Long-term toxicity of chlorpromazine, diclofenac and two lanthanides on three generations of Ceriodaphnia dubia.

Amultigenerational study on Ceriodaphnia dubia was carried out by exposing three subsequent generations to pharmaceuticals chlorpromazine (CPZ) and diclofenac (DCF), and two lanthanide chlorides, gadolinium as GdCl3 and europium as EuCl3. As the treatments, environmentally relevant concentrations were chosen (0.001, 0.01 and 0.1 mg/L for CPZ; 0.1, 1 and 10 mg/L for DCF; 0.425, 4.25 and 42.5 µg/L for Gd and 0.41, 4.1 and 41 µg/L for Eu). Survival, population growth and reproduction success were evaluated at 21 and 30 days of exposure, and the whole observation period lasted 40 days. The least sensitive to all selected substances was the first daphnid generation (F1). Within 21-day exposure, no significant effects of the psychotropic drug CPZ on C. dubia survival were observed in generations F1-F3. The anti-inflammatory drug DCF did not affect survival in the F1 generation; however, it significantly reduced survival in the F3 generation at 1-10 mg/L. Both lanthanides did not affect survival in the F1 and F2 generations of C. dubia but considerably decreased survival in the F3 at 4-42 µg/L. Both pharmaceuticals stimulated the reproduction of C. dubia in the F1 generation, while inhibition occurred at the highest tested concentrations in generations F2 and F3. The inhibitory effect on the reproductive success of lanthanides in the F2 generation resembled that for CPZ but not for DCF. The dynamics of adverse effects during the 21-30-day period revealed that despite increased mortality in the controls (up to 30%), concentrations used in the study minified, in most instances, the survival and aggravated population growth and reproduction success of C. dubia. Our data suggest that C. dubia as a test organism can be used for 21 days in multigenerational investigations, especially when testing close to environmental concentrations. In this respect, the standard C. dubia chronic toxicity assay seems limited since prolonged observations and several generations of daphnids are required to obtain reliable information for the risk assessment of potentially aggressive chemicals.

Assessment of the biotoxicity of lanthanides (La, Ce, Gd, and Ho) on zebrafish (Danio rerio) in different water environments.

The expanding applications of lanthanides (Ln) in various aspects have raised concerns about their biosafety. Slight changes in the chemical composition of environmental media can significantly affect the biological effectiveness of poorly water-soluble Ln; however, the knowledge of the effects of environmental factors on Ln toxicity remains limited. Here, the effects of pH, HCO3-, Ca2+, Mg2+, Na+, K+, Cl-, and SO42- on the bioefficacy and biotoxicity of Ln (La, Ce, Gd, and Ho) were comparatively studied using zebrafish (Danio rerio) as the test organism. In the standard water, the toxicity of Ln in zebrafish was significantly correlated with pH, HCO3-, and Ca2+-Mg2+ levels in the medium but not with the levels of Cl-, Na+, K+, and SO42-. At the beginning of the test, the four Ln were complexed with HCO3- in the medium to form precipitates. A decrease in pH or HCO3- concentration can promote the conversion of granular Ln to a soluble state, thus enhancing their bioavailability, biotoxicity, and bioaccumulation. At a pH of 5.0 and 0.2 mmol·L-1 HCO3-, where Ln precipitates were not found, the four Ln showed a consistent trend of 96 h-LC50 in zebrafish. These data indicate that the differences in the toxicities of the four Ln in the standard water may be due to differences in the effective states of the individual elements rather than the different toxicities of the elements. Overall, in biological toxicity assessments, Ln can be regarded as a group of elements with additive patterns of toxicity until the differences in their biological toxicity mechanisms are revealed, and the effects of pH and carbonate should be considered.

Toxicity of lanthanides on various fish cell lines.

