Silver Toxicity

Etiology

Exposure to silver can occur through various mechanisms, including ingestion, inhalation, and dermal exposure.[1][4]

Common Products Containing Silver

Silver compounds can be found in different products. A review by Drake and Hazelwood in 2005 listed numerous uses of silver compounds, including, but not limited to, photographic plates, batteries, bactericides, catalysts, medicinals, lubrications, cloud seeding, window coatings, mirrors, flower preservatives, electroplating, sanitation products, and acupuncture needles. In the same review, products containing silver and silver alloys include jewelry, silverware, electronic components, heat sinks, solders, brazing alloys, superconductors, bactericides, dental fillings, bearings, coins, and medals.

Occupational Exposure

Occupational exposure can be associated with repeated exposure to small silver particles. Professions at risk include silversmiths, miners, welders, jewelers, and those in the photographic industry. Occupational exposure limits can vary by organization. The European Commission recommends an 8-hour time-weighted average of 0.1 mg/m³ for total silver dust. Other European countries have set separate recommended exposure levels of 0.1 mg/m³ for metallic silver and 0.01 mg/m³ for soluble silver. The Occupational Safety and Health Administration and the Mine Safety and Health Administration recognize a Permissible Exposure Limit of 0.01 mg/m³. Similarly, the National Institute for Occupational Safety and Health has a recommended exposure limit of the same value for metallic and soluble silver.

Medical Uses

Medical uses of silver include silver nitrate for cauterization and silver sulfadiazine for the topical treatment of burns and wounds. Minute levels of silver cations have microbicidal properties that are effective in wound and burn treatment. Medical device catheters are also layered with silver to prevent microbial growth.[5] The antimicrobial property of silver is hypothesized to be related to the ability of silver ions to combine with and permanently damage bacterial membranes.[6]

Consumer Uses

Due to the proposed oligodynamic effect, consumer use includes colloidal silver as an over-the-counter dietary and health supplement in alternative and homeopathic medicine. Silver has also been utilized in grooming and hygiene products, such as bandages, shower gels, and deodorants.[7] The 1994 Dietary Supplement Health and Education Act allows silver to be sold as a supplement as long as no claim of treatment or prevention of any disease is apparent.[8]

The most common adverse effects linked to silver are argyria, irreversible bluish-gray skin pigmentation, and argyrosis, irreversible pigmentation of the eyes. These effects are most noticeable in areas that are exposed to sunlight.[9] Argyria is typically associated with prolonged exposure to silver, including applying silver-containing materials to the skin or body, inhalation in occupational settings, ingestion, and use of colloidal silver and silver-containing medicinals, smoking deterrents, dental materials, and silver solder.[3] The toxicity of silver nanoparticles in different organs is hypothesized to be due to the same proposed mechanisms of the antimicrobial effects of silver nanoparticles—vigorous oxidation due to ample discharge of silver ions.[10]

Epidemiology

Silver has been used dating back to ancient civilizations. The discovery and development of antibiotics in the early to mid-20th century led to a decline in the use of silver as an antimicrobial agent. Although rare, cases of argyria still occur. These instances are generally associated with consuming colloidal silver as a form of alternative and homeopathic medicine as readily available in pharmacies, grocery stores, and online.[9] Recent re-emergence in cases of argyria has occurred due to these alternative health treatment trends.[11] The 1994 Dietary Supplement Health and Education Act allowed silver to be sold as a supplement as long as no claim of treatment or prevention of any disease was apparent.[8] In 1999, the United States Food and Drug Administration issued a final rule that all over-the-counter drug products containing colloidal silver ingredients or silver salts for internal or external use are not generally recognized as safe and effective and are misbranded.[12]

Recently, there has been an increase in the use of ionic and nanoparticulate silver in medical and commercial products.[3] Colloidal silver comprises silver particles and ions less than 100 nm (nanoparticles) and less than 1000 nm (microparticles) in size dispersed in an aqueous suspension. Most products containing colloidal on the market are claimed to contain 10 to 30 mg/L of silver. The World Health Organization (WHO) has given a Reference Dose (RfD) of 6.5 mcg/kg body weight/day for all exposure routes for the general population, based on argyria development, which is not the most sensitive toxicity endpoint.[10]

