Pulmonary toxicity of well-dispersed cerium oxide nanoparticles following intratracheal instillation and inhalation.

Yasuo Morimoto,Shinichi Kitajima,Manabu Shimada,Kazuhiro Yamamoto,Toshihiko Myojo,Kazuhiro Yatera,Kenji Kawaguchi,Takako Oyabu,Takeshi Sasaki,Etsushi Kuroda,Yukiko Yoshiura,Kazuaki Kawai,Taisuke Tomonaga,Hiroto Izumi,Masaru Kubo

doi:10.1007/s11051-015-3249-1

Abstract

We performed inhalation and intratracheal instillation studies of cerium dioxide (CeO2) nanoparticles in order to investigate their pulmonary toxicity, and observed pulmonary inflammation not only in the acute and but also in the chronic phases. In the intratracheal instillation study, F344 rats were exposed to 0.2 mg or 1 mg of CeO2 nanoparticles. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed from 3 days to 6 months following the instillation. In the inhalation study, rats were exposed to the maximum concentration of inhaled CeO2 nanoparticles (2, 10 mg/m3, respectively) for 4 weeks (6 h/day, 5 days/week). The same endpoints as in the intratracheal instillation study were examined from 3 days to 3 months after the end of the exposure. The intratracheal instillation of CeO2 nanoparticles caused a persistent increase in the total and neutrophil number in BALF and in the concentration of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2, chemokine for neutrophil, and heme oxygenase-1 (HO-1), an oxidative stress marker, in BALF during the observation time. The inhalation of CeO2 nanoparticles also induced a persistent influx of neutrophils and expression of CINC-1, CINC-2, and HO-1 in BALF. Pathological features revealed that inflammatory cells, including macrophages and neutrophils, invaded the alveolar space in both studies. Taken together, the CeO2 nanoparticles induced not only acute but also chronic inflammation in the lung, suggesting that CeO2 nanoparticles have a pulmonary toxicity that can lead to irreversible lesions.

Highlights

Cerium (Ce) is a rare earth lanthanide metal, there are large amounts of it in the earth’s crust
Considering that the pulmonary toxicity of crystalline silica was induced in the chronic phase, it is important to evaluate its harmful effects after sufficient recovery time
In order to explore the pulmonary toxicity of CeO2 nanoparticles we performed intratracheal instillation and inhalation studies with more than 3 months of observation time and examined the pulmonary inflammation and fibrosis as the endpoints of toxicity

Summary

Introduction

Cerium (Ce) is a rare earth lanthanide metal, there are large amounts of it in the earth’s crust. CeO2 is widely used in abrasives for optical glass and glass substrates for liquid crystal displays and hard disks. As for CeO2 nanoparticles, some intratracheal instillation and inhalation studies have shown pulmonary inflammation, suggesting that CeO2 nanoparticles may have harmful effects on humans. Most of those reports show acute pulmonary inflammation, and there were no reports evaluating chronic responses such as persistent inflammation. A material with high toxicity, have revealed an exacerbation of inflammation in the lung 1 or 2 months postexposure, and inhalation of crystalline silica induced pulmonary damage in rats at 10 weeks and 16 weeks after exposure (Sellamuthu et al 2011; Langley et al 2004). In order to explore the pulmonary toxicity of CeO2 nanoparticles we performed intratracheal instillation and inhalation studies with more than 3 months of observation time and examined the pulmonary inflammation and fibrosis as the endpoints of toxicity

Methods

Results

Conclusion