The growing use of Lanthanides in new technologies has increased their anthropogenic releases into the aquatic environment over the last decades. However, knowledge on their ecotoxicological impacts is still incomplete, especially with regard to biological effects of Lanthanides mixtures and the possible regular variation in toxicity along the Lanthanides series. The present study evaluated the individual toxicity of all Lanthanides and the toxicity of mixtures of three of them, namely Neodymium (Nd3+), Gadolinium (Gd3+), and Ytterbium (Yb3+) on Danio rerio fibroblast-like cells (ZF4). Individual and mixtures toxicity of Neodymium (Nd3+) and Ytterbium (Yb3+) were also assessed on Danio rerio hepatic cells (ZFL) and Oncorhynchus mykiss epithelial cells (RTgill-W1). The measured Lanthanide concentrations were close to the nominal ones in the culture media of ZF4, ZFL, and RTgill-W1 cells (85-99%). A toxic impact was observed on the three fish cell lines exposed to all Lanthanides tested individually. RTgill-W1 appeared as the less sensitive cells, compared to the two others. Four Lanthanides, Erbium (Er3+), Thulium (Tm3+), Ytterbium (Yb3+) and Lutetium (Lu3+) showed a higher toxicity than the others on ZF4 cells but no correlation could be established between the toxicity of Lanthanides and the order of the elements within the Lanthanides series. Exposures to binary mixtures highlighted the presence of synergistic effects on cell viability for all cell lines.

Investigating the toxically homogenous effects of three lanthanides on zebrafish.

The adverse effects of rare earth elements (REEs) have been increasingly reported in the past decades and have raised concern about their environmental toxicities. However, the available data is insufficient to elucidate the toxic effects, mechanisms, and whether the toxicity across all REEs is uniform. In this study, zebrafish were exposed to 0, 0.8, 1.6, 3.2, 6.4, 12.8 and 25.6 mg/L Ln(NO3)3•6H2O to test the acute toxicity of La(III), Ce(III), and Nd(III). LC50 of the three lanthanides was compared to the extent of the impact on gene expression. We carried out the functionally grouped network-based transcriptome analysis using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to explore the molecular mechanisms. The acute toxicity test showed that LC50 of La(III), Ce(III), and Nd(III) were 2.53, 2.03, and 2.76 mg/L, respectively. Consistent with acute toxicity, Ce(III) caused a little more DEGs than La(III) and Nd(III). Some biological processes such as metabolism of xenobiotics, oocyte meiosis, steroid biosynthesis, DNA replication, and p53 signaling pathway were affected following exposure of all the three lanthanides. Ce(III) also induced changes in the chemokine-mediated signaling pathway. The results indicated that the lethality is comparable, and the toxic patterns are similar across the three lanthanides. This study gives comparative research on the toxicities of three lanthanides to model organism zebrafish.

Toxicity of lanthanide coagulants assessed using four in vitro bioassays.

Rare earth element (REE) coagulants are prime contenders in wastewater treatment plants to remove phosphorus; unlike typical coagulants, they are not affected by pH. However, the use of REEs in wastewater treatment could mean increased human exposure to lanthanides (Ln) through wastewater effluent discharge to the environment or through water reuse. Information on the toxicity of lanthanides is scarce and, where available, there are conflicting views. Using in vitro bioassays, we assessed lanthanide toxicity by evaluating four relevant endpoints: the change in mitochondrial membrane potential (Δψm), intracellular adenosine triphosphate (I-ATP), genotoxicity, and cell viability. At less than 5000 µmol-Ln3+/L, lanthanides increased the Δψm, while above 5000 µmol-Ln3+/L, the Δψm level plummeted. The measure of I-ATP indicated constant levels of ATP up to 250 µmol-Ln3+/L, above which the I-ATP decreased steadily; the concentration of La, Ce, Gd, and Lu that triggered half of the cells to become ATP-inactive is 794, 1505, 1488, 1115 µmol-Ln3+/L, respectively. Although La and Lu accelerated cell death in shorter studies (24 h), chronic studies using three cell growth cycles showed cell recovery. Lanthanides exhibited antagonistic toxicity at less than 1000 µmol-Ln3+/L. However, the introduction of heavy REEs in a solution amplified lanthanide toxicity. Tested lanthanides appear to pose little risk, which could pave the way for lanthanide application in wastewater treatment.

