Siderite (FeCO₃) and magnetite (Fe₃O₄) overload-dependent pulmonary toxicity is determined by the poorly soluble particle not the iron content.
The two poorly soluble iron containing solid aerosols of siderite (FeCO₃) and magnetite (Fe₃O₄) were compared in a 4-week inhalation study on rats at similar particle mass concentrations of approximately 30 or 100 mg/m³. The particle size distributions were essentially identical (MMAD ≈1.4 μm). The iron-based concentrations were 12 or 38 and 22 or 66 mg Fe/m³ for FeCO₃ and Fe₃O₄, respectively. Modeled and empirically determined iron lung burdens were compared with endpoints suggestive of pulmonary inflammation by determinations in bronchoalveolar lavage (BAL) and oxidative stress in lung tissue during a postexposure period of 3 months. The objective of study was to identify the most germane exposure metrics, that are the concentration of elemental iron (mg Fe/m³), total particle mass (mg PM/m³) or particle volume (μl PM/m³) and their associations with the effects observed. From this analysis it was apparent that the intensity of pulmonary inflammation was clearly dependent on the concentration of particle-mass or -volume and not of iron. Despite its lower iron content, the exposure to FeCO₃ caused a more pronounced and sustained inflammation as compared to Fe₃O₄. Similarly, borderline evidence of increased oxidative stress and inflammation occurred especially following exposure to FeCO₃ at moderate lung overload levels. The in situ analysis of 8-oxoguanine in epithelial cells of alveolar and bronchiolar regions supports the conclusion that both FeCO₃ and Fe₃O₄ particles are effectively endocytosed by macrophages as opposed to epithelial cells. Evidence of intracellular or nuclear sources of redox-active iron did not exist. In summary, this mechanistic study supports previous conclusions, namely that the repeated inhalation exposure of rats to highly respirable pigment-type iron oxides cause nonspecific pulmonary inflammation which shows a clear dependence on the particle volume-dependent lung overload rather than any increased dissolution and/or bioavailability of redox-active iron.
Experimental Toxicology, Bayer Pharma AG, D-42096 Wuppertal, Germany. juergen.pauluhn@bayer.com
Jürgen
J
Pauluhn
Martin
M
Wiemann
D000818:Animals; D018893:Bronchoalveolar Lavage; D002254:Carbonates / Q000493:pharmacokinetics / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005290:Ferric Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D005293:Ferritins / Q000378:metabolism; D052203:Ferrosoferric Oxide / Q000493:pharmacokinetics / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D002254:Carbonates; D005290:Ferric Compounds; D017392:Thiobarbituric Acid Reactive Substances; C024829:8-hydroxyguanine; D006147:Guanine; D005293:Ferritins; D007501:Iron; D051547:Heme Oxygenase-1; C486982:siderite; D052203:Ferrosoferric Oxide