The yin: an adverse health perspective of nanoceria: uptake, distribution, accumulation, and mechanisms of its toxicity

Abstract

This critical review evolved from a SNO Special Workshop on Nanoceria panel presentation addressing the toxicological risks of nanoceria: accumulation, target organs, and issues of clearance; how exposure dose/concentration, exposure route, and experimental preparation/model influence the different reported effects of nanoceria; and how can safer by design concepts be applied to nanoceria? It focuses on the most relevant routes of human nanoceria exposure and uptake, disposition, persistence, and resultant adverse effects. The pulmonary, oral, dermal, and topical ocular exposure routes are addressed as well as the intravenous route, as the latter provides a reference for the pharmacokinetic fate of nanoceria once introduced into blood. Nanoceria reaching the blood is primarily distributed to mononuclear phagocytic system organs. Available data suggest nanoceria’s distribution is not greatly affected by dose, shape, or dosing schedule. Significant attention has been paid to the inhalation exposure route. Nanoceria distribution from the lung to the rest of the body is less than 1% of the deposited dose, and from the gastrointestinal tract even less. Intracellular nanoceria and organ burdens persist for at least months, suggesting very slow clearance rates. The acute toxicity of nanoceria is very low. However, large/accumulated doses produce granuloma in the lung and liver, and fibrosis in the lung. Toxicity, including genotoxicity, increases with exposure time; the effects disappear slowly, possibly due to nanoceria’s biopersistence. Nanoceria may exert toxicity through oxidative stress. Adverse effects seen at sites distal to exposure may be due to nanoceria translocation or released biomolecules. An example is elevated oxidative stress indicators in the brain, in the absence of appreciable brain nanoceria. Nanoceria may change its nature in biological environments and cause changes in biological molecules. Increased toxicity has been related to greater surface Ce3+, which becomes more relevant as particle size decreases and the ratio of surface area to volume increases. Given its biopersistence and resulting increased toxicity with time, there is a risk that long-term exposure to low nanoceria levels may eventually lead to adverse health effects. This critical review provides recommendations for research to resolve some of the many unknowns of nanoceria’s fate and adverse effects.

Toxicity and Protective Effects of Cerium Oxide Nanoparticles (Nanoceria) Depending on Their Preparation Method, Particle Size, Cell Type, and Exposure Route

“…[28,29] In the case of nanoceria, a larger ratio of surface area to volume leads to a larger surface Ce 3+ /Ce 4+ ratio, which could be related to a higher toxicity for smaller ceria NPs. [6] However, this is not always applicable for all ceria materials. In fact, a study demonstrated that larger ceria particles can have a higher toxicity towards eukaryotic cells.…”

“…[50] These different reports demonstrated various protective as well as toxic effects for nanoceria, as already pointed out in other reviews on other nanomaterials as well. [6,28,32,51] Furthermore, the combination of materials, for example the use of nanoceria with other particles such as those in diesel exhaust, may increase their toxicity [52] and render the biosafety of nanoceria more challenging to determine. Table 1 lists representative examples of all reported effects of nanoceria materials according to their preparation method, size, and the tested organism.…”

“…However, as noted in most of these reviews, toxicity tests are often hardly reproducible among different research groups. For example, the size of NPs, [4] their surface properties, [5] the type of cells, [4] and the exposure method [6] all influence the outcome of studies on their toxicity in such a way that it may lead to different results. On the other hand, the increased use of NPs and nanoparticulate materials as well as their potential in various applications render the study of their toxicity highly essential.…”

Environmental release, fate and ecotoxicological effects of manufactured ceria nanomaterials

“…Of critical importance are the redox properties of ceria which enables it to transition between Ce (III) and Ce (IV), which are the key to understanding its potential toxicity. 7 While there has been somewhat extensive investigation into the mammalian toxicity of ceria (as well as it's therapeutic uses), 8 based on the present review, there has been considerably less effort invested into investigation of the environmental fate and effects of nanoceria. In this critical review, we discuss the likely points of environmental release along product life-cycles and resulting environmental exposure to nanoceria, methods of detection in the environment, fate and transport, as well as the available toxicity literature for ecological receptor species.…”

Magneto-acoustic Interfacial Reaction-Based Nanoparticle Synthesis: A Direct Path to Manufacturing Metal Matrix Nanocomposites

“…A more chemically flexible nanoparticle production approach is mechanical attrition of a bulk material into small particles in a ''top down'' approach [6] like rotary mills, but this process has inherent limitations with regard to input material. If insoluble particles are formed in situ within a fluid, the airborne release of particles is minimized, lessening the risk of environmental contamination [7][8][9][10] and respiratory distress, [11] while concurrently inhibiting agglomeration. The addition of cavitation to in situ approaches can enhance particle formation and enhance the wettability of particles.…”