Biokinetics and effects of barium sulfate nanoparticles

Abstract

Background: Nanoparticulate barium sulfate has potential novel applications and wide use in the polymer and paint industries. A short-term inhalation study on barium sulfate nanoparticles (BaSO₄ NPs) was previously published [Part Fibre Toxicol 11:16, 2014]. We performed comprehensive biokinetic studies of ¹³¹BaSO₄ NPs administered via different routes and of acute and subchronic pulmonary responses to instilled or inhaled BaSO₄ in rats.

Methods: We compared the tissue distribution of ¹³¹Ba over 28 days after intratracheal (IT) instillation, and over 7 days after gavage and intravenous (IV) injection of ¹³¹BaSO₄. Rats were exposed to 50 mg/m³ BaSO₄ aerosol for 4 or 13 weeks (6 h/day, 5 consecutive days/week), and then gross and histopathologic, blood and bronchoalveolar lavage (BAL) fluid analyses were performed. BAL fluid from instilled rats was also analyzed.

Results: Inhaled BaSO₄ NPs showed no toxicity after 4-week exposure, but a slight neutrophil increase in BAL after 13-week exposure was observed. Lung burden of inhaled BaSO₄ NPs after 4-week exposure (0.84 ± 0.18 mg/lung) decreased by 95% over 34 days. Instilled BaSO₄ NPs caused dose-dependent inflammatory responses in the lungs. Instilled BaSO₄ NPs (0.28 mg/lung) was cleared with a half-life of ≈ 9.6 days. Translocated ¹³¹Ba from the lungs was predominantly found in the bone (29%). Only 0.15% of gavaged dose was detected in all organs at 7 days. IV-injected ¹³¹BaSO₄ NPs were predominantly localized in the liver, spleen, lungs and bone at 2 hours, but redistributed from the liver to bone over time. Fecal excretion was the dominant elimination pathway for all three routes of exposure.

Conclusions: Pulmonary exposure to instilled BaSO₄ NPs caused dose-dependent lung injury and inflammation. Four-week and 13-week inhalation exposures to a high concentration (50 mg/m³) of BaSO₄ NPs elicited minimal pulmonary response and no systemic effects. Instilled and inhaled BaSO₄ NPs were cleared quickly yet resulted in higher tissue retention than when ingested. Particle dissolution is a likely mechanism. Injected BaSO₄ NPs localized in the reticuloendothelial organs and redistributed to the bone over time. BaSO₄ NP exhibited lower toxicity and biopersistence in the lungs compared to other poorly soluble NPs such as CeO₂ and TiO₂.

Figure 1

Structural characterization by representative SEM scans of as-produced BaSO ₄ nanomaterial and after incubation for testing of persistence. (A) reproduced batch, as-produced powder; (B) NM-220 batch, as-produced powder; (C) pellet of NM-220 after 28d incubation in PBS; (D) pellet of NM-220 after 28d incubation in PSF; (E) pellet of NM-220 after 1d incubation in 0.1 N HCl.

Figure 2

Clearance and translocation of ¹³¹ BaSO ₄ NPs following IT instillation. (A) Lung clearance of ¹³¹BaSO₄ over time. The clearance half life was approximately 9.6 days. By 28 days, 84% of dose has been cleared from the lungs. (B) Translocated ¹³¹Ba from the lungs gradually accumulated in other organs. By 28 days, 29% of the instilled ¹³¹Ba dose was retained in the bone and 7% in all the other organs. Data are mean ± standard error of the mean, n = 5 per group.

Figure 3

Cumulative fecal and urinary excretion of ¹³¹ Ba following IT instillation. Elimination of ¹³¹Ba was mainly via the feces. By 28 days post-dosing, 30% of the instilled dose was excreted in the feces (A) and only 4.4% in the urine (B). Data are mean ± standard error of the mean, n = 5 per group.

Figure 4

Tissue distribution of ¹³¹ Ba following gavage. A. Immediately post-gavage, 100% of dose was recovered in the stomach. B. At 7 days post-gavage, ¹³¹Ba was negligible in all tissues. Very low percentages of the dose were detected in bone and bone marrow. Data are mean ± standard error of the mean, n = 5 per group.

Figure 5

Cumulative fecal and urinary excretion of ¹³¹ Ba post-gavage. A. Elimination of ¹³¹Ba was nearly 100% via the feces. B. By 7 days post-gavage, only 0.02% of the administered dose was excreted in the urine. Data are mean ± standard error of the mean, n = 5 per group.

Figure 6

Tissue distribution of ¹³¹ Ba post-IV injection. Two hours post-injection, 58% of the injected dose was recovered in the liver and lower percentages in the spleen, bone, bone marrow and the lungs. Over time, ¹³¹Ba levels in the liver and lungs decreased with accompanying increases in bone and bone marrow. Data are mean ± standard error of the mean, n = 5 per group. *P <0.05, decrease over time, ^#P <0.05, increase over time, MANOVA).