Pulmonary clearance kinetics and extrapulmonary translocation of seven titanium dioxide nano- and submicron materials following intratracheal administration in rats.
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.
a Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology (AIST) , Tsukuba , Ibaraki , Japan .
Naohide
N
Shinohara
b Chemicals Evaluation and Research Institute (CERI) , Hita , Oita , Japan .
Yutaka
Y
Oshima
b Chemicals Evaluation and Research Institute (CERI) , Hita , Oita , Japan .
Toshio
T
Kobayashi
c Chemicals Evaluation and Research Institute (CERI) , Bunkyo , Tokyo , Japan .
Nobuya
N
Imatanaka
b Chemicals Evaluation and Research Institute (CERI) , Hita , Oita , Japan .
Makoto
M
Nakai
d Toray Research Center, Inc. , Otsu , Shiga , Japan , and.
Takayuki
T
Ichinose
e Nanosystem Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) , Tsukuba , Ibaraki , Japan.
Takeshi
T
Sasaki
e Nanosystem Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) , Tsukuba , Ibaraki , Japan.
Kenji
K
Kawaguchi
a Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology (AIST) , Tsukuba , Ibaraki , Japan .
Guihua
G
Zhang
a Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology (AIST) , Tsukuba , Ibaraki , Japan .
Masashi
M
Gamo
D000818:Animals; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution; D014025:Titanium / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D014132:Trachea / Q000378:metabolism*
C009495:titanium dioxide; D014025:Titanium
Distribution; liver; lymph node; rate constant; toxicokinetics