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Source document:
SCHER (2010)

Summary & Details:
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Depleted Uranium

5. What other effects can depleted uranium have on human health?

The SCHER Opinion states

Since all isotopes of an element have the same chemical properties, they also have an identical chemical toxicity; therefore, the chemical toxicity of DU is identical to that of natural U. Thus, the toxicity data on natural U can be applied to assess potential human health risks from DU exposures. Since DU has a much lower radioactivity as compared to natural U and U-containing ores, it is generally agreed that the chemical toxicity of U is the major hazard descriptor regarding assessment of health risk due to potential exposures to DU. The higher radioactivity may result in a higher toxic potency of natural U as compared to that of DU regarding potential radiation-mediated effects (ATSDR, 1999; Bleise et al., 2003; Konietzka et al., 2005; McDiarmid, 2001; WHO, 2001, 2003b). This was confirmed by the observation that chromosomal damage from U is more pronounced then that of DU when applying identical concentrations to cultured cells (Miller et al., 2002b)

Depending on the solubility of the U salt administered, systemic absorption of U from the gastrointestinal tracts is from 0.02 to 6 %. Respirable U particles in air may be deposited in the respiratory tract. Approximately 95% of inhaled particles with aerodynamic equivalent diameter (AED) larger than 10 micrometers deposit in the upper respiratory tract, most of these clear to the pharynx and thus to the GI tract. Particles <10 micrometers can reach deeper pulmonary regions (bronchioles and alveoli) and stay there for considerable time (Bleise et al., 2003). The extent of systemic availability of U particles inhaled also depends on particle characteristics such as specific surface area (Chazel et al., 1998), elemental composition, and U oxidation states.

Most (> 98 %) of the U introduced into the gastrointestinal tract is excreted with faeces (Leggett and Harrison, 1995; Tracy et al., 1992). Absorbed U is distributed to the bone and to the kidney and accumulates there. Elimination half-lives for U from the different compartments in the organism vary widely with a half-life of up to 6 days for renal excretion and predicted half-lives of up to 500 days for elimination from bone (ATSDR, 1999; WHO, 2001, 2003b).

The toxicity of U is comparatively well studied. Toxicity of U salts is highly depending on solubility in water and tissues; many U oxides are of low solubility and thus also have a low potential for toxicity. As with other heavy metals, the major target organ for the toxicity of soluble U salts is the kidney. Long-term administration of U causes damage to the glomeruli and the proximal tubuli (Gilman et al., 1998a; Gilman et al., 1998b; Gilman et al., 1998c; McDonald-Taylor et al., 1992; McDonald-Taylor et al., 1997) with Lowest-Observed-Effect-Levels (LOAELs) of 0.06 mg/kg bw/day (Table 3). High concentrations of natural U given to mice during pregnancy have shown decreased fertility, toxicity to the fetus, some neurobehavioral effects, and an increased incidence of developmental variations with an overall LOAEL of 2.8 mg/kg bw/day (Albina et al., 2005; Arfsten et al., 2009; Belles et al., 2005; Domingo, 2001). As many other metals (Figgitt et al., 2010; Tsaousi et al., 2010), both U and DU have been reported to cause genotoxic effects in short term in vitro test often applied to assess genotoxicity (ATSDR, 1999; Coryell and Stearns, 2006; Hartsock et al., 2007; Knobel et al., 2006; Miller et al., 2005; Miller et al., 2004; Miller et al., 2001; Miller et al., 2002a; Wise et al., 2007; Xie et al., 2010). However, the positive in vitro tests with U are not predictive of carcinogenicity in vivo since carcinogenic effects have not been observed in animals ingesting soluble or insoluble U compounds (ATSDR, 1999). There is also no evidence for a carcinogenicity of natural U from studies of workers in U mines. The higher cancer incidence in these cohorts is likely due to inhalation exposure to radon and its decay products and not due to U particle inhalation (ATSDR, 1999; Harley, 2001; Kreuzer et al., 2009; NRC, 1991). Both in rodents and in rabbits, repeated administration of U with drinking water gave No- Observed-Adverse-Effect-Levels (NOAELs) or LOAELs of 60 μg/kg bw per day based on subtle histopathological changes in the kidney (Table 3). These NOAELs/LOAELs have been transformed in tolerable daily intakes for natural U with an uncertainty factor of 100 to give a Tolerable-Daily-Intake (TDI) of 0.6 μg/kg bw per day. Some studies also suggest small functional changes in the kidney when humans are exposed to high (natural) U doses with drinking water at doses of 20 to 200 μg U/day (ATSDR, 1999; Zamora et al., 1998; Zamora et al., 2009). Since DU shows an identical toxicity as natural U, the TDI for natural U is also applicable to DU.

Table 3. Assessment of the chemical toxicity of U. TDI, tolerable daily intake; LOAEL, Lowest observed adverse effect level; NOAEL, No observed adverse effect level; WHO, World Health Organisation; UBA, Umweltbundesamt (Germany); BfR, Bundesinstitut für Riskikobewertung (Germany)

Agency Data base for derivation L/NOAEL [µg/kg x d] TDI [µg/kg x d]
(WHO, 1998) rats 60; LOAEL 0.60
(EPA, 2000) rats 60; LOAEL 0.60
(UBA, 2000) rabbits < 60; NOAEL < 0.60
(WHO, 2003a) rats 60; LOAEL 0.60
(BfR, 2004) rats 60; LOAEL 0.60
(UBA, 2004) Rat and human data 50; NOAEL 0.2

A large number of recent studies have specifically addressed DU toxicity (Arnault et al., 2008; Berradi et al., 2008; Briner and Murray, 2005; Bussy et al., 2006; Coryell and Stearns, 2006; Dublineau et al., 2007; Feugier et al., 2008; Fukuda et al., 2006; Goldman et al., 2006; Grignard et al., 2008; Gueguen et al., 2007; Gueguen et al., 2006; Hahn et al., 2002; Hartsock et al., 2007; Hu and Zhu, 1990; Kalinich et al., 2002; Kundt et al., 2009; Kurttio et al., 2005; Lestaevel et al., 2005; Lestaevel et al., 2009; Miller et al., 2002a; Monleau et al., 2006a; Monleau et al., 2006b; Monleau et al., 2006c; Periyakaruppan et al., 2007; Periyakaruppan et al., 2009; Pourahmad et al., 2006; Racine et al., 2009; Souidi et al., 2005; Stearns et al., 2005; Thiebault et al., 2007; Tissandie et al., 2007; Tissandie et al., 2006; Wan et al., 2006; Wise et al., 2007; Xie et al., 2010; Zhu et al., 2009). Many studies confirm that DU toxicity is identical to that of U. Some of the other studies have focused on U and DU effects after administration of single or repeated high doses, used a short time frame of observation, or focused on selected biochemical changes without characterizing functional or pathologic consequences. Other studies used inappropriate routes of administration such as intraperitoneal injection. Studies useful for risk assessment should apply the chemical of interest by a route of exposure relevant to humans for a significant part of the life-span of an experimental animal such as the studies used to derive the tolerable intakes. Therefore, all these studies do not add new relevant information to be used in risk assessment of human exposures to U and DU.

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