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Barium sulfate (BaSo 4) was considered to be poorly-soluble and of low toxicity, but BaSO 4 NM-220 showed a surprisingly short retention after intratracheal instillation in rat lungs, and incorporation of Ba within the bones. Here we show that static abiotic dissolution cannot rationalize this result, whereas two dynamic abiotic dissolution systems (one flow-through and one flow-by) indicated 50% dissolution after 5 to 6 days at non-saturating conditions regardless of flow orientation, which is close to the in vivo half-time of 9.6 days. Non-equilibrium conditions were thus essential to simulate in vivo biodissolution. Instead of shrinking from 32 nm to 23 nm (to match the mass loss to ions), TEM scans of particles retrieved from flow-cells showed an increase to 40 nm. Such transformation suggested either material transport through interfacial contact or Ostwald ripening at super-saturating conditions and was also observed in vivo inside macrophages by high-resolution TEM following 12 months inhalation exposure. The abiotic flow cells thus adequately predicted the overall pulmonary biopersistence of the particles that was mediated by non-equilibrium dissolution and recrystallization. The present methodology for dissolution and transformation fills a high priority gap in nanomaterial hazard assessment and is proposed for the implementation of grouping and read-across by dissolution rates. Knowledge about pulmonary retention kinetics of inhaled particles is an essential element of hazard assessment and of understanding the mechanisms by which adverse health outcomes may occur. Barium sulfate was generally assumed to be poorly-soluble and of low toxicity unless delivered at high concentrations over an extended period 1,2. However, Konduru and colleagues reported that intratracheally instilled 131 BaSO 4 NM-220 exhibited a lung retention half-time of only 9.6 days in rats and that 131 Ba was incorporated into the bones, suggesting nanoparticle dissolution and/or translocation to extrapulmonary sites 3. A subsequent 90-day inhalation study in rats with a high concentration of aerosolized BaSO 4 NM-220 (50 mg/m 3) 4 revealed no signs of lung overload and a retention half-time of 56 days, which is close to the normal range for the rat lung 4. A two-year rat inhalation study with BaSO 4 NM-220 (50 mg/m 3), however, demonstrated an increase of retained Ba in the lung during the first year of exposure, after which a steady-state was achieved 5. Since significant Ba accumulation in bone and bone marrow was also observed and, given that the measurements of Ba distribution [1-3] provide no information about its physicochemical characteristics, the complex in vivo dissolution and/or transformation of BaSO 4 secondary to inhalation exposure require more detailed investigation.

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Following inhalation and deposition in the alveolar region at sufficient dose, biopersistent (nano)materials generally provoke pulmonary inflammation. Alveolar macrophages (AMs) are mediators of pulmonary immune responses and were broadly categorized in pro-inflammatory M1 and anti-inflammatory M2 macrophages. This study aimed at identifying AM phenotype as M1 or M2 upon short-term inhalation exposure to different (nano)materials followed by a postexposure period. Phenotyping of AM was retrospectively performed using immunohistochemistry. M1 (CD68+iNOS+) and M2 (CD68+CD206+ and CD68+ArgI+) AMs were characterized in formalin-fixed, paraffin-embedded lung tissue of rats exposed for 6 hours/day for 5 days to air, 100 mg/m3 nano-TiO2, 25 mg/m3 nano-CeO2, 32 mg/m3 multiwalled carbon nanotubes, or 100 mg/m3 micron-sized quartz. During acute inflammation, relative numbers of M1 AMs were markedly increased, whereas relative numbers of M2 were generally decreased compared to control. Following an exposure-free period, changes in iNOS or CD206 expression correlated with persistence, regression, or progression of inflammation, suggesting a role of M1/M2 AMs in the pathogenesis of pulmonary inflammation. However, no clear correlation of AM subpopulations with qualitatively distinct histopathological findings caused by different (nano)materials was found. A more detailed understanding of the processes underlaying these morphological changes is needed to identify biomarkers for different histopathological outcomes.

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