Mesoporous silica nanoparticles with manganese and lanthanide salts: synthesis, characterization and cytotoxicity studies.

Several organic salts based on the combination of two different choline derivative cations and MnCl3-, GdCl4- and TbCl4- as anions were immobilized in mesoporous silica nanoparticles (MSNs) by a two-step synthetic method. Firstly, MSNs were functionalized with choline derivative cations with chloride anions and then the metals were incorporated by the reaction of the chloride with the respective metal chloride salts. These nanomaterials were fully characterized by different characterization techniques such as 1H-NMR, FT-IR, elemental analysis, TEM, TGA, N2 adsorption, XRD and DLS. These characterization data were important to confirm the successful functionalization of the nanomaterials and to access their textural properties and colloidal stability. The final materials were also characterized by ICP-MS that indicated the metal contents. The cytotoxicity profile was evaluated in four different cell lines (3T3, 293T, HepG2 and Caco-2), which shows some relevant differences between the metal organic salts and their immobilized analogues.

Genome-wide toxicogenomic study of the lanthanides sheds light on the selective toxicity mechanisms associated with critical materials.

Lanthanides are a series of critical elements widely used in multiple industries, such as optoelectronics and healthcare. Although initially considered to be of low toxicity, concerns have emerged during the last few decades over their impact on human health. The toxicological profile of these metals, however, has been incompletely characterized, with most studies to date solely focusing on one or two elements within the group. In the current study, we assessed potential toxicity mechanisms in the lanthanide series using a functional toxicogenomics approach in baker's yeast, which shares many cellular pathways and functions with humans. We screened the homozygous deletion pool of 4,291 Saccharomyces cerevisiae strains with the lanthanides and identified both common and unique functional effects of these metals. Three very different trends were observed within the lanthanide series, where deletions of certain proteins on membranes and organelles had no effect on the cellular response to early lanthanides while inducing yeast sensitivity and resistance to middle and late lanthanides, respectively. Vesicle-mediated transport (primarily endocytosis) was highlighted by both gene ontology and pathway enrichment analyses as one of the main functions disturbed by the majority of the metals. Protein-protein network analysis indicated that yeast response to lanthanides relied on proteins that participate in regulatory paths used for calcium (and other biologically relevant cations), and lanthanide toxicity included disruption of biosynthetic pathways by enzyme inhibition. Last, multiple genes and proteins identified in the network analysis have human orthologs, suggesting that those may also be targeted by lanthanides in humans.

The effect of four lanthanides onto a rat kidney cell line (NRK-52E) is dependent on the composition of the cell culture medium.

Lanthanide (Ln) exposure poses a serious health risk to animals and humans. In this study, we investigated the effect of 10-9-10-3 M La, Ce, Eu, and Yb exposure onto the viability of rat renal NRK-52E cells in dependence on Ln concentration, exposure time, and composition of the cell culture medium. Especially, the influence of fetal bovine serum (FBS) and citrate onto Ln cytotoxicity, solubility, and speciation was investigated. For this, in vitro cell viability studies using the XTT assay and fluorescence microscopic investigations were combined with solubility and speciation studies using TRLFS and ICP-MS, respectively. The theoretical Ln speciation was predicted using thermodynamic modeling. All Ln exhibit a concentration- and time-dependent effect on NRK-52E cells. FBS is the key parameter influencing both Ln solubility and cytotoxicity. We demonstrate that FBS is able to bind Ln3+ ions, thus, promoting solubility and reducing cytotoxicity after Ln exposure for 24 and 48 h. In contrast, citrate addition to the cell culture medium has no significant effect on Ln solubility and speciation nor cytotoxicity after Ln exposure for 24 and 48 h. However, a striking increase of cell viability is observable after Ln exposure for 8 h. Out of the four Ln elements under investigation, Ce is the most effective. Results from TRLFS and solubility measurements correlate well to those from in vitro cell culture experiments. In contrast, results from thermodynamic modeling do not correlate to TRLFS results, hence, demonstrating that big gaps in the database render this method, currently, inapplicable for the prediction of Ln speciation in cell culture media. Finally, this study demonstrates the importance and the synergistic effects of combining chemical and spectroscopic methods with cell culture techniques and biological methods.

