title: Acute and subacute pulmonary toxicity and mortality in mice after intratracheal instillation of ZnO nanoparticles in three laboratories.
abstract: Inhalation is the main pathway of ZnO exposure in the occupational environment but only few studies have addressed toxic effects after pulmonary exposure to ZnO nanoparticles (NP). Here we present results from three studies of pulmonary exposure and toxicity of ZnO NP in mice. The studies were prematurely terminated because interim results unexpectedly showed severe pulmonary toxicity. High bolus doses of ZnO NP (25 up to 100 μg; ≥1.4 mg/kg) were clearly associated with a dose dependent mortality in the mice. Lower doses (≥6 μg; ≥0.3 mg/kg) elicited acute toxicity in terms of reduced weight gain, desquamation of epithelial cells with concomitantly increased barrier permeability of the alveolar/blood as well as DNA damage. Oxidative stress was shown via a strong increase in lipid peroxidation and reduced glutathione in the pulmonary tissue. Two months post-exposure revealed no obvious toxicity for 12.5 and 25 μg on a range of parameters. However, mice that survived a high dose (50 μg; 2.7 mg/kg) had an increased pulmonary collagen accumulation (fibrosis) at a similar level as a high bolus dose of crystalline silica. The recovery from these toxicological effects appeared dose-dependent. The results indicate that alveolar deposition of ZnO NP may cause significant adverse health effects.
authors.affiliation: National Research Centre for the Working Environment, Lersø Parkallé 105, DK, 2100 Copenhagen Ø, Denmark. Electronic address: nrj@nrcwe.dk.
authors.forename: Nicklas Raun
authors.initials: NR
authors.lastname: Jacobsen
authors.affiliation: Institute of Lung Biology and Disease, Comprehensive Pneumology Center Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Stoeger
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology, Université catholique de Louvain, Avenue E. Mounier 52 - bte B1.52.12, 1200 Brussels, Belgium.
authors.forename: Sybille
authors.initials: S
authors.lastname: van den Brule
authors.affiliation: National Research Centre for the Working Environment, Lersø Parkallé 105, DK, 2100 Copenhagen Ø, Denmark.
authors.forename: Anne Thoustrup
authors.initials: AT
authors.lastname: Saber
authors.affiliation: Institute of Lung Biology and Disease, Comprehensive Pneumology Center Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Beyerle
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology, Université catholique de Louvain, Avenue E. Mounier 52 - bte B1.52.12, 1200 Brussels, Belgium.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vietti
authors.affiliation: National Food Institute, Technical University of Denmark, Søborg, Denmark.
authors.forename: Alicja
authors.initials: A
authors.lastname: Mortensen
authors.affiliation: Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland.
authors.forename: Józef
authors.initials: J
authors.lastname: Szarek
authors.affiliation: National Research Centre for the Working Environment, Lersø Parkallé 105, DK, 2100 Copenhagen Ø, Denmark.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Budtz
authors.affiliation: Department of Public Health, University of Copenhagen, DK, 1014 Copenhagen K, Denmark.
authors.forename: Ali
authors.initials: A
authors.lastname: Kermanizadeh
authors.affiliation: Department of Chemistry, Missouri University of Science and Technology, Rolla, MO, USA.
authors.forename: Atrayee
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry, Missouri University of Science and Technology, Rolla, MO, USA.
authors.forename: Nuran
authors.initials: N
authors.lastname: Ercal
authors.affiliation: National Research Centre for the Working Environment, Lersø Parkallé 105, DK, 2100 Copenhagen Ø, Denmark; Department of Micro- and Nanotechnology, Technical University of Denmark, DK, 2800 Lyngby, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.affiliation: National Research Centre for the Working Environment, Lersø Parkallé 105, DK, 2100 Copenhagen Ø, Denmark; Department of Public Health, University of Copenhagen, DK, 1014 Copenhagen K, Denmark.
authors.forename: Håkan
authors.initials: H
authors.lastname: Wallin
authors.affiliation: Department of Public Health, University of Copenhagen, DK, 1014 Copenhagen K, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Møller
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D003433:Crosses, Genetic; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D019570:Inhalation Exposure / Q000009:adverse effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D010316:Particle Size; D010865:Pilot Projects; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis; D023382:Toxicity Tests, Acute; D059551:Toxicity Tests, Subacute; D015430:Weight Gain / Q000187:drug effects; D015034:Zinc Oxide / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D015034:Zinc Oxide
keywords: Cytotoxicity; DNA damage; Fibrosis; Inflammation; Mortality; Oxidative stress