title: Systemic and immunotoxicity of silver nanoparticles in an intravenous 28 days repeated dose toxicity study in rats.
abstract: Because of its antibacterial activity nanosilver is one of the most commonly used nanomaterials. It is increasingly used in a variety of both medical and consumer products resulting in an increase in human exposure. However, the knowledge on the systemic toxicity of nanosilver is relatively limited. To determine the potential systemic toxicity of silver nanoparticles (Ag-NP) with different sizes (20 nm and 100 nm) a 28-days repeated dose toxicity study was performed in rats using intravenous administration. The toxic effect of the 20 nm Ag-NP was performed using the bench mark dose (BMD) approach. Treatment with a maximum dose of 6 mg/kg body weight was well tolerated by the animals. However, both for 20 nm and 100 nm Ag-NP growth retardation was observed during the treatment. A severe increase in spleen size and weight was present which was due to an increased cell number. Both T and B cell populations showed an increase in absolute cell number, whereas the relative cell numbers remained constant. At histopathological evaluation brown and black pigment indicating Ag-NP accumulation was noted in spleen, liver, and lymph nodes. Ag-NP was also detected incidentally in other organs. Clinical chemistry indicated liver damage (increased alkaline phosphatase, alanine transaminase, and aspartate transaminase) that could not be confirmed by histopathology. Hematology showed a decrease in several red blood cell parameters. The most striking toxic effect was the almost complete suppression of the natural killer (NK) cell activity in the spleen at high doses. Other immune parameters affected were: decreased interferon-γ and interleukin (IL)-10 production by concanavalin-A stimulated spleen cells, increased IL-1β and decreased IL-6, IL-10 and TNF-α production by lipopolysaccharide stimulated spleen cells, increase in serum IgM and IgE, and increase in blood neutrophilic granulocytes. For the spleen weight a critical effect dose of 0.37 mg/kg body weight (b.w.) could be established. The lowest critical effect dose (CED) for a 5% change compared to control animals was observed for thymus weight (CED05 0.01 mg/kg b.w.) and for functional immune parameters, i.e. decrease in NK cell activity (CED05 0.06 mg/kg b.w.) and LPS stimulation of spleen cells (CED05 0.04 mg/kg b.w.). These results show that for nanosilver the most sensitive parameters for potential adverse responses were effects on the immune system.
authors.affiliation: Centre for Health Protection, National Institute for Public Health and The Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. wim.de.jong@rivm.nl
authors.forename: Wim H
authors.initials: WH
authors.lastname: De Jong
authors.forename: Leo T M
authors.initials: LT
authors.lastname: Van Der Ven
authors.forename: Annemarie
authors.initials: A
authors.lastname: Sleijffers
authors.forename: Margriet V D Z
authors.initials: MV
authors.lastname: Park
authors.forename: Eugene H J M
authors.initials: EH
authors.lastname: Jansen
authors.forename: Henk
authors.initials: H
authors.lastname: Van Loveren
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Vandebriel
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D005260:Female; D007107:Immune System / Q000187:drug effects / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012834:Silver / Q000737:chemistry*; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D012834:Silver
keywords: 28 Days repeated dose study; Intravenous; Nanosilver; Nanotoxicity