ToxSci Advance Access published online on February 27, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp046
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Pulmonary Toxicity and Fate of Agglomerated 10 nm and 40 nm Aluminum Oxyhydroxides (AlOOH) following 4-week Inhalation Exposure of Rats: Toxic Effects are determined by agglomerated, not primary Particle Size
Institute of Toxicology, Bayer Schering Pharmaceuticals, 42096 Wuppertal, Germany
Correspondence: Prof. Dr. Jürgen Pauluhn, Department of Inhalation Toxicology, Bayer Schering Pharmaceuticals, Building no. 514, 42096 Wuppertal, Germany, Tel. ++49 (202) 363909, Fax. ++49 (202) 364589, email: juergen.pauluhn{at}bayerhealthcare.com
Received February 16, 2009; revision received February 16, 2009; accepted February 20, 2009
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Abstract |
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Inhaled polydisperse micronsized agglomerated particulates composed of nanosized primary particles may exert their pulmonary toxicity in either form, depending on whether these tightly associated structures are disintegrated within the biological system or not. This hypothesis was tested in a rat bioassay using two calcined aluminum oxyhydroxides (AlOOH) consisting of primary particles in the range of 10-40 nm. Male Wistar rats were nose-only exposed to 0.4, 3, and 28 mg/m3 in two 4-week (6 hrs/day, 5 days/week) inhalation studies followed by a 3-months postexposure period. The respective mass median aerodynamic diameter (MMAD) of agglomerated particles in inhalation chambers was 1.7 µm and 0.6 µm. At serial sacrifices, pulmonary toxicity was characterized by bronchoalveolar lavage (BAL) and histopathology. The retention kinetics of aluminum (Al) was determined in lung tissue, BAL-cells, and selected extrapulmonary organs, including lung-associated lymph nodes (LALNs). Significant changes in BAL, lung and LALN weights occurred at 28 mg/m3. Histopathology revealed alveolar macrophages with enlarged and foamy appearance, increased epithelial cells, inflammatory cells, and focal septal thickening. The determination of aluminum in lung tissue shows that the cumulative lung dose was higher following exposure to AlOOH-40 nm/MMAD-0.6 µm than to AlOOH-10 nm/MMAD-1.7 µm, despite identical exposure concentrations. The associated pulmonary inflammatory response appears to be principally dependent on the agglomerated rather than primary particle size. Despite high lung burdens, conclusively increased extrapulmonary organ burdens did not occur at any exposure concentration and postexposure time point. Particle-induced pulmonary inflammation was restricted to cumulative doses exceeding approximately 1 mg AlOOH/g lung following 4-week exposure at 28 mg/m3. It is concluded that the pulmonary toxicity of nanosized, agglomerated AlOOH particles appears to be determined by the size of agglomerated rather than primary particles while the clearance half-time of particles appears to increase with decreased primary particle size. However, in regard to toxicokinetics, this outcome is highly contingent upon the total lung burden and especially whether overloading or non-overloading conditions were attained or not. In order to reliably demonstrate retention-related different characteristics in toxicity and fate of poorly soluble (nano)particles postexposure periods of at least 3 months appear to be indispensible.
Key Words: Nanoparticles; repeated inhalation exposure; disposition; respirability; clearance; aggregates; pulmonary and extrapulmonary toxicity.