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3
Toxicology

This chapter presents information about the toxicology of uranium.1 Studies of laboratory animals and other nonhuman systems are essential for understanding mechanisms of action, biologic plausibility, and possible health effects when experimental research in humans is not ethically or practically possible (Cohrssen and Covello, 1989; NRC, 1991). Such studies permit a potentially toxic agent to be introduced under conditions—such as dose, duration, and route of exposure—controlled by the researcher to probe health effects on many body systems. Nonhuman studies are also a valuable complement to human studies of genetic susceptibility. Although nonhuman studies often focus on one agent at a time, they enable investigation of chemical mixtures and their potential interactions more easily.

Research on health effects of toxic substances includes animal studies that characterize absorption, distribution, metabolism, and elimination. Animal studies may examine acute (short-term) exposures or chronic (long-term) exposures. Animal research may focus on the mechanism of action (how a toxicant exerts its deleterious effects at the cellular and molecular levels). Mechanism-of-action (or mechanistic) studies encompass an array of laboratory approaches with whole animals and with in vitro systems that use tissues or cells from humans or animals. Structure-activity relationships, in which the molecular structure and chemical and physical properties of a potential toxicant are compared with those of a known toxicant, are an important source of hypotheses about mechanism of action.

1

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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3 Toxicology T his chapter presents information about the toxicology of uranium.1 Stud- ies of laboratory animals and other nonhuman systems are essential for understanding mechanisms of action, biologic plausibility, and possible health effects when experimental research in humans is not ethically or practi- cally possible (Cohrssen and Covello, 1989; NRC, 1991). Such studies permit a potentially toxic agent to be introduced under conditions—such as dose, duration, and route of exposure—controlled by the researcher to probe health effects on many body systems. Nonhuman studies are also a valuable complement to human studies of genetic susceptibility. Although nonhuman studies often focus on one agent at a time, they enable investigation of chemical mixtures and their potential interactions more easily. Research on health effects of toxic substances includes animal studies that characterize absorption, distribution, metabolism, and elimination. Animal stud- ies may examine acute (short-term) exposures or chronic (long-term) exposures. Animal research may focus on the mechanism of action (how a toxicant exerts its deleterious effects at the cellular and molecular levels). Mechanism-of-action (or mechanistic) studies encompass an array of laboratory approaches with whole animals and with in vitro systems that use tissues or cells from humans or animals. Structure-activity relationships, in which the molecular structure and chemical and physical properties of a potential toxicant are compared with those of a known toxicant, are an important source of hypotheses about mechanism of action. 1Some sections of this chapter have been adapted from Gulf war and Health, volume 1: Depleted Uranium, Pyridostigmine Bromide, sarin, vaccines (IOM, 2000). 2

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2 UPDateD literatUre review oF DePleteD UraniUm In carrying out its charge, the committee used animal and other nonhu- man studies in several ways, particularly to look for markers of health effects that might be important for humans. If animal studies showed absorption and deposition in specific tissues or organs, the committee looked especially closely for possible abnormalities at these sites in human studies, as it did for uranium deposition in bone and kidney. One of the problems with animal studies, however, is the difficulty of finding animal models to study symptoms that are related to uniquely human attributes, such as cognition, purposive behavior, and the per- ception of pain. The toxic effects of uranium also have been reviewed in a recent National Research Council report, review of toxicologic and radiologic risks to military Personnel from exposure to Depleted Uranium During and after Combat (NRC, 2008), which assessed the US Army’s “Capstone report” (USACHPPM, 2004) on toxicologic and radiologic risks to soldiers posed by exposure to depleted uranium. This chapter begins with a summary of the findings presented in Gulf war and Health, volume 1: Depleted Uranium, Pyridostigmine Bromide, sarin, vac- cines (IOM, 2000), hereafter referred to as volume 1. It next addresses experi- mental data from toxicokinetic (also called pharmacokinetic), animal, and in vitro studies published since volume 1. The chapter ends with a discussion of how the committee applied the experimental data. Tables 3-1 to 3-10 are included at the end of this chapter. SuMMARY OF PREvIOuS REPORT Chapter 4 of volume 1 includes a review of studies of the toxicology of ura- nium. It covers toxicokinetics and animal and in vitro studies. Uranium is both a heavy metal and a low-specific-activity radioactive ele- ment. Studies on the toxicity of uranium have examined both its chemical and its radiologic effects. The primary routes of human exposure to uranium are ingestion and inhalation; the effects of dermal exposure and embedded fragments have also been studied. The amount of uranium that the body absorbs depends largely on the route of exposure and the solubility of the uranium compounds to which a person is exposed. 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. Renal dysfunction and lung injury are the best-characterized consequences of exposure to uranium compounds. The chemical and radiologic properties of uranium could act cooperatively to cause tissue damage, so it cannot be assumed that excess cancers would be due solely to the radiologic effects of uranium or that organ damage is due exclusively to its heavy-metal properties.

