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SILVER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Silver is a metal used in the manufacture of jewelry, tableware, ornaments, mirrors, and in photography.
    B) Metallic silver is used as a antibacterial coating on a variety of medical devices, such as prosthetic heart valves. It is also used as an antibacterial coating in wound dressings.

Specific Substances

    1) Argentum
    2) CAS 7440-22-4
    3) CERARCYKITE
    4) SILVER AND COMPOUNDS
    5) SILVER COMPOUNDS
    6) SILVER DUST
    7) SILVER FUME
    1.2.1) MOLECULAR FORMULA
    1) Ag

Available Forms Sources

    A) FORMS
    1) Silver is available in the following forms: powder, grains, pieces, wire, foil, sheet, tubing, and as ingots. Sterling silver contains 92.5% silver. Silver may be alloyed with cadmium, and is often alloyed with copper (Ashford, 1994).
    2) Silver is an element that occurs naturally in the earth's crust with an average abundance of 0.1 ppm. It is also present in seawater with an abundance of 0.01 ppm. Silver has an atomic number of 47. Considered to be a precious metal, silver can occur in its pure metallic form but is more likely to be found as a sulfide mineral such as argentite, proustite, or pyrargyrite. Cerargyrite is a chloride mineral of silver (Budavari, 2000).
    3) Silver can also occur in ores of lead, copper, zinc, and gold (Bingham et al, 2001a; Budavari, 2000; Lewis, 2001). In recent years, much silver has been recovered and reclaimed from photographic processes and other waste streams because overall consumption has exceeded silver production (ATSDR , 1997; Bingham et al, 2001a).
    4) COLLOIDAL SILVER: Produced by suspending tiny silver particles in a liquid and sold as dietary supplement and homeopathic remedy. It is available in health food stores and on the internet. The product purportedly can be used for multiple conditions and to boost the immune system.
    a) A manufacturer has produced a micro-particle colloidal silver generator (the Silver Edge(R)) that can be used in the home to produce colloidal silver for ingestion. The product contains pure (.999) fine silver rods. Distilled water is added to the generator and reportedly produces silver particles as small as .0008 microns (compared to health food store colloidal silver that may contain silver particles of 20 microns). A 3 hour batch of micro-particle colloidal silver can produce a concentration of 7 to 10 ppm, using a quart container (http://www.thesilveredge.com/howto.shtml) (The Silver Edge, 2013).
    b) The site also describes the use of a home nebulizer machine to create nebulized colloidal silver (by adding the colloidal silver liquid created by the generator to the chamber of a hand held nebulizer) for the treatment of respiratory conditions (http://www.thesilveredge.com/howto.shtml) (The Silver Edge, 2013).
    B) SOURCES
    1) Silver can be extracted from ore using cyanidation/reduction (Ashford, 1994).
    2) Silver is extracted and refined from ore and then may be formed into ingots, bullion, plates, sheets, wires, tubes, castings, moss, or powder. It can also be formed into whiskers, single crystals, or a colloidal form. Grades of silver may include pure, high purity (less than 100 ppm impurities), various alloys, or sterling, an alloy containing 7.5 percent copper (Bingham et al, 2001a; Lewis, 2001).
    C) USES
    1) Silver is used for: dental alloys; electrical contacts; printed circuits; electroplating; high-capacity batteries; and solder (ACGIH, 2001).
    2) Silver is second only to gold in malleability and ductility. It is an excellent conductor of heat and electricity (Budavari, 2000).
    3) Because of these above mentioned properties, silver is used in electrical products such as switches, circuits, contacts, batteries, and solders (Bingham et al, 2001a).
    4) Coinage has been a common use for silver, although coins made from silver have been removed from general circulation in the United States since 1970 (ATSDR , 1997).
    5) One of the largest uses of silver is in photography. Various silver salts are photosensitive and are applied in emulsions to photographic films and papers. Silver is used to make cutlery, jewelry, mirrors, medical and dental equipment. It is used in dental amalgams and in medicines (ATSDR , 1997).
