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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

Study design of short-term studies with 5 days and 4 weeks of exposure
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Fig1: Study design of short-term studies with 5 days and 4 weeks of exposure

Mentions: In general, the animals were whole-body exposed to dust aerosols for 6 h/day on 5 consecutive days/week with a respective post-exposure period (see Fig. 1). The highest aerosol concentration was 25 mg/m3, which was expected to cause biological effects and should lead to lung overload at least for 20 exposures. The mid and low aerosol concentrations were 5 and 0.5 mg/m3. The low aerosol concentration with an expected lung burden far below the overload condition should not lead to any adverse effects. The mid aerosol concentration, which was spaced tenfold higher than the low concentration, was expected to cause some biological effects. The post-exposure period and the examination time points were scheduled to address the progression or regression of the biological effects, with their correlation to lung burden and lung clearance kinetics.Fig. 1


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)

Study design of short-term studies with 5 days and 4 weeks of exposure
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Study design of short-term studies with 5 days and 4 weeks of exposure
Mentions: In general, the animals were whole-body exposed to dust aerosols for 6 h/day on 5 consecutive days/week with a respective post-exposure period (see Fig. 1). The highest aerosol concentration was 25 mg/m3, which was expected to cause biological effects and should lead to lung overload at least for 20 exposures. The mid and low aerosol concentrations were 5 and 0.5 mg/m3. The low aerosol concentration with an expected lung burden far below the overload condition should not lead to any adverse effects. The mid aerosol concentration, which was spaced tenfold higher than the low concentration, was expected to cause some biological effects. The post-exposure period and the examination time points were scheduled to address the progression or regression of the biological effects, with their correlation to lung burden and lung clearance kinetics.Fig. 1

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