Immunotoxicity of silver nanoparticles in an intravenous 28-day repeated-dose toxicity study in rats

Abstract

BackgroundNanosilver is used in a variety of medical and consumer products because of its antibacterial activity. This wide application results in an increased human exposure. Knowledge on the systemic toxicity of nanosilver is, however, relatively scarce. In a previous study, the systemic toxicity of 20 nm silver nanoparticles (Ag-NP) was studied in a 28-day repeated-dose toxicity study in rats. Ag-NP were intravenously administered with a maximum dose of 6 mg/kg body weight (bw)/day. Several immune parameters were affected: reduced thymus weight, increased spleen weight and spleen cell number, a strongly reduced NK cell activity, and reduced IFN-γ production were observed.MethodsPrompted by these affected immune parameters, we wished to assess exposure effects on the functional immune system. Therefore, in the present study the T-cell dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) was measured in a similar 28-day intravenous repeated-dose toxicity study. In addition, a range of immunological parameters was measured. Data obtained using the benchmark dose (BMD) approach were analyzed by fitting dose-response models to the parameters measured.ResultsA reduction in KLH-specific IgG was seen, with a lowest 5% lower confidence bound of the BMD (BMDL) of 0.40 mg/kg bw/day. This suggests that Ag-NP induce suppression of the functional immune system. Other parameters sensitive to Ag-NP exposure were in line with our previous study: a reduced thymus weight with a BMDL of 0.76 mg/kg bw/day, and an increased spleen weight, spleen cell number, and spleen cell subsets, with BMDLs between 0.36 and 1.11 mg/kg bw/day. Because the effects on the spleen are not reflected by increased KLH-specific IgG, they, however, do not suggest immune stimulation.ConclusionsIntravenous Ag-NP administration in a 28-day repeated-dose toxicity study induces suppression of the functional immune system. This finding underscores the importance to study the TDAR to evaluate immunotoxicity and not to rely solely on measuring immune cell subsets.

Silver nanoparticles rapidly induce atypical human neutrophil cell death by a process involving inflammatory caspases and reactive oxygen species and induce neutrophil extracellular traps release upon cell adhesion

“…AgNPs are known for their antimicrobial properties [26,27]. On the other hand, some studies have associated potential harmful effects to these NPs [28,29]. In this study, evaluation of the physico-chemical characteristics of AgNP 15 when dispersed in different physiological solutions, such as RPMI culture medium + autologous serum or HBSS buffer alone demonstrated that the NPs remain relatively stable under these conditions.…”

The immunomodulatory effects of titanium dioxide and silver nanoparticles

“…Interestingly, increases in spleen weight and spleen cell number are observed, which are not entirely consistent with the reduced KLH-specific IgG production. (Vandebriel et al, 2014) In line with these observations, the 28 day oral administration of 0.25, 2.5 or 25 ppm Ag nanoparticles has been shown to modulate the proliferative activity and cytokine production of murine splenocytes. Administration of 0.25 ppm Ag nanoparticles results in a significant inhibition of T cell proliferation and an augmentation of pro-inflammatory cytokine production by unstimulated and LPSstimulated cells.…”

Current Development of Silver Nanoparticle Preparation, Investigation, and Application in the Field of Medicine

“…Also, AgNPs have been reported to cross the blood-brain barrier in rats and induce neuronal degeneration and necrosis through accumulation in the brain over a long period of time [82]. Additionally, Vandebriel et al and de Jong et al found that intravenous administration of both 20 and 100 nm AgNPs in a 28-day repeated-dose toxicity study in SD rats induces suppression of the functional immune system [83,84]. In the area of development, a study reported that AgNPs less than 12 nm in size affected early development of fish embryos, caused chromosomal aberrations and DNA damage, and induced proliferation arrest in cell lines of zebrafish indicating that AgNPs must be investigated for their potential teratogenic effects in humans [85].…”