    6) Silver may be used as a sterilant and in water purification (ATSDR , 1997).
    7) Silver is also used as a catalyst in chemical processes such as hydrogenation and oxidation (Lewis, 2001).
    8) A silver acetate-containing chewing gum, which gives tobacco smoke an unpleasant taste, has been used as a smoking deterrent (Jensen et al, 1988).
    9) With increasing concerns about resistant bacterial infections, silver coatings are being applied to a number of medical devices such as artificial heart valves, and is also being used topically in burn treatment (Carrel et al, 1998; Illingworth et al, 1998; Wright et al, 1998).
    10) Colloidal silver and hydrolyzed silver have been used in alternative medical therapies, herbal teas, dietary supplements, and naturopathic remedies touted for their antibacterial, immune boosting or anti-allergy properties (Gulbranson et al, 2000; Newman & Kolecki, 2001; Hori et al, 2002; McIntyre et al, 2001).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Silver is a natural element used in the manufacturing of ornaments, jewelry, utensils and industrial manufacturing. In addition, silver compounds are used in film processing, disinfectants, and microbiocides (eg, silver sulfadiazine). Colloidal silver is manufactured by suspending silver particles in a liquid, which is sold as a dietary supplement and homeopathic remedy.
    B) PHARMACOLOGY: Silver has no known biological functions in humans. Silver sulfadiazine is bacteriostatic; it competitively inhibits bacterial or fungal dihydropteroate synthetase, preventing PABA conversion to folic acid. Upon contact with skin surface, silver sulfadiazine separates into sulfadiazine and silver, and the silver is absorbed into the blood circulation.
    C) TOXICOLOGY: Other than argyria, systemic silver toxicity is rare due to rapid binding of silver to various proteins and precipitation of silver chloride. Tissue damage only occurs when this binding ability is overwhelmed by a massive dose.
    D) EPIDEMIOLOGY: Hundreds of exposures to silver (colloidal and silver compounds such as silver nitrate and silver oxide batteries) are reported to poison centers every year. Exposures rarely cause significant symptoms and are never fatal.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Adverse effects from the us of topical silver preparations such as silver sulfadiazine include a temporary painful burning sensation and the formation of aseptic exudates on the wound's surface. In addition, hypersensitivity reactions such as urticaria can result from silver exposure. Finally, incorporation of silver ions into the skin can lead to localized argyria, especially in the setting of UV radiation.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most patients remain asymptomatic. Patients require chronic exposure for significant absorption to occur. Argyria, a blue-grey discoloration of the skin, mucous membranes, and conjunctiva, cornea, or lens that is not associated with clinical symptoms, can develop after chronic exposure. Silver salts such as silver oxide or silver nitrate are irritating and corrosive. Chronic inhalation has been associated with mild chronic bronchitis. Unusual or rare complications of medicinal treatment with silver or silver salts include leukopenia, anemia, hemorrhage and elevated liver enzymes.
    2) SEVERE TOXICITY: One case report exists of a workman exposed to high concentration of heated metallic silver vapor for 4 hours developing acute lung injury with pulmonary edema. There are rare cases of patients with neurologic symptoms after large exposures to silver, including symptoms of peripheral neuropathy, decreased mental status, and seizures.
    0.2.4) HEENT
    A) Argyria may be generalized or localized to the conjunctiva, cornea, or lens. This blue-grey discoloration is not accompanied by vision loss.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were found in available references to assess the potential effects of exposure to this agent in humans during pregnancy.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of silver in humans.

