title: Quantitative biokinetics of titanium dioxide nanoparticles after intravenous injection in rats: Part 1.
abstract: Submicrometer TiO2particles, including nanoparticulate fractions, are used in an increasing variety of consumer products, as food additives and also drug delivery applications are envisaged. Beyond exposure of occupational groups, this entails an exposure risk to the public. However, nanoparticle translocation from the organ of intake and potential accumulation in secondary organs are poorly understood and in many investigations excessive doses are applied. The present study investigates the biokinetics and clearance of a low single dose (typically 40-400 μg/kg BW) of48V-radiolabeled, pure TiO2anatase nanoparticles ([48V]TiO2NP) with a median aggregate/agglomerate size of 70 nm in aqueous suspension after intravenous (IV) injection into female Wistar rats. Biokinetics and clearance were followed from one-hour to 4-weeks. The use of radiolabeled nanoparticles allowed a quantitative [48V]TiO2NP balancing of all organs, tissues, carcass and excretions of each rat without having to account for chemical background levels possibly caused by dietary or environmental titanium exposure. Highest [48V]TiO2NP accumulations were found in liver (95.5%ID after one day), followed by spleen (2.5%), carcass (1%), skeleton (0.7%) and blood (0.4%). Detectable nanoparticle levels were found in all other organs. The [48V]TiO2NP content in blood decreased rapidly after 24 h while the distribution in other organs and tissues remained rather constant until day-28. The present biokinetics study is part 1 of a series of studies comparing biokinetics after three classical routes of intake (IV injection (part 1), ingestion (part 2), intratracheal instillation (part 3)) under identical laboratory conditions, in order to test the common hypothesis that IV-injection is a suitable predictor for the biokinetics fate of nanoparticles administered by different routes. This hypothesis is disproved by this series of studies.
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: 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: 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: 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; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D065669:Hepatobiliary Elimination; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D053758:Nanoparticles / Q000008:administration & dosage; D009928:Organ Specificity; D010316:Particle Size; D011868:Radioisotopes; D051381:Rats; D017208:Rats, Wistar; 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 organs and tissues; hepato-biliary nanoparticle clearance; intravenous injection; translocation across organ membranes