The mass production and subsequent commercialization of colloidal silver have adverse effects, including a lack of production standardization and unanticipated adverse effects. Regulatory bodies such as the Food and Drug Administration and the European Commission have taken a stance against health claims without scientific basis. Although they do not prohibit selling colloidal silver, unsubstantiated health claims are prohibited.[7]

Pathophysiology

The complications of silver toxicity include dermatologic, cardiovascular, hematologic, hepatic, gastrointestinal, neurologic, and renal findings.[8] The most common manifestation of excessive silver exposure is argyria, a condition characterized by bluish-gray skin discoloration. Argyria can be generalized, localized, or ocular. However, more severe manifestations of silver toxicity have been demonstrated. In a large enough dose, silver is acutely toxic. An intravenous dose of about 50 mg of silver is considered fatal, leading to bone marrow, renal, and hepatic necrosis, hemorrhage, and pulmonary edema.[9] Although silver is not considered carcinogenic, genotoxic effects have been reported. There are no known effective chelators for treating silver toxicity.[4]

Although the exact antimicrobial mechanism of silver is unknown, the proposed mechanisms include induction of oxidative stress, interaction with cellular membranes, and inhibition of cellular processes.[5][6] Silver has various oxidation states, including Ag⁺, Ag²⁺, and Ag³⁺, with Ag⁺ being the most biologically active oxidation state. Silver induces reactive oxygen species by inactivating the respiratory chain dehydrogenase. This inactivation blocks the respiratory chain electron transfer, leading to decreased ATP production by inhibiting cellular respiration and growth. Oxidative stress plays an important role in the cytotoxicity of silver, leading to inflammation and apoptosis.[13]

Silver's proposed activity is related to silver ion interactions with thiol groups in enzymes by binding to electron donor groups of proteins, inhibiting enzymatic activities and causing protein denaturation and precipitation.[8] This process can occur by destroying the cell wall and membrane, increasing the cytoplasmic membrane's permeability and causing the destruction of the bacterial envelope. Silver nanoparticles transport silver ions to bacterial cells, reducing pH and increasing silver ion release.[14] In addition, silver binding to DNA affects the replication of DNA and cell proliferation.[15] Silver disrupts sodium-potassium-ATPase by interacting with sulfhydryl groups, causing rapid and potent enzymatic inhibition.[16]

Histopathology

Silver particles have a dark brown to black granular appearance. In the dermis, they are scattered extracellularly and are concentrated in the basement membrane of nerves, capillary walls, perifollicular sheath, and elastic fibers. In old lesions, electron-dense granules are observed in lysosomes of macrophages or extracellularly using scanning electron microscopy.[17]

Toxicokinetics

Absorption

The absorption of silver can occur through multiple modalities, including inhalation, oral ingestion, or skin contact. The rate of silver absorption depends on both the route of exposure and the form of silver. Specifically, particle size plays a role as smaller nanoparticles are more easily absorbed into the bloodstream, possibly leading to systemic exposure. An in vivo study using radiolabeled silver showed accumulation after 2 to 8 hours of exposure, with clearance within 28 days. Oral absorption through the gastrointestinal tract can vary based on other dietary components potentially affecting silver's bioavailability.[8] The estimated absorption of ingested silver is up to 10%.[3] Dermal exposure can be affected by prolonged exposure and exposure to areas of skin breakdown, which is important for specific medical devices and dressings.

Distribution

After silver is absorbed, it is distributed through the bloodstream, binding to plasma proteins and transporting them to various organs and tissues. Detectable levels of silver were reported in the blood within 6 hours and in the urine within 24 hours after the application of silver sulfadiazine. Silver binds with sulfur-containing molecules, accumulating in the skin, hair, and nails. Silver can cross the blood-brain and placental barriers.

Metabolism

Silver metabolism is limited in the body. However, interaction with other molecules can lead to biotransformation, which affects its bioavailability.[6][18] The biological half-life of silver in the liver is 50 days.

