Siderite (FeCO₃) and magnetite (Fe₃O₄) overload-dependent pulmonary toxicity is determined by the poorly soluble particle not the iron content

Abstract

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.

Keywords::

• Insoluble particles
• iron
• oxidative stress
• magnetite
• siderite
• repeated inhalation exposure
• disposition
• particle clearance
• pulmonary and extrapulmonary toxicity
• lung overload

Acknowledgment

The authors thank Dr. I. Loof (Bayer HealthCare) for determinations in lung lavage and Dr. Schweer (Currenta) for determinations of iron in tissues. There is no financial interest or any involvement of the sponsor that would have influenced the design, conduct or interpretation of study. This manuscript reflects solely the opinion of the authors and not of the Lanxess GmbH or of Bayer HealthCare AG.

Declaration of interest

This study was performed on behalf of LANXESS Deutschland GmbH, Leverkusen during the course of normal employment with Bayer Pharma AG (JP). Measurements requiring PCR and immunohistochemistry were contracted at IBE R&D GmbH, Institute for Lung Health, Münster. MW is CEO at IBE.