Kinetic time courses of inhaled silver nanoparticles in rats.

Silver nanoparticles (Ag NPs) are priority substances closely monitored by health and safety agencies. Despite their extensive use, some aspects of their toxicokinetics remain to be documented, in particular following inhalation, the predominant route of exposure in the workplace. A same experimental protocol and exposure conditions were reproduced two times (experiments E1 and E2) to document the kinetic time courses of inhaled Ag NPs. Rats were exposed nose-only to 20 nm Ag NPs during 6 h at a target concentration of 15 mg/m3 (E1: 218,341 ± 85,512 particles/cm3; E2, 154,099 ± 5728 particles/cm3). The generated aerosol showed a uniform size distribution of nanoparticle agglomerates with a geometric mean diameter ± SD of 79.1 ± 1.88 nm in E1 and 92.47 ± 2.19 nm in E2. The time courses of elemental silver in the lungs, blood, tissues and excreta were determined over 14 days following the onset of inhalation. Excretion profiles revealed that feces were the dominant excretion route and represented on average (± SD) 5.1 ± 3.4% (E1) and 3.3 ± 2.5% (E2) of the total inhaled exposure dose. The pulmonary kinetic profile was similar in E1 and E2; the highest percentages of the inhaled dose were observed between the end of the 6-h inhalation up to 6-h following the end of exposure, and reached 1.9 ± 1.2% in E1 and 2.5 ± 1.6% in E2. Ag elements found in the GIT followed the trend observed in lungs, with a peak observed at the end of the 6-h inhalation exposure and representing 6.4 ± 4.9% of inhaled dose, confirming a certain ingestion of Ag NPs from the upper respiratory tract. Analysis of the temporal profile of Ag elements in the liver showed two distinct patterns: (i) progressive increase in values with peak at the end of the 6-h inhalation period followed by a progressive decrease; (ii) second increase in values starting at 72 h post-exposure with maximum levels at 168-h followed by a progressive decrease. The temporal profiles of Ag elements in lymphatic nodes, olfactory bulbs, kidneys and spleen also followed a pattern similar to that of the liver. However, concentrations in blood and extrapulmonary organs were much lower than lung concentrations. Overall, results show that only a small percentage of the inhaled dose reached the lungs-most of the dose likely remained in the upper respiratory tract. The kinetic time courses in the gastrointestinal tract and liver showed that part of the inhaled Ag NPs was ingested; lung, blood and extrapulmonary organ profiles also suggest that a small fraction of inhaled Ag NPs progressively reached the systemic circulation by a direct translocation from the respiratory tract.

Gelatin Hydrogels Loaded with Lactoferrin-Functionalized Bio-Nanosilver as a Potential Antibacterial and Anti-Biofilm Dressing for Infected Wounds: Synthesis, Characterization, and Deciphering of Cytotoxicity.

Gelatin hydrogels are attractive for wound applications owing to their well-defined structural, physical, and chemical properties as well as good cell adhesion and biocompatibility. This study aimed to develop gelatin hydrogels incorporated with bio-nanosilver functionalized with lactoferrin (Ag-LTF) as a dual-antimicrobial action dressing, to be used in treating infected wounds. The hydrogels were cross-linked using genipin prior to loading with Ag-LTF and characterized for their physical and swelling properties, rheology, polymer and actives interactions, and in vitro release of the actives. The hydrogel's anti-biofilm and antibacterial performances against S. aureus and P. aeruginosa as well as their cytotoxicity effects were assessed in vitro, including primary wound healing gene expression of human dermal fibroblasts (HDFs). The formulated hydrogels showed adequate release of AgNPs and LTF, with promising antimicrobial effects against both bacterial strains. The Ag-LTF-loaded hydrogel did not significantly interfere with the normal cellular functions as no alteration was detected for cell viability, migration rate, and expression of the target genes, suggesting the nontoxicity of Ag-LTF as well as the hydrogels. In conclusion, Ag-LTF-loaded genipin-cross-linked gelatin hydrogel was successfully synthesized as a new approach for fighting biofilms in infected wounds, which may be applied to accelerate healing of chronic wounds.

