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of the skin (argyria) or the eyes (argyrosis), and exposure to soluble silver compounds may produce toxic effects like liver and kidney damage; eye, skin, respiratory and intestinal tract irritations; and untoward changes in blood cells. Numerous reports suggest that nano silver cannot differentiate between the microbes that are harmful or useful to the ecology. Only limited studies have been performed to evaluate the toxicity of nanosilver. It was demonstrated by in vitro toxicity assay of AgNP that rat liver cells on low level exposure elicit oxidative stress and damaged mitochondrial function. By interrupting mitochondrial function and causing leakage through the cell membrane, silver nanoparticles manifested to be toxic to in vitro mouse germ line stem cells. On male reproductive system they adversely affect sperm cells by crossing the blood–testis barrier and get deposited in the testes. The tar- get organ in mouse for the nanosilver is liver as revealed by in vivo studies on the oral toxicity on rats. The higher occur- rence of bile duct hyperplasia, with or without necrosis, fibro- sis and pigmentation in the study animals revealed that when the nanoparticles are stored for a long span of time there is let out of silver assuring that aged nanosilver is more toxic than new nanosilver [10]. Nanosilver also has toxic effects on aquatic animals and hinders osmoregulation in fish by interacting with the gills of fish and impedes basolateral Naþ–Kþ-ATPase activity suggest- ing that the release of nano silver into the environment has to be heedfully reviewed [10]. The toxicity of silver nanoparticles is affected by a number of factors such as particle size, shape and surface chemistry, crystallinity, capping agents, environmental factors, such as ionic strength, pH and the presence of ligands, divalent cati- ons and macromolecules. Hence, to reach final conclusion on its toxicity it is mandatory to carry out more studies to check the toxic effects of nanosilver has in vivo [76]. a) Oral toxicity In mammals and in humans, the orally administered silver has been manifested in the range of 0.4–18 and 18%, respectively. Silver seems to be allocated to all the organs probed, with the maximum being seen in intestine and stom- ach. Silver induces a blue-grey discoloration in the skin termed argyria [16]. Increased plasma alkaline phosphatase and decreased plasma urea were seen following ionic silver oral administration in the form of silver acetate (9mg of sil- ver/kg of bw/day) or nanoparticulate silver (9mg of 14nm particles/kg of bw/day) after 28d oral analysis. Enhanced serum cholesterol levels were noted at the 125 mg/kg of bw/ day dose and above for males and were noted for females following the oral administration of 500mg/kg of bw/day [78]. b) Neurotoxicity Silver induced neurotoxic effects occur via secondary mole- cules that are released from periphery, even in the absence of silver in the brain extracellular fluid. Hadrup and Lama stated the effects of the ionic and 14 nm nanoparticulate sil- ver for 28 d on neurotransmitters in rats, and noticed changes ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY S123 in noradrenaline, dopamine and 5-HT concentrations in brain at doses of 2.25mg/kg of bw/day of nanoparticulate silver and 9mg/kg of bw/day of ionic silver [16]. Mirsattari et al. observed that following oral administration of large amounts of colloidal silver, myoclonic status epilepticus was observed in man [79]. c) Immunotoxicity [13] After feeding high doses of 13nm nanoparticulate or 2–3.5 micro particulate silver, lymphocyte infiltration was docu- mented in mice by Cha et al. [80]. Havarinasab et al. reported an autoimmune condition in H-2s mouse strain following 0.5g of silver nitrate/L in the drinking water for 10weeks [81]. Van der Zande et al. reported no sign of immunotoxicity following the oral ingestion of 90 mg/kg of bw of silver nano- particles (15 and 20nm) or 9mg/kg of bw/day of ionic silver for 28d [18]. Hadrup and Lama also demonstrated the decrease in thymus weight following the oral ingestion of nanoparticulate and ionic silver for 28 d [16]. d) Environmental toxicity In the aquatic environment, the response of nanotoxins including AgNP has a considerable impact. With the help of algal growth inhibition assays, various studies probed AgNP toxicity to primary producers. These studies included: LC50 Median lethal concentration, EC50 Median effective concentra- tion, IC50 Median Immobilizing Concentration. Silver barbs, zebra fish and god fish have been employed in toxicity evalu- ation of in vivo fish studies. Aquatic ecotoxicological studies exploit primary fish cells and continuous fish cell lines [5]. e) Reproductive toxicity Following oral administration of AgNPs ($15nm in size) for 2–4weeks, at 30 or 300mg/kg/d caused changes in histo- pathology including inflammation, apoptosis and degener- ated follicles in the ovaries of female rats. Male and female mice fertility was checked by intravenously injecting with AgNPs and it was concluded that that their gene expressions were down regulated resulting in debilitated development of spermatocytes and oocytes. Oral AgNPs (15 nm) exhibit ovar- ian toxic potential at 30mg/kg/d. Intravenous AgNPs (20nm) lowers the number of follicles and augment embryonic deaths at 0.5 mg/kg [1]. Conclusion and future prospects Silver has been most broadly studied and used since early times to fight against infections and hinder spoilage in com- parison to other antimicrobial agents. Silver is also found to be non-toxic to humans in minute concentrations. The resist- ance developed by microorganism in silver in less as com- pared to antibiotics as a broad range of microorganisms is being targeted by silver. The uses of silver nanoparticles are varied and many, but the most utilized and desired aspect is their antimicrobial capacity and anti-inflammatory capacity. The toxicity inducedPDF Image | Artificial Cells, Nanomedicine, and Biotechnology
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