Effect of the dose on the toxicokinetics of a quaternary mixture of rare earth elements administered to rats.

Large human biomonitoring studies are starting to assess exposure to rare earth elements (REEs). Yet, there is a paucity of data on the toxicokinetics of these substances to help interpret biomonitoring data. The objective of the study was to document the effect of the administered dose on the toxicokinetics of REEs. Male Sprague-Dawley rats were injected intravenously with 0.3, 1 or 10 mg/kg body weight (bw) of praseodynium chloride (PrCl3), cerium chloride (CeCl3), neodymium chloride (NdCl3) and yttrium chloride (YCl3) administered together as a mixture. Serial blood samples were withdrawn up to 72 h following injection, and urine and feces were collected at predefined time intervals up to 7 days post-dosing. The REEs were measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). For a given REE dose, the time courses in blood, urine and feces were similar for all four REEs. However, the REE dose administered significantly impacted their kinetics, as lower cumulative excretion in urine and feces was associated with higher REE doses. The fraction of REE remaining in rat tissues at the terminal necropsy on post-dosing day 7 also increased with the dose administered, most notably in the lungs and spleen at the 10 mg/kg bw dose. The toxicokinetic parameters calculated from the blood concentration-time profiles further showed significant increases in the mean residence time (MRTIV) for all four REEs at the 10 mg/kg bw dose. The shift in the REE kinetics at high dose may be explained by a higher retention in lysosomes, the main organelle responsible for accumulation of these REEs in different tissues.

Behavioral deficits and neural damage of Caenorhabditis elegans induced by three rare earth elements.

Rare earth elements (REEs) are widely used in industry, agriculture, medicine and daily life in recent years. However, environmental and health risks of REEs are still poorly understood. In this study, neurotoxicity of trichloride neodymium, praseodymium and scandium were evaluated using nematode Caenorhabditis elegans as the assay system. Median lethal concentrations (48 h) were 99.9, 157.2 and 106.4 mg/L for NdCl3, PrCl3 and ScCl3, respectively. Sublethal dose (10-30 mg/L) of these trichloride salts significantly inhibited body length of nematodes. Three REEs resulted in significant declines in locomotor frequency of body bending, head thrashing and pharyngeal pumping. In addition, mean speed and wavelength of crawling movement were significantly reduced after chronic exposure. Using transgenic nematodes, we found NdCl3, PrCl3 and ScCl3 resulted in loss of dendrite and soma of neurons, and induced down-expression of dat-1::GFP and unc-47::GFP. It indicates that REEs can lead to damage of dopaminergic and GABAergic neurons. Our data suggest that exposure to REEs may cause neurotoxicity of inducing behavioral deficits and neural damage. These findings provide useful information for understanding health risk of REE materials.

Molecular distribution and toxicity assessment of praseodymium by Spirodela polyrrhiza.

Aquatic macrophytes are known to accumulate and bioconcentrate metals. In this study, the physiological, biochemical, and ultrastructural responses of Spirodela polyrrhiza to elevated concentrations of praseodymium (Pr), ranging from 0 to 60µM, were investigated over 20 d exposure. The results showed that the accumulation of Pr in S. polyrrhiza occurred in a concentration-dependent manner. The accumulation of Pr in biomacromolecules decreased in the order of cellulose and pectin (65-69%), crude proteins (18-25%), crude polysaccharides (6-10%), crude lipids (3%-4%). Significant increases in malondialdehyde (MDA), and decreases in photosynthetic pigment, soluble protein, and unsaturated fatty acids showed that Pr induced oxidative stress. Inhibitory effects on photosystem II and the degradation of the reaction center proteins D1 and D2 were revealed by chlorophyll a fluorescence transients, immunoblotting, and damage to chloroplast ultrastructure. Significant increases in cell death were observed in Pr-treated plants. However, S. polyrrhiza can combat Pr induced oxidative injury by activating various enzymatic and non-enzymatic antioxidants. These results will improve understanding of the biological consequences of rare earth elements (REEs) contamination, particularly in aquatic bodies.

[Studies on effects of yttrium chloride and praseodymium chloride on frequency of micronucleus in human blood lymphocytes].

OBJECTIVE: To explore genotoxicity of rare-earth elements, yttrium and praseodymium. METHODS: Effects of yttrium chloride and praseodymium chloride on human lymphocytes cultured in vitro were studied by micronucleus test. RESULTS: Frequency of micronucleus in human blood lymphocytes increased significantly by treatment with yttrium chloride and praseodymium chloride, and it increased with the concentration of the both agents, to a certain range. CONCLUSION: It suggests that rare-earth elements yttrium and praseodymium have certain genotoxicity.

Clastogenicity of lanthanides: induction of chromosomal aberration in bone marrow cells of mice in vivo.

Clastogenic properties of two lanthanide elements praseodymium (Pr) and neodymium (Nd) were evaluated by employing mouse in vivo chromosomal aberrations (CAs) assay. Praseodymium oxide (Pr6O11) and neodymium oxide (Nd2O3) administered intraperitoneally to Swiss albino mice in vivo induced significant increase in the frequency of CAs in bone marrow cells, when compared to negative control. The number of CAs/cell and percent aberrant cells increased with an increase in the concentration and period of treatment. The effect was maximum when the cells were analysed 12 h after treatment, as compared to 6 and 24 h. This is the first report on the clastogenicity of these elements in mouse in vivo.