Cold atmospheric plasma induces silver nanoparticle uptake, oxidative dissolution and enhanced cytotoxicity in glioblastoma multiforme cells.

Silver nanoparticles (AgNP) emerged as a promising reagent for cancer therapy with oxidative stress implicated in the toxicity. Meanwhile, studies reported cold atmospheric plasma (CAP) generation of reactive oxygen and nitrogen species has selectivity towards cancer cells. Gold nanoparticles display synergistic cytotoxicity when combined with CAP against cancer cells but there is a paucity of information using AgNP, prompting to investigate the combined effects of CAP using dielectric barrier discharge system (voltage of 75 kV, current is 62.5 mA, duty cycle of 7.5kVA and input frequency of 50-60Hz) and 10 nm PVA-coated AgNP using U373MG Glioblastoma Multiforme cells. Cytotoxicity in U373MG cells was >100-fold greater when treated with both CAP and PVA-AgNP compared with either therapy alone (IC50 of 4.30 µg/mL with PVA-AgNP alone compared with 0.07 µg/mL after 25s CAP and 0.01 µg/mL 40s CAP). Combined cytotoxicity was ROS-dependent and was prevented using N-Acetyl Cysteine. A novel darkfield spectral imaging method investigated and quantified AgNP uptake in cells determining significantly enhanced uptake, aggregation and subcellular accumulation following CAP treatment, which was confirmed and quantified using atomic absorption spectroscopy. The results indicate that CAP decreases nanoparticle size, decreases surface charge distribution of AgNP and induces uptake, aggregation and enhanced cytotoxicity in vitro.

Quantitative biokinetics over a 28 day period of freshly generated, pristine, 20 nm silver nanoparticle aerosols in healthy adult rats after a single 1½-hour inhalation exposure.

BACKGROUND: There is a steadily increasing quantity of silver nanoparticles (AgNP) produced for numerous industrial, medicinal and private purposes, leading to an increased risk of inhalation exposure for both professionals and consumers. Particle inhalation can result in inflammatory and allergic responses, and there are concerns about other negative health effects from either acute or chronic low-dose exposure. RESULTS: To study the fate of inhaled AgNP, healthy adult rats were exposed to 1½-hour intra-tracheal inhalations of pristine 105Ag-radiolabeled, 20 nm AgNP aerosols (with mean doses across all rats of each exposure group of deposited NP-mass and NP-number being 13.5 ± 3.6 µg, 7.9 ± 3.2•1011, respectively). At five time-points (0.75 h, 4 h, 24 h, 7d, 28d) post-exposure (p.e.), a complete balance of the [105Ag]AgNP fate and its degradation products were quantified in organs, tissues, carcass, lavage and body fluids, including excretions. Rapid dissolution of [105Ag]Ag-ions from the [105Ag]AgNP surface was apparent together with both fast particulate airway clearance and long-term particulate clearance from the alveolar region to the larynx. The results are compatible with evidence from the literature that the released [105Ag]Ag-ions precipitate rapidly to low-solubility [105Ag]Ag-salts in the ion-rich epithelial lining lung fluid (ELF) and blood. Based on the existing literature, the degradation products rapidly translocate across the air-blood-barrier (ABB) into the blood and are eliminated via the liver and gall-bladder into the small intestine for fecal excretion. The pathway of [105Ag]Ag-salt precipitates was compatible with auxiliary biokinetics studies at 24 h and 7 days after either intravenous injection or intratracheal or oral instillation of [110mAg]AgNO3 solutions in sentinel groups of rats. However, dissolution of [105Ag]Ag-ions appeared not to be complete after a few hours or days but continued over two weeks p.e. This was due to the additional formation of salt layers on the [105Ag]AgNP surface that mediate and prolonge the dissolution process. The concurrent clearance of persistent cores of [105Ag]AgNP and [105Ag]Ag-salt precipitates results in the elimination of a fraction > 0.8 (per ILD) after one week, each particulate Ag-species accounting for about half of this. After 28 days p.e. the cleared fraction rises marginally to 0.94 while 2/3 of the remaining [105Ag]AgNP are retained in the lungs and 1/3 in secondary organs and tissues with an unknown partition of the Ag species involved. However, making use of our previous biokinetics studies of poorly soluble [195Au]AuNP of the same size and under identical experimental and exposure conditions (Kreyling et al., ACS Nano 2018), the kinetics of the ABB-translocation of [105Ag]Ag-salt precipitates was estimated to reach a fractional maximum of 0.12 at day 3 p.e. and became undetectable 16 days p.e. Hence, persistent cores of [105Ag]AgNP were cleared throughout the study period. Urinary [105Ag]Ag excretion is minimal, finally accumulating to 0.016. CONCLUSION: The biokinetics of inhaled [105Ag]AgNP is relatively complex since the dissolving [105Ag]Ag-ions (a) form salt layers on the [105Ag]AgNP surface which retard dissolution and (b) the [105Ag]Ag-ions released from the [105Ag]AgNP surface form poorly-soluble precipitates of [105Ag]Ag-salts in ELF. Therefore, hardly any [105Ag]Ag-ion clearance occurs from the lungs but instead [105Ag]AgNP and nano-sized precipitated [105Ag]Ag-salt are cleared via the larynx into GIT and, in addition, via blood, liver, gall bladder into GIT with one common excretional pathway via feces out of the body.

