrafish) , male DU + 233U: 2376 Bq/L catalase activities, total glutathione 2007 adults content in liver extracts NOTE: ALT = alanine amino transferase, AST = aspartate amino transferase, CYP = cytochrome P450, DU = depleted uranium, i.p.
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in F1 generation Sprague Dawley, Implanted in gastrocnemius P1 generation mated 30, 120 days Exposure to DU did not adversely Arfsten et al., male and female muscle after implantation affect male reproductive success, sperm 2006 concentration, sperm velocity compared with DU pellets: 1 mm in diameter controls × 2 mm long, up to 10 pellets per calf (P1 generation) Sprague Dawley, Subcutaneous injection Administered on gestation days Exposure to DU led to maternal toxicity Albina et al., male and female 6-15 with or without restraint and embryotoxicity in high-dose group; 2003 Uranyl acetate dehydrate at stress for 2 hours/day; cesarean fetotoxicity (reduction in fetal body weight, 0.415, 0.830 mg/kg per day sections performed on gestation increase in total number of skeletally day 20 affected fetuses)
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Experiment 4: administered uranium or DES for 10 days beginning at age of 50 days (C57Bl/6) , intraperitoneal injection of ICI 182,780 Swiss Webster, Ingestion in drinking water Exposed for 2 weeks, then mated; Exposure to uranium acetate did not lead to Briner and Byrd, female exposure of dams and offspring maternal toxicity; no gross malformations 2000 Uranium acetate at 19, 37, continued until sacrifice observed in pups 75 mg/L Exposed offspring developed more quickly than controls on behavior indexes (righting reflexes, forelimb placing and grasping, swimming development)
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64 days Testicular function and spermatogenesis Llobet et al., 1991 were not affected by exposure to uranium Uranyl acetate dihydrate: 0, 10, 20, 40, or 80 mg/kg/day Swiss, male and Intragastic administration Males: 60 days prior to mating Uranium exposure did not lead to adverse Paternain et al., female effects on fertility; increased embryolethality 1989 Uranyl acetate dihydrate: 0, 5, Females: 60 days prior to mating was observed in the highest dose group 10, 25 mg/kg/day and throughout mating, gestation, parturition, and nursing NOTE: DES = diethylstilbestrol, DU = depleted uranium, ICI 182,780 = a steroidal estrogen antagonist.
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; or 3 hours ± 70 mg/m3 (375 mg/m3) UO4 at 116 ± 60 mg/m3 UO4: 30 minutes Sprague Dawley, male Ingestion in drinking water 3, 6, 9 months DU exposure led to decrease in intestinal Dublineau et al., mast cell number, increase in IL-1β and 2007 Uranyl nitrate at 40 mg/L IL-10 concentrations, decrease in mRNA (1 mg/day per animal)
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Sprague Dawley, male DU pellets: 1 × 2 mm P1 generation mated 30 days No significant difference among 8-week- Arfsten et al., and female after surgery; P1 females nursed old F1 treatment groups in mean thymus 2005 0, 4, 8, 12 implants/rat (P1 offspring until PND 20 and spleen mass, mean total number of generation) thymocytes per spleen Sprague Dawley, sex Implanted in gastrocnemius 1 day, 1, 6, 12, 18 months Significant concentrations of uranium Pellmar et al., not specified muscle found in spleen 1999a DU pellets: 1 mm in diameter × 2 mm long; up to 20 pellets per thigh In vitro studies Macrophages from Uranyl nitrate: 10-1,000 µM Cells incubated for 2 hours Lymphoproliferation assay: uranyl Wan et al., 2006 BALB/c and DO11.10 nitrate exposure at 200 µM for 2 hours T-cell receptor mice led to altered macrophage accessory-cell function Macrophage cell line, DU-uranyl chloride: 1, 10, Cells incubated for up to 24 hours Exposure at all concentrations led to Kalinich et al., J774 100 µM decreased viability of cells; appeared to 2002 be apoptotic death NOTE: CCL = chemokine ligand 2, DU = depleted uranium, IFN = interferon, IL = interleukin, MCP = monocyte chemoattractant protein, PND = post natal day, TGF = transforming growth factor, TNF = tumor necrosis factor, UO 2 = uranium dioxide, UO4 = uranium peroxide.
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64 TABLE 3-10 Musculoskeletal Effects Species Route of Exposure and Dose Frequency or Duration Outcomes Reference Rat Sprague Dawley, Ingestion in drinking water 9 months Decrease in vitamin D concentration Tissandie et al., male in plasma compared with controls; 2007 Uranyl nitrate at 1 mg/day per expression of CYP genes involved in animal vitamin D metabolism unaltered in liver of treated animals; significant decrease in cyp24a1 mRNA concentrations in kidneys of treated animals Sprague Dawley, Gavage Single dose Significant decreases in vitamin D Tissandie et al., male and PHT in plasma compared with 2006 Uranyl nitrate at 204 mg/kg of Animals were euthanized 1 or 3 controls; treatment modulated mRNA body weight (LD50 at 14 days) days after exposure concentrations and activity of CYP enzymes involved in vitamin D metabolism Wistar, sex not Oral Single dose No statistically significant difference Pujadas Bigi and specified in mandibular length observed in Ubios, 2007 Uranyl nitrate at 90 mg/kg of Animals were euthanized 7 or 27 treated vs control animals; mandibular body weight days after exposure area and height, tooth eruption, dental development decreased in treated animals at 7 days but similar to controls by 27 days Wistar, male Intramuscular injection Single dose Increases in concentrations of Fukuda et al., osteocalcin, tartrate-resistant acid 2006 DU nitrate at 0.2, 1.0, 2.0 mg/kg Animals euthanized 28 days after phosphatase, pyridinoline, parathyroid of body weight exposure hormone in all treated groups compared with controls
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significantly lower in intoxicated animals compared with controls Rabbit New Zealand Uranyl nitrate hexahydrate at 91 days No significant exposure-related effect on Gilman et al., White, males and 0.96, 4.8, 24, 120, 600 mg/L hematologic, biochemical endpoints 1998b females (0.49-43.02 mg/kg of body weight for females; 0.05-28.7 mg/kg of body weight for males) NOTE: DU = depleted uranium, LD50 = dose required to kill half the test population, PHT = parathyroid hormone.
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2006. Chronic ingestion of uranyl nitrate perturbs acetylcholinesterase activity and monoamine me tabolism in male rat brain.
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2006. Basic information about radionuclides in drinking water.
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1998c. Uranyl nitrate: 28-day and 91-day toxicity studies in the Sprague-Dawley rat.
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1988. Presynaptic action of uranyl nitrate on the phrenic nerve-diaphragm preparation of the mouse.
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1998a. Transformation of human osteoblast cells to the tumorigenic phenotype by depleted uranium-uranyl chloride.
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2004. In vitro evaluation of percutaneous diffusion of uranyl nitrate through intact or excoriated skin of rat and pig.
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counteracts the inhibitory effect of uranyl nitrate on bone formation. Archives of En vironmental Health 45(6)
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