title: Quantitative biokinetics of titanium dioxide nanoparticles after intratracheal instillation in rats: Part 3.
abstract: The biokinetics of a size-selected fraction (70 nm median size) of commercially available and48V-radiolabeled [48V]TiO2nanoparticles has been investigated in healthy adult female Wistar-Kyoto rats at retention time-points of 1 h, 4 h, 24 h, 7 d and 28 d after intratracheal instillation of a single dose of an aqueous [48V]TiO2-nanoparticle suspension. A completely balanced quantitative biodistribution in all organs and tissues was obtained by applying typical [48V]TiO2-nanoparticle doses in the range of 40-240 μg·kg-1bodyweight and making use of the high sensitivity of the radiotracer technique. The [48V]TiO2-nanoparticle content was corrected for residual blood retained in organs and tissues after exsanguination and for48V-ions not bound to TiO2-nanoparticles. About 4% of the initial peripheral lung dose passed through the air-blood-barrier after 1 h and were retained mainly in the carcass (4%); 0.3% after 28 d. Highest organ fractions of [48V]TiO2-nanoparticles present in liver and kidneys remained constant (0.03%). [48V]TiO2-nanoparticles which entered across the gut epithelium following fast and long-term clearance from the lungs via larynx increased from 5 to 20% of all translocated/absorbed [48V]TiO2-nanoparticles. This contribution may account for 1/5 of the nanoparticle retention in some organs. After normalizing the fractions of retained [48V]TiO2-nanoparticles to the fraction that reached systemic circulation, the biodistribution was compared with the biodistributions determined after IV-injection (Part 1) and gavage (GAV) (Part 2). The biokinetics patterns after IT-instillation and GAV were similar but both were distinctly different from the pattern after intravenous injection disproving the latter to be a suitable surrogate of the former applications. Considering that chronic occupational inhalation of relatively biopersistent TiO2-particles (including nanoparticles) and accumulation in secondary organs may pose long-term health risks, this issue should be scrutinized more comprehensively.
authors.affiliation: a Helmholtz Center Munich - German Research Center for Environmental Health, Comprehensive Pneumology Center, Institute of Lung Biology and Disease , Neuherberg/Munich , Germany.|b Helmholtz Center Munich - German Research Center for Environmental Health, Institute of Epidemiology 2 , Neuherberg/Munich , Germany.
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Kreyling
authors.affiliation: c European Commission , Joint Research Centre, Directorate F - Health, Consumers and Reference Materials , Ispra , Italy.
authors.forename: Uwe
authors.initials: U
authors.lastname: Holzwarth
authors.affiliation: a Helmholtz Center Munich - German Research Center for Environmental Health, Comprehensive Pneumology Center, Institute of Lung Biology and Disease , Neuherberg/Munich , Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Haberl
authors.affiliation: c European Commission , Joint Research Centre, Directorate F - Health, Consumers and Reference Materials , Ispra , Italy.
authors.forename: Ján
authors.initials: J
authors.lastname: Kozempel
authors.affiliation: a Helmholtz Center Munich - German Research Center for Environmental Health, Comprehensive Pneumology Center, Institute of Lung Biology and Disease , Neuherberg/Munich , Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wenk
authors.affiliation: a Helmholtz Center Munich - German Research Center for Environmental Health, Comprehensive Pneumology Center, Institute of Lung Biology and Disease , Neuherberg/Munich , Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hirn
authors.affiliation: a Helmholtz Center Munich - German Research Center for Environmental Health, Comprehensive Pneumology Center, Institute of Lung Biology and Disease , Neuherberg/Munich , Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schleh
authors.affiliation: a Helmholtz Center Munich - German Research Center for Environmental Health, Comprehensive Pneumology Center, Institute of Lung Biology and Disease , Neuherberg/Munich , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schäffler
authors.affiliation: a Helmholtz Center Munich - German Research Center for Environmental Health, Comprehensive Pneumology Center, Institute of Lung Biology and Disease , Neuherberg/Munich , Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Lipka
authors.affiliation: a Helmholtz Center Munich - German Research Center for Environmental Health, Comprehensive Pneumology Center, Institute of Lung Biology and Disease , Neuherberg/Munich , Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Semmler-Behnke
authors.affiliation: c European Commission , Joint Research Centre, Directorate F - Health, Consumers and Reference Materials , Ispra , Italy.
authors.forename: Neil
authors.initials: N
authors.lastname: Gibson
mesh_terms: D000818:Animals; D015824:Blood-Air Barrier / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D019570:Inhalation Exposure; D008657:Metabolic Clearance Rate; D053758:Nanoparticles / Q000008:administration & dosage; D009928:Organ Specificity; D011868:Radioisotopes; D051381:Rats; D011921:Rats, Inbred WKY; D013997:Time Factors; D014018:Tissue Distribution; D014025:Titanium / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014639:Vanadium
chemical_list: D004785:Environmental Pollutants; D011868:Radioisotopes; D014639:Vanadium; C009495:titanium dioxide; D014025:Titanium
keywords: Size-selected, radiolabeled titanium dioxide nanoparticles; accumulation in secondary organs and tissues; different biokinetics patterns after intratracheal instillation and gavage versus intravenous injection; gut-absorption of swallowed nanoparticles; intratracheal instillation; nanoparticle translocation across the air-blood-barrier