Laboratory Monitoring

    A) No specific studies are needed for most patients.
    B) Specific concentrations of silver are not readily available and are unlikely to be useful in the acute setting, but can be used to confirm exposure. A normal serum silver concentration is less than 0.05 mcg/dL.
    C) Depending on the patient's presentation and symptoms, other tests may be useful or necessary. Suicidal patients should receive an ECG, basic chemistry panel, and testing for acetaminophen and salicylates, while patients with respiratory distress may need pulse oximetry monitoring and patients with seizures require a thorough neurologic exam and a head CT or MRI.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) For most silver exposures, no treatment is necessary beyond discontinuing exposure. Discoloration with argyria is mostly permanent and there is no good evidence for treatment with local therapies or chelation. Patients with respiratory symptoms can be treated with supplemental oxygen and inhaled beta agonists as needed.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity secondary to silver is extremely rare, and consists of supportive care as needed (eg, intubation for severe respiratory distress).
    2) INHALATION EXPOSURE: Move patient from toxic environment to fresh air, and monitor and treat for respiratory symptoms as needed.
    3) OCULAR EXPOSURE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation or photophobia persists, referral for medical care may be warranted.
    4) DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area thoroughly with soap and water. Localized irritation can be treated with standard treatments (eg, topical steroids for hypersensitivity reactions, etc).
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is not indicated as absorption is minimal; toxicity has only been reported after long term chronic ingestion. Wash exposed skin with soap and water. There is no evidence for the use of ipecac or prehospital activated charcoal for silver.
    2) HOSPITAL: GI decontamination is not indicated as absorption is minimal; toxicity has only been reported after long term chronic ingestion. Wash exposed skin with soap and water.
    D) ANTIDOTE
    1) There is no specific antidote.
    E) MONITORING OF PATIENT
    1) No specific studies are needed for most patients.
    2) Specific concentrations of silver are not readily available and are unlikely to be useful in the acute setting, but can be used to confirm exposure. A normal serum silver concentration is less than 0.05 mcg/dL.
    3) Depending on the patient's presentation and symptoms, other tests may be useful or necessary. Suicidal patients should receive an ECG, basic chemistry panel, and testing for acetaminophen and salicylates, while patients with respiratory distress may need pulse oximetry monitoring and patients with seizures may require neurology exams and a head CT.
    F) ENHANCED ELIMINATION
    1) There is no evidence for enhanced elimination techniques. In one case, hemodialysis was ineffective in reducing serum silver concentrations, and plasma exchange and hemofiltration do not significantly reduce the body burden of silver. Chelation therapy has not been successful for treatment because silver is relatively inert after being deposited into tissues.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with mild symptoms that simply require decontamination for treatment may remain at home.
    2) OBSERVATION CRITERIA: Patients with persistent or worsening symptoms should be sent to a healthcare facility for evaluation. Patients should be observed until they are stable and symptoms have clearly improved.
    3) ADMISSION CRITERIA: Patients exposed to silver or silver compounds should rarely need admission to the hospital. Patients with more severe symptoms (eg, corrosive damage to mucosa membranes from silver salts or seizures may require admission to the hospital for further evaluation or observation). Most patients can be admitted to the hospital ward, but patients with severe symptoms (eg, respiratory distress requiring intubation, seizures) may require ICU care. Patients should remain in the hospital until they are stable and symptoms have clearly improved.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with significant toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) Pitfalls may include using treatments that are ineffective (ie, activated charcoal or chelation) and mistaking argyria for other medical conditions such as cyanosis.
    I) PHARMACOKINETICS
    1) Topical silver sulfadiazine has approximately 1% systemic silver absorption with approximately 25% of absorbed silver excreted in urine.
    J) TOXICOKINETICS
    1) Soluble silver salts are absorbed from the respiratory and GI tracts and complex silver slats are absorbed into the blood stream through intact skin. Up to 90 to 99% of oral silver doses are not absorbed. Absorbed silver is strongly retained after deposition into elastic and connective tissues throughout the body. The primary route of excretion is thought to be through bile. In humans, the biological half-life of silver in lungs has been estimated to be 1 day.
    K) PREDISPOSING CONDITIONS
    1) A patient with renal failure may be more predisposed to toxicity due to partial excretion of silver through urine.
    L) DIFFERENTIAL DIAGNOSIS
    1) Argyria may be mistaken for cyanosis, methemoglobinemia, metastatic melanoma with melanogenuria, or hemochromatosis.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Acute toxicity is usually low; toxicity usually occurs following chronic exposure. The estimated average daily intake (from most foods) is 0.088 mg.
    B) INGESTION: CHRONIC EXPOSURE: The minimum oral dosage necessary to cause systemic argyria has been estimated to be about 25 to 30 g over 6 months.
    C) INHALATION: LACK OF EFFECT: Exposure to silver concentrations in air of less than 0.01 mg/m(3) has not caused argyria.

