PMID- 19251949
OWN - NLM
STAT- MEDLINE
DCOM- 20090824
LR  - 20131121
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 109
IP  - 1
DP  - 2009 May
TI  - Pulmonary toxicity and fate of agglomerated 10 and 40 nm aluminum oxyhydroxides 
      following 4-week inhalation exposure of rats: toxic effects are determined by 
      agglomerated, not primary particle size.
PG  - 152-67
LID - 10.1093/toxsci/kfp046 [doi]
AB  - 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/m(3) in two 4-week (6 h/day, 5 days/week) inhalation studies followed by a 
      3-month postexposure period. The respective mass median aerodynamic diameter 
      (MMAD) of agglomerated particles in inhalation chambers was 1.7 and 0.6 mum. 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/m(3). 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 mum than to AlOOH-10 nm/MMAD-1.7 mum, 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/m(3). 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, whereas 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.
FAU - Pauluhn, Jurgen
AU  - Pauluhn J
AD  - Institute of Toxicology, Bayer Schering Pharmaceuticals, 42096 Wuppertal, 
      Germany. juergen.pauluhn@bayerhealthcare.com
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090227
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 5QB0T2IUN0 (Aluminum Hydroxide)
RN  - 63957-70-0 (aluminum oxide hydroxide)
RN  - CPD4NFA903 (Aluminum)
RN  - LMI26O6933 (Aluminum Oxide)
SB  - IM
MH  - Aluminum/analysis
MH  - Aluminum Hydroxide/*toxicity
MH  - Aluminum Oxide/*toxicity
MH  - Analysis of Variance
MH  - Animals
MH  - Atmosphere Exposure Chambers
MH  - Body Weight/drug effects
MH  - Bronchoalveolar Lavage Fluid/chemistry
MH  - Dose-Response Relationship, Drug
MH  - *Inhalation Exposure
MH  - Lung/chemistry/*drug effects
MH  - Lymph Nodes/chemistry/drug effects
MH  - Male
MH  - Nanoparticles/*toxicity
MH  - Organ Size/drug effects
MH  - Particle Size
MH  - Rats
MH  - Rats, Wistar
MH  - Time Factors
EDAT- 2009/03/03 09:00
MHDA- 2009/08/25 09:00
CRDT- 2009/03/03 09:00
PHST- 2009/03/03 09:00 [entrez]
PHST- 2009/03/03 09:00 [pubmed]
PHST- 2009/08/25 09:00 [medline]
AID - kfp046 [pii]
AID - 10.1093/toxsci/kfp046 [doi]
PST - ppublish
SO  - Toxicol Sci. 2009 May;109(1):152-67. doi: 10.1093/toxsci/kfp046. Epub 2009 Feb 
      27.