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Stensberg et al. Page 6 Recently, a fourth chemometric of Ag NP-induced toxicity has been reported. Rat coronary endothelial cells exposed for 24 h to high doses of Ag NPs (100 μg/ml) responded with an increased production of nitric oxide, which also increased cell proliferation [81]. At lower doses (<10 μg/ml), only a decrease in mitochondrial function was observed. Nitric oxide is known to have an important role in the cardiovascular system, suggesting another direction for the biological effects of Ag NPs. n In vivo studies Compared with in vitro studies, significantly less information is available on the potential mechanisms of toxicity of Ag NPs from in vivo studies. As reviewed below, exposure of laboratory rodents to Ag NPs has resulted in a myriad of toxicological responses, including effects on circulatory, respiratory, central nervous and hepatic systems. Effects on dermal tissues have also been reported after topical administration of Ag NPs. In vivo studies Compared with in vitro studies, significantly less information is available on the potential mechanisms of toxicity of Ag NPs from in vivo studies. As reviewed below, exposure of laboratory rodents to Ag NPs has resulted in a myriad of toxicological responses, including effects on circulatory, respiratory, central nervous and hepatic systems. Effects on dermal tissues have also been reported after topical administration of Ag NPs. Ingestion or inhalation of Ag NPs results in their transport to the circulatory system [22,82]. Only one whole animal study is available on the effects of Ag NPs on hematological parameters. Mice injected with Ag NPs responded with a decrease in platelet aggregation [83]. The mechanisms of such a response remain unknown. With regard to adverse respiratory effects of Ag NPs, only one complete study has been reported [84]. In this study, rats were exposed to 18–19 nm Ag NPs at a concentration of 0.7–2.9 × 106 particles/cm3 for 90 days. Lung function, measured as tidal volume, minute volume and peak inspiration flow, was impaired in the highest concentration tested. Inflammatory responses (total protein, alveolar wall thickening and macrophage infiltration) were also increased in some animals [84]. A second, independent study indicated a rapid clearance of silver from rat lungs after an acute (6 h) inhalation exposure to Ag NPs, but an autopsy revealed the translocation of Ag NPs to the brain a week after initial exposure [85]. A pharmacokinetic study of Ag NPs injected into the bloodstream also confirmed their movement through the blood–brain barrier with subsequent accumulation in the brain, accompanied by neuronal d egeneration and necrosis [86]. Recent evidence indicates that liver and bile ducts are targets of toxicity for Ag NPs: Ag+ has been found to accumulate in liver following exposure to Ag NPs [82,84,87,88]. Histopathological analyses of liver and bile ducts of mice after Ag NP exposure also revealed vacuolization and hepatic focal necrosis, hyperplasia of bile ducts, increased infiltration of inflammatory cells and dilation of central veins. Increases in the expression of genes involved in apoptotic and inflammatory pathways have also been detected in mice livers exposed to Ag NPs [75]. Toxic effects were also observed during zebrafish development. Mortality, heart rate and hatching rate were all impacted by Ag NPs. Each of these end points was affected in a dose- dependent manner (5–100 μg/l Ag NPs). Changes in morphology, edema and an overall slowing of development were also detected. In this study, uniform distribution of the nanoparticles within the zebrafish embryos was also observed [89]. A single study is available on the morphological alterations of skin cells following exposure to Ag NPs [7]. In this study, pigs were topically dosed with Ag NPs (20–50 nm, 0.34–34 μg/ ml) for 14 days. The highest doses caused edema, epidermal hyperplasia and focal inflammation. Nanomedicine (Lond). Author manuscript; available in PMC 2012 May 24. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptPDF Image | Toxicological studies on silver nanoparticles
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