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International efforts to promote predictive toxicology incorporate some form of modeling based on the regularities, insights, and hypotheses gained from analyzing laboratory studies compiled in databases. While there has been a broad commentary on definitions, metadata, and test methodologies, all necessary to establishing data repositories, there has been less on translating the resulting insights into computational models. The recent use of a computational model to support a recommended exposure limit for nanoparticulate silver is an opportunity to examine physiologically based toxicokinetics in terms of data availability, model verification and validation, and regulatory acceptance. The resulting suggestions align with findings from the EU-US Roadmap Nanoinformatics 2030 and the 2018 acceptance of a computational model by the European Food Safety Authority., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Argyria is a rare condition characterized by gray/blue dislocation of the skin caused by chronic exposure to silver salts., Case Report: We review the case of an 81-year-old man who presented to the emergency department after a motor vehicle accident, was incidentally found to have skin discoloration, and was ultimately diagnosed with argyria. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although most emergency physicians will not complete a toxicology fellowship, all emergency physicians are on the front line of toxicological presentations and should be able to recognize argyria and differentiate this condition from other causes of skin discoloration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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/m 3 . 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: None

A biopsy specimen from the nasal mucosa of a 37-year-old man disclosed a subepithelial accumulation of black granules mainly running parallel to the surface in the absence of any inflammatory infiltrate. Since the mucosal pigment was negative with Perls' stain and resisted to melanin bleach, an exogenous pigmentation was suspected. The biopsy specimen had been taken because of a diffuse steel-blue pigmentation of the nasal mucosa, incidentally discovered during routine clinical examination. A diagnosis of occupational argyria of the nasal mucosa was finally made since the patient was a silver cleaner. Argyria is a rare cause of nasopharyngeal mucosal pigmentation; it is not a precancerous condition, but it can be mistaken for a melanosis or a melanocytic tumor both clinically and histopathologically. Clinicopathological correlation is mandatory, since the final diagnosis is based on a history of chronic silver exposure.

Silver cutlery and serving dishes are a potential source of exposure of humans that was never quantified. Release of silver was assessed in vitro in an acidic solution mimicking food fluid in two conditions: i] the JRC guidelines for hot fill conditions with stable high temperature over a 2 hour-period of time, and ii] a more realistic condition with spontaneous progressive decline from 90̊C to ambient temperature over the same period of time. Massive silver 95% strips were exposed to a 5% citric acid solution: i) cooling down from 90̊C to ambient or ii) 70̊C maintained, during 2 hours. Spectrometry with optical emission was used to measure silver in solution. In the spontaneous cooling down study, the time-course of temperature was close to the Newton's law of cooling and the released quantities were detected but too low to be measured. The 70̊C exposition resulted in a non-linear release that became quantifiable after one hour of heating up to an apparent plateau at 120 min with a mean concentration [extreme] of 24.6 [22.3-26.8] μg/L. The results of the present study allow concluding that 95% silver used for cutlery and serving dishes may be released in foods. However, the extent of release depends on the condition of use. At a stable 70̊C temperature over a 2 h-period of time, silver is released in a non-linear model up to a mean concentration of 24.6 μg/L. In contrast, in conditions fitting with the routine recommendations of use, infinitesimal detectable amounts of silver were released.

Purpose: The aim of this report is to present a case of a patient, metal foundry worker, who had been exposed to industrial silver salts for over 20 years. It is well established that chronic exposure to silver compounds can cause accumulation of silver deposits in various tissues. This condition is referred to as argyrosis or argyria, whereas changes related to eye tissues are defined as ocular argyrosis., Methods: A complete eye examination, corneal confocal microscopy, kinetic and static visual field test, posterior segment optical coherent tomography, pattern visual evoked potentials (PVEP), flash visual evoked potentials, multifocal electroretinogram, pattern electroretinogram (PERG), full-field electroretinography (FERG) and electrooculogram were all performed., Results: Eye examination revealed decreased visual acuity, corneal deposits and drusenoid changes within the macula. Although electrophysiology tests did not show changes in the function of retinal pigment epithelium, they revealed abnormal function of photoreceptors in the central and peripheral retina. PERG abnormalities and delayed latency of P100 wave in PVEP confirmed impaired function of the inner layers of the retina in the macular region., Conclusions: Corneal confocal microscopy and electrophysiological tests may help confirm the diagnosis of ocular argyrosis., Competing Interests: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interests; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Medical University of Silesia, Katowice, Poland. Informed consent Informed consent was obtained from all individual participants included in the study. Statement of human rights and statement on the welfare of animals The study protocol was adhered to the tenets of the Declaration of Helsinki. 10.1007/s10633-016-9552-z

