Kinetics and dissolution of intratracheally administered nickel oxide nanomaterials in rats

Abstract

Background: The toxicokinetics of nanomaterials are an important factor in toxicity, which may be affected by slow clearance and/or distribution in the body.

Methods: Four types of nickel oxide (NiO) nanoparticles were single-administered intratracheally to male F344 rats at three doses of 0.67-6.0 mg/kg body weight. The rats were sacrificed under anesthesia and the lung, thoracic lymph nodes, bronchoalveolar lavage fluid, liver, and other organs were sampled for Ni burden measurement 3, 28, and 91 days post-administration; Ni excretion was measured 6 and 24 h after administration. Solubility of NiO nanoparticles was determined using artificial lysosomal fluid, artificial interstitial fluid, hydrogen peroxide solution, pure water, and saline. In addition, macrophage migration to trachea and phagosome-lysosome-fusion rate constants were estimated using pulmonary clearance and dissolution rate constants.

Results: The wire-like NiO nanoparticles were 100% dissolved by 24 h when mixed with artificial lysosomal fluid (dissolution rate coefficient: 0.18/h); spherical NiO nanoparticles were 12% and 35% dissolved after 216 h when mixed with artificial lysosomal fluid (1.4 × 10^-3 and 4.9 × 10^-3/h). The largest irregular-shaped NiO nanoparticles hardly dissolved in any solution, including artificial lysosomal fluid (7.8 × 10^-5/h). Pulmonary clearance rate constants, estimated using a one-compartment model, were much higher for the NiO nanoparticles with a wire-shape (0.069-0.078/day) than for the spherical and irregular-shaped NiO nanoparticles (0-0.012/day). Pulmonary clearance rate constants of the largest irregular-shaped NiO nanoparticles showed an inverse correlation with dose. Translocation of NiO from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner for three spherical and irregular-shaped NiO nanoparticles, but not for the wire-like NiO nanoparticles. Thirty-five percent of the wire-like NiO nanoparticles were excreted in the first 24 h after administration; excretion was 0.33-3.6% in that time frame for the spherical and irregular-shaped NiO nanoparticles.

Conclusion: These findings suggest that nanomaterial solubility differences can result in variations in their pulmonary clearance. Nanoparticles with moderate lysosomal solubility may induce persistent pulmonary inflammation.

Keywords: Artificial biological fluid (Gamble’s solution); Clearance rate constant; Dissolubility; Intratracheal administration; Lymph node; Toxicokinetics.

Fig. 1

One-compartment model for the clearance of NiO nano and submicron particles. This model is expressed using a first-order decay equation with rate constant k

Fig. 2

Concentration of dissolved Ni ions in the artificial fluids for four types of NiO. Ultrapure water, saline, hydrogen peroxide (H₂O₂) solutions (10 and 200 μM), artificial lysosomal fluid, and Gamble’s solution (artificial interstitium fluid) were used as the artificial fluids. The broken line indicates the Ni concentrations (both particle and ion) in the suspension. a NiO A. b NiO B. c NiO C. d NiO D

Fig. 3

NiO burden per initial body weight at the time of administration in the lung. Bronchoalveolar lavage fluid (BALF) (a), total thoracic lymph nodes (right mediastinal lymph node and left and right mediastinal lymph nodes) (b), trachea (c), and liver (d) following intratracheal NiO administration. Horizontal axis indicates the administered dose per initial body weight. The body weights of the rats were 256 ± 11 g. The column and error bars indicate the mean and standard deviation, respectively. Asterisks indicate statistically significant differences, compared with the control group (** P < 0.01, * P < 0.05). Samples with NiO levels below the quantification limit were assigned values corresponding to half the quantification limit

Fig. 4

Dose-dependent clearance rate constants (a) and lung-to-lymph nodes translocation rate constants (b). Broken line in (a) shows the 2-month half-life (0.0115/day). The rate constants of seven types of TiO₂ from a previous study [9] are also described in this figure

Fig. 5

Ni content in organs and excretion 6 h and 24 h post-administration. The total recovery 6 h post-administration was 94, 74, 41, and 90% for NiO A, B, C, and D, respectively

Fig. 6

Representative images of H&E-stained lung tissue sections after intratracheal administration of NiO A, B, C, and D (6 mg/kg BW) and vehicle

Fig. 7

Estimated macrophage migration to end of the bronchi rate constant and phagosome-lysosome fusion rate constant. The estimate was calculated for 0.01, 0.05, and 0.1 /h dissolution rate constants in the lysosome