Pulmonary clearance kinetics and extrapulmonary translocation of seven titanium dioxide nano- and submicron materials following intratracheal administration in rats

Abstract

We evaluated and compared the pulmonary clearance kinetics and extrapulmonary translocations of seven titanium dioxide (TiO₂) nano- and submicron particles with different characteristics, including size, shape and surface coating. Varying doses of TiO₂ nano- and submicron particles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats. The rats were euthanized under anesthesia for 3, 28 and 91 days after administration. Ti levels in pulmonary and various extrapulmonary organs were determined using inductively coupled plasma-sector field mass spectrometry (ICP-SFMS). The lungs, including bronchoalveolar lavage fluid (BALF), contained 55–89% of the administered TiO₂ dose at 3 days after administration. The pulmonary clearance rate constants, estimated using a one-compartment model, were higher after administration of 0.375–2.0 mg/kg body weight (bw) (0.016–0.020/day) than after administration of 3.0–6.0 mg/kg bw (0.0073–0.013/day) for six uncoated TiO₂. In contrast, the clearance rate constant was 0.011, 0.0046 and 0.00018/day following administration of 0.67, 2.0 and 6.0 mg/kg bw TiO₂ nanoparticle with Al(OH)₃ coating, respectively. Translocation of TiO₂ from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner. Furthermore, the translocation of TiO₂ from the lungs to the thoracic lymph nodes after 91 days was higher when Al(OH)₃ coated TiO₂ was administered (0.93–6.4%), as compared to uncoated TiO₂ (0.016–1.8%). Slight liver translocation was observed (<0.11%), although there was no clear trend related to dose or elapsed time. No significant translocation was observed in other organs including the kidney, spleen and brain.

• Distribution
• liver
• lymph node
• rate constant
• toxicokinetics

Declaration of interest

This work is part of the research program “Development of innovative methodology for safety assessment of industrial nanomaterials” supported by the Ministry of Economy, Trade and Industry (METI) of Japan.

Supplementary material available online

Supplementary Tables S1-S7.