Background: Silver is a transition metal, toxic when ingested in significant amounts, causing argyria (skin deposition) and argyrosis (eye deposition). It is excreted mainly via the gastrointestinal tract with only small amounts eliminated by the kidneys, and rarely have cases of nephrotoxicity due to silver been reported. Here we present the case of a woman who used colloidal silver as an alternative remedy for a T cell lymphoma, who subsequently developed argyria and a pauci-immune crescentic glomerulonephritis with evidence of extensive glomerular basement membrane silver deposition., Case Presentation: A 47 year old woman of Indo-Asian descent with a T-cell lymphoma who refused conventional chemotherapy for 18 months but self-medicated with a remedy containing colloidal silver, was admitted with acute dialysis-dependent kidney injury. A kidney biopsy demonstrated a pauci-immune crescentic glomerulonephritis with deposition of silver particles in the mesangium and along the glomerular basement membranes. The patient was treated with intravenous methylprednisolone and intravenous cyclophosphamide and recovered independent renal function., Conclusion: Chronological evolution of the the pauci-immune glomerulonephritis suggests that a cellular immune-mediated process was induced, potentially mediated by lymphomatous T cells directed at the glomerular basement membrane, following silver deposition. Immunosuppressive therapy improved the situation and allowed cessation of haemodialysis, supporting the hypothesis of an immune-mediated process.

Orally administered silver has been described to be absorbed in a range of 0.4-18% in mammals with a human value of 18%. Based on findings in animals, silver seems to be distributed to all of the organs investigated, with the highest levels being observed in the intestine and stomach. In the skin, silver induces a blue-grey discoloration termed argyria. Excretion occurs via the bile and urine. The following dose-dependent animal toxicity findings have been reported: death, weight loss, hypoactivity, altered neurotransmitter levels, altered liver enzymes, altered blood values, enlarged hearts and immunological effects. Substantial evidence exists suggesting that the effects induced by particulate silver are mediated via silver ions that are released from the particle surface. With the current data regarding toxicity and average human dietary exposure, a Margin of Safety calculation indicates at least a factor of five before a level of concern to the general population is reached., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Silver-coated grafts are designed to prevent vascular graft infections. Silver is a safe element but toxic effects have been reported. We describe two cases of possible localized argyria after silver graft implantation., Report: Two patients presented with perigraft groin collections after implantation of silver grafts. During reoperation, an ashen-grey necrotic substance was seen surrounding the grafts. The grafts were explanted and lower limb perfusion restored. Cultures were negative and both patients had uneventful recoveries., Discussion: Our cases are highly suggestive of a possible unique adverse effect: a combination of localized silver toxicity and neutrophilic mediated tissue destruction., (Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

The aims of this study were to evaluate the incidence of local argyria in patients with silver-coated megaprostheses and to identify a possible association between argyria and elevated levels of silver both locally and in the blood. Between 2004 and 2011, 32 megaprostheses with silver coatings were implanted in 20 female and 12 male patients following revision arthroplasty for infection or resection of a malignant tumour, and the levels of silver locally in drains and seromas and in the blood were determined. The mean age of the patients was 46 years (10 to 81); one patient died in the immediate post-operative period and was excluded. Seven patients (23%) developed local argyria after a median of 25.7 months (interquartile range 2 to 44.5). Patients with and without local argyria had comparable levels of silver in the blood and aspiration fluids. The length of the implant did not influence the development of local argyria. Patients with clinical evidence of local argyria had no neurological symptoms and no evidence of renal or hepatic failure. Thus, we conclude that the short-term surveillance of blood silver levels in these patients is not required.

When silver nitrate is administered to rats in their drinking water for many months, they develop a generalized argyria. In the central nervous system, the deposition of silver follows the pattern of the so called hematoencephalic barrier (Wislocki and Leduc, (2); Dempsey and Wislocki, (3)). The present observations concern the deposition of silver in the rat's eye, investigated by both light microscopy and the electron microscope. In the eye, silver is not detected in the specific neural elements of the retina. Instead, it is heavily deposited in the basement membrane of the epithelium of the ciliary processes and in Bruch's basal membrane between the choriocapillary layer and the retinal epithelium. Traces of silver are visible in the basement membranes of the retinal capillaries with the electron microscope, but cannot be identified with the light microscope. In all of these respects, the pattern of the silver resembles the mode of its deposition in the brain. The heavy accumulation of metal in Bruch's membrane and the ciliary processes is analogous to that observed in the chorioid plexuses, and the traces encountered in the walls of the retinal capillaries correspond to traces observed in the basement membranes of the cerebral capillaries. Hence, with respect to silver, the eye possesses a blood-ocular barrier similar to the hematoencephalic barrier. Silver appears to be restrained from entering the aqueous humor by a barrier in the basement membrane of the ciliary processes, from reaching the photoreceptor elements of the retina by Bruch's basal membrane, and from penetrating the inner layers of the retina by a barrier in the basement membrane surrounding the retinal capillaries.

