title: Time course of lung retention and toxicity of inhaled particles: short-term exposure to nano-Ceria.
abstract: Two Ceria nanomaterials (NM-211 and NM-212) were tested for inhalation toxicity and organ burdens in order to design a chronic and carcinogenicity inhalation study (OECD TG No. 453). Rats inhaled aerosol concentrations of 0.5, 5, and 25 mg/m(3) by whole-body exposure for 6 h/day on 5 consecutive days for 1 or 4 weeks with a post-exposure period of 24 or 129 days, respectively. Lungs were examined by bronchoalveolar lavage and histopathology. Inhaled Ceria is deposited in the lung and cleared with a half-time of 40 days; at aerosol concentrations higher than 0.5 mg/m(3), this clearance was impaired resulting in a half-time above 200 days (25 mg/m(3)). After 5 days, Ceria (>0.5 mg/m(3)) induced an early inflammatory reaction by increases of neutrophils in the lung which decreased with time, with sustained exposure, and also after the exposure was terminated (during the post-exposure period). The neutrophil number observed in bronchoalveolar lavage fluid (BALF) was decreasing and supplemented by mononuclear cells, especially macrophages which were visible in histopathology but not in BALF. Further progression to granulomatous inflammation was observed 4 weeks post-exposure. The surface area of the particles provided a dose metrics with the best correlation of the two Ceria's inflammatory responses; hence, the inflammation appears to be directed by the particle surface rather than mass or volume in the lung. Observing the time course of lung burden and inflammation, it appears that the dose rate of particle deposition drove an initial inflammatory reaction by neutrophils. The later phase (after 4 weeks) was dominated by mononuclear cells, especially macrophages. The progression toward the subsequent granulomatous reaction was driven by the duration and amount of the particles in the lung. The further progression of the biological response will be determined in the ongoing long-term study.
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Keller
authors.forename: Wendel
authors.initials: W
authors.lastname: Wohlleben
authors.forename: Lan
authors.initials: L
authors.lastname: Ma-Hock
authors.forename: Volker
authors.initials: V
authors.lastname: Strauss
authors.forename: Sibylle
authors.initials: S
authors.lastname: Gröters
authors.forename: Karin
authors.initials: K
authors.lastname: Küttler
authors.forename: Karin
authors.initials: K
authors.lastname: Wiench
authors.forename: Christiane
authors.initials: C
authors.lastname: Herden
authors.forename: Günter
authors.initials: G
authors.lastname: Oberdörster
authors.forename: Bennard
authors.initials: B
authors.lastname: van Ravenzwaay
authors.forename: Robert
authors.initials: R
authors.lastname: Landsiedel
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002563:Cerium / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006099:Granuloma / Q000139:chemically induced / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D049329:Nanostructures; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000336:Aerosols; D002563:Cerium; C030583:ceric oxide