Pulmonary toxicity of silver vapours, nanoparticles and fine dusts: A review.

Silver is used in a wide range of products, and during their production and use, humans may be exposed through inhalation. Therefore, it is critical to know the concentration levels at which adverse effects may occur. In rodents, inhalation of silver nanoparticles has resulted in increased silver in the lungs, lymph nodes, liver, kidney, spleen, ovaries, and testes. Reported excretion pathways of pulmonary silver are urinary and faecal excretion. Acute effects in humans of the inhalation of silver include lung failure that involved increased heart rate and decreased arterial blood oxygen pressure. Argyria-a blue-grey discoloration of skin due to deposited silver-was observed after pulmonary exposure in 3 individuals; however, the presence of silver in the discolorations was not tested. Argyria after inhalation seems to be less likely than after oral or dermal exposure. Repeated inhalation findings in rodents have shown effects on lung function, pulmonary inflammation, bile duct hyperplasia, and genotoxicity. In our evaluation, the range of NOAEC values was 0.11-0.75 mg/m3. Silver in the ionic form is likely more toxic than in the nanoparticle form but that difference could reflect their different biokinetics. However, silver nanoparticles and ions have a similar pattern of toxicity, probably reflecting that the effect of silver nanoparticles is primarily mediated by released ions. Concerning genotoxicity studies, we evaluated silver to be positive based on studies in mammalian cells in vitro and in vivo when considering various exposure routes. Carcinogenicity data are absent; therefore, no conclusion can be provided on this endpoint.

Health Impact of Silver Nanoparticles: A Review of the Biodistribution and Toxicity Following Various Routes of Exposure.

Engineered nanomaterials (ENMs) have gained huge importance in technological advancements over the past few years. Among the various ENMs, silver nanoparticles (AgNPs) have become one of the most explored nanotechnology-derived nanostructures and have been intensively investigated for their unique physicochemical properties. The widespread commercial and biomedical application of nanosilver include its use as a catalyst and an optical receptor in cosmetics, electronics and textile engineering, as a bactericidal agent, and in wound dressings, surgical instruments, and disinfectants. This, in turn, has increased the potential for interactions of AgNPs with terrestrial and aquatic environments, as well as potential exposure and toxicity to human health. In the present review, after giving an overview of ENMs, we discuss the current advances on the physiochemical properties of AgNPs with specific emphasis on biodistribution and both in vitro and in vivo toxicity following various routes of exposure. Most in vitro studies have demonstrated the size-, dose- and coating-dependent cellular uptake of AgNPs. Following NPs exposure, in vivo biodistribution studies have reported Ag accumulation and toxicity to local as well as distant organs. Though there has been an increase in the number of studies in this area, more investigations are required to understand the mechanisms of toxicity following various modes of exposure to AgNPs.