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2 toxiColoGY TOxICOKINETICS The toxicokinetics of a substance has to do with the routes and rates of absorption, distribution, metabolism, and excretion. Toxicokinetics can be used to determine the amount of a substance that reaches particular organs or cells and might therefore lead to a toxic effect. For a review on biokinetic models of exposure to different forms of uranium with emphasis on depleted uranium, the reader may consult Leggett (2006). Absorption Where uranium particles are deposited in the respiratory tract is the result of a combination of physical forces that govern particle behavior in an air stream and the anatomy of the respiratory tract (Gordon and Amdur, 1991). The site of deposition affects the degree of uranium absorption, the clearance mechanisms that are available to remove uranium particles, and the severity of the conse- quences of damage of tissue of the respiratory system. Which of the various regions of the respiratory tract and lung (extrathoracic, tracheobronchial, and deep pulmonary or alveolar) inhaled uranium-dust particles are deposited in depends on the particles’ aerodynamic diameter and inspiratory flow rate. An aerodynamic diameter that incorporates both the density and the diameter of particles and their aerodynamic drag is typically assigned to nonspheri- cal particles. It represents a particle as having the diameter of a unit-density sphere that has the same terminal velocity as the particle, whatever its size, shape, or den- sity (Gordon and Amdur, 1991). Larger particles are deposited in the tracheobron- chial region; mucociliary action transports the particles to the pharynx, where they are swallowed. Smaller particles reach the terminal bronchioles and the alveoli. The International Commission on Radiological Protection has developed extensive models of the dosimetry of inhaled radioactive materials (ICRP, 2002). At the alveolar level, the more soluble uranium compounds (categorized as type F for fast dissolution) are taken up by the systemic circulation within days. The less soluble uranium compounds (type M for medium dissolution) are likely to remain in the pulmonary tissue and associated lymph nodes for weeks. The relatively insoluble compounds (categorized as type S for slow dis- solution) are least likely to enter the systemic circulation and may remain in the lung and tracheobronchial lymph nodes for several years (ATSDR, 1999). (See Table 3-1 for examples of uranium compounds of each type.) 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). Given their high density, most inhaled uranium-particle–containing dusts have an aerodynamic diameter that does not permit them to be carried to the

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26 UPDateD literatUre review oF DePleteD UraniUm peripheral part of the lungs (Berlin and Rudell, 1986; Morris et al., 1992). Esti- mates based on measurements in uranium-processing plants suggest that only 1-5% of uranium-particle–containing dusts will enter the lungs (Davies, 1961). The rest will deposit in the upper respiratory tract and eventually be swallowed and go through the gastrointestinal tract. Inhalation studies of depleted-uranium particles in animals suggest that pat- terns of exposure may be important in the bioaccumulation of uranium (Monleau et al., 2006a,b). For example, repeated pre-exposure to insoluble depleted-uranium dioxide by inhalation has been shown to increase later uranium peroxide bioac- cumulation in the kidneys and femurs and decrease it in the gastrointestinal tract and excreta concurrently with enhanced genotoxic effects in several of these tis- sues (Monleau et al., 2006b). No change in uranium peroxide bioaccumulation was found in the lungs. Gastrointestinal absorption of uranium has been studied after single oral administration of soluble compounds to rats, swine, dogs, hamsters, and baboons (for review, see Thorne, 2003). 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. Gastrointestinal absorption was estimated at up to 5% and was highly variable between experiments. Uranium absorption occurs predominantly in the small intestine, and there is no absorption from the buccal cavity, stomach, or large intestine (Dublineau et al., 2005). The apparent uranium permeability measured with ex vivo techniques was similar in the various parts of the small intestine (Dublineau et al., 2005) and probably occurs through a transcellular pathway. The relationship between uranium speciation and gastroin- testinal absorption was investigated in rats after ingestion of five samples of water contaminated with different forms of uranium. The average fractional absorption was about 0.4% for each of the samples, so it was concluded that the chemical form of uranium in the water did not influence its absorption into the systemic circulation (Frelon et al., 2005). Peyer’s patches, the aggregated structures of gut-associated lymphoid tissue, have specific electrophysiologic characteristics of ion conductance and secretory capacity (Brayden and Baird, 1994) and have recognized sites of transport of nanoparticles, microparticles, and macromolecules (Pappo and Ermak, 1989; Powell et al., 1996). A recent quantitative analysis of uranium deposition by inductively coupled plasma-mass spectrometry (ICP-MS) after chronic exposure of rats to depleted uranium during 3 or 9 months demonstrated preferential accu- mulation of uranium in Peyer’s patches compared with epithelium (Dublineau et al., 2006a). However, the apparent uranium permeability of the rat intestine was higher (by a factor of 10) in the mucosa than in Peyer’s patches, and this suggests that the small intestinal epithelium was the preferential pathway for the transmucosal passage of uranium.

