Chapter II.

 

Organ and Organism Response to Uranium and
Depleted Uranium Exposure
(Including  Reproductive Effects)

 

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Summary

 

Uranium toxicity has been studied for many decades.  The nephrotoxicity of uranium was recognized in the 19th century.  Hodge (1) gives a good review of the history of uranium poisoning prior to the Manhattan Project.  Other reviews of uranium toxicity in the decades following World War II, when the nuclear industry grew in those countries with nuclear capabilities, focus mostly on the kidney damage caused by uranium.

 

However, animal experiments have shown that inhaled uranium dioxide aerosols, such as those produced when DU is machined or when a DU weapon explodes and/or burns have a very long retention time in the lungs and slowly distribute DU throughout the body, coming to rest in bones, liver, kidney, heart, brain, spleen, lymph nodes and testicles. Tests on Gulf War veterans have shown measurable urinary DU even 10 years after their exposure, reinforcing the conclusions from the rat experiments. DU residing in the testicles may explain the observed teratogenic effects of DU exposure in which children of Gulf War veterans have a 50% greater risk of severe birth defects. DU-exposed rats have lower fertility, give rise to low birth weight offspring with a significantly higher rate of fetal skeletal malformations.The urine and blood tests of rats with embedded DU pellets or patches or injected DU solutions show dose and time-dependent mutagenic toxicity, and neurological disorders.

 

McClain, a researcher at the US Armed Forces Radiobiology Research Institute reports conclusions from his research that “DU is mutagenic and transforms human osteoblastic cells into a tumorigenic phenotype. It alters neurophysiological parameters in rat hippocampus, crosses the placental barrier, and enters fetal tissue.”

 

Additional research specifically related to Gulf War veterans is presented in Chapters IV and V. Further studies into health effects of low level ionizing radiation is presented in Chapter III.

 

Details

 

Several reviews have been written dealing with the general body toxicity of uranium, including that by Hodge (6) in 1973. Durakovic (20) provides a 1999 review on the medical affects of contamination from depleted uranium. In 2000, Hartmann (26) reviews toxicity data with regard to risk assessment and evaluation of acceptable exposure levels. Bleise (42) provides a 2003 review on the properties, use and health effects of depleted uranium.

 

Uranium exposure to skin by Orcutt (1), and Ubios (17) and to sub-cutaneous implantation by Lopez (25) have been studied for over 50 years.

 

Inhalation of uranium and uranium oxide dust particles leads to internal exposure of bronchial, lung and lymph tissues to the chemical and radiological effects of uranium. Wilson (2), (3) and Walinder (4) first reported studies on these effects in the ‘50s and ‘60s. Leach’s animal studies of inhaled uranium dioxide dust showed 90% retention in lungs and associated lymph nodes in monkeys, dogs and rats and found fibrotic changes suggestive of radiation damage after 3 years even though no sign of kidney damage had been observed (5). Butler (8) found the solubility of U3O8 in simulated lung fluid to be less than 12%. In 1988, Stradling (10) reported on the metabolism of uranium particles embedded in rat lung tissue. In the early ‘90s, Morris (15) and Eidsen (16) studied the long-term clearance of uranium particles embedded in pulmonary tissues. Katsaros (24) published a review with 15 references on effects of inhaled uranium in 1999 and Mould (32) addressed the issue of lung cancer and leukaemia resulting from exposure to inhaled depleted uranium in 2001. Dewit (32m) exposed rats to inhaled uranium dust in first half of life and followed bone and muscle accumulation of uranium in later life drawn from lung reserves of retained uranium. In 2002, Yang (38) conclusively showed that DU is carcinogenic in vitro by following gene expression characteristics in rat lung tissue cells exposed to DU. In 2003, Durakovic (45), using urinary analysis for DU and known biological half-life values of uranium clearance from lung tissue, was able to determine the time-zero lung burden of DU in veterans nine years after their initial exposure to DU aerosols. Results showed exposed veterans had inhaled 0.34 mg of DU, over 2200 times the time-zero estimated DU lung burden of non-exposed veterans. Mitchel (47) characterized DU-oxides formed from actual test firing of DU munitions and reported their retention rates in lung tissues (inhaled) and muscle tissues (implanted), finding both a soluble component and an insoluble component in the samples studied.

 

Ingestion of uranium, primarily through drinking water, has been found to affect primarily the kidneys and renal functions through its chemical toxicity. Wrenn (9) provides a 1985 review of the effects of ingested uranium, and Leggett (14), 1989, suggests a reassessment of uranium toxicity values. Zamora’s 1998 report (18) indicates that the renal tubules are the primary site for renal uranium toxicity. Mirto (22) reports further on this issue and Kurttio (37) suggests appropriate uranium levels in drinking water based on well studies in Finland.

 

Studies have also shown that uranium and depleted uranium affect brain tissues and neurological behaviours in exposed individuals. Pellmar (23) discovered electrophysiological changes in hypocampal brain slices taken from rats with embedded DU fragments. Briner (35) reports in 2002 that elevated uranium levels in drinking water of mice lead to observable behavioural changes and increased lipid oxidation in the brain. Also in 2002, Abou-Donia (39) reports distinct sensorimotor deficits in rats injected with uranyl nitrate (inclined plane performance, grip time, beam walk score and beam walk time) and an increase in nitric oxide production in their central nervous systems. Houpert (45a) in 2004 reports on the effect of chronic contamination by depleted U or 137Cs on the metabolism of two neurotransmitters, dopamine and serotonin, in cerebral areas of rats, while Barber (48) in 2005 reports on the effects of stress in the distribution and clearance rate of DU in the brain. Brain lipid oxidation and behavior abnormalities in rats exposed to uranium acetate in drinking water were studied by Briner (49) in 2005. Lestaevel (51) studied sleep disturbances in rats resulting from uranium exposure. 

 

Exposure to uranium and depleted uranium has been shown to have reproductive effects on the exposed animals. Domingo (13) in 1989 (BEFORE the 1991 Gulf War) reported on serious skeletal malformations such as cleft palate, bipartitie sternebrae, reduced ossification and ossified skeletal variations observed in offspring of mice exposed to uranyl nitrate while pregnant. Arfsten (30) and Domingo (33) have published 2001 reviews of the research into the mutagenic and teratogenic effects of uranium exposure. More recently (2005) Arfsten (52) has published research showing no affect on rat spermatozoa resulting from embedded uranium pellets.

 

Kathren reports in 1989 on the body distribution of uranium contamination from an autopsy of a chemical worker employed in a uranium processing plant for 26 years, finding a uranium deposition pattern of  63 to 2.8 to 1 in the worker’s skeleton, liver and kidney (11).

 

Soluble uranium compounds such as uranyl nitrate have been injected into rats to study the metabolic pathways and distribution of uranium in animal bodies. Cooper (7) reports on these studies in 1982 as does Walinder (12) in 1989. Solid pellet implantation of uranium and depleted uranium metal have also been used. In 1998, Miller (19) reported the urine and serum mutagenicity from rats with embedded DU pellets, finding dose and time-dependent mutagenic toxicity in only the rats with embedded DU pellets. Pellmar (21) reported in 1999 on body distribution of DU from implanted pellets in rats. Autopsies on sacrificed rats throughout the 18-month study showed significant U levels in bone and kidney, with elevated U levels also found in the muscle, spleen, liver, heart, lung, brain, lymph nodes, and testicles, strongly suggesting unanticipated physiological consequences of U exposure from embedded fragments. Hahn (34), in 2002, reported soft tissue sarcomas resulting from embedded DU strips in rat muscle tissue, with sarcoma incidence dependent on strip size and no sarcomas developing in rats with embedded strips of tantalum. McClain (36) in 2002 summarizes studies at the US Army’s own Armed Forces Radiobiology Research Institute in Bethesda, MD, (which includes the work of Pellmar and Miller) with the following: “Results indicate that uranium from implanted DU fragments distributes to tissues distant from implantation sites, including bone, kidney, muscle, and liver. Despite levels of uranium in kidney that would be nephrotoxic after acute exposure, no histological or functional kidney toxicity was observed with embedded DU, indicating that the kidney adapts when exposed chronically. Nonetheless, further studies of the long-term health impact are needed. DU is mutagenic and transforms human osteoblastic cells into a tumorigenic phenotype. It alters neurophysiological parameters in rat hippocampus, crosses the placental barrier, and enters fetal tissue. Preliminary data also indicate decreased rodent litter size when animals are bred 6 months or longer after DU implantation.”  Leggett (43) reports a biokinetic model to describe the migration of DU from embedded fragments to other tissues, while Li (50) in 2005 developed a model to describe the distribution and behavior of natural uranium in the human body.