Moderate Static Magnetic Field (6 mT)-Induced Lipid Rafts Rearrangement Increases Silver NPs Uptake in Human Lymphocytes.

One of the most relevant drawbacks in medicine is the ability of drugs and/or imaging agents to reach cells. Nanotechnology opened new horizons in drug delivery, and silver nanoparticles (AgNPs) represent a promising delivery vehicle for their adjustable size and shape, high-density surface ligand attachment, etc. AgNPs cellular uptake involves different endocytosis mechanisms, including lipid raft-mediated endocytosis. Since static magnetic fields (SMFs) exposure induces plasma membrane perturbation, including the rearrangement of lipid rafts, we investigated whether SMF could increase the amount of AgNPs able to pass the peripheral blood lymphocytes (PBLs) plasma membrane. To this purpose, the effect of 6-mT SMF exposure on the redistribution of two main lipid raft components (i.e., disialoganglioside GD3, cholesterol) and on AgNPs uptake efficiency was investigated. Results showed that 6 mT SMF: (i) induces a time-dependent GD3 and cholesterol redistribution in plasma membrane lipid rafts and modulates gene expression of ATP-binding cassette transporter A1 (ABCA1), (ii) increases reactive oxygen species (ROS) production and lipid peroxidation, (iii) does not induce cell death and (iv) induces lipid rafts rearrangement, that, in turn, favors the uptake of AgNPs. Thus, it derives that SMF exposure could be exploited to enhance the internalization of NPs-loaded therapeutic or diagnostic molecules.

Hazard characterization of silver nanoparticles for human exposure routes.

Silver nanoparticles (AgNPs) have been widely used for a multitude of applications without full comprehensive knowledge regarding their safety. In particular, lack of data on hazard characterization may lead to uncertainties regarding potential human health risk. To provide the foundation for human health risk assessment of AgNPs, this study evaluates existing hazard characterization data, including reported pharmacokinetics, symptoms, and their corresponding dose-response relationships. Human equivalent relationships are also provided by extrapolation from animal dose-response relationships. From the data analyzed, it appears that AgNPs may persist for long periods (from days to years) in the human body. It was found that AgNP toxicity on traditional major targets of exogenous substances were generally underestimated. Some omissions of toxicity on sensitive systems in the AgNP toxicity assessment require attention, such as reprotoxicity and neurotoxicity. The necessity of the establishment of toxicity tests specifically for nanomaterials is highlighted. The scientific basis of a toxicity testing strategy is advised by this study, which paves the way for the monitoring and regulation of the ENP utilization in various industries.

Lobar evenness of deposition/retention in rat lungs of inhaled silver nanoparticles: an approach for reducing animal use while maximizing endpoints.

BACKGROUND: Information on particle deposition, retention and clearance are important for the evaluation of the risk of inhaled nanomaterials to human health. Recent revised OECD inhalation toxicity test guidelines require to evaluate the lung burden of nanomaterials after rodent subacute and subchronic inhalation exposure (OECD 412, OECD 413). These revised test guidelines require additional post-exposure observation (PEO) periods that include lung burden measurements that can inform on lung clearance behavior and translocation. The latter being particularly relevant when the testing chemical is a solid poorly soluble nanomaterial. Therefore, in the spirit of 3 R's, we investigated whether measurement of retained lung burden of inhaled nanoparticles (NPs) in individual lung lobes is sufficient to determine retained lung burden in the total lung. If it is possible to use only one lobe, it will reduce animal use and maximize the number of endpoints evaluated. RESULTS: To achieve these goals, rats were exposed nose-only for 1 or 5 days (6 h/day) to an aerosol of 20 nm well-dispersed silver nanoparticles (AgNPs), which is the desired particle diameter resulting in maximum deposition in the pulmonary region when inhaled as singlets. After exposure, the five lung lobes were separated and silver concentration was measured using inductively coupled plasma-mass spectrophotometer (ICP-MS). The results showed that the retention of deposited silver nanoparticle in the different lung lobes did not show any statistically significant difference among lung lobes in terms of silver mass per gram lung lobe. This novel finding of evenness of retention/deposition of inhaled 20 nm NPs in rats for all five lobes in terms of mass per unit tissue weight contrasts with earlier studies reporting greater apical lobe deposition of inhaled micro-particles in rodents. The difference is most likely due to preferred and efficient deposition of inhaled NPs by diffusion vs. additional deposition by sedimentation and impaction for micron-sized particles. CONCLUSION: AgNPs following acute inhalation by rats are evenly retained in each lung lobe in terms of mass per unit lung tissue weight. Accordingly, we suggest sampling any of the rat lung lobes for lung burden analysis can be used to determine deposited or retained total lung burden after short-term inhalation of NPs and using the other lobes for collecting and analyzing bronchoalveolar lavage fluid (BALF) and for histopathological analysis. Therefore, by combining lung burden measurement, histopathological tissue preparation, and BALF assay in the same rat will reduce the number of animals used and maximize the number of endpoints measured.

