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.

Deriving a provisional tolerable intake for intravenous exposure to silver nanoparticles released from medical devices

“…The De Jong et al (2013) study, a 28-day study in rats investigating a series of immunotoxicological endpoints after exposure to 20 nm AgNP, qualified to serve as the critical study for the pTI derivation. De Jong et al (2013) reported the lowest dose-dependent critical health effect, which was a BMDL05 of 0.14 mg/kg bw/day for increased spleen weight. To derive the pTI, a modifying factor (MF) of 1,000 was applied to the POD to account for interindividual variability (10), potential interspecies difference in potency (10), and the lack of chronic toxicity study data (10) based on scientific review.…”

Immunomodulatory properties of silver nanoparticles contribute to anticancer strategy for murine fibrosarcoma

“…14 The intravenous administration of AgNPs also showed immunotoxicity in murine models. 15 Respiratory tract immune toxicity has also been associated with AgNPs. 16 AgNP treatment of peripheral blood mononuclear cells and human mesenchymal stem cells showed inhibition of the production of cytokines, such as IFN-c, IL-6, IL-8, IL-11, TNF-a and more weakly, IL-5.…”

Potential risks and benefits of nanotechnology: perceptions of risk in sunscreens

“…In addition, other in vitro studies showed that cytokine production in macrophages can be induced by nanosilver (Martinez-Gutierrez et al 2012)(Also, human peripheral blood mononuclear cells produced IL-6 and IL8 after exposure to Ag-NP, whereas TNFα production was not affected In contrast, in an intravenous 28-day repeated dose toxicity study in rats with 20 nm and 100 nm nanosilver, no cytokine level changes were found -although ex vivo cytokine induction and production by isolated spleen cells were affected (De Jong et al 2013). In this study, Wistar rats were treated with a maximum dose of 6 mg/kg body weight, which was well tolerated by the animals.…”