 

Nor is the plant world immune to the effects of exposure to DU. Panda found that uranyl nitrate inhibits plant growth and observed sister chromatid exchange, suggesting U inhibits DNA replication and/or repair processes (29). In 2002, Kuhne (40) reported an estimated 14-day LC50 for the Hyalella azteca assay was 1.52 mg/Liter of water.

 

General concerns on the overall health risks associated with exposure to depleted uranium has been the subject of several articles, including those by Kulev (27), Stadbauer (28), Durovic (31),  and Murray (44), with particular emphasis given to the indiscriminate use of depleted uranium weapons and the resulting contamination of the environmment. Ushakov (41) showed that radiation and chemical damage to kidneys, lungs and other internal organs was observed in a study of over 600 humans exposed to DU. Craft’s review (46) in 2004 covers the chemistry, pharmacokinetics, and toxicological effects of depleted and natural uranium on several systems in the mammalian body.

 

In a related study, Kalinich (53) in 2005 reports that embedded tungsten alloy particles (proposed substitute materials for DU in advanced weapons systems) also produce significant and rapidly developing sarcomas in rats.

 

 

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1.      The toxicology of compounds of uranium following application to the skin, by JA  Orcutt, in  Pharmacology and Toxicology of Uranium Compounds Vol 1, C Voegtlin, HC Hodge, eds., McGraw-Hill, New York, 1949. Chapter 8 (pp 377-414).

[Orcutt1949xxPTUCv1nxp377].

 

2.      Relation of particle size of uranium dioxide dust to toxicity following inhalation by animals: II, by HB Wilson, et al., Archives of Industrial Hygiene and Occupational Medicine Vol. 6(2), 1952 (pp. 93-104).

[Wilson1952xxAIHOMv6n2p93].

 

3.      Relation of particle size of U3O8 dust to toxicity following inhalation by animals, by HB Wilson, et al., A.M.A. Archives of Industrial Health Vol. 11, 1955 (pp. 11-16).

[Wilson1955xxAMAAIHv11nxp11].

 

4.      Incorporation of uranium: II. Distribution of uranium absorbed through the lungs and the skin, by G. Walinder, et al., British J. Industrial Medicine Vol. 24, 1967 (pp. 313-319).

[Walinder1967xxBJIMv24nxp313].

 

5.      A five-year inhalation study with natural uranium dioxide (UO2) dust - I. retention and biologic effect in the monkey, dog and rat, by LJ Leach, et al., Health Physics Vol. 18, 1970 (pp. 599-612). 

Found >90% of U retained in body in lungs and tracheobronchial lymph nodes.  No evidence of U toxicity related to body weight or mortality. Kidney damage did not occur.  Some fibrotic changes suggestive of radiation injury was observed in lymph of dogs and monkeys and in monkey lungs after more than 3 years.  Implies minor risk from exposure to UO2 dust.

[Leach1970xxHPv18nxp599].

 

6.      A history of uranium poisoning (1824-1942), by H.C. Hodge, in Handbook of Experimental Pharmacology, New Series XXXVI, Uranium, Plutonium, Transplutonic Elements, H.C. Hodge, et al., eds., Springer-Verlag, New York, 1973 (pp. 5-69)

[Hodge1973Handbookp5]

 

7.      The behaviour of uranium-233 oxide and uranyl-233 nitrate in rats, by JR Cooper, et al., Int. J. Radiat. Biol., Vol. 41(4), 1982 (pp. 421-433).

[Cooper1982xxIJRBv41n4p421].

 

8.      A summary report on the solubility of depleted uranium oxide (U3O8) in simulated lung fluid, Ringers solution, and Ringers lactate, by WD Butler, et al., USAF Academy, CO. Gov. Rep. Announce. Index (US) Vol. 82(19), 1982 (p. 3780).

Less than 12% solubility was shown in the biological fluids studied.

[Butler1982xxGRAIv82n19p3780].

 

9.      Metabolism of ingested U and Ra, by M.E. Wrenn, et al., Health Physics Vol. 48, 1985 (pp. 601-633).

Reviews the literature and discusses absorption, distribution and elimination of consumed U. Recommends  <100 ...g/L in drinking water to limit toxic effects of U to kidney.

[Wrenn1985xxHPv48nxp610]

 

10.    The metabolism of ceramic and non-ceramic forms of uranium dioxide after deposition in the rat lung, by GN Stradling, et al., Human Toxicol. Vol. 7, 1988 (pp. 133-139).

[Stradling1988xxHTv7nxp133].

 

11.    Uranium in the tissues of an occupationally exposed individual, by R.L. Kathren, et al., Health Physics Vol. 57, 1989 (pp. 17-21). 

This group from Hanford and Los Alamos used radiochemical determination to analyze lung, kidney, liver and bone collected at autopsy of a 50 yr old male employed from 1952 to 1978 as a chemical operator in a U processing plant and died of cardiac event at work.  The U deposition pattern was 63:2.8:1 in skeleton: liver: kidney. Numerous data are given in the paper over the life of this individual.  Authors indicate that in vivo chest counts for this individual indicate long term U-deposition more than twice that estimated from postmortem analysis of lung and associated lymph, and argue that in vivo estimates may be high and therefore conservative from the standpoint of operational radiation protection.  [ED.NOTE: They do not indicate any consideration of rib cage contribution to this comparison, suggesting there may be flaws in their model.]

[Kathren1989xxHPv57nxp17]

 

12.    Metabolism and sites of effects of uranium after incorporation along different routes in mice, rabbits and piglets, by G. Walinder, Radiation Protection Dosimetry Vol. 26(1/4), 1989 (pp. 89-95). 

[Walinder198901RPDv26n1to4p89].

 

13.    The developmental toxicity of uranium in mice, by J.L. Domingo, et al., Toxicology Vol. 56, 1989 (pp. 143-152). 

Treatment of pregnant mice with uranyl acetate resulted in decreased maternal weight gain and food consumption and increased liver weight.  There was no change in the number of fetuses or fetal resorptions or dead fetuses, but there were dose related fetal effects, including reduced body weight and body length, and increased skeletal malformations, such as cleft palate, bipartitie sternebrae, reduced ossification and ossified skeletal variations.  The lowest dosage of uranyl acetate dihydrate was 5 mg/kg, which produced a toxic effect.

[Domingo1989xxTv56nxp143].

 

14.    The behavioral and chemical toxicity of U in the kidney: a reassessment, by RW Leggett, Health Physics Vol 57(3), 1989 (pp. 365-383).

[Leggett1989xxHPv57n3p365].

 

15.    Long-trem clearance of inhaled UO2 particles from the pulmonary region of the rat, by KJ Morris, et al., Health Physics Vol. 58(4), 1990 (pp. 477-485).

[Morris1990xxHPv58n4p477].

 

16.    The effect of solubility on inhaled uranium compound clearance: a review, by AF Eidson, Health Physics Vol. 67(1), 1994 (pp. 1-14).

[Eidson1994xxHPv67n1p1].

 

17.    Skin alterations induced by long-term exposure to uranium and their effect on permeability, by AM Ubios, et al, Health Physics, Vol. 72(5), 1997 (pp. 713-715).

