Distribution, Elimination, and Biopersistence to 90 Days of a Systemically Introduced 30 nm Ceria-Engineered Nanomaterial in Rats

Abstract

Nanoceria is used as a catalyst in diesel fuel, as an abrasive in printed circuit manufacture, and is being pursued as an antioxidant therapeutic. Our objective is to extend previous findings showing that there were no reductions of cerium in organs of the mononuclear phagocyte (reticuloendothelial) system up to 30 days after a single nanoscale ceria administration. An ~5% aqueous dispersion of citrate-stabilized 30 nm ceria, synthesized and characterized in-house, or vehicle, was iv infused into rats terminated 1, 7, 30, or 90 days later. Cageside observations were obtained daily, body weight weekly. Daily urinary and fecal cerium outputs were quantified for 2 weeks. Nine organs were weighed and samples collected from 14 tissues/organs/systems, blood and cerebrospinal fluid for cerium determination. Histology and oxidative stress were assessed. Less than 1% of the nanoceria was excreted in the first 2 weeks, 98% in feces. Body weight gain was initially impaired. Spleen weight was significantly increased in some ceria-treated groups, associated with abnormalities. Ceria was primarily retained in the spleen, liver, and bone marrow. There was little decrease of ceria in any tissue over the 90 days. Granulomas were observed in the liver. Time-dependent oxidative stress changes were seen in the liver and spleen. Nanoscale ceria was persistently retained by organs of the mononuclear phagocyte system, associated with adverse changes. The results support concern about the long-term fate and adverse effects of inert nanoscale metal oxides that distribute throughout the body, are persistently retained, and produce adverse changes.

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

“…Values listed under blots represent relative ratios of p-DRP1 S616 to total DRP1 protein normalized to actin nanoparticles to cross the BBB strikingly increased after injury (resulting in increased ROS/RNS). 57,58 By contrast, another study reported very small (2.9 nm diameter), citrate/ EDTA-stabilized CeO 2 nanoparticles administered intravenously to healthy rats appeared to cross the intact BBB, 56 suggesting that particle modifications might help improve neuronal delivery. In sum, considering the variability in findings to date, efficient delivery of nanoceria to neurons remains an important issue requiring further research and investigation.…”

“…[56][57][58] In two of these studies, CeO 2 nanoparticles were administered intravenously and the concentration of nanoparticles was very low in the normal brain. 57,58 The study by Kim et al 57 used nanoceria that were surface modified with an artificial polymer phospholipid-polyethylene glycol, which is often added to nanoparticles to improve uptake and biodistribution, 59 yet these particles were also found only in low amounts in brain tissue. However, the ability of (a) Western blots of p-DRP1 S616, total DRP1 and actin protein levels from neurons exposed for 3 h to aged SNOC (100 mM), nanoceria (100 nM; 3 h pretreatment) or fresh SNOC (100 mM) alone or a combination of nanoceria (100 nM) and fresh SNOC (100 mM).…”

Frameworks and tools for risk assessment of manufactured nanomaterials

“…Advanced REACH Tool (ART) (Fransman et al, 2009) Occupational exposure assessment (Gorman et al, 2012) Occupational/consumer exposure assessment (Gottschalk et al, 2010a, 2010b, Sun et al, 2014, Gottschalk et al, 2009, Gottschalk et al, 2011 (Yokel et al, 2009, Yokel et al, 2012, Hardas et al, 2010, Dan et al, 2011 In vivoIkinetic tools for human exposure and hazard assessment (Lammel et al, 2013, Lammel andNavas, 2014) In vitro and in vivo tools for human hazard assessment…”

“…In order to fill this gap, several projects have developed and/or applied in vivo kinetic protocols. For instance, the U.S. STAR project developed methods to determine the distribution, persistence, translocation on and biotransformation of metal oxide MNs, their tolerability, and effects, focusing on oxidative stress endpoints (Yokel et al, 2009, Yokel et al, 2012, Hardas et al, 2010. This tool is an in vivo protocol including comprehensive physicochemical characterization for properties such as size, shape, zeta potential, extent of surface coating, and solubility.…”

“…This tool is an in vivo protocol including comprehensive physicochemical characterization for properties such as size, shape, zeta potential, extent of surface coating, and solubility. It includes investigation of multiple oxidative stress and inflammatory markers (Yokel et al, 2009, Yokel et al, 2012, Dan et al, 2011. Moreover, the EU-funded SUN project adapted and applied the Short-term Inhalation Studies (STIS) protocol developed in the NANOSAFE2 and NANOCARE projects (Klein et al, 2012).…”