BMP-2-Loaded HAp:Ln3+ (Ln = Yb, Er, Gd) Nanorods with Dual-Mode Imaging for Efficient MC3t3-E1 Cell Differentiation Regulation.

Effective bone tissue reconstitution improves the treatment success rate of dental implantation and preserves natural teeth during periodontal tissue repair. Hydroxyapatite (HAp) has received much attention in bone remodeling field because its mineralized structure is similar to that of the natural bone tissue. For this reason, it has been used as a carrier for growth factors. Although HAp possesses outstanding biomedical properties, its capacity of loading and releasing bone growth factors and promoting osteogenesis is not well understood. In this study, Ln3+ (Ln = Yb3+, Er3+, Gd3+)-doped HAp (HAp:Ln3+) nanorods were synthesized by one-step hydrothermal method. To improve its biocompatibility and surface properties, bone morphogenetic protein-2 (BMP-2) was loaded onto the surface of HAp:Ln3+ nanorods. The results showed that BMP-2 incorporation promoted bone formation and enhanced the expression of early bone-related gene and protein (RunX2, SP7, OPN). In addition, Yb3+- and Er3+-doped HAp nanorods were examined by upconversion luminescence with 980 nm near-infrared laser irradiation to monitor the delivery position of BMP-2 protein. Furthermore, due to the positive magnetism correlated with the concentration of Gd3+, HAp:Ln3+ with enhanced contrast brightening can be deemed as T1 MIR contrast agents. These findings indicate that HAp doped with rare-earth ions and loaded with BMP-2 has the potential to promote bone tissue repair and execute dual-mode imaging.

Effect of four lanthanides onto the viability of two mammalian kidney cell lines.

Exposure to lanthanides (Ln) poses a serious health risk to animals and humans. Since Ln are mainly excreted with urine, we investigated the effect of La, Ce, Eu, and Yb exposure on renal rat NRK-52E and human HEK-293 cells for 8, 24, and 48 h in vitro. Cell viability studies using the XTT assay and microscopic investigations were combined with solubility and speciation studies using ICP-MS and TRLFS. Thermodynamic modeling was applied to predict the speciation of Ln in the cell culture medium. All Ln show a concentration- and time-dependent effect on both cell lines with Ce being the most potent element. In cell culture medium, the Ln are completely soluble and most probably complexed with proteins from fetal bovine serum. The results of this study underline the importance of combining biological, chemical, and spectroscopic methods in studying the effect of Ln on cells in vitro and may contribute to the improvement of the current risk assessment for Ln in the human body. Furthermore, they demonstrate that Ln seem to have no effect on renal cells in vitro at environmental trace concentrations. Nevertheless, especially Ce has the potential for harmful effects at elevated concentrations observed in mining and industrial areas.

Selective cellular imaging with lanthanide-based upconversion nanoparticles.

Upconversion nanoparticles (UCNPs) with sodium yttrium fluoride, NaYF4 (host lattice) doped with Yb3+ (sensitizer) and Er3+ (activator) were synthesized via hydrothermal route incorporating polyethyleneimine (PEI) for their long-term stability in water. The cationic PEI-modified UCNPs with diameter 20 ± 4 nm showed a zeta potential value of +36.5 mV and showed an intense, visible red luminescence and low-intensity green emission with 976 nm laser excitation. The particles proven to be nontoxic to endothelial cells, with a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay, showing 90% to 100% cell viability, across a wide range of UCNP concentrations (0.3 ng/mL-0.3 mg/mL) were used in multiphoton imaging. Multiphoton cellular imaging and emission spectroscopy data reported here prove that the UCNPs dispersed in cell culture media are predominantly concentrated in the cytoplasm than the cell nucleus. The energy transfer from PEI-coated UCNPs to surrounding media for red luminescence in the biological system is also highlighted with spectroscopic measurements. Results of this study propose that UCNPs can, therefore, be used for cytoplasm selective imaging together with multiphoton dyes (eg, 4',6-diamidino-2-phenylindole (DAPI)) that are selective to cell nucleus.

