Subchronic inhalation toxicity of iron oxide (magnetite, Fe(3) O(4) ) in rats: pulmonary toxicity is determined by the particle kinetics typical of poorly soluble particles

Wistar rats were nose‐only exposed to pigment‐sized iron oxide dust (Fe₃O₄, magnetite) in a subchronic 13‐week inhalation study according to the OECD testing guidelines TG#413 and GD#39. A 4 week pilot study with a 6 month post exposure period served as basis for validating the kinetic modeling approaches utilized to design the subchronic study. Kinetic analyses made during this post exposure period demonstrated that a diminution in particle clearance and lung inflammation occurred at cumulative exposure levels exceeding the lung overload threshold. Animals were exposed 6 h per day, five days per week for 13 consecutive weeks at actual concentrations of 0, 4.7, 16.6 and 52.1 mg m^?3 (mass median aerodynamic diameter ≈1.3 μm, geometric standard deviation = 2). The exposure to iron oxide dust was tolerated without mortality, consistent changes in body weights, food and water consumption or systemic toxicity. While general clinical pathology and urinalysis were unobtrusive, hematology revealed changes of unclear toxicological significance (minimally increased differential neutrophil counts in peripheral blood). Elevations of neutrophils in bronchoalveolar lavage (BAL) appeared to be the most sensitive endpoint of study. Histopathology demonstrated responses to particle deposition in the upper respiratory tract (goblet cell hyper‐ and/or metaplasia, intraepithelial eosinophilic globules in the nasal passages) and the lower respiratory tract (inflammatory changes in the bronchiolo‐alveolar region). Consistent changes suggestive of pulmonary inflammation were evidenced by BAL, histopathology, increased lung and lung‐associated‐lymph node (LALN) weights at 16.6 and 52.1 mg m^?3. Increased septal collagenous fibers were observed at 52.1 mg m^?3. Particle translocation into LALN occurred at exposure levels causing pulmonary inflammation. In summary, the retention kinetics iron oxide reflected that of poorly soluble particles. The empirical no‐observed‐adverse‐effect level (NOAEL) and the lower bound 95% confidence limit on the benchmark concentration (BMCL) obtained by benchmark analysis was 4.7 and 4.4 mg m^?3, respectively, and supports an OEL (time‐adjusted chronic occupational exposure level) of 2 mg m^?3 (alveolar fraction). Copyright © 2011 John Wiley & Sons, Ltd.     

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 (6 h/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 40 nm, and synthetic iron oxide black (Fe₃O₄ 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 ≈0.5 μm yielded a higher pulmonary dose than MMADs in the range of 1–2 μm, 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.     

Interrelating the acute and chronic mode of action of inhaled methylenediphenyl diisocyanate (MDI) in rats assisted by computational toxicology

Polymeric methylenediphenyl diisocyanate (MDI) is a high production volume chemical intermediate consisting of monomeric 4,4′-MDI, its 2,2′- and 2,4′-isomers, and higher oligomeric homologues. The toxicity of pMDI has systematically been investigated in previous regulatory and mechanistic studies. One cornerstone of toxicological risk assessment is to understand the critical Mode of Action (MoA) of inhaled MDI aerosol. This paper compares the no-observed-adverse effect levels (NOAELs) in rats from two published whole-body exposure chronic inhalation bioassays with the lung irritation-based point of departures (PODs) from acute and subacute nose-only inhalation studies. Acute irritation was related to elevated concentrations of protein in bronchoalveolar lavage fluid (short-term studies), whilst the chronic events were characterized by histopathology. In the chronic bioassay the exposure duration was either 6 or 18 h/day while in all other studies a 6 h/day regimens were applied. The major objective of this paper is to analyze the interrelationship of acute pulmonary irritation and the acute-on-chronic manifestations of pulmonary disease following recurrent chronic inhalation exposure. This included considerations on the most critical metrics of exposure with regard to the acute concentration × exposure duration per day (C × T_day) and the chronic cumulative dose metrics. In summary, this analysis supports the conclusion that the C × T_day relative to the acute pulmonary irritation threshold is more decisive for the chronic outcome than the concentration per se or the time-adjusted cumulative dose. For MDI aerosols, the acute threshold C × T_day was remarkably close to the NOAELs of the chronic inhalation studies, independent on their differing exposure mode and regimens. This evidence is supportive of a simple, direct MoA at the site of initial deposition of aerosol. Accordingly, for chemicals reactive to the endogenous nucleophilic agents contained in the lining fluid of the lung, one unifying essential prerequisite for pulmonary injury appears to be a C × T_day that exhausts the homeostatic pool of MDI-scavenging agents. In the case that threshold is exceeded, the secondary compensatory chronic response may then cause additional superimposed types of chronic pathologies.