title: Identification of the appropriate dose metric for pulmonary inflammation of silver nanoparticles in an inhalation toxicity study.
abstract: A number of studies have shown that induction of pulmonary toxicity by nanoparticles of the same chemical composition depends on particle size, which is likely in part due to differences in lung deposition. Particle size mostly determines whether nanoparticles reach the alveoli, and where they might induce toxicity. For the risk assessment of nanomaterials, there is need for a suitable dose metric that accounts for differences in effects between different sized nanoparticles of the same chemical composition. The aim of the present study is to determine the most suitable dose metric to describe the effects of silver nanoparticles after short-term inhalation. Rats were exposed to different concentrations (ranging from 41 to 1105 µg silver/m(3) air) of 18, 34, 60 and 160 nm silver particles for four consecutive days and sacrificed at 24 h and 7 days after exposure. We observed a concentration-dependent increase in pulmonary toxicity parameters like cell counts and pro-inflammatory cytokines in the bronchoalveolar lavage fluid. All results were analysed using the measured exposure concentrations in air, the measured internal dose in the lung and the estimated alveolar dose. In addition, we analysed the results based on mass, particle number and particle surface area. Our study indicates that using the particle surface area as a dose metric in the alveoli, the dose-response effects of the different silver particle sizes overlap for most pulmonary toxicity parameters. We conclude that the alveolar dose expressed as particle surface area is the most suitable dose metric to describe the toxicity of silver nanoparticles after inhalation.
authors.affiliation: a Department of Toxicogenomics , Maastricht University , Maastricht , The Netherlands .|b Centre for Health Protection, Centre for Sustainability, Environment and Health, Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands .
authors.forename: Hedwig M
authors.initials: HM
authors.lastname: Braakhuis
authors.affiliation: b Centre for Health Protection, Centre for Sustainability, Environment and Health, Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands .|c Environmental Epidemiology, Institute of Risk Assessment Sciences, Utrecht University , TD Utrecht , The Netherlands , and.
authors.forename: Flemming R
authors.initials: FR
authors.lastname: Cassee
authors.affiliation: b Centre for Health Protection, Centre for Sustainability, Environment and Health, Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands .
authors.forename: Paul H B
authors.initials: PH
authors.lastname: Fokkens
authors.affiliation: b Centre for Health Protection, Centre for Sustainability, Environment and Health, Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands .
authors.forename: Liset J J
authors.initials: LJ
authors.lastname: de la Fonteyne
authors.affiliation: b Centre for Health Protection, Centre for Sustainability, Environment and Health, Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands .
authors.forename: Agnes G
authors.initials: AG
authors.lastname: Oomen
authors.affiliation: d Philips Innovation Services , Eindhoven , The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Krystek
authors.affiliation: b Centre for Health Protection, Centre for Sustainability, Environment and Health, Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands .
authors.forename: Wim H
authors.initials: WH
authors.lastname: de Jong
authors.affiliation: a Department of Toxicogenomics , Maastricht University , Maastricht , The Netherlands .|b Centre for Health Protection, Centre for Sustainability, Environment and Health, Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands .
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.affiliation: b Centre for Health Protection, Centre for Sustainability, Environment and Health, Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands .
authors.forename: Margriet V D Z
authors.initials: MV
authors.lastname: Park
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D019570:Inhalation Exposure; D008168:Lung / Q000378:metabolism; D008297:Male; D053768:Metal Nanoparticles / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D011014:Pneumonia / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D012834:Silver / Q000378:metabolism / Q000633:toxicity*
chemical_list: D016207:Cytokines; D012834:Silver
keywords: Dose metrics; inhalation exposure; nanotoxicology; risk assessment