[Ubios1997xxHPv72n5p713].

 

18.    Chronic ingestion of uranium in drinking water: a study of kidney bioeffects in humans, by M.L. Zamora, et al., Toxicological Sciences Vol. 43, 1998 (pp. 68-77). 

This Canadian study compared low-exposure (<1 :g U/L) to high-exposure (2-781 :g U/L) levels in drinking water and found urinary glucose was significantly elevated in the high U intake group.  Alkaline phosphatase and $-microglobulin correlated with U intake.  Indicators for glomerular injury were not altered in the two groups, indicating the renal tubules are the primary site for renal uranium toxicity.

[Zamora1998xxTSv43nxp68].

 

19.    Urinary and serum mutagenicity studies with rats implanted with depleted uranium or tantalum pellets, by AC Miller, et al., Applied Cellular Radiobiology Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603, USA. millera@mx.afrri.usuhs.mil. Mutagenesis. Vol. 13(6), Nov. 1998 (pp. 643-648).

During the 1991 Persian Gulf War several US military personnel were wounded by shrapnel fragments consisting of depleted uranium. These fragments were treated as conventional shrapnel and were not surgically removed to spare excessive tissue damage. Uranium bioassays conducted over a year after the initial uranium injury indicated a significant increase in urine uranium levels above natural background levels. The potential mutagenic effects of depleted uranium are unknown. To assess the potential mutagenic effects of long-term exposure to internalized depleted uranium, Sprague-Dawley rats were implanted with depleted uranium and their urine and serum were evaluated for mutagenic potential at various times after pellet implantation using the Ames Salmonella reversion assay. Tantalum, an inert metal widely used in prosthetic devices was used for comparison. Enhancement of mutagenic activity in Salmonella typhimurium strain TA98 and the Ames II mixed strains (TA7001-7006) was observed in urine samples from animals implanted with depleted uranium pellets. In contrast, urine samples from animals implanted with tantalum did not show a significant enhancement of mutagenic activity in these strains. In depleted uranium-implanted animals, urine mutagenicity increased in a dose- and time-dependent manner demonstrating a strong positive correlation with urine uranium levels (r = 0.995, P < 0.001). There was no mutagenic enhancement of any bacterial strain detected in the sera of animals implanted with either depleted uranium or tantalum pellets. The results suggest that uranium content in the urine is correlated with urine mutagenicity and that urinary mutagenicity might be used as a biomarker to detect exposure to internalized uranium.

[Miller199811Mv13n6p643]. (PMID: 9862198 [PubMed - indexed for MEDLINE].

 

20.    Medical effects of internal contamination with uranium, by A. Durakovic, Department of Radiology and Nuclear Medicine, Georgetown University School of Medicine, 3430 Connecticut Avenue, Washington, DC 20008, USA. ASAF@compuserve.com. Croat Med J. Vol. 40(1), Mar 1999 (pp. 49-66).

The purpose of this work is to present an outline of the metabolic pathways of uranium isotopes and compounds, medical consequences of uranium poisoning, and an evaluation of the therapeutic alternatives in uranium internal contamination. The chemical toxicity of uranium has been recognized for more than two centuries. Animal experiments and human studies are conclusive about metabolic adverse affects and nephro- toxicity of uranium compounds. Radiation toxicity of uranium isotopes has been recognized since the beginning of the nuclear era, with well documented evidence of reproductive and developmental toxicity, as well as mutagenic and carcinogenic consequences of uranium internal contamination. Natural uranium (238U), an alpha emitter with a half-life of 4.5x10(9) years, is one of the primordial substances of the universe. It is found in the earth's crust, combined with 235U and 234U, alpha, beta, and gamma emitters with respective half-lives of 7.1x10(8) and 2.5x10(5) years. A special emphasis of this paper concerns depleted uranium. The legacy of radioactive waste, environmental and health hazards in the nuclear industry, and, more recently, the military use of depleted uranium in the tactical battlefield necessitates further insight into the toxicology of depleted uranium. The present controversy over the radiological and chemical toxicity of depleted uranium used in the Gulf War warrants further experimental and clinical investigations of its effects on the biosphere and human organisms.

[Durakovic199903CMJv40n1p49]. (PMID: 9933897 [PubMed - indexed for MEDLINE])

 

21.    Distribution of uranium in rats implanted with depleted uranium pellets, by TC Pellmar, et al.,  Radiation Pathophysiology and Toxicology Department, Armed Forces Radiobiology Research Institute, Bethesda, Maryland 20889-5603, USA. tpellmar@nas.edu . Toxicol Sci. Vol. 49(1), May 1999 (pp. 29-39).

During the Persian Gulf War, soldiers were injured with depleted uranium (DU) fragments. To assess the potential health risks associated with chronic exposure to DU, Sprague Dawley rats were surgically implanted with DU pellets at 3 dose levels (low, medium and high). Biologically inert tantalum (Ta) pellets were used as controls. At 1 day and 6, 12, and 18 months after implantation, the rats were euthanized and tissue samples collected. Using kinetic phosphorimetry, uranium levels were measured. As early as 1 day after pellet implantation and at all subsequent sample times, the greatest concentrations of uranium were in the kidney and tibia. At all time points, uranium concentrations in kidney and bone (tibia and skull) were significantly greater in the high-dose rats than in the Ta-control group. By 18 months post-implantation, the uranium concentration in kidney and bone of low-dose animals was significantly different from that in the Ta controls. Significant concentrations of uranium were excreted in the urine throughout the 18 months of the study (224 +/- 32 ng U/ml urine in low-dose rats and 1010 +/- 87 ng U/ml urine in high-dose rats at 12 months). Many other tissues (muscle, spleen, liver, heart, lung, brain, lymph nodes, and testicles) contained significant concentrations of uranium in the implanted animals. From these results, we conclude that kidney and bone are the primary reservoirs for uranium redistributed from intramuscularly embedded fragments. The accumulations in brain, lymph nodes, and testicles suggest the potential for unanticipated physiological consequences of exposure to uranium through this route.

[Pellmar199905TSv49n1p29]. (PMID: 10367339 [PubMed - indexed for MEDLINE]).

 

22.    Intracellular behaviour of uranium(VI) on renal epithelial cell in culture (LLC-PK1): influence of uranium speciation, by H. Mirto, et al., Toxicology Letters Vol. 104, 1999 (pp. 249-256).

Used this kidney cell line in culture to study uranium toxicity to kidney tubule epithelium.  Uranyl bicarbonate, but not uranyl citrate, was entered cells and precipitated in the cytoplasmic compartment as uranyl phosphate crystals.

[Mirto1999xxTLv104nxp249]

 

23.    Electrophysiological changes in hippocampal slices isolated from rats embedded with depleted uranium fragments, by TC Pellmar, et al., Radiation Pathophysiology and Toxicology Department, Armed Forces Radiobiology Research Institute, Bethesda, Maryland 20889-5603, USA. tpellmar@nas.edu . Neurotoxicology Vol. 20(5), Oct 1999 (pp. 785-792).

Although nephrotoxicity is considered to be the most serious consequence of uranium exposure, several studies have previously suggested the potential for neurotoxicity. In Operation Desert Storm, U.S. military personnel were wounded by fragments of depleted uranium (DU). This study was initiated to test the potential for DU fragments to cause electrophysiological changes in the central nervous system. Rats were surgically implanted with pellets of DU or tantalum (Ta) as a control metal. After 6, 12 and 18 months rats were euthanized, hippocampi removed and electrophysiological potentials analyzed by extracellular field potential recordings. Six months after implantation, synaptic potentials in DU-exposed tissue were less capable of eliciting spikes (E/S coupling). At 12 months, amplitudes of synaptic potentials were significantly increased in tissue from DU treated rats compared to Ta controls. E/S coupling was reduced. The differences between the electrophysiological measurements in DU-treated and control tissue were no longer evident at the 18 month time point. An analysis of the changes in the synaptic potentials and E/S coupling over the three time points suggests that by 18 months, the effects of aging and DU exposure converge, thereby obscuring the effects of the metal. Since kidney toxicity was not evident in these animals, effects secondary to nephrotoxicity are unlikely. This study raises the possibility that physiological changes occur in the brain with chronic exposure to DU fragments, which could contribute to neurological deficits.