Clastogenicity of lanthanides--induction of micronuclei in root tips of Vicia faba.

The clastogenic property of two lanthanides, Praseodymium and Neodymium, was evaluated by scoring the frequencies of micronucleated cells in the interphase and chromosome/chromatid aberrations at ana-telophases in root tips of Vicia faba L. The significant increase in the frequency of micronucleated cells coupled with the increase in the frequency of chromosome/chromatid bridges and lagging chromosomes/chromatids suggest that these two are clastogenic for Vicia faba root cells.

Protective activity of silipide on liver damage in rodents.

The activity of silipide, a silybin-phosphatidylcholine complex (IdB 1016), was tested in different models of liver damage in rodents. After oral administration, silipide exhibited a significant and dose-related protective effect against the hepatotoxicity induced by CCl4, praseodymium, ethanol and galactosamine. The ED50 values for inhibition of the rise in ASAT and ALAT levels caused by CCl4 and praseodymium and for antagonism of the increase in liver triglycerides caused by ethanol ranged from 93 to 156 mg/kg (as silybin). At a dose of 400 mg/kg (as silybin), silipide was also active in protecting against paracetamol-induced hepatotoxicity. Silybin and phosphatidylcholine at doses equivalent to those contained in the active doses of silipide failed to show any significant protective activity in these models. The liver protective effect of silipide is probably related to its antioxidant activities and to a stimulating effect on the hepatic synthesis of RNA and proteins.

Erythrocyte alterations in praseodymium-induced lecithin:cholesterol acyltransferase (LCAT) deficiency in the rat: comparison with familial LCAT deficiency in man.

The intravenous administration of praseodymium nitrate (PrN) to rats was associated with parallel decreases in plasma lecithin: cholesterol acyltransferase (LCAT) activity and erythrocyte osmotic fragility at low doses (20 and 40 mg/kg) while higher doses (80 mg/kg) resulted in increases in both. Erythrocyte membranes from rats with PrN-induced LCAT deficiency exhibited small increases in cholesterol content, but not other alterations (e.g., in phospholipid profiles and sulfhydryl group latency) which characterize erythrocytes in familial LCAT deficiency in man. The administration of PrN caused a time- and dose-dependent accumulation of praseodymium in liver with hepatic levels being substantially greater in animals given the high (protective) as compared with the low (toxic) doses of PrN. Hepatic levels of glutathione were not altered by PrN administration, but hexobarbital sleeping time was markedly prolonged in animals receiving a toxic dose of PrN. It is suggested that dose-dependent alterations in the subcellular distribution of praseodymium may explain the paradoxical pathophysiological effects of high and low doses of PrN.

The influence of silybin on the hepatotoxic and hypoglycemic effects of praseodymium and other lanthanides.

In rats, i.v. administration of praseodymium, cerium and lanthanum (3 to 14 mg/kg) produced a dose-dependent increase in the serum activities of GOT, GPT and SDH. These dose-response curves of serum enzyme activities were shifted to the right by simultaneous treatment with silybin (75 mg/kg i.p.). Silybin also attenuated the increase of bromosulphthaleine retention and prevented the accumulation of liver triglycerides induced by praseodymium (7 mg/kg i.v.). Furthermore, silybin reduced the mortality rate of rats treated with high doses of the lanthanides. Rats treated with praseodymium (7 mg/kg i.v.) developed a pronounced hypoglycemia. On the 3rd day after praseodymium injection liver glycogen decreased to 4%, liver glutathione (GSH) to 82%, hepatic microsomal cytochrome P-450 content to 53%, aniline hydroxylase activity to 58% and aminophenazone demethylase activity to 40% of the control values. Silybin prevented praseodymium-induced hypoglycemia completely and the changes in the biochemical parameters of liver function partially but did not influence the decrease of liver GSH.

Lanthanon-induced hepatotoxicity and its prevention by pretreatment with the same lanthanon.

Intravenous injection of the light lanthanon praseodymium nitrate (10 mg/kg) into rats causes a marked liver toxicity which becomes manifest in hypoglycemia, inhibition of RNA and protein synthesis and accumulation of fat in liver tissue. All these effects can be nearly abolished by pretreating rats with a small dose (5 mg/kg) of the same lanthanon. This is neither due to a decreased uptake into the liver nor to an increased excretion rate of the lanthanon. It is assumed that the pretreatment may increase unspecific binding sites or reversibly block them, thus protecting the organism from the irreversible lethal effect.

Effect of praseodymium nitrate on hepatocytes and Kupffer cells in the rat.

Intravenous administration of the rare earth metal salt, praseodymium nitrate, induced hepatic damage in the rat, as assessed by morphologic examination (light and electron microscopy) and biochemical parameters (serum glutamic-pyruvic transaminase (EC 2.6.1.2) and glutamic-oxalacetic transaminase (EC 2.6.1.1) activity as well as hepatic triglyceride content). Praseodymium hepatotoxicity was only attained with lower doses (10, 20, or 40 mg/kg), whereas a larger dose (80 mg/kg) was inactive in this respect. As detected by electron microscopy, lower doses of the metal salt caused hepatocytic alterations consisting of degranulation and dilatation of rough endoplasmic reticulum, accumulation of smooth endoplasmic reticulum as well as numerous lipid droplets. No abnormalities were detected in the cell organelles following administration of a large dose of the metal salt; however, vacuoles containing markedly electron-dense material were seen in the cytoplasm of the hepatocytes and the sinusoidal Kupffer cells.