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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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Related in: MedlinePlus

Inflammatory potency of the short-term studies with 5 days and 4 weeks of exposure over post-exposure period: absolute neutrophil counts in BALF in the short-term studies: 3 and 24 days after end of exposure to 25 mg/m3 Ceria NM-211 (orange 5-day exposure) and NM-212 (light blue 5-day exposure) or one and 35 days after the end of exposure to 25 mg/m3 NM-212 (dark blue 4-week exposure)
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Fig8: Inflammatory potency of the short-term studies with 5 days and 4 weeks of exposure over post-exposure period: absolute neutrophil counts in BALF in the short-term studies: 3 and 24 days after end of exposure to 25 mg/m3 Ceria NM-211 (orange 5-day exposure) and NM-212 (light blue 5-day exposure) or one and 35 days after the end of exposure to 25 mg/m3 NM-212 (dark blue 4-week exposure)

Mentions: The dose rate of particles seems to influence the acute inflammatory reaction in the lung (Baisch et al. 2014). Despite the same lung burdens but different dose rates, a stronger neutrophil response in BALF was observed after the shorter exposure time (Figs. 8, 9). The decay in neutrophil numbers after 4 weeks was by far slower than after 5 days, suggesting that inflammation developing at lower dose rate is longer lasting and more persistent. Moreover, BALF effects almost completely regressed after the end of the 5 days exposure to 5 mg/m3 even though the lung burden was only cleared by about 10 % (Fig. 9).Fig. 8


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)

Inflammatory potency of the short-term studies with 5 days and 4 weeks of exposure over post-exposure period: absolute neutrophil counts in BALF in the short-term studies: 3 and 24 days after end of exposure to 25 mg/m3 Ceria NM-211 (orange 5-day exposure) and NM-212 (light blue 5-day exposure) or one and 35 days after the end of exposure to 25 mg/m3 NM-212 (dark blue 4-week exposure)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig8: Inflammatory potency of the short-term studies with 5 days and 4 weeks of exposure over post-exposure period: absolute neutrophil counts in BALF in the short-term studies: 3 and 24 days after end of exposure to 25 mg/m3 Ceria NM-211 (orange 5-day exposure) and NM-212 (light blue 5-day exposure) or one and 35 days after the end of exposure to 25 mg/m3 NM-212 (dark blue 4-week exposure)
Mentions: The dose rate of particles seems to influence the acute inflammatory reaction in the lung (Baisch et al. 2014). Despite the same lung burdens but different dose rates, a stronger neutrophil response in BALF was observed after the shorter exposure time (Figs. 8, 9). The decay in neutrophil numbers after 4 weeks was by far slower than after 5 days, suggesting that inflammation developing at lower dose rate is longer lasting and more persistent. Moreover, BALF effects almost completely regressed after the end of the 5 days exposure to 5 mg/m3 even though the lung burden was only cleared by about 10 % (Fig. 9).Fig. 8

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