 [Pellmar199910Nv20n5p785]. (PMID: 10591514 [PubMed - indexed for MEDLINE]).

 

24.    Inhalation of depleted uranium and its effect on health, (in Greek), by N. Katsaros, Inst. Phys. Chem., EKEPhE, Dimokritos, Greece. Chemika Chronika, Genike Ekdose Vol. 61(7-8), 1999 (pp. 210-211).

A review with 15 references.

[Katsaros1999xxCCGEv61n7to8p210].

 

25.    Percutaneous toxicity of uranyl nitrate: its effect in terms of exposure area and time, by R. López, et al, Health Physics, Vol. 78(4), 434-437, 2000.

[Lopez2000xxHPv78n4p434].

 

26.    Overview of toxicity data and risk assessment methods for evaluating the chemical effects of depleted uranium compounds, by HM Hartmann, et al., Argonne Natl. Lab, Argonne, IL.  Human and Ecological Risk Assessment Vol. 6(5), 2000 (pp. 851-874).

A heavily reference review discussing the chemical toxicity from DU exposure and using these data to determine reference values for risk assessments for both chronic and acute exposure.

[Hartmann2000xxHERAv6n5p851].

 

27.    More about uranium and the danger from it, in Bulgarian, by I Kulev. Khimiya (Sofiya, Bulgaria) Vol. 10(2), 2001 (p. 115-124).

Covers background facts on DU and migration paths and toxicity of U to humans. [Kulev2001xxKhv10n2p114].

 

28.    Uranium Ammunition: heavy metal and radio-toxicity, in German, by EA Stadbauer, FH Giessen-Friedberg Labor fur Entsorgungstechnik, Giessen, Germany.  Git Labor-Fachzeitschrift Vol. 45(4), 2001 (pp. 350-353).

A review with 6 references. Concludes that tank crew radiation dose is less than 40 mSv and concentration of U in kidneys less than 4 ppm, less than the 50 mSv/yr dose limit for occupationally radiation-exposed persons.

[Stadbauer200100GLFv45n4p350].

 

29.    Evaluation of phytotoxicity and genotoxicity of uranyl nitrate in Allium assay system, by  B.B. Panda, et al., Indian Journal of Experimental Biology Vol. 39, 2001 (pp. 57-62). 

Uranyl nitrate inhibited growth of Allium cepa at >25 :M conc, with uranyl entry into root cells.  U failed to induce micronuclei and was neither clastogenic nor aneugenic, but between 25 and 100 :M conc it increased significantly the frequency of sister chromatid exchange vs controls, that possibly interfered with DNA replication and/or repair processes.

[Panda2001xxIJEBv39nxp57]

 

30.    Review of the effects of uranium and depleted uranium exposure on reproduction and fetal development, by DP Arfsten, et al., Naval Health Research Center Detachment-Toxicology, Wright-Patterson Air Force Base (WPAFB), Ohio 45433-7903, USA. darryl.arfsten@wpafb.af.mil. Toxicol Ind Health. Vol. 17(5-10), Jun 2001 (pp. 180-191).

Depleted uranium (DU) is used in armor-penetrating munitions, military vehicle armor, and aircraft, ship and missile counterweighting/ballasting, as well as in a number of other military and commercial applications. Recent combat applications of DU alloy [i.e., Persian Gulf War (PGW) and Kosovo peacekeeping objective] resulted in human acute exposure to DU dust, vapor or aerosol, as well as chronic exposure from tissue embedding of DU shrapnel fragments. DU alloy is 99.8% 238Uranium, and emits approximately 60% of the alpha, beta, and gamma radiation found in natural uranium (4.05 x 10(-7) Ci/g DU alloy). DU is a heavy metal that is 160% more dense than lead and can remain within the body for many years and slowly solubilize. High levels of urinary uranium have been measured in PGW veterans 10 years after exposure to DU fragments and vapors. In rats, there is strong evidence of DU accumulation in tissues including testes, bone, kidneys, and brain. In vitro tests indicate that DU alloy may be both genotoxic and mutagenic, whereas a recent in vivo study suggests that tissue-embedded DU alloy may be carcinogenic in rats. There is limited available data for reproductive and teratological deficits from exposure to uranium per se, typically from oral, respiratory, or dermal exposure routes. Alternatively, there is no data available on the reproductive effects of DU embedded. This paper reviews published studies of reproductive toxicity in humans and animals from uranium or DU exposure, and discusses ongoing animal research to evaluate reproductive effects in male and female rats embedded with DU fragments, and possible consequences in F1 and F2 generations.

[Arfsten200106TIHv17n5to10p180]. (PMID: 12539863 [PubMed - indexed for MEDLINE]).

 

31.    Biomedical aspects of using ammunition with depleted uranium, in Serbian, by AB Durovic. Hemijska Industrija Vol. 55(7-8), 2001 (pp. 325-329).

Aspects of DU poisoning and internal contamination, medical consequences, diagnostics, and therapeutic procedures are presented in this review.

[Durovic2001xxHIv55n7to8p325].

 

32.    Depleted uranium and radiation-induced lung cancer and leukaemia, by RF Mould, richardfmould@hotmail.com.  British Journal of Radiology, Vol. 74(884), Aug. 2001 (pp. 677-683).

[Mould200108BJRv74n884p677].

 

32m. Uranium and uranium decay series radionuclide dynamics in bone of rats following chronic uranium ore dust inhalation, by T Dewit, et al., Department of Biology, Laurentian University, Sudbury, ON, Canada.. Health Phys. Vol. 81(5), Nov. 2001 (pp. 502-13).

The accumulation and release of uranium and some uranium decay chain radionuclides were measured in the bones of rats that had been chronically exposed to inhaled uranium ore dust during the first half (approximately) of their natural adult lifespan. Endochondral bone (femur, tibia, humerus, radius, and ulna), membrane bone (skull roofing bones) and muscle of Sprague-Dawley rats (n = 55) that died at various times up to 65 weeks after the end of chronic inhalation of uranium ore dust aerosol (4.2 h d(-1) for 65 wk) and from age matched controls (n = 10), were analyzed for uranium, 230Th, 226Ra, 210Pb, and 210Po. Overall, during the period of dust inhalation, the nuclides accumulated in the above order of decreasing concentration in dry bone. However, the results demonstrate that there was some differential accumulation of uranium and uranium decay series radionuclides in muscle and two bone types of rats during the chronic inhalation period. The data also show that the bone levels of some, but not all, radionuclides decreased significantly with time after inhalation ceased. Lung uranium concentration at the time of death was a highly significant covariant for temporal changes in the levels of some radionuclides in both endochondral bone and membrane bone, indicating that lung remained a major source of these isotopes for accumulation in these bone types after ore dust inhalation had ceased. For some isotopes, the two bone types behaved differently during the dust inhalation period, and differently again after the dust inhalation ceased. The relative behavior of one bone type compared to the other for a particular isotope during the dust inhalation period did not predict the relative behavior after dust inhalation ceased. However, a faster accumulation of one bone type compared to the other for a particular isotope during the dust inhalation period predicted a faster decrease after dust inhalation ended.

[Dewit200111HPv81n5p501].

 

33.    Reproductive and developmental toxicity of natural and depleted uranium: a review, by JL Domingo, Laboratory of Toxicology and Environmental Health, School of Medicine, Rovira i Virgili University, Reus 43201, Spain. jlldr@fmcs.urv.es. Reprod Toxicol. Vol. 15(6), Nov-Dec 2001 (pp 603-609).