The clinical pharmacokinetics impact of medical nanometals on drug delivery system.

Nanometals are widely being used for diagnosis, treatment and monitoring of medical conditions. Majorly, nanometals are used to facilitate the delivery of drug to targeted site, minimize drug's penetration to healthy tissues, increase drug's bioavailability, and inhibit its uptake and elimination from the blood by reticuloendothelial process. Despite several benefits, use of nanoparticles as drug carriers is also associated with many problems including instability in blood during circulation, undesirable biodistribution, and toxicity. Research has shown that modification in physicochemical properties including shape, size, and surface can develop a nanometal with desired properties but devoid of associated problems. This review introduces the clinical impact of important physicochemical properties of nanometals such as surface modification, shape, and size. Further, the review focuses on evidence reporting the impact of these properties on pharmacokinetics of nanometals with focus on gold, silver, and iron oxide due to their wide use in the medical field.

Biodegradable silver-loaded polycation modified nanodiamonds/polyurethane scaffold with improved antibacterial and mechanical properties for cartilage tissue repairing.

For cartilage tissue repairing, it remains a key challenge to design implant materials with antibacterial activity, proper degradation rate and mechanical property. In this research, antibacterial nanodiamonds (QND, QND-Ag) modified acrylate-terminated polyurethanes (APU) were prepared. By the addition of nanocomposites, the crystallinity of modified APU obviously increased, which indicates a strong interaction between NDs and APU. Tensile and compression tests were carried out to evaluate the improved mechanical properties. Compared with APU, APU(10%PEG)/QND-Ag possessed the increased modulus and strength, a nevertheless slight decrease in elongation at break. Due to the dual actions of contact-killing of cationic polymers and release-killing of the Ag NPs, QND-Ag-containing polyurethane showed excellent antibacterial activity against Staphylococcus aureus. Moreover, APU containing polyethylene glycol showed a significant increase in degradability rates. Consequently, owing to the dual effect of crystallinity and hydrophilicity, our modified APU exhibited the proper degradation rate adaptable to the healing rate of cartilage tissue. Furthermore, the CCK-8 results demonstrated that synthesized samples were low toxic. Therefore, APU(10%PEG)/QND-Ag holds great promise for the application of cartilage tissue repairing.

Mucus and microbiota as emerging players in gut nanotoxicology: The example of dietary silver and titanium dioxide nanoparticles.

Given the growing use of nanotechnology in many common consumer products, including foods, evaluation of the consequences of chronic exposure to nanoparticles in humans has become a major public health issue. The oral route of exposure has been poorly explored, despite the presence of a fraction of nanosized particles in certain food additives/supplements and the incorporation of such particles into packaging in contact with foods. After their ingestion, these nanoparticles pass through the digestive tract, where they may undergo physicochemical transformations, with consequences for the luminal environment, before crossing the epithelial barrier to reach the systemic compartment. In this review, we consider two examples, nanosilver and nanotitanium dioxide. Despite the specific features of these particles and the differences between them, both display a close relationship between physicochemical reactivity and bioavailability/biopersistence in the gastrointestinal tract. Few studies have focused on the interactions of nanoparticles of silver or titanium dioxide with the microbiota and mucus. However, the microbiota and mucus play key roles in intestinal homeostasis and host health and are undoubtedly involved in controlling the distribution of nanoparticles in the systemic compartment.