Excretion

Silver is primarily excreted through the feces by biliary secretion and is also excreted through the urine in smaller quantities. The mean urinary excretion of silver was approximately 1100 µg/L compared to levels of less than 1 µg/L in control levels. The elimination of silver is estimated at 46.4 days from serum, with a median elimination rate of 1.5% per day.[19] The efficiency of urinary excretion is impacted by renal clearance.[20] Additional routes of excretion include sweat, saliva, and breast milk.[6]

History and Physical

A medical diagnosis of silver toxicity requires a high level of clinical suspicion, often accompanied by a history of silver exposure through occupational, medicinal, or consumer exposures. An emphasis on obtaining an extended history of over-the-counter, natural, alternative, or homeopathic supplements may heighten clinical suspicion. The onset of pigmentation can vary widely, ranging from days to years. Given that the deposition is permanent, the diagnosis of argyria can be made regardless of the time that has passed since the initial exposure.[4]

Physical examination findings include localized and generalized blue to slate-gray skin pigmentation secondary to silver deposition.[2] Generalized argyria progresses in stages, beginning with staining of the gingiva, followed by hyperpigmentation in sun-exposed areas, and then affecting the nail beds, sclerae, and mucosa. In addition, viscera are noted to appear blue on autopsy. Sun-exposed areas are typically darker secondary to sunlight, leading to a decrease in elemental silver and causing a darker pigmented discoloration.[3][9] The photoactivation of sun-exposed areas reduces silver, which accelerates the stimulation of melanocytes by silver to increase melanin production.[8] The increased production can be observed in the skin, nails, eyes, and mucosal surfaces.

Evaluation

The normal value of silver in blood is less than 1 mcg/L. Silver can be measured in the blood, feces, and urine.[3] The lowest level for silver buildup to result in generalized argyria varies considerably, and thus, argyria is typically diagnosed through history and physical exams. No minimum serum silver levels are consistent with early argyria.[18] Estimated cumulative doses leading to generalized argyria in humans have been reported as low as 70 mg/kg body weight.[13] A skin biopsy and histopathological analysis are useful, with the gold standard being energy-dispersive x-ray spectroscopy. This technique allows for unequivocal diagnosis by identification of the chemical elements found in the granules through analysis of their emitted energy spectrum.[4][9]

Treatment / Management

There is no specific antidote available to silver toxicity, and treatment of toxicity is supportive.[8] The treatment for argyria is limited with overall poor response and is historically considered permanent. A major focus of management is to limit exacerbating factors, such as avoiding further exposure to silver, limiting sun exposure, and utilizing sun protection.[21] Potential treatments with hydroquinone, dermabrasions, and D-penicillamine have been attempted without notable results.(B3)

In recent reports, Q-switched frequency neodymium-doped yttrium aluminum garnet (Nd:YAG) laser therapy, which is used for removing certain tattoos, has also been attempted with documentation of successful improvement of discoloration after treatments with low-fluence Q-switched 1064-nm Nd:YAG laser and 755-nm alexandrite laser.[9][22][23] Persistent skin color restoration up to 1 year after treatment has been reported; however, argyria relapse 11 months after has also been reported. Adverse effects of the laser procedure include intense pain, which may require various types of anesthesia, including general anesthesia.[4](B3)

Differential Diagnosis

The differential diagnosis of silver toxicity includes:

• Addison disease
• Amiodarone use
• Chrysiasis
• Cyanosis
• Dapsone use
• Hemochromatosis
• Melanoma
• Methemoglobinemia
• Minocycline use
• Ochronosis
• Phenothiazine use
• Polycythemia
• Porphyria
• Wilson disease

Toxicity and Adverse Effect Management

When silver is ingested, approximately 10% is absorbed in the gastrointestinal tract and circulated by the vasculature. Silver is primarily excreted in bile and eliminated through feces, and to a lesser extent, eliminated in urine.[3][8] In today’s society, presentations of generalized argyria are most commonly observed in patients who utilize colloidal silver as a form of complementary health supplementation.[9] Inhaling silver particulates or aerosols leads to the accumulation of silver in the lungs and bloodstream.[4][20] The Recommended Exposure Level and Permissible Exposure Level for both are 0.1 mg/m³, according to the National Institute of Occupational Safety and Health established by the Occupational Health and Safety Administration. Contact exposure to silver can occur through wound dressings, jewelry, and nasal or ophthalmologic drops, typically leading to localized argyria. However, contact exposure can still lead to generalized argyria.[2][13]

Prognosis

Argyria is mainly irreversible and does not improve after discontinuation of exposure. Argyria is not a life-threatening condition; however, the metal demonstrates systemic absorption and distribution of silver, leading to an unfavorable cosmetic appearance with permanent skin discoloration in the affected areas.[9] The highest concentrations of silver are found in the skin, liver, kidneys, cornea, and gingiva, as indicated by autopsy analysis of individuals treated with silver for burns.[4]