Although the biokinetics, metabolism, and chemical toxicity of uranium are well known, until recently little attention was paid to the potential toxic effects of uranium on reproduction and development in mammals. In recent years, it has been shown that uranium is a developmental toxicant when given orally or subcutaneously (SC) to mice. Decreased fertility, embryo/fetal toxicity including teratogenicity, and reduced growth of the offspring have been observed following uranium exposure at different gestation periods. The reproductive toxicity, maternal toxicity, embryo/fetal toxicity, and postnatal effects of uranium, as well as the prevention by chelating agents of uranium-induced maternal and developmental toxicity are reviewed here. Data on the toxic effects of depleted uranium on reproduction and development are also reviewed.

[Domingo200111RTv15n6p603]. (PMID: 11738513 [PubMed - indexed for MEDLINE]).

 

34.    Implanted depleted uranium fragments cause soft tissue sarcomas in the muscles of rats, by FF Hahn, et al., Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA. fhahn@lrri.org.  Environ Health Perspect. Vol. 110(1), Jan 2002 (pp 51-59).

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.

[Hahn200201EHPv110n1p51]. (PMID: 11781165 [PubMed - indexed for MEDLINE]).

 

35.    Lipid Oxidation and behavior are correlated in depleted uranium exposed mice, by  W. Briner, et al., Department of Psychology, University of Nebraska at Kearney, Kearney, NB. Metal Ions in Biology and Medicine, Vol. 7, 2002 (pp. 59-63).

“DU exposure via drinking water produces behavioural changes in mice. DU exposure also produces increased lipid oxidation in the brains of mice”

[Briner2002xxMIBMv7nxp59]

 

36.    Health effects of embedded depleted uranium, by DE McClain, et al., Armed Forces Radiobiology Research Institute, 8901 Wisconsin Avenue, Bethesda, MD 20889-5603, USA. Mil Med. Vol. 167(2 Suppl), Feb. 2002 (pp. 117-119).

The health effects of embedded fragments of depleted uranium (DU) are being investigated to determine whether current surgical fragment-removal policies are appropriate for this metal. The authors studied rodents implanted with DU pellets as well as cultured human cells exposed to DU compounds. Results indicate that uranium from implanted DU fragments distributes to tissues distant from implantation sites, including bone, kidney, muscle, and liver. Despite levels of uranium in kidney that would be nephrotoxic after acute exposure, no histological or functional kidney toxicity was observed with embedded DU, indicating that the kidney adapts when exposed chronically. Nonetheless, further studies of the long-term health impact are needed. DU is mutagenic and transforms human osteoblastic cells into a tumorigenic phenotype. It alters neurophysiological parameters in rat hippocampus, crosses the placental barrier, and enters fetal tissue. Preliminary data also indicate decreased rodent litter size when animals are bred 6 months or longer after DU implantation.

[McClain200201MMv167n2suppp117]. (PMID: 11873491 [PubMed - indexed for MEDLINE]).

 

37.    Renal effects of uranium in drinking water, by P. Kurttio, et al., Environmental Health Perspectives Vol. 110, 2002 (pp. 337-342).

This Finish study showed U in drilled wells in this study had a median of 28 :g/L (max. 1920 :g/L).  Median daily intake was 39 :g (7-224 :g/d). Found U excretion in urine associated with increased Ca and P excretion. U conc. in drinking water and daily U intake were associated with Ca fractional excretion, but not with P or glucose excretion. Results indicate U affects renal proximal tubules and not glomerulus.  Authors indicate safe conc of U in drinking water may be within range of proposed (Finish) guidelines of 2-30 :g/L.

[Kurttio2002xxEHPv119bxp337].

 

38.    Malignant transformation of human bronchial epithelial cell (BEAS-2B) induced with depleted uranium [Article in Chinese], by Yang  Zhi-hua,  et al., Institute of Radiation Medicine, Academy of Military Medicine Science, Beijing, China.  Ai Zheng Vol. 21(9), Sept. 2002 (pp. 944-948).

BACKGROUND & OBJECTIVE: It is clear from works already reported that depleted uranium (DU) affect human health. However, the late effect, especially the carcinogenesis, was not clearly understood. This study was designed to investigate the malignant transformation of human bronchial epithelial cell induced by insoluble DU and lung cancer related gene expression pattern, through imitating the condition that human absorbs depleted uranium aerosol. METHODS: Adenovirus-12/SV40 virus immortalized human bronchial epithelial cells (BEAS-2B) were reacted with insoluble DU oxide (dUO2); the characteristics of malignant transformation of cells were identified through observing the multiplication time of different generation cells, serum resistance, colony formation rate of semi-solid agar, and tumorigenesis in nude mice. Gene expression pattern of transferred BEAS-2B cell induced by DU was determined using 213 lung cancer related gene arrays. RESULTS: The multiplication time of BEAS-2B cell treated with DU was obviously decreased and the serum reistance was significantly increased in 5th generation; the anchorage independent growth (semi-solid agar colony formation) was appeared in 10th generation cell. The 15th generation cell formed tumor in nude mice. DMSO showed overt protection effect on malignant transformation of BEAS-2B cell. The analyzing results of 213 lung cancer related gene arrays showed that the expression level changed in more than 70 genes of transferred cells, including the overt decrease of level of gene expression in more than 10 genes. CONCLUSION: DU has carcinogenesis in vitro.

[Yang200209AZv21n9p944]. ( PMID: 12508538 [PubMed - indexed for MEDLINE]).

 

39.    Uranyl acetate-induced sensorimotor deficit and increased nitric oxide generation in the central nervous system in rats, by MB Abou-Donia, et al., Pharmacology, Biochemistry and Behavior Vol. 72, 2002 (pp. 881-890).

The study was designed to follow effects of daily injections of 0.1, 1, 10 and 100 mg/kg in rats for 7 days, with an observation period up to 30 days.  All rats in the 10 and 100 mg/kg group died before the 7th injection.  Animals in the lower dose groups survived but showed neurological deficits wrt inclined plane performance, grip time, beam walk score and beam walk time. There were some specific changes in NO in cortex and midbrain of lowest dose group and increased AChE acty in cortex of the 1 mg/kg dose group.  These results indicate subtle neurological deficits in relatively low dose U exposure as uranyl acetate.

[AbouDonia2002xxPBBv72nxp881]

 

40.    Effects of depleted uranium on the health and survival of Ceriodaphnia dubia and Hyalella azteca, by WW Kuhne, et al.,  U.S. Geological Survey, New Mexico Cooperative Fish and Wildlife Research Unit, New Mexico State University, Las Cruces 88003-8001, USA. wkuhne@lamar.colostate.edu. Environ Toxicol Chem. Vol. 21(10), Oct 2002 (pp 2198-2203).

Depleted uranium (DU) has been used as a substitute for the fissionable enriched uranium component of atomic weapons tested at Los Alamos National Laboratory (LANL) (Los Alamos, NM, USA) since the early 1950s, resulting in considerable concentrations of DU in the soils within the test sites. Although the movement of DU into major aquatic systems has been shown to be minimal, there are many small-order ephemeral streams and areas of standing water in canyons throughout LANL that may be affected by inputs of DU via runoff, erosion, and leaching. Ninety-six-hour acute and 7-d chronic toxicity assays were conducted to measure the toxicity of DU on survival and reproduction of Ceriodaphnia dubia. A 14-d water-only assay was conducted to measure survival and growth of Hyalella azteca. The estimated median lethal concentration (LC50) to produce 50% mortality of the test population for the 96-h Ceriodaphnia dubia assay was 10.50 mg/L. Reproductive effects occurred at a lowest-observable-effect concentration > or = 3.91 mg/L with a no-observable-effect concentration of 1.97 mg/L. The estimated 14-d LC50 for the Hyalella azteca assay was 1.52 mg/L. No significant relationship was detected between growth and DU concentrations. Concentrations at which toxicity effects were observed in this study for both invertebrates exceeded concentrations of total uranium observed in runoff from LANL lands. Thus, it is likely that current runoff levels of uranium do not pose a threat to these types of aquatic invertebrates.