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2 toxiColoGY As described in volume 1, skin absorption is an effective route for the entry of soluble uranium compounds into the systemic circulation. Substantial diffusion of soluble uranium through human or mammalian intact skin has been described (de Rey et al., 1983; Lopez et al., 2000; Tymen et al., 2000; Petitot et al., 2004). Absorption of uranium via deep wounds has also been shown to depend on the solubility of the metal. Pellmar et al. (1999a) assessed distribution of uranium that was implanted in the gastrocnemius (lower leg) muscle of rats in the form of depleted-uranium pellets. A dose-dependent increase in uranium concentra- tion was noted 1 day after implantation, reaching 82.0 ± 9.7 and 31.3 ± 6.5 ng of uranium per gram in the kidneys and tibias, respectively, of high-dose animals. Those concentrations were about 58 and 26 times higher than seen in the same tissues of the control group. A recent study evaluated the influence of wounds on the short-term distribu- tion and excretion of uranium in rats (Petitot et al., 2007). The authors reported substantial uptake of a uranyl nitrate solution through intact rat skin within the first 6 hours of exposure. Skin excoriation increased percutaneous absorption of uranyl nitrate, and this suggested that percutaneous diffusion of uranyl nitrate depends heavily on compromised skin-barrier integrity (Petitot et al., 2007). Similar studies with other forms of uranium were not found. However, in vitro studies corroborated greater diffusion of uranium through excoriated skin than intact skin; substantial uptake of uranium through excoriated skin occurred as early as 30 minutes after exposure (Petitot et al., 2004). Transport and Biotransformation Once absorbed, uranium forms soluble complexes with bicarbonate, citrate, or proteins in the plasma (Dounce, 1949; Stevens et al., 1980; Cooper et al., 1982). Little is known about the cellular and molecular mechanisms underlying the uptake of uranium in tissues. In the kidneys, a cytotoxic fraction of uranium was found to be a phosphate complex of uranyl whose uptake is mediated by a sodium-dependent phosphate cotransporter system (Muller et al., 2006). No other information on the mechanisms of transport could be found. The role of nonspe- cific metal transporters, such as divalent metal transporter-1, in the transport of uranium has yet to be defined. Distribution The percentages of uranium absorbed into blood, transferred to tissues, and excreted in urine are independent of the deposition of soluble uranium compounds, such as uranium peroxide or uranium tetrafluoride dust, in the lungs (Houpert et al., 1999). The ratio of K to (K + U), where K equals the percentage of uranium retained in the kidneys and U equals the percentage excreted in urine 24 hours after

