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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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Persistence of Ceria NM-211 (a), NM-212 (b), and Titania NM-105 (c) as benchmark. Transmission electron microscopy (TEM) and selected area diffraction (SAD) after 28-day incubation in phagolysosomal simulant fluid (PSF) [see Table 1 for dissolution detected by ions in the supernatant (ICP-MS)]. The large almost spherical structures are no contaminations, but are confirmed as Ceria in the same crystalline phase
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Fig3: Persistence of Ceria NM-211 (a), NM-212 (b), and Titania NM-105 (c) as benchmark. Transmission electron microscopy (TEM) and selected area diffraction (SAD) after 28-day incubation in phagolysosomal simulant fluid (PSF) [see Table 1 for dissolution detected by ions in the supernatant (ICP-MS)]. The large almost spherical structures are no contaminations, but are confirmed as Ceria in the same crystalline phase

Mentions: The solubility in physiological media was investigated by 28-day abiotic incubation in different fluids and detection of both the remaining particulate fraction (by SEM, centrifugation, LD, zeta-potential) and of the released metal ions (by ICP-MS). Both Ceria were insoluble except for marginal solubility in 0.1 N HCl (simulate oral ingestion), whereas a nanoscale precipitated Silica as positive control dissolved readily and Titania (NM-105) showed marginal solubility in phagolysosomal simulant fluid (PSF, simulate uptake and digestion in macrophages) (Wohlleben et al. 2013). In buffers with organic constituents (PSF, fasted state simulated intestinal fluid = FaSSIF), the surface charge reversed to negative zeta-potentials, which was identified earlier as indicator for the adsorption of constituents of the buffer for a range of the nano-Ceria (Wohlleben et al. 2013). Under all conditions, primary particles remained recognizable in TEM scans, but both Ceria NM-211 and NM-212 formed large structures after 28-day incubation in the acidic PSF medium that simulates the lysosome of macrophages (see Fig. 3). We found by selected area electron diffraction (SAD) that these aged structures retained the same cubic cerianite crystalline phase of the as-produced powder for both Ceria NM-211 and NM-212. Under identical conditions, also other nanomaterials, e.g., the Titania (NM-105), aged into similar structures, and we added the respective TEM and SAD for comparison (Wohlleben et al. 2013).Fig. 3


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)

Persistence of Ceria NM-211 (a), NM-212 (b), and Titania NM-105 (c) as benchmark. Transmission electron microscopy (TEM) and selected area diffraction (SAD) after 28-day incubation in phagolysosomal simulant fluid (PSF) [see Table 1 for dissolution detected by ions in the supernatant (ICP-MS)]. The large almost spherical structures are no contaminations, but are confirmed as Ceria in the same crystalline phase
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Persistence of Ceria NM-211 (a), NM-212 (b), and Titania NM-105 (c) as benchmark. Transmission electron microscopy (TEM) and selected area diffraction (SAD) after 28-day incubation in phagolysosomal simulant fluid (PSF) [see Table 1 for dissolution detected by ions in the supernatant (ICP-MS)]. The large almost spherical structures are no contaminations, but are confirmed as Ceria in the same crystalline phase
Mentions: The solubility in physiological media was investigated by 28-day abiotic incubation in different fluids and detection of both the remaining particulate fraction (by SEM, centrifugation, LD, zeta-potential) and of the released metal ions (by ICP-MS). Both Ceria were insoluble except for marginal solubility in 0.1 N HCl (simulate oral ingestion), whereas a nanoscale precipitated Silica as positive control dissolved readily and Titania (NM-105) showed marginal solubility in phagolysosomal simulant fluid (PSF, simulate uptake and digestion in macrophages) (Wohlleben et al. 2013). In buffers with organic constituents (PSF, fasted state simulated intestinal fluid = FaSSIF), the surface charge reversed to negative zeta-potentials, which was identified earlier as indicator for the adsorption of constituents of the buffer for a range of the nano-Ceria (Wohlleben et al. 2013). Under all conditions, primary particles remained recognizable in TEM scans, but both Ceria NM-211 and NM-212 formed large structures after 28-day incubation in the acidic PSF medium that simulates the lysosome of macrophages (see Fig. 3). We found by selected area electron diffraction (SAD) that these aged structures retained the same cubic cerianite crystalline phase of the as-produced powder for both Ceria NM-211 and NM-212. Under identical conditions, also other nanomaterials, e.g., the Titania (NM-105), aged into similar structures, and we added the respective TEM and SAD for comparison (Wohlleben et al. 2013).Fig. 3

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