[Kuhne200210ETCv21n10p2198]. (PMID: 12371498 [PubMed - indexed for MEDLINE]).

 

41.    Depleted uranium: radiation and ecological safety aspects [Article in Russian],  by I.B. Ushakov, et al., Voen Med Zh. Vol. 324(4), 2003 (pp. 56-58, 80).

The authors have analyzed the ecological, sanitary-and-hygienic and medicobiologic aspects of using the impoverished uranium in armaments and military equipment. The influence of impoverished uranium on human body (600 cases) was studied using medicobiologic investigation. It was shown that the particles of aerosol of mixed uranium oxide cause the radiation and chemical damage of kidneys, lungs and other internals. Uranium's alpha-radiation is very effective in induction of biologic effects during internal irradiation. Taking into account that bone tissue is the critical organ for uranium isotopes the medullar tissue is exposed to alpha-radiation. In the armed conflicts of the last decade wide use of armour-piercing means with elements consisted of impoverished uranium has led to the appearance of new technogenic risk factor for the environment and the man.

[Ushakov2003xxVMZv324n4p56]. ( PMID: 12825370 [PubMed - indexed for MEDLINE]).

 

42.        Properties, use and health effects of depleted uranium: a general overview, A Bleise, et.al., Journal of Environmental Radioactivity Vol. 64(2-3), 2003 (pp. 93-112). International Atomic Energy Agency (IAEA), Dept. of Nuclear Sciences and Applications.

Depleted uranium (DU), a waste product of uranium enrichment, has several civilian and military applications. It was used as armor-piercing ammunition in international military conflicts and was claimed to contribute to health problems, known as the Gulf War Syndrome and recently as the Balkan Syndrome. This led to renewed efforts to assess the environmental consequences and the health impact of the use of DU. The radiological and chemical properties of DU can be compared to those of natural uranium, which is ubiquitously present in soil at a typical concentration of 3 mg/kg. Natural uranium has the same chemotoxicity, but its radiotoxicity is 60% higher. Due to the low specific radioactivity and the dominance of alpha-radiation no acute risk is attributed to external exposure to DU. The major risk is DU dust, generated when DU ammunition hits hard targets. Depending on aerosol speciation, inhalation may lead to a protracted exposure of the lung and other organs. After deposition on the ground, resuspension can take place if the DU containing particle size is sufficiently small. However, transfer to drinking water or locally produced food has little potential to lead to significant exposures to DU. Since poor solubility of uranium compounds and lack of information on speciation precludes the use of radioecological models for exposure assessment, biomonitoring has to be used for assessing exposed persons. Urine, feces, hair and nails record recent exposures to DU. With the exception of crews of military vehicles having been hit by DU penetrators, no body burdens above the range of values for natural uranium have been found. Therefore, observable health effects are not expected and residual cancer risk estimates have to be based on theoretical considerations. They appear to be very minor for all post-conflict situations, i.e. a fraction of those expected from natural radiation.

[Bleise2003xxJERv64n2to3p93]. (PMID: 12500797 [PubMed - indexed for MEDLINE]).

 

43.        The biokinetics of uranium migrating from embedded DU fragments, by R.W. Leggett, et al., Life Sciences Division of Oak Ridge National Laboratory, Oak Ridge, TN, Journal of Environmental Radioactivity, Vol. 64(2-3), 2003 (pp. 205-225).

Military uses of depleted uranium (DU) munitions have resulted in casualties with embedded DU fragments. Assessment of radiological or chemical health risks from these fragments requires a model relating urinary U to the rate of migration of U from the fragments, and its accumulation in systemic tissues. A detailed biokinetic model for U has been published by the International Commission on Radiological Protection (ICRP), but its applicability to U migrating from embedded DU fragments is uncertain. Recently, Pellmar and colleagues (1999) conducted a study at the Armed Forces Radiobiology Research Institute (AFRRI) on the redistribution and toxicology of U in rats with implanted DU pellets, simulating embedded fragments. This paper compares the biokinetic data from that study with the behavior of commonly studied forms of U in rats (e.g., intravenously injected U nitrate). The comparisons indicate that the biokinetics of U migrating from embedded DU is similar to that of commonly studied forms of U with regard to long-term accumulation in kidneys, bone and liver. The results provide limited support for the application of the ICRP’s model to persons with embedded DU fragments. Additional information is needed with regard to the short term behavior of migrating U and its accumulation in lymph nodes, brain, testicles and other infrequently studied U repositories.

[Leggett200300JERv64n2p205]. ( PMID: 12500806 [PubMed - indexed for MEDLINE]).

 

44.    Depleted uranium: a new battlefield hazard, by VSG Murray, et al., Lancet (Supplement) Vol. 360, (pp. S31-S32).

The authors are members of the Royal Society Working Group on the Hazards of Depleted Uranium Munitions. They conclude that the radiation from DU is not sufficient to warrant concern about increases in lung cancer or other cancers such as leukemia. They go on to say that the critical organ for chemical toxicity effects is the renal proximal tubule epithelium, but with severe exposures could cause hepatic, haemological, respiratory and cardiac toxic effects. They mention that data regarding exposures are poor and there are problems with trying to predict long term effects. They suggest the health hazards of long-term DU are minimal compared to the inherent hazards of war.

[Murray200300Lv360nxpS31].

 

45.        Estimate of the time zero lung burden of depleted uranium in Persian Gulf War veterans by the 24-hour urinary excretion and exponential decay analysis, by A. Durakovic, et al., Uranium Medical Research Centre, 3430 Connecticut Avenue/11854, Washington, DC 20008, USA, Mil Med. Vol. 168(8), Aug. 2003 (pp. 600-605).

The aim of this study was to estimate the amount of depleted uranium (DU) in the respiratory system of Allied Forces Gulf War Veterans. Mass spectrometry (thermal ionization mass spectrometry) analysis of 24-hour urinary excretion of DU isotopes in five positive (238U/235U > 191.00) and six negative (238U/235U > 138.25) veterans was utilized in the mathematical estimation of the pulmonary burden at the time of exposure.  A minimum value for the biological half-life of ceramic DU oxide in the lungs was derived from the Battelle report of the minimum dissolution half-time in simulated interstitial lung fluid corresponding to 3.85 years. The average DU concentration was 3.27 x 10(-5) mg per 24 hours in DU-positive veterans and 1.46 x 10(-8) mg in DU-negative veterans. The estimated lung burden was 0.34 mg in the DU-positive and 0.00015 mg in the DU-negative veterans. Our results provide evidence that the pulmonary concentration of DU at time zero can be quantitated as late as 9 years after inhalational exposure.

[Durakovic200308MMv168n8p600]. (PMID: 12943033 [PubMed - in process])

 

45a.   Effect of U and 137Cs chronic contamination on dopamine and serotonin metabolism in the central nervous system of the rat, by Houpert P, et al., Institut de Radioprotection et de Surete Nucleaire, Department de a la RadioProtection de l'Homme, Service de RadioBiologie et d'Epidemiologie, Laboratoire RadioToxicologie experimentale, BP 166, 26702 Pierrelatte, France. Can J Physiol Pharmacol. Vol. 82 (2), Feb. 2004 (pp. 161-166).