Restriction of in vivo infection by antifouling coating on urinary catheter with controllable and sustained silver release: a proof of concept study.

BACKGROUND: Catheter Associated Urinary Tract Infections are among the most common urological infections world-wide. Bacterial biofilms and encrustation cause significant complications in patients with urinary catheters. The objective of the study is to demonstrate the efficacy and safety of an anti-microbial and anti-encrustation silver nanoparticle (AgNP) coating on silicone urinary catheter in two different animal models. METHODS: Antifouling coating (P3) was prepared with alternate layers of polydopamine and AgNP and an outermost antifouling layer. Sixteen C57BL/6 female mice and two female PWG Micropigs® were used to perform the experiments. In mice, a 5 mm long silicone catheter with or without P3 was transurethrally placed into the urinary bladder. Micropigs were transurethrally implanted - one with P3 silicone catheter and the other with commercially available silver coated silicone catheter. Both models were challenged with E. coli. Bacteriuria was evaluated routinely and upon end of study (2 weeks for mice, 3 weeks for micropigs), blood, catheters and bladders were harvested and analysed for bacterial colonization and encrustation as well as for toxicity. RESULTS: Lower bacterial colonization was seen on P3 catheters as well as in bladders of animals with P3 catheter. Bacteriuria was consistently less in mice with P3 catheter than with uncoated catheters. Encrustation was lower on P3 catheter and in bladder of micropig with P3 catheter. No significant toxicity of P3 was observed in mice or in micropig as compared to controls. The numbers were small in this proof of concept study and technical issues were noted especially with the porcine model. CONCLUSIONS: Antifouling P3 coating reduces bacterial colonization on catheter and in animal bladders without causing any considerable toxicity for 2 to 3 weeks. This novel coating could potentially reduce the complications of indwelling urethral catheters.

Silver in the meat and organs of broiler chickens in case of using colloidal silver as an alternative to antibiotics.

The search for new antibacterial products, the mechanisms of action of which differ from conventional antibiotics is a current a topical issue. The objective of our research is to identify the presence of silver in meat and organs of broiler chicks that had been given colloidal silver. The results show that the broiler chick meat contains silver in quantities safe for humans regardless of the use of colloidal silver. Comparison of meat analysis results in experimental and control groups indicate that the ratio of parameters distribution variance for all birds to the mean variance by group for each measured no statistical differences in the chemical composition of bird's meat of experimental and control groups. The analysis also confirmed the existing difference in chemical composition of leg muscle meat and chest muscle meat (P < 0.05), whereas leg muscle contains more fat (6.81% vs. 2.85%) and less protein (20.25% vs. 22.81%).

Tissue distribution of gold and silver after subacute intravenous injection of co-administered gold and silver nanoparticles of similar sizes.