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28 UPDateD literatUre review oF DePleteD UraniUm instillation, may be used to characterize kidney clearance of uranium. The ratio was constant when the concentration of uranium, in the form of the two compounds mentioned, in the kidneys increased from 0.02 to 12.5 µg/g. Inhaled uranium accumulates readily in the central nervous system (Monleau et al., 2005). Repeated exposure (4 days/week for 3 weeks) to depleted-uranium dioxide at a high air concentration (197 mg/m3) has been associated with ura- nium accumulation in the following rank order: olfactory bulb > hippocampus > frontal cortex > cerebellum. Accumulation in brain regions appears to be route- dependent: injection of uranium results in homogeneous distribution in various brain regions, whereas inhalation and ingestion result in heterogeneous and specific accumulation (Houpert et al., 2007c). Those differences were thought to reflect differential mechanisms of delivery of uranium to the brain; however, the nature of the transporters remains unknown. Lemercier and colleagues (2003) demonstrated transfer of uranium across the blood-brain barrier in an in situ rat brain perfusion study in which brain uranium was measured with ICP-MS. In chronic exposure to uranium, tissue deposition does not appear linear (Paquet et al., 2006). For example, Tracy et al. (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. In the case for the kidneys, uranium concentration increased by a factor of 1.8 from 28 to 91 days. Similarly, in Sprague Dawley rats that had implanted depleted-uranium pellets, Pellmar et al. (1999a) showed that uranium concentrations in kidneys peaked 6 months after exposure began and then decreased by a factor of 1.4-1.6 until 18 months of exposure. That pattern of accumulation was also observed in urine, in which a peak uranium concentration was noted at 12 months of exposure. Similarly, rats exposed to uranyl nitrate via drinking water during their entire adult life at a constant concentration of 40 mg/L showed fluctuations in uranium concentration in almost every tissue (Paquet et al., 2006); this suggested that accumulation of uranium in tissues may vary over the course of chronic expo- sure. Thus, chronic exposure may be associated with physiologic phenomena that modify the pharmacokinetics of uranium over time. Excretion and Retention No new studies were identified on systemic clearance or excretion and retention of uranium after inhalation or oral exposure. As described in volume 1, Pellmar and colleagues (1999a) reported that bone and kidneys were the primary reservoirs of uranium that had dissolved from embedded depleted-uranium frag- ments. Dissolved uranium also localized in various nuclei of the brain, lymph nodes, testes, and spleen, and low serum concentrations of uranium were noted at all times of measurement whereas the size of the pellets diminished with time (Pellmar et al., 1999a; Fitsanakis et al., 2006). Adult male and female rats with surgically implanted depleted uranium were shown to excrete uranium in urine in

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2 toxiColoGY a dose-dependent manner, but tissue concentrations of uranium were not reported (Arfsten et al., 2005). In mice, 60 days after implantation of depleted uranium, the highest concentration of uranium was noted in the kidneys, but bone marrow, hind limbs, and spleen also had substantial increases in uranium (Miller et al., 2005). Those studies establish that depleted uranium from implanted fragments will readily distribute to various tissues over the life span of an animal. Additional details from multiple studies on the accumulation of uranium in the brain are presented below in the section on “Nonmalignant Neurologic Effects.” TOxICITY STuDIES This section reviews key animal and in vitro studies of the toxic effects of uranium published since volume 1. Studies of cancer and noncancer health end points have used inhalation and oral and dermal exposure. There are also studies of the effects of injected uranium and embedded depleted-uranium fragments. Kathren and Burklin (2008) 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. 1973; Filippova et al., 1978). Since the publication of volume 1, three studies were found that examined cancer in depleted-uranium–exposed animals. The experimental details are presented in Table 3-2. In the first study, rats received thigh-muscle implants of depleted-uranium pellets or fragments and were held for their life span (Hahn et al., 2002). At death, necropsies and histopathologic examinations were conducted. A statistically sig- nificant increase in the incidence of soft-tissue sarcoma at the implantation site was reported in rats that received 5.0 × 5.0-mm squares of depleted uranium and a slight increase in rats that received 2.5 × 2.5-mm squares. No tumors were observed in the rats that received 2.0 × 1.0-mm depleted-uranium pellets. The second study used an in vivo leukemogenesis mouse model (Miller et al., 2005). Mice received implants two to eight depleted-uranium pellets in the gastrocnemius muscle, and 60 days later received intravenous injections of murine multicolony-stimulation-factor–dependent hematopoietic cells. Leukemia developed in 68-75% of the mice that received depleted-uranium implants and 12% of the mice that had no implants. In the third study, Mitchel et al. (1999) exposed rats by nose-only inhalation 4.2 hours/day 5 days per week for 65 weeks to natural uranium-ore dust aerosol (44% uranium) in the absence of substantial radon content at 50 or 19 mg/m3. Lung uranium burdens, determined at the time of death, decreased exponentially

