title: Quantitative biokinetics of titanium dioxide nanoparticles after oral application in rats: Part 2.
abstract: The biokinetics of a size-selected fraction (70 nm median size) of commercially available and48V-radiolabeled [48V]TiO2nanoparticles has been investigated in female Wistar-Kyoto rats at retention timepoints 1 h, 4 h, 24 h and 7 days after oral application of a single dose of an aqueous [48V]TiO2-nanoparticle suspension by intra-esophageal instillation. A completely balanced quantitative body clearance and biokinetics in all organs and tissues was obtained by applying typical [48V]TiO2-nanoparticle doses in the range of 30-80 μg•kg-1bodyweight, making use of the high sensitivity of the radiotracer technique. The [48V]TiO2-nanoparticle content was corrected for nanoparticles in the residual blood retained in organs and tissue after exsanguination and for48V-ions not bound to TiO2-nanoparticles. Beyond predominant fecal excretion about 0.6% of the administered dose passed the gastro-intestinal-barrier after one hour and about 0.05% were still distributed in the body after 7 days, with quantifiable [48V]TiO2-nanoparticle organ concentrations present in liver (0.09 ng•g-1), lungs (0.10 ng•g-1), kidneys (0.29 ng•g-1), brain (0.36 ng•g-1), spleen (0.45 ng•g-1), uterus (0.55 ng•g-1) and skeleton (0.98 ng•g-1). Since chronic, oral uptake of TiO2particles (including a nano-fraction) by consumers has continuously increased in the past decades, the possibility of chronic accumulation of such biopersistent nanoparticles in secondary organs and the skeleton raises questions about the responsiveness of their defense capacities, and whether these could be leading to adverse health effects in the population at large. After normalizing the fractions of retained [48V]TiO2-nanoparticles to the fraction that passed the gastro-intestinal-barrier and reached systemic circulation, the biokinetics was compared to the biokinetics determined after IV-injection (Part 1). Since the biokinetics patterns differ largely, IV-injection is not an adequate surrogate for assessing the biokinetics after oral exposure to TiO2nanoparticles.
authors.affiliation: a Helmholtz Zentrum München - 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 Zentrum München - 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: 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 Zentrum München - 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 Zentrum München - 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: a Helmholtz Zentrum München - 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 Zentrum München - 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 Zentrum München - 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 Zentrum München - 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: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism; D008657:Metabolic Clearance Rate; D053758:Nanoparticles / Q000008:administration & dosage; D010316:Particle Size; D011868:Radioisotopes; D051381:Rats; D011921:Rats, Inbred WKY; D013499:Surface Properties; 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 pattern after gavage versus intravenous injection; gavage; gut-absorption