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Time course of lung retention and toxicity of inhaled particles: short-term exposure to nano-Ceria.

Keller J, Wohlleben W, Ma-Hock L, Strauss V, Gröters S, Küttler K, Wiench K, Herden C, Oberdörster G, van Ravenzwaay B, Landsiedel R - Arch. Toxicol. (2014)

Bottom Line: 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.

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.

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Dose–response curves using different dose metrics after 5 days of exposure to 0.5 and 25 mg/m3 Ceria NM-211 and 0.5, 5, and 25 mg/m3 Ceria NM-212; a mass, b surface, c volume
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Fig7: Dose–response curves using different dose metrics after 5 days of exposure to 0.5 and 25 mg/m3 Ceria NM-211 and 0.5, 5, and 25 mg/m3 Ceria NM-212; a mass, b surface, c volume

Mentions: Morrow assumed overload conditions when particle volume exceeds 60 µm3/alveolar macrophage (Morrow 1988). Oberdoerster et al. (1994a) suggested retained surface area as appropriate metrics for correlating overload with retarded clearance, particularly if nanoparticles are involved. Tran et al. (2000) proposed overload threshold values of 0.02–0.03 m2/g lung. In the current study, 4 weeks of exposure to an aerosol concentration of 25 mg/m3 caused a particle surface burden of 0.07 m2/lung and 5 mg/m3 resulted in 0.014 m2 surface burden per lung (see Fig. 7; Table S9). This is slightly below the surface burden threshold proposed by Tran et al. and caused already inflammation and retarded clearance in the lung. Therefore, it can be assumed that a threshold, however, is highly material-dependent and may not be based on one or two particle types alone. The thresholds published previously may need adaptations for the specific type of nanomaterial in order to address its toxicological properties.Fig. 7


Time course of lung retention and toxicity of inhaled particles: short-term exposure to nano-Ceria.

Keller J, Wohlleben W, Ma-Hock L, Strauss V, Gröters S, Küttler K, Wiench K, Herden C, Oberdörster G, van Ravenzwaay B, Landsiedel R - Arch. Toxicol. (2014)

Dose–response curves using different dose metrics after 5 days of exposure to 0.5 and 25 mg/m3 Ceria NM-211 and 0.5, 5, and 25 mg/m3 Ceria NM-212; a mass, b surface, c volume
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4555363&req=5

Fig7: Dose–response curves using different dose metrics after 5 days of exposure to 0.5 and 25 mg/m3 Ceria NM-211 and 0.5, 5, and 25 mg/m3 Ceria NM-212; a mass, b surface, c volume
Mentions: Morrow assumed overload conditions when particle volume exceeds 60 µm3/alveolar macrophage (Morrow 1988). Oberdoerster et al. (1994a) suggested retained surface area as appropriate metrics for correlating overload with retarded clearance, particularly if nanoparticles are involved. Tran et al. (2000) proposed overload threshold values of 0.02–0.03 m2/g lung. In the current study, 4 weeks of exposure to an aerosol concentration of 25 mg/m3 caused a particle surface burden of 0.07 m2/lung and 5 mg/m3 resulted in 0.014 m2 surface burden per lung (see Fig. 7; Table S9). This is slightly below the surface burden threshold proposed by Tran et al. and caused already inflammation and retarded clearance in the lung. Therefore, it can be assumed that a threshold, however, is highly material-dependent and may not be based on one or two particle types alone. The thresholds published previously may need adaptations for the specific type of nanomaterial in order to address its toxicological properties.Fig. 7

Bottom Line: 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.

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.

Show MeSH
Related in: MedlinePlus