Basement membranes in the kidney are made up of a homogeneous matrix. In argyria, silver passes from the blood in the ionic form and diffuses into the kidney basement membranes in which it is precipitated. X-ray diffraction studies of "silver-stained" rat kidneys show that most of the silver in the kidneys is combined with some form of sulfur. Histochemical staining for sulfhydryls and disulfides demonstrates the presence of these groups in basement membranes. It appears that silver ions combine with either or both the sulfhydryl or disulfide groups in the basement membranes and also in mitochondria (when the silver diffuses into a cell).

The absorption of silver presents as a grayish coloration in different locations as the skin and eye. Corneal argyrosis is characterized by micro-deposits in the stroma, Bowman or Descemt membranes. This metal could also affect other structures as the retina. We describe the case of a male jeweler with corneal argyrosis. Small whitish–grayish predescemetic depositis were observed by biomicroscopy, which were described as punctate and extra-cellular by in vivo confocal microscopy. Our patient presented a significative impairment of contrast sensitivity under scotopic conditions which could not be attributed to other condition. This test could be helpful in detecting retinal functional alteration before the structural anatomical alteration are visible.

Aim: Prosthetic joint infection (PJI) is a common complication following orthopedic megaprosthetic implantations (EPR), estimated up to 50%. Silver coatings were introduced in order to reduce the incidence of PJI, by using the antibacterial activity of silver. Three different silver coatings are available: MUTARS® (Implantcast), Agluna® (Accentus Medical), PorAg® (Waldemar Link). The aim of this review is to provide an overview on efficacy and safety of silver-coated EPR both in primary and revision surgery, comparing infection rate according to the type of implant. Methods: Through an electronic systematic search, we reviewed the articles concerning silver-coated EPRs. Infection rate, silver-related complications, local and blood concentrations of the silver were evaluated. Meta-analyses were performed to compare results from each study included. Results: Nineteen studies were included. The overall infection rate in patients with silver-coated implants was 17.6% (133/755). Overall infection rate in primary silver-coated EPR was been 9.2% (44/445), compared to 11.2% (57/507) of non-silver-coated implants. The overall infection rate after revisions was 13.7% (25/183) in patients with silver-coated EPR and 29.2% (47/161) when uncoated EPR were used, revealing a strength statistically significative utility of silver coatings in preventing infections in this group (p: 0.019). Generally, the use of MUTARS® EPR had produced an almost constant decrease in the incidence of primary PJI but there are few data on the effectiveness in revisions. The results from the use of Agluna® in both primary and revisions implants are inconstant. Conversely, PorAg® had proven to be effective both in PJI prevention but, especially, when used in PJI revision settings. Local argyria was reported in 8 out of 357 patients (2.2%), while no systemic complications were described. Local and blood concentrations of silver were always reported very far to the threshold of toxicity, with the lowest concentration found using PorAg®. Conclusions: Silver-coated EPRs are safe and effective in reduction in PJI and re-infection rate, in particular when used in higher risk patients and after two-stage revisions to fight PJI. [ABSTRACT FROM AUTHOR]

Background: Argyria results from silver accumulation in the skin. It is a stressful condition for patients due to skin discoloration. In the past, no effective treatments were available. However, it has been recently reported laser treatments showed promising results. Aim: To review and summarize all reported laser treatment options for argyria patients. Methods: We reviewed all laser treatment options for argyria in the database of the US National Library of Medicine PubMed. The search of the words "argyria and laser" was performed on the March 4, 2020. Results: We found 11 studies that reported laser treatment for argyria. All of the studies were case reports demonstrating treatment responses of laser devices such as 1064 nm Nd:Yag laser and 755 nm alexandrite laser. Despite various treatment parameters, 1064 nm Nd:Yag and alexandrite lasers showed good responses in argyria. However, severe pain during the laser procedure was the main concern. We summarized laser treatment options for argyria including their parameters, treatment response, and anesthesia for laser treatment in argyria. We also report a case of argyria, which successfully responded to low fluence 1064 nm Nd:Yag laser. Conclusion: Laser therapies resulted in almost complete clearing of pigment in argyria. Earlier reports showed that 1064 nm Nd:Yag laser successfully treated argyria but recent studies suggested 755 nm alexandrite was also a good treatment option for argyria. Additionally, our case achieved excellent results even in one session of low fluence Q‐switched Nd:Yag laser, though we need to ensure pain control during the laser treatment. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • Silver is an ingredient in certain dermal and mucosal medical applications. • Silver can deposit in the body as particles causing a discoloration called argyria. • Silver seems to have a low potential for skin irritation. Eye irritation and allergic contact dermatitis have been reported. • Silver may cause genotoxicity, but additional data on its carcinogenic potential are required. [ABSTRACT FROM AUTHOR]