Gold (AuNPs, 12.8 nm) and silver nanoparticles (AgNPs, 10 nm), mixed or separate, were injected into the caudal vein of male Sprague-Dawley rats for 4 weeks. The rats were allowed to recover for further 4 weeks to examine the differences in AuNP/AgNP tissue distribution and clearance. The size distribution of injected AuNPs and AgNPs were not statistically different. The dose groups (five males per group for the administration and three males for the recovery) consisted of seven divisions, i.e., control, AgNPs (with a low dose of 10 µg/kg/day, and, a high dose of 100 µg/kg/day), AuNPs (with a low dose of 10 µg/kg/day, and, a high dose of 100 µg/kg/day), as well as mixed AgNPs/AuNPs (with a low dose of 10/10 µg/kg/day, and a high dose of 100/100 µg/kg/day). The AgNPs accumulated in a dose-dependent manner in the liver, spleen, kidneys, lung, brain, testis or blood. Au concentration increased also in a dose-dependent manner in the liver, kidneys, spleen and lungs, but not in the brain, testis and blood. Ag concentration in the tissues increased dose-dependently after 4 weeks of AgNP/AuNP mixed administration, but to a much lower extent than those observed when they were administered separately. Ag concentration in the tissues after 4 weeks of AgNP/AuNP mixed administration cleared dose-dependently after 4 weeks of recovery. Au concentration in the tissues increased dose-dependently after 4 weeks of AgNp/AuNP mixed administration, while Au concentration in the tissues did not clear as seen in Ag after 4 weeks recovery. Au concentration showed biopersistency or accumulation in the liver, kidneys, spleen and brain of the 4 weeks of recovery. In conclusion, AgNPs and AuNPs showed different toxicokinetic properties and the mixed administration of AgNPs with AuNPs resulted in mutual reduction of their tissue distribution which appeared to be due to competitive inhibition. Furthermore, this subacute intravenous injection study has suggested that these nanoparticles were distributed to the organs in particulate instead of ionic forms.

In vitro percutaneous penetration of silver nanoparticles in pig and human skin.

In this study, the effects of surface charge, dose, and cosmetic vehicle on the penetration of silver nanoparticles (AgNPs) into pig and human skin were compared. AgNPs (20 nm) with varying surface-charges (polyethylene glycol (PEG; neutral), citrate (CIT; negative), and branched polyethylenimine (bPEI; positive) were dosed onto skin in in vitro diffusion cells using an aqueous solution and an oil-in-water emulsion formulation. Samples were analyzed by inductively coupled plasma mass spectroscopy (ICP-MS) and transmission electron microscope (TEM) to assess AgNP skin penetration. The results showed that neutral and positive AgNPs penetrate human skin when applied in a high dose aqueous solution and less with the emulsion vehicle. A mass balance percutaneous penetration study in human skin found the majority of AgNPs were washed from the skin or remained mostly in the stratum corneum (3.4% of the applied dose for AgbPEI and 1.7% for AgPEG). Very little silver was found in the epidermis (1.2% AgbPEI and 0.3% AgPEG) and dermis (0.1% AgbPEI and none detected for AgPEG). These results indicate low dermal penetration of AgNPs that is not greatly affected by surface coating charge. The results will facilitate dermal exposure assessments by better understanding how nanoparticle properties affect skin absorption of nanoparticles found in personal care products.

Toxicity of silver ions, metallic silver, and silver nanoparticle materials after in vivo dermal and mucosal surface exposure: A review.

Silver is used in different applications that result in contact with skin and mucosal surfaces (e.g., jewelry, wound dressings, or eye drops). Intact skin poses an effective barrier against the absorption of silver. Mucosal surfaces are observed to be less effective barriers and compromised skin is often a poor barrier. Silver can deposit as particles in the human body causing a blue-gray discoloration known as argyria. Urine and feces are reported pathways of excretion. Acute human mortality has been observed following an abortion procedure involving the intrauterine administration of 7 g silver nitrate (64 mg silver/kg body weight). Localized argyria has been reported with exposure to silver ions, metallic surfaces, and nanocrystalline silver. Generalized argyria was observed with ionic and nanocrystalline silver in humans at cumulative doses in the range of 70-1500 mg silver/kg body weight. Silver is observed to have a low potential for skin irritation. Eye irritation and some cases of allergic contact dermatitis have been reported. Silver may cause genotoxicity, but additional data are required to assess its carcinogenic potential. Other reported toxicities include hepatic, renal, neurological, and hematological effects.

Silver absorption and toxicity evaluation of silver wound dressings in 40 patients with chronic wounds.