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0 UPDateD literatUre review oF DePleteD UraniUm after cessation of exposure independently of the initial burden. The frequency of primary malignant lung tumors was dose-dependent: 0.016, 0.175, and 0.328 in the control, low-aerosol, and high-aerosol groups, respectively. The groups were indistinguishable with respect to tumor latency. The average radiation doses received at the low and high dust-aerosol concentrations were 0.87 and 1.64 Gy, respectively, and resulted in an average risk of malignant lung tumors of about 0.20 tumor per animal per gray in both exposure groups. The tumor frequency was not directly proportional to the dose; but when malignant lung-tumor frequency was calculated as a function of dose rate (measured on the basis of lung burden at the end of dust inhalation), a direct linear relationship was noted and suggested that radiation dose rate may be a more important determinant of lung-cancer risk than absolute chemical exposure. The authors concluded that chronic inhalation of natural uranium-ore dust alone in rats creates a risk of primary malignant lung- tumor formation. The study also provided details on urinalysis, which was carried out once per month throughout the animals’ lifetime. The results demonstrated a constant urinary concentration of uranium throughout weeks 13-55 of exposure, with average concentrations of 0.117 and 0.274 mg/L in the low-uranium and high-uranium groups, respectively. Mitchel et al. (1999) also assessed the effects of inhaled uranium on the incidence of nonmalignant lung tumors in rats. They exposed rats to one of two concentrations of natural uranium-ore dust aerosol by nose-only inhalation for 4.2 hours/day 5 days per week for 65 weeks. The propor- tion of animals with nonmalignant lung tumors was 0.016, 0.135, and 0.131 in the control, low-aerosol, and high-aerosol groups, respectively. Genotoxic Effects volume 1 describes two genotoxicity studies (Miller et al., 1998a,b), both of which reported positive findings. 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). However, no significant difference in chromosomal aberrations was reported between high-exposure and low-exposure groups in the 8-, 12-, and 14-year postwar followup assessments (McDiarmid et al., 2001; McDiarmid, June 28, 2007, presentation to the com- mittee). Hypoxanthine-guanine phosphoribosyl transferase mutation frequencies were nonsignificantly higher in the high-exposure group than in the low-exposure group (McDiarmid, June 28, 2007, presentation to the committee). An increase in chromosomal aberrations in peripheral blood lymphocytes was reported in a cohort of 69 people in southern Serbia and Montenegro who were exposed to depleted uranium during air strikes in 1999 (Milacic et al., 2004). Statistically significant increases in micronuclei frequencies in peripheral blood lymphocytes

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1 toxiColoGY were found in 30 people who lived near Sarajevo (Krunic et al., 2005). Urinalysis to determine body burden of uranium was not conducted on that cohort, but water from two local wells contained traces of depleted uranium. As detailed in Table 3-3, uranium-induced genotoxicity was demonstrated in a number of studies of rats; human, hamster, and rat cells; and calf thymus DNA. Respiratory Effects Six toxicologic studies of respiratory effects in several animal species are described in volume 1; their results were inconsistent. 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) acetate was associated with increased oxidative stress and decreased cell proliferation (Periyakaruppan et al., 2007). The authors attributed the decrease in cell proliferation to loss of total cellular redox potential due mainly to depletion of the tripeptide glutathione and superoxide dismutase. In light of uranium’s ability to induce pulmonary fibrosis, which is often associated with inflammation, Gazin et al. (2004) evaluated the effects of uranium on cytokine secretion—tumor-necrosis factor-alpha (TNF-alpha), interleukin- 1beta (IL-1beta), and IL-10—in alveolar macrophages. TNF-alpha secretion was increased by exposure to uranium but not by exposure to the metallic ele- ment gadolinium. Uranium-treated and control cells were indistinguishable with respect to IL-1beta and IL-10 secretions. In another study, a 48-hour exposure of a human type II epithelial cell line (A549) to 0.5 mM uranyl bicarbonate solution triggered differential expression of cytokeratin 8 (CK8) and CK8 fragments; this suggested dysfunction of the ubiquitin-proteasome system or a regulator pathway involving CK ubiquitinyl- ation (Malard et al., 2005). Renal Effects It is well established that uranium causes low-level metallotoxic effects on the renal system in animals (IOM, 2000). In general, renal injury occurs within days of exposure and is manifested as a change in the proximal convoluted tubules, which results in increased urinary enzyme excretion (excretion of alka- line phosphatase, lactate dehydrogenase, and leucine aminopeptidase). Hyaline casts (casts containing necrotic cells shed from the tubular epithelium) are present at all levels of the tubular system (Berlin and Rudell, 1986). Glomerular changes occur in parallel with tubular damage, principally in the basement membranes of glomerular capillaries. The corresponding functional changes in the kidney are proteinuria, impairment of p-aminohippurate clearance, increase in clearance of amino acids and glucose, and decrease in sodium reabsorption. After severe