Evaluation of the potential hazard of lanthanides to freshwater microcrustaceans.

The use of lanthanides in different sectors of industry has significantly increased during the last decades. Although the "anthropogenic" anomalies of lanthanides in the soils, surface and ground waters have already been registered, the ecotoxicological effects of these elements and their fate in the environment are still insufficiently investigated. In this study acute and long-term toxicity of selected lanthanides (La, Ce, Pr, Nd and Gd) nitrates to freshwater crustaceans Daphnia magna, Thamnocephalus platyurus and Heterocypris incongruens were studied and critically evaluated. The data obtained show that (i) due to the methodical nuances the acute toxicity data of lanthanides are not reliable and have doubtful scientific value even for preliminary toxicity screening and thus should not be used for risk assessment; (ii) toxicity of lanthanides in the 21-day D. magna reproduction test was high whereas the mortality of parent daphnids was more sensitive endpoint than reproduction; (iii) the long-term LC50 values for lanthanides varied from 0.3 to 0.5 mg Ln/L and the differences between individual Ln were not statistically significant. All in all, the results of this study allow us to conclude that the environmental risk assessment of lanthanides should be performed only using long-term toxicity tests. In the environmental risk assessment, lanthanides may be considered as a uniform group of elements with additive mode of action until future investigations will not reveal differences in the ecotoxicity mechanisms of these elements.

Assessment of the hazard of nine (doped) lanthanides-based ceramic oxides to four aquatic species.

The risk of environmental pollution with rare earth oxides rises in line with increasing application of these compounds in different sectors. However, data on potential environmental hazard of lanthanides is scarce and concerns mostly Ce and Gd. In this work, the aquatic toxicity of eight doped lanthanide-based ceramic oxides (Ce0.9Gd0.1O2, LaFeO3, Gd0.97CoO3, LaCoO3, (La0.5Sr0.5)0.99MnO3, Ce0.8Pr0.2O2, (La0.6Sr0.4)0.95CoO3, LaNiO4) and one non-doped oxide (CeO2) with primary size from 23 to 590nm were evaluated in four short-term laboratory assays with freshwater crustaceans and duckweeds. Results showed no acute toxicity (EC50>100mg/L) or very low acute toxicity for most studied oxides. Observed toxicity was probably due to bioavailable fraction of dopant metals (Ni and Co) but in the case of aquatic plants, decrease of nutrient availability (complexing of phosphorus by lanthanides) was also presumed. Studied oxides/metals accumulated in the aquatic plant tissue and in the gut of crustaceans and thus may be further transferred via the aquatic food chain. Accumulation of metals in the duckweed Lemna minor may be recommended as a cost-effective screening bioassay for assessment of potential hazard of poorly soluble oxides to aquatic ecosystems.

Perspectives and challenges of photon-upconversion nanoparticles - Part II: bioanalytical applications.

In Part II of this review series on lanthanide-doped photon-upconversion nanoparticles (UCNPs), we present and critically discuss the performance and suitability of UCNPs as background-free luminescent reporters in bioimaging and bioanalytical applications. The preparation of a biocompatible nanoparticle surface is an integral step for all life - science-related applications. UCNPs have found their way into a large number of diagnostic platforms, homogeneous and heterogeneous assay formats, and sensor applications. Many bioanalytical detection schemes involve Förster resonance energy transfer (FRET), which is still debated for UCNPs and needs to be much improved. The need for dedicated and standardized instruments as well as recent studies on the dissolution and potential toxicity of UCNPs are addressed. Finally we outline future trends and challenges in the field of upconversion. Graphical Abstract Both synthesis / spectroscopy as well bioanalytical applications of UCNPs are driven by the COST Action CM1403 "The European Upconversion Network".

Characteristics of water and ion exchange of Elodea nuttallii cells at high concentrations of lanthanides.

