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.