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2 UPDateD literatUre review oF DePleteD UraniUm damage, renal inulin and creatinine clearance decreases (Stopps and Todd, 1982). Generally, if the uranium dose is sublethal, regeneration of the damaged epithe- lium commences within 2-3 days of the end of exposure (Stopps and Todd, 1982; Berlin and Rudell, 1986; Gilman et al., 1998a; ATSDR, 1999). Renal injury was not observed in dogs and monkeys exposed for 5 years to inhaled dust that con- tained insoluble uranium dioxide at a uranium concentration of 5 mg/m3 (Leach et al., 1970). 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). Pathologic changes included lesions of tubular epithelial cells (apical nuclear displacement and vesiculation, cytoplasmic vacuolation, and dilation), glomeruli (capsular sclerosis), and renal interstitium (reticulin sclerosis and lymphoid cuffing). Studies of dermal and ocular absorption of uranium trioxide in rabbits indicated that uranium was suf- ficiently well absorbed to cause renal damage and even death from renal failure (Voegtlin and Hodge, 1949). Several mechanisms may account for uranium-induced renal damage. A mech- anism involving bicarbonate activity in the kidney has been postulated. Uranium combines with bicarbonate, citrate, or plasma proteins in blood. At low pH, the bicarbonate-uranyl and citrate-uranyl complexes split (Bassett et al., 1948), and the resulting uranyl ion may combine with proteins on the tubular wall and cause renal damage. A second possibility is that uranium compounds inhibit mitochondrial oxidative phosphorylation and sodium-dependent and sodium-independent adenosine triphosphate (ATP) use in renal tubules (Brady et al., 1989). Few animal and in vitro studies of renal effects of depleted uranium have been conducted since volume 1 (see Table 3-5). In one study, concentrations of n-acetyl-β-D-glucosaminidase and creatinine in rats given depleted uranium nitrate by a single intramuscular injection peaked 3 days later, and there was a high correlation between injected dose and those concentrations (Fukuda et al., 2006). Depleted-uranium concentrations in urine decreased rapidly for the first 3 days after exposure. Another study reported a decrease in glucose transport in brush-border membrane vesicles of rats given depleted uranium in the form of uranyl acetate (Goldman et al., 2006). Donnadieu-Claraz et al. (2007) exposed rats to uranium nitrate at 40 mg/L of water for up to 18 months and observed that the proximal tubular cells had more vesicles with dense granular inclusions. The granules were found to be iron oxides; uranium was not associated with them. The authors suggested that the mechanisms of iron homeostasis in the kidneys could be affected by chronic uranium exposure. Neurologic Effects The earlier animal studies considered in volume 1 indicated that uranium crosses the blood-brain barrier and deposits within the brain parenchyma. In this