Changes of diffusive permeability of membranes of Elodea nuttallii cells following a short-term (60 min) treatment with high concentrations of lanthanides were recorded by the 1H NMR-diffusometry and conductometry methods. The 1-h infiltration of segments of Elodea nuttallii internodes in 10 mM solutions of nitrates of La, Nd and Lu resulted in the increased leakage of electrolytes from cells, but has no effect on a water diffusive permeability of membranes. In samples subjected to a 30 min pretreatment with a water channel inhibitor HgCl2 the water diffusive permeability of membranes (Pd) drops down under the influence of lanthanides, as well as an outcome of electrolytes. To explain the observed effects the change of spontaneous curvature of membrane lipid layer has been taken into consideration. The interaction of lanthanides with lipids of plasmalemma leads to the negative spontaneous curvature of lipid layer at which membrane channels are unclosed. Blocking of the ionic and water channels by mercury ions compensate the effect of change of spontaneous curvature of lipid layer.

Interaction between lanthanide ions and Saccharomyces cerevisiae cells.

Lanthanides are a group of non-essential elements with important imaging and therapeutic applications. Although trivalent lanthanide ions (Ln³âº) are used as potent blockers of Ca²âº channels, the systematic studies correlating Ln³âº accumulation and toxicity to Ca²âº channel blocking activity are scarce. In this study, we made use of the eukaryotic model Saccharomyces cerevisiae to investigate the correlation between Ln³âº accumulation, their toxicity and their capacity to block the exogenous stress-induced Ca²âº influx into the cytosol. It was found that the Ln³âº blocked the Ca²âº entry into the yeast cells only when present at concentration high enough to allow rapid binding to cell surface. At lower concentrations, Ln³âº were taken up by the cell, but Ca²âº blockage was no longer achieved. At 1 mM concentration, all ions from the Ln³âº series could block Ca²âº entry into cytosol with the exception of La³âº, and to a lesser extent, Pr³âº and Nd³âº. The plasma membrane Ca²âº-channel Cch1/Mid1 contributed to La³âº and Gd³âº entry into the cells, with a significant preference for La³âº. The results open the possibility to obtain cells loaded with controlled amounts and ratios of Ln³âº.

Lanthanide ecotoxicity: first attempt to measure environmental risk for aquatic organisms.

The geochemical cycles of lanthanides are being disrupted by increasing global production and human use, but their ecotoxicity is not fully characterized. In this study, the sensitivity of Aliivibrio fischeri and Pseudokirchneriella subcapitata to lanthanides increased with atomic number, while Daphnia magna, Heterocypris incongruens, Brachionus calyciflorus and Hydra attenuata were equally sensitive to the tested elements. In some cases, a marked decrease in exposure concentrations was observed over test duration and duly considered in calculating effect concentrations and predicted no effect concentrations (PNEC) for hazard and risk assessment. Comparison of PNEC with measured environmental concentrations indicate that, for the present, environmental risks deriving from lanthanides should be limited to some hotspots (e.g., downstream of wastewater treatment plants). However, considering the increasing environmental concentrations of lanthanides, the associated risks could become higher in the future. Ecotoxicological and risk assessment studies, along with monitoring, are required for properly managing these emerging contaminants.

Hydrophobic sodium fluoride-based nanocrystals doped with lanthanide ions: assessment of in vitro toxicity to human blood lymphocytes and phagocytes.