Following the Chernobyl accident, the most significant problem for the population of the former Soviet Union for the next 50-70 years will be chronic internal contamination by radionuclides. One of the few experiments carried out in this field reported that neurotransmitter metabolism in the central nervous system of the rat was disturbed after feeding with oats contaminated by 137Cs for 1 month. The present study assessed the effect of chronic contamination by depleted U or 137Cs on the metabolism of two neurotransmitters in cerebral areas of rats. Dopamine and serotonin were chosen because their metabolism has been shown to be disturbed after external irradiation, even at moderate doses. Dopamine, serotonin, and some of their catabolites were measured by high-pressure liquid chromatography coupled with an electrochemical detector in five cerebral structures of rats contaminated over a 1-month period by drinking water (40 mg U.L -1 or 6500 Bq 137Cs.L -1). In the striatum, hippocampus, cerebral cortex, thalamus, and cerebellum, the dopamine, serotonin, and catabolite levels were not significantly different between the control rats and rats contaminated by U or 137Cs. These results are not in accordance with those previously described. [Houpert200402CJPPv82n2p161] (PMID: 15052298 [PubMed - indexed for MEDLINE]).

 

46.    Depleted and natural uranium: chemistry and toxicological effects, by E. Craft, et al., Nicholas School of the Environment and Earth Sciences, Duke University, Durham, North Carolina 27710, USA. J Toxicol Environ Health B Crit Rev. Vol. 7(4),  Jul-Aug, 2004 (pp. 297-317).

Depleted uranium (DU) is a by-product from the chemical enrichment of naturally occurring uranium. Natural uranium is comprised of three radioactive isotopes: (238)U, (235)U, and (234)U. This enrichment process reduces the radioactivity of DU to roughly 30% of that of natural uranium. Nonmilitary uses of DU include counterweights in airplanes, shields against radiation in medical radiotherapy units and transport of radioactive isotopes. DU has also been used during wartime in heavy tank armor, armor-piercing bullets, and missiles, due to its desirable chemical properties coupled with its decreased radioactivity. DU weapons are used unreservedly by the armed forces. Chemically and toxicologically, DU behaves similarly to natural uranium metal. Although the effects of DU on human health are not easily discerned, they may be produced by both its chemical and radiological properties. DU can be toxic to many bodily systems, as presented in this review. Most importantly, normal functioning of the kidney, brain, liver, and heart can be affected by DU exposure. Numerous other systems can also be affected by DU exposure, and these are also reviewed. Despite the prevalence of DU usage in many applications, limited data exist regarding the toxicological consequences on human health. This review focuses on the chemistry, pharmacokinetics, and toxicological effects of depleted and natural uranium on several systems in the mammalian body. A section on risk assessment concludes the review.

[Craft200407JTEHBCRv7n4p297].

 

47.    Depleted uranium dust from fired munitions: physical, chemical and biological properties, by RE Mitchel, et al., Atomic Energy of Canada Limited, Chalk River Laboratories, Chalk River Ontario, K0J 1J0, Canada. mitchelr@aecl.ca. Health Phys. Vol. 87(1), Jul. 2004 (pp. 57-67).     

This paper reports physical, chemical and biological analyses of samples of dust resulting from munitions containing depleted uranium (DU) that had been live-fired and had impacted an armored target. Mass spectroscopic analysis indicated that the average atom% of U was 0.198 +/- 0.10, consistent with depleted uranium. Other major elements present were iron, aluminum, and silicon. About 47% of the total mass was particles with diameters <300 microm, of which about 14% was <10 microm. X-ray diffraction analysis indicated that the uranium was present in the sample as uranium oxides-mainly U3O7 (47%), U3O8 (44%) and UO2 (9%). Depleted uranium dust, instilled into the lungs or implanted into the muscle of rats, contained a rapidly soluble uranium component and a more slowly soluble uranium component. The fraction that underwent dissolution in 7 d declined exponentially with increasing initial burden. At the lower lung burdens tested (<15 microg DU dust/lung) about 14% of the uranium appeared in urine within 7 d. At the higher lung burdens tested (~80-200 microg DU dust/lung) about 5% of the DU appeared in urine within 7 d. In both cases about 50% of that total appeared in urine within the first day. DU implanted in muscle similarly showed that about half of the total excreted within 7 d appeared in the first day. At the lower muscle burdens tested (<15 microg DU dust/injection site) about 9% was solubilized within 7 d. At muscle burdens >35 microg DU dust/injection site about 2% appeared in urine within 7 d. Natural uranium (NU) ore dust was instilled into rat lungs for comparison. The fraction dissolving in lung showed a pattern of exponential decline with increasing initial burden similar to DU. However, the decline was less steep, with about 14% appearing in urine for lung burdens up to about 200 microg NU dust/lung and 5% at lung burdens >1,100 microg NU dust/lung. NU also showed both a fast and a more slowly dissolving component. At the higher lung burdens of both DU and NU that showed lowered urine excretion rates, histological evidence of kidney damage was seen. Kidney damage was not seen with the muscle burdens tested. DU dust produced kidney damage at lower lung burdens and lower urine uranium levels than NU dust, suggesting that other toxic metals in DU dust may contribute to the damage.

[Mitchel200407HPv87n1p57]. PMID: 15194923 [PubMed - indexed for MEDLINE]

 

48.       The effect of stress on the temporal and regional distribution of uranium in rat brain after acute uranyl acetate exposure, by Barber DS, et al., Department of Physiological Sciences, Center for Human and Environmental Toxicology, University of Florida, Gainesville, Florida 32611, USA. barberd@mail.vetmed.ufl.edu.  J Toxicol Environ Health A. Vol. 68 (2), January, 2005 (pp. 99-111).

Long-term exposure to depleted uranium (DU) has been shown to increase brain uranium and alter hippocampal function; however, little is known about the short-term kinetics of DU in the brain. To address this issue, temporal and regional distribution of brain uranium was investigated in male Sprague-Dawley rats treated with a single intraperitoneal injection of 1 mg uranium/kg as uranyl acetate. Due to the inherent stress of combat and the potential for stress to alter blood-brain barrier permeability, the impact of forced swim stress on brain uranium distribution was also examined in this model. Uranium in serum, hippocampus, striatum, cerebellum, and frontal cortex was quantified by inductively coupled plasma-mass spectrometry (ICP-MS) at 8 h, 24 h, 7 d, and 30 d after exposure. Uranium entered the brain rapidly and was initially concentrated in hippocampus and striatum. While multiple phases of uranium clearance were observed, overall clearance was relatively slow and the uranium content of hippocampus, cerebellum, and cortex remained elevated for more than 7 d after a single exposure. Prior exposure to stress significantly reduced hippocampal and cerebellar uranium 24 h post-exposure and tended to reduce uranium in all brain regions 7 d after exposure. The application of stress appeared to increase brain uranium clearance, as initial tissue levels were similar in stressed and unstressed rats. [Barber200501JTEHAv68n2p99] (PMID: 15762549 [PubMed - indexed for MEDLINE]).

 

49.       Effects of short-term and long-term depleted uranium exposure on open-field behavior and brain lipid oxidation in rats, by Briner W, et al., Department of Psychology, University of Nebraska at Kearney, Kearney, NE 68849, USA. BrinerW@unk.edu . Neurotoxicol Teratol. Vol. 27 (1), Jan-Feb. 2005 (pp. 135-144).

Male and female rats were exposed to depleted uranium acetate (DU) in drinking water at doses of 0, 75, or 150 mg/L for either 2 weeks or 6 months. After exposure, the animals were tested for behaviors in the open-field. After testing in the open-field, the brains were examined for levels of lipid oxidation using the thiobarbituric acid (TBA) assay. Behavioral differences (line crossing and rearing) were seen in male rats after 2 weeks exposure to DU in drinking water for the highest dose group. Increased brain lipid oxidation was seen for the highest dose group for both genders. Lipid oxidation levels correlated significantly with line crossing and rearing in the open-field. After 6 months exposure, behavioral differences for male rats in the open-field remained and expanded to include other behaviors (grooming, defecation, and urination). Female rats also demonstrated some behavioral changes after 6 months exposure. Lipid oxidation in the brain continued to be seen; however, these levels no longer correlated with open-field behaviors. These data suggest that DU is a toxin that crosses the blood-brain barrier, producing behavioral changes in male rats and lipid oxidation regardless of gender in as little as 2 weeks in the rat. Longer exposures to DU may produce greater behavioral changes but compensatory mechanisms may reduce the effects of lipid oxidation. Males appear to be more sensitive to the behavioral effects of DU. [Briner200501NTv27n1p135](PMID: 15681127 [PubMed - indexed for MEDLINE]).