Complications

Systemic Complications

Systemic complications of silver toxicity have been described in the literature in the form of animal studies and case reports. Silver has been demonstrated to accumulate throughout the body in animal research. Systemic complications include cardiovascular, dermatologic, hematologic, hepatic, gastrointestinal, neurologic, and renal findings.[8][9] 

Dermatologic: Argyria, the development of bluish-gray skin discoloration, is the most well-known complication of silver exposure. There are 3 main subtypes of argyria—generalized argyria, localized argyria, and argyrosis. Generalized argyria occurs after systemic exposure, resulting in gray-blue or metallic diffuse skin pigmentation, most prominent in sun-exposed areas. Early signs include pigmentation of the gingiva and oral mucosa followed by bluish discoloration of the fingernails called azure lunula. Localized argyria is caused by local silver deposition due to transdermal absorption by sweat gland pores or skin incisions. This condition is observed after prolonged contact with silver-containing products, creams, solutions, or cautery. The most common form of localized argyria is amalgam tattoo, a flat, dark-blue mucosal lesion. Argyrosis is an ocular silver deposition that can occur as a manifestation of generalized or localized argyria. Argyrosis can be observed in the cornea, conjunctivae, and lacrimal caruncle and may have dark lesions with greenish and brownish tones.[4] 

Neurologic: Neurologic complications include accumulation of silver in neuron and glial cells of the brain and spinal cord, potential central nervous system dysfunction in mice exposed to silver salts, and a decrease in emergent hippocampal pyramidal cells in fetal rats. In addition, a report described a 55-year-old woman who experienced increasing vertigo, weakness, hyposmia, gait disturbance, and cutaneous hypoesthesia after self-treating oral mycosis with silver products for 9 years. This prolonged use of silver products led to silver sulfide depositions found in basal membranes, macrophages, elastic and collagenous fibers, perineurium of peripheral nerves, and necrotic cells of the oral submucosa. A case reported by Ohbo et al suggests a causal relationship of convulsive seizures in a patient with schizophrenia with argyria secondary to addiction to antismoking pills containing silver with serum levels of 12 mcg/L.[24]

Renal: Reported renal findings include proteinuria and damaged glomeruli in other cases. A patient developed chronic abdominal pain after using topical silver for 2 and a half years to help with recurrent gingival bleeding, which led to generalized argyria. The patient underwent an abdominal operation, during which diffuse argyria of multiple internal organs was observed.

Hematologic: In the bone marrow, silver sulfadiazine use has been shown to suppress leukocyte progenitor cells in mice studies, along with leukopenia and lowered granulocyte counts in patients with burn wounds.[18] 

Hepatic: Rats deficient in vitamin E or selenium developed hepatic necrosis due to selenium deficiency caused by silver, which obstructed the production of the seleno-enzyme glutathione peroxidase.

Cardiovascular: In a case report by Steininger et al, a 52-year-old patient who died from cardiac failure was found to have silver deposits in the walls of most blood vessels on autopsy. This patient was treated for a duodenal ulcer for over 18 years with 35 g of silver. In a study by Olcott, rats given silver nitrate drinking water developed left ventricular enlargement. [ATSDR. Toxicological Profile for Silver]

Respiratory: Inhalation of silver can lead to pneumonitis, with reports of both upper and lower respiratory irritation. Tracheal epithelium structural damage was observed in rabbits who experienced inhalation exposure to colloidal silver. A case report by Forycki et al described a man hospitalized approximately 36 hours after exposure to silver vapors from melting silver ingots, presenting with severe circulatory and respiratory symptoms requiring controlled respiration with positive end-expiratory pressure.[3][25]

Fatal Dose

The reported fatal dose of intravenous colloidal silver is 50 mg acutely, leading to bone marrow, renal, and hepatic necrosis, hemorrhage, and pulmonary edema.[9] Additional sources report an average fatal dose of 10 g, although survival after 30 g is also reported.[8] The World Health Organization reports a lifetime intake of approximately 10 g of silver can be considered the no-observed-adverse-effect level in humans.[18] In a review by Fung et al, the systemic effects of silver are discussed. Human mortality has been reported in the literature, including a case involving intrauterine silver nitrate administration of 7 g (approximately 64 mg silver/kg by weight) following an abortion procedure.[13]