Retrospective analysis of 4-week inhalation studies in rats with focus on fate and pulmonary toxicity of two nanosized aluminum oxyhydroxides (boehmite) and pigment-grade iron oxide (magnetite): the key metric of dose is particle mass and not particle surface area.
This paper compares the pulmonary toxicokinetics and toxicodynamics of three different types of poorly soluble dusts examined in repeated rat inhalation bioassays (6h/day, 5 days/week, 4 weeks). In these studies the fate of particles was studied during a 3-6-month postexposure period. This retrospective analysis included two types of aluminum oxyhydroxides (AlOOH, boehmite), high purity calcined, and agglomerated nanosized aluminas of very low solubility with primary isometric particles of 10 or 40nm, and synthetic iron oxide black (Fe(3)O(4) pigment grade). Three metrics of dose (actual mass concentration, surface area concentration, mass-based lung burden) were compared with pulmonary toxicity characterized by bronchoalveolar lavage. The results of this analysis provide strong evidence that pulmonary toxicity (inflammation) corresponds best with the mass-based cumulative lung exposure dose. The inhalation study with a MMAD of approximately 0.5microm yielded a higher pulmonary dose than MMADs in the range of 1-2microm, a range most commonly used in repeated exposure inhalation studies. Hence, a key premise for the dosimetric adjustment across species is that comparable lung tissue doses should cause comparable effects. From that perspective, the determination of mass-based pulmonary lung burdens appears to be amongst the most important and critical nominator of dose and dose-related pulmonary toxicity.
Institute of Toxicology, Bayer Schering Pharma, Department of Inhalation Toxicology, Building no. 514, 42096 Wuppertal, Germany. juergen.pauluhn@bayerhealthcare.com
Jürgen
J
Pauluhn
D000280:Administration, Inhalation; D000536:Aluminum Hydroxide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000537:Aluminum Oxide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D052203:Ferrosoferric Oxide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D049329:Nanostructures / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D012189:Retrospective Studies; D013047:Specific Pathogen-Free Organisms
D000536:Aluminum Hydroxide; C069471:aluminum oxide hydroxide; D000537:Aluminum Oxide; D052203:Ferrosoferric Oxide