title: Dose-dependent clearance kinetics of intratracheally administered titanium dioxide nanoparticles in rat lung.
abstract: AEROSIL(®) P25 titanium dioxide (TiO2) nanoparticles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats at doses of 0 (control), 0.375, 0.75, 1.5, 3.0, and 6.0 mg/kg. The rats were sacrificed under anesthesia at 1 day, 3 days, 7 days, 4 weeks, 13 weeks, and 26 weeks after administration. Ti levels in various pulmonary and extrapulmonary organs were determined using sensitive inductively coupled plasma sector field mass spectrometry. One day after administration, the lungs contained 62-83% of TiO2 administered dose. Twenty-six weeks after administration, the lungs retained 6.6-8.9% of the TiO2 administered at the 0.375, 0.75, and 1.5 mg/kg doses, and 13% and 31% of the TiO2 administered at the 3.0 and 6.0 mg/kg doses, respectively. The pulmonary clearance rate constants from compartment 1, k1, were estimated using a 2-compartment model and were found to be higher for the 0.375 and 0.75 mg/kg doses of TiO2 (0.030/day for both) than for TiO2 doses of 1.5-6.0 mg/kg (0.014-0.022/day). The translocation rate constants from compartment 1 to 2, k12, were estimated to be 0.015 and 0.018/day for the 0.375 and 0.75 mg/kg doses, and 0.0025-0.0092/day for doses of 1.5-6.0mg/kg. The pulmonary clearance rate constants from compartment 2, k2, were estimated to be 0.0086 and 0.0093/day for doses of 0.375 and 0.75 mg/kg, and 0-0.00082/day for 1.5-6.0 mg/kg doses. Translocation of TiO2 from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner, accounting for 0.10-3.4% of the administered dose at 26 weeks. The measured thoracic lymph node burdens were a much better fit to the thoracic lymph node burdens estimated assuming translocation from compartment 1 to the thoracic lymph nodes, rather than those estimated assuming translocation from compartment 2 to the thoracic lymph nodes. The translocation rate constants from the lungs to the thoracic lymph nodes, kLung→Lym, were 0.000037-0.00081/day, and these also increased with increasing doses of TiO2. Although a small amount of TiO2 had translocated to the liver by 3 days after the administration (0.0023-0.012% of the highest dose administered, 6.0 mg/kg), translocation to the other extrapulmonary organs was not detected.
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8569, Japan. Electronic address: n-shinohara@aist.go.jp.
authors.forename: Naohide
authors.initials: N
authors.lastname: Shinohara
authors.affiliation: Chemicals Evaluation and Research Institute (CERI), Hita, Oita 877-0061, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oshima
authors.affiliation: Chemicals Evaluation and Research Institute (CERI), Hita, Oita 877-0061, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Chemicals Evaluation and Research Institute (CERI), Bunkyo, Tokyo 112-0004, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Imatanaka
authors.affiliation: Chemicals Evaluation and Research Institute (CERI), Hita, Oita 877-0061, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakai
authors.affiliation: Toray Research Center, Inc., Otsu, Shiga 520-8567, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ichinose
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8569, Japan.
authors.forename: Guihua
authors.initials: G
authors.lastname: Zhang
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8569, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Fukui
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8569, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Gamo
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001822:Body Burden; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008657:Metabolic Clearance Rate; D053768:Metal Nanoparticles; D008954:Models, Biological; D010316:Particle Size; D011916:Rats, Inbred F344; D014025:Titanium / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D066007:Toxicokinetics
chemical_list: C009495:titanium dioxide; D014025:Titanium
keywords: Clearance; Compartment model; Distribution; Nanomaterial; Overload; Toxicokinetics