 

50.       Biokinetic modeling of uranium in man after injection and ingestion, by Li WB, et al., GSF-National Research Center for Environment and Health, Institute of Radiation Protection, 85764, Neuherberg, Germany, wli@gsf.de.  Radiat Environ Biophys. Vol. 44 (1), May, 2005 (pp. 29-40).

Uranium is a naturally occurring primordial radioactive element. Small amounts found in air, water, and food are regularly consumed and inhaled by humans. Even the military, medical, and industrial use of depleted uranium can affect humans. There is an appreciable retention of incorporated uranium in skeleton, kidneys, and liver, and a review of respective effective dose coefficients has been given by the International Commission on Radiological Protection (ICRP) in its "Publication 69"; however, data regarding retention in organs or tissues and rates of urinary and fecal excretion for different age groups are incomplete. Therefore, the present study provides retention data that have been calculated for uranium in all compartments and for urinary and fecal excretion, following acute and chronic injection and ingestion for six age groups. The calculations are based on the current ICRP biokinetic model for uranium, and the data can be plotted by using any mathematical software to obtain the retention data at any time after incorporation or to calculate the internal average organ dose induced by uranium provided that specific absorbed fractions are available. The dynamic relationship of the retention in plasma and blood after intravenously and orally administered uranium can easily be derived from the database for injection and ingestion. The calculated contents of uranium in organs or tissues (using the uranium concentration in foodstuffs published by UNSCEAR for Europeans) are compared with autopsy data available in the literature. According to this model, the whole body of a 75-year-old man contains 7 mug uranium, of which 76% is in the skeleton, 1% in the kidneys, and 2.1% in the liver. [Li200505REBv44n1p29] (PMID: 15830205 [PubMed - in process]).

 

51.       The brain is a target organ after acute exposure to depleted uranium, by Lestaevel P, et al., Institut de Radioprotection et de Surete Nucleaire, Departement de Radio-Protection de l'Homme, Laboratoire de Radio-Toxicologie Experimentale, BP 166, 26702 Pierrelatte, France. Toxicology Prepub., June 2005. [Lestaevel200506Tprepub]

The health effects of depleted uranium (DU) are mainly caused by its chemical toxicity. Although the kidneys are the main target organs for uranium toxicity, uranium can also reach the brain. In this paper, the central effects of acute exposure to DU were studied in relation to health parameters and the sleep-wake cycle of adult rats. Animals were injected intraperitoneally with 144+/-10mug DUkg(-1) as nitrate. Three days after injection, the amounts of uranium in the kidneys represented 2.6mug of DUg(-1) of tissue, considered as a sub-nephrotoxic dosage. The central effect of uranium could be seen through a decrease in food intake as early as the first day after exposure and shorter paradoxical sleep 3 days after acute DU exposure (-18% of controls). With a lower dosage of DU (70+/-8mug DUkg(-1)), no significant effect was observed on the sleep-wake cycle. The present study intends to illustrate the fact that the brain is a target organ, as are the kidneys, after acute exposure to a moderate dosage of DU. The mechanisms by which uranium causes these early neurophysiological perturbations shall be discussed.  [Lestaevel200506Tprepub] (PMID: 15951092 [PubMed - as supplied by publisher]).

 

52.     Evaluation of the effect of implanted depleted uranium on male reproductive success, sperm concentration, and sperm velocity, by Arfsten DP, et al., Naval Health Research Center Detachment, Environmental Health Effects Laboratory, Wright-Patterson AFB, OH 45433, USA. Environ Res. 2005 Jun 3; [Preprint]  

Depleted uranium (DU) projectiles have been used in battle in Iraq and the Balkans and will continue to be a significant armor-penetrating munition for the US military. As demonstrated in the Persian Gulf War, battle injury from DU projectiles and shrapnel is a possibility, and removal of embedded DU fragments from the body is not always practical because of their location in the body or their small size. Previous studies in rodents have demonstrated that implanted DU mobilizes and translocates to the gonads, and natural uranium may be toxic to spermatazoa and the male reproductive tract. In this study, the effects of implanted DU pellets on sperm concentration, motility, and male reproductive success were evaluated in adult (P1) Sprague-Dawley rats implanted with 0, 12, or 20, DU pellets of 1x2 mm or 12 or 20 tantalum (Ta) steel pellets of 1x2mm. Twenty DU pellets of 1x2mm (760mg) implanted in a 500-g rat are equal to approximately 0.2 pound of DU in a 154-lb (70-kg) person. Urinary analysis found that male rats implanted with DU were excreting uranium at postimplantation days 27 and 117 with the amount dependent on dose. No deaths or evidence of toxicity occurred in P1 males over the 150-day postimplantation study period. When assessed at postimplantation day 150, the concentration, motion, and velocity of sperm isolated from DU-implanted animals were not significantly different from those of sham surgery controls. Velocity and motion of sperm isolated from rats treated with the positive control compound alpha-chlorohydrin were significantly reduced compared with sham surgery controls. There was no evidence of a detrimental effect of DU implantation on mating success at 30-45 days and 120-145 days postimplantation. The results of this study suggest that implantation of up to 20 DU pellets of 1x2mm in rats for approximately 21% of their adult lifespan does not have an adverse impact on male reproductive success, sperm concentration, or sperm velocity. [Arfsten200506ERprepub] (PMID: 15939419 [PubMed - as supplied by publisher]).

 

 

53.       Embedded weapons-grade tungsten alloy shrapnel rapidly induces metastatic high-grade rhabdomyosarcomas in F344 rats, by Kalinich JF, et al., Heavy Metals Research Team, Armed Forces Radiobiology Research Institute, Bethesda, Maryland 20889-5603, USA. kalinich@afrri.usuhs.mil .  Environ Health Perspect., Vol. 113 (6), June, 2005 (pp. 729-734).

Continuing concern regarding the potential health and environmental effects of depleted uranium and lead has resulted in many countries adding tungsten alloy (WA)-based munitions to their battlefield arsenals as replacements for these metals. Because the alloys used in many munitions are relatively recent additions to the list of militarily relevant metals, very little is known about the health effects of these metals after internalization as embedded shrapnel. Previous work in this laboratory developed a rodent model system that mimicked shrapnel loads seen in wounded personnel from the 1991 Persian Gulf War. In the present study, we used that system and male F344 rats, implanted intramuscularly with pellets (1 mm times 2 mm cylinders) of weapons-grade WA, to simulate shrapnel wounds. Rats were implanted with 4 (low dose) or 20 pellets (high dose) of WA. Tantalum (20 pellets) and nickel (20 pellets) served as negative and positive controls, respectively. The high-dose WA-implanted rats (n = 46) developed extremely aggressive tumors surrounding the pellets within 4-5 months after implantation. The low-dose WA-implanted rats (n = 46) and nickel-implanted rats (n = 36) also developed tumors surrounding the pellets but at a slower rate. Rats implanted with tantalum (n = 46), an inert control metal, did not develop tumors. Tumor yield was 100% in both the low- and high-dose WA groups. The tumors, characterized as high-grade pleomorphic rhabdomyosarcomas by histopathology and immunohistochemical examination, rapidly metastasized to the lung and necessitated euthanasia of the animal. Significant hematologic changes, indicative of polycythemia, were also observed in the high-dose WA-implanted rats. These changes were apparent as early as 1 month postimplantation in the high-dose WA rats, well before any overt signs of tumor development. These results point out the need for further studies investigating the health effects of tungsten and tungsten-based alloys. [Kalinich200506EHPv113n6p729] (PMID: 15929896 [PubMed - in process]).

 

 

 

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