In vitro immunotoxicity of hydrophobic sodium fluoride-based nanocrystals (NCs) doped with lanthanide ions was examined in this study. Although there is already a significant amount of optical and structural data on NaYF4 NCs, data on safety assessment are missing. Therefore, peripheral whole blood from human volunteers was used to evaluate the effect of 25 and 30 nm hydrophobic NaYF4 NCs dissolved in cyclohexane (CH) on lymphocytes, and of 10 nm NaYF4 NCs on phagocytes. In the concentration range 0.12-75 µg cm(-2) (0.17-106 µg ml(-1) ), both 25 and 30nm NaYF4 NCs did not induce cytotoxicity when measured as incorporation of [(3) H]-thymidine into DNA. Assessment of lymphocyte function showed significant suppression of the proliferative activity of T-lymphocytes and T-dependent B-cell response in peripheral blood cultures (n = 7) stimulated in vitro with mitogens phytohemagglutinin (PHA) and pokeweed (PWM) (PHA > PWM). No clear dose-response effect was observed. Phagocytic activity and respiratory burst of leukocytes (n = 5-8) were generally less affected. A dose-dependent suppression of phagocytic activity of granulocytes in cultures treated with 25 nm NCs was observed (vs. medium control). A decrease in phagocytic activity of monocytes was found in cells exposed to higher doses of 10 and 30 nm NCs. The respiratory burst of phagocytes was significantly decreased by exposure to the middle dose of 30 nm NCs only. In conclusion, our results demonstrate immunotoxic effects of hydrophobic NaYF4 NCs doped with lanthanide ions to lymphocytes and to lesser extent to phagocytes. Further research needs to be done, particularly faze transfer of hydrophobic NCs to hydrophilic ones, to eliminate the solvent effect.

Environmental fate and ecotoxicity of lanthanides: are they a uniform group beyond chemistry?

Lanthanides are a chemically uniform group of metals (La-Lu) that, together with yttrium (Y) and scandium (Sc), form the group of rare earth elements (REEs). Because of their many applications (e.g., agriculture, medicine, motor industry), their global production has increased exponentially in the last decades and their biogeochemical cycles are being disrupted by human uses (e.g., gadolinium anomalies in freshwater and tap water, REEs enrichment of soils as a consequence of agricultural practices). However, ecotoxicological effects and mechanism of action of these elements are still poorly understood. In particular, there is no consensus as to lanthanides showing a coherent and predictable pattern of (eco)toxicity in the same way as their atomic properties. For aquatic organisms, contradictory conclusions on this issue can be found in the bibliography. This review shows that the variable composition of culture media used in ecotoxicology, and the associated differences in lanthanide's speciation, are the most likely cause for such discrepancies. In particular, the formation of insoluble species in some highly complexing media likely leads to changes in the soluble concentration of lanthanide during some tests; with the potential for a generalized underestimation of their toxicity at the present state of knowledge. For terrestrial organisms, suitable studies to establish trends in lanthanides' toxicity are practically nonexistent; with most research focusing on the effects of REE mixtures. Molecular level studies to elucidate the mechanisms of action of lanthanides are essentially limited to La, pointing to the need for further research to identify common mechanisms of action or modes of action across lanthanides. Overall, agreement on the correct procedures to follow to obtain reliable and comparable data for individual lanthanide is the first action to take in order to arrive at a reliable risk assessment for this group of elements in both aquatic and terrestrial systems.

Immune dysfunction and liver damage of mice following exposure to lanthanoids.

In an effort to investigate the effects of exposure to lanthanoids (Ln) on the immune response and liver function, mice were orally exposed to LaCl3 , CeCl3 , and NdCl3 at 2, 10, and 20 mg/kg doses for 30 days, respectively; lymphocyte counts, serum IgM level, hematological indices, biochemical parameters of liver functions, and histopathological changes in Ln(3+) -treated mice were assessed. Indeed, 20 mg/kg Ln(3+) significantly inhibited mice growth and reduced the counts of white blood cells, platelets, and reticulocyte in mice blood. Specifically, in these Ln(3+) -treated mice, CD3+, CD4+, CD8+, CD19+ and NK cells, and CD4+/CD8+ ratio as well as serum IgM level were decreased. Furthermore, liver function was disrupted, as evidenced by the increased alanine aminotransferase, total bilirubin, total bile acid and triglycerides, and the decreased glucose and ratio of albumin to globulin. The cytoarchitecture damage and fatty degeneration in liver caused by Ln(3+) at 20 mg/kg dose were also observed. Our findings showed that exposure to Ln affected the cell and humoral immunity and disturbed liver function in mice. In addition, Ce(3+) was found to exhibit higher toxicity than La(3+) and Nd(3+).