BACKGROUND: Silver-containing dressings are considered to be safe even though there have been some reports of complications, including argyria and various organ system dysfunctions. Despite the widespread use of silver dressings, little research has been done regarding the absorption and toxicity of silver. OBJECTIVE: We aimed to study the systemic absorption of silver in patients with chronic inflammatory wounds and to determine associated factors of systemic silver absorption and evaluated its association with silver toxicity. PATIENTS AND METHOD: Prospective, longitudinal, observational, multicentre, open-label pilot study. Patients from the Dermatology Departments of Lorraine (France) with the following inclusion criteria: (i) a chronic wound of more than 6 weeks and (ii) an ulcer needing silver-containing dressing were included. Before and after 28 days of treatment, clinical characteristics of the wound were recorded; hemogram, hepatic and renal functions, albumin sera and serum silver level were measured. RESULTS: Half of the cases displayed raised levels of silver after 1 month of treatment. Predictive factors for systemic silver absorption were wound area, anaemia and malnutrition with anaemia and malnutrition confirmed on multivariate analysis. Wound vascularization may also play a role, as a higher absorption was observed in cases of wound granulation without arterial components. No toxicity was detected. This work has also emphasized the slow elimination of silver from the body. CONCLUSION: Both long-term application and iterative treatments with silver dressings should be discouraged, especially in the elderly, who often suffer from malnutrition and anaemia to avoid potential cumulative toxicity.

Mechanisms Underlying Neurotoxicity of Silver Nanoparticles.

The potent antimicrobial properties of nanoparticulate silver (AgNPs) have led to broad interest in using them in a wide range of commercial and medical applications. Although numerous in vivo and in vitro studies have provided evidence of toxic effects, rapid commercialization of AgNP-based nanomaterials has advanced without characterization of their potential environmental and health hazards. There is evidence that AgNPs can be translocated from the blood to the brain, regardless the route of exposure, and accumulate in the brain over time. As the brain is responsible for basic physiological functions and controls all human activities, it is important to assess the hazardous influence of AgNPs released from widely used nanoproducts and possible side effects of AgNP-based therapies. A number of studies have suggested that the size, shape and surface coating, as well as rates of silver ion release and interactions with proteins are the key factors determining the neurotoxicity of AgNPs. AgNPs target endothelial cells forming the blood-brain barrier, neurons and glial cells and leads finally to oxidative stress-related cell death. In this chapter, we review in detail current data on the impact of AgNPs on the central nervous system and discuss the possible mechanisms of their neurotoxic effects.

Influence of silver nanoparticles on the enhancement and transcriptional changes of glucosinolates and phenolic compounds in genetically transformed root cultures of Brassica rapa ssp. rapa.

Glucosinolates (GSLs) and phenolic compounds (PCs) are biologically active and involved in the defense reaction of plants; these compounds have a beneficial effect on human health. In this study, we described the influence of biologically synthesized silver nanoparticles (Ag NPs) to enhance the phytochemicals (GSLs and PCs), their transcription levels, and their biological activities in genetically transformed root cultures (hairy root cultures) of Brassica rapa. The concentrations of silver and reactive oxygen species (malondialdehyde and hydrogen peroxide) were highly elevated in the Ag NP-elicited hairy roots (HRs). Glucosinolates (glucoallysin, glucobrassicanapin, sinigrin, progoitrin, gluconapin, 4-methoxyglucobrassicin, 4-hydroxyglucobrassicin, glucobrassicin, neoglucobrassicin, and gluconasturtiin) and their transcripts (MYB34, MYB51, MYB28, and MYB29) were significantly enhanced in the Ag NP-elicited HRs. Moreover, the phenolic compounds (flavonols, hydroxybenzoic, and hydroxycinnamic acids) were significantly enriched in the Ag NP-elicited HRs. Total phenolic and flavonoid concentrations and their transcripts (PAL, CHI, and FLS) were higher in the Ag NP-elicited HRs than in the non-elicited HRs. Additionally, biological (antioxidant, antimicrobial, and anticancer) activities were significantly higher in the Ag NP-elicited HRs than in the non-elicited HRs. The Ag NP-elicited HR cultures offered an efficient and promising in vitro method to increase the production of health-promoting bioactive compounds, which may be useful in nutraceutical and pharmaceutical industries.