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 toxiColoGY volume, several relevant in vitro studies will be discussed in addition to animal studies on neurological effects published since volume 1. Study details can be found in Table 3-6. In vitro Models to Assess Neurologic Effects Lemercier and colleagues (2003) demonstrated transfer of uranium across the blood-brain barrier in an in situ rat brain perfusion study in which brain uranium was measured with ICP-MS. They found that substantial uranium accu- mulated in the brain and that the transport was efficient and rapid, with uranium localized to the brain parenchyma as early as 2 minutes after the initial perfusion. The nature of the uranium transporter is unknown. No functional end points were assessed in the study. One of the earliest studies of the specific effects of uranium on functional end points in the nervous system focused on the presynaptic action in phrenic nerve preparations from mice. This in vitro study demonstrated that uranyl nitrate at very high concentrations (0.2-0.8 mM) facilitated the release of acetylcholine from the nerve terminals and potentiated muscle contraction (Lin et al., 1988). The cytotoxicity of depleted uranium was investigated in an in vitro model of the blood-brain barrier with rat brain endothelial cells (RBE4 cells). The cells were derived from rat brain microvascular endothelial cells immortalized with the plasmid pE1A-neo that contained the E1A region of adenovirus 2 and a neomycin-resistance gene. Cytotoxicity was evaluated with assays for cell- volume increase, heat-shock protein 90 expression, 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide (MTT) reduction, and lactate dehydrogenase (LDH) activity. The results of the assays showed that uptake of the triuranium octaoxide uranyl chloride form of depleted uranium into RBE4 cells is efficient, but no overt cytotoxicity was detected by common biomarkers (Dobson et al., 2006). In vitro studies in rat cortical neuron cultures exposed to uranyl acetate showed little cytotoxicity at concentrations below 100 µM (Jiang et al., 2007). There were no statistically significant changes in F2-isoprostanes, biomarkers of oxidative stress, or thiol metabolites. The lack of cytotoxicity was corroborated with the MTT-reduction and LDH-activity assays and the finding of only mini- mal changes in total adenosine nucleotides. Additional studies in Caenorhabditis elegans using green fluorescent protein reporter worm strains corroborated the primary neuron culture observations, showing no statistically significant neuronal degeneration after uranium exposure (Jiang et al., 2007). Although in vitro models may not recapitulate human health and disease fully, those focused studies indicate that cultured neurons can tolerate high con- centrations of uranyl acetate without important oxidative injury or death (Dobson et al., 2006; Jiang et al., 2007). The studies have examined neuronal lethality after a relatively acute exposure, but impairment of neuronal function may occur in the absence of acute lethality, and effects might arise after longer exposure. Other

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62 TABLE 3-9 Immunologic Effects Species or Cell Line Route of Exposure and Dose Frequency or Duration Outcomes Reference animal studies Sprague Dawley, male Nose-only inhalation Inflammatory cytokine expression Monleau et al., UO2: 30 minutes (190 mg/m3), acute and repeated exposure; 2 increased 2006c hours (375 mg/m3); or 3 hours UO2 at 190 ± 41 mg/m3, 375 ± 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) CCL-2 concentrations, decrease in intestinal macrophage density, increase in number of neutrophils Sprague Dawley, male Gavage Single administration DU appeared to modulate the expression Dublineau et al., and/or production of IFNγ, MCP-1 in 2006b Uranyl nitrate at 204 mg/kg Animals euthanized 1 or 3 days intestine after administration Sprague Dawley, male Ingestion in drinking water 3, 9 months DU preferentially accumulated in Peyer’s Dublineau et al., (harvested intestines) patches compared with epithelium; 2006a Uranyl nitrate at 1 mg/day per no induction of apoptosis pathway animal after chronic DU contamination in Peyer’s patches; no change in cytokine expression (Il-10, TGF-β, IFN-γ, TNF-a, MCP-1) in Peyer’s patches and mesenteric lymph nodes; no modification in uptake of yeast cells by Peyer’s patches

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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. 6

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6 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 cyp2a1 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 days after exposure concentrations and activity of CYP body weight (LD50 at 14 days) 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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Sprague Dawley, Ingestion in drinking water 91 days No significant exposure-related effect on Gilman et al., male and female hematologic, biochemical endpoints 1998c Uranyl nitrate hexahydrate at 0.96, 4.8, 24, 120, 600 mg/L (0.09-53.56 mg/kg of body weight for females; 0.06-36.73 mg/kg of body weight for males) Wistar, male Intraperitoneal injection Single dose Alveolar bone volume (15 × 105 µm2 vs Guglielmotti et 34 × 105 µm2), total bone formation areas al., 1985 Uranyl nitrate at 2 mg/kg (4.85% vs 19.55%), volume density of bone in the alveolar apical third (0.26 vs 0.40) 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. 6

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