Clinical Effects

Summary Of Exposure

    A) USES: Silver is a natural element used in the manufacturing of ornaments, jewelry, utensils and industrial manufacturing. In addition, silver compounds are used in film processing, disinfectants, and microbiocides (eg, silver sulfadiazine). Colloidal silver is manufactured by suspending silver particles in a liquid, which is sold as a dietary supplement and homeopathic remedy.
    B) PHARMACOLOGY: Silver has no known biological functions in humans. Silver sulfadiazine is bacteriostatic; it competitively inhibits bacterial or fungal dihydropteroate synthetase, preventing PABA conversion to folic acid. Upon contact with skin surface, silver sulfadiazine separates into sulfadiazine and silver, and the silver is absorbed into the blood circulation.
    C) TOXICOLOGY: Other than argyria, systemic silver toxicity is rare due to rapid binding of silver to various proteins and precipitation of silver chloride. Tissue damage only occurs when this binding ability is overwhelmed by a massive dose.
    D) EPIDEMIOLOGY: Hundreds of exposures to silver (colloidal and silver compounds such as silver nitrate and silver oxide batteries) are reported to poison centers every year. Exposures rarely cause significant symptoms and are never fatal.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Adverse effects from the us of topical silver preparations such as silver sulfadiazine include a temporary painful burning sensation and the formation of aseptic exudates on the wound's surface. In addition, hypersensitivity reactions such as urticaria can result from silver exposure. Finally, incorporation of silver ions into the skin can lead to localized argyria, especially in the setting of UV radiation.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most patients remain asymptomatic. Patients require chronic exposure for significant absorption to occur. Argyria, a blue-grey discoloration of the skin, mucous membranes, and conjunctiva, cornea, or lens that is not associated with clinical symptoms, can develop after chronic exposure. Silver salts such as silver oxide or silver nitrate are irritating and corrosive. Chronic inhalation has been associated with mild chronic bronchitis. Unusual or rare complications of medicinal treatment with silver or silver salts include leukopenia, anemia, hemorrhage and elevated liver enzymes.
    2) SEVERE TOXICITY: One case report exists of a workman exposed to high concentration of heated metallic silver vapor for 4 hours developing acute lung injury with pulmonary edema. There are rare cases of patients with neurologic symptoms after large exposures to silver, including symptoms of peripheral neuropathy, decreased mental status, and seizures.

Heent

    3.4.1) SUMMARY
    A) Argyria may be generalized or localized to the conjunctiva, cornea, or lens. This blue-grey discoloration is not accompanied by vision loss.
    3.4.3) EYES
    A) ARGYRIA: A blue-gray discoloration, may be generalized, or localized in the conjunctiva of the eye (ACGIH, 2001).
    1) The eyes usually are discolored, first apparent in the conjunctiva with some localization in the inner canthus. The cornea may also be involved and in prolonged exposures, the lens (Clayton & Clayton, 1994).
    2) This discoloration is not accompanied by vision loss, but there may be some disturbances of dark adaptation (Moss et al, 1979).
    3) CASE REPORT: Following a chemical explosion, microscopic particles of silver were found in the epithelial basement membrane, Bowman's layer, and Descemet's membrane of the cornea of one patient. In the corneal stroma, intracellular accumulations of silver in stromal keratocytes was seen. The researcher concluded that silver accumulation in stromal keratocytes may lead to visual impairment and possible cellular damage (Schlotzer-Schrehardt et al, 2001).
    3.4.5) NOSE
    A) ARGYRIA may be present throughout the body or be localized in the nasal septum (ACGIH, 2001). Nasal localization most often occurs when the silver compound has been inhaled.
    3.4.6) THROAT
    A) ARGYRIA may be generalized throughout the body or localized to the posterior pharynx or gums (ACGIH, 2001).
    B) AMALGAM TATTOO: Localized soreness and occasional swelling as well as systemic symptoms of fatigue, headaches, sinusitis, and weight loss occurred in a 33-year-old who had an amalgam tattoo for 2 years (Weaver et al, 1987).
    1) Amalgam tattoos result from accidental implantation of dental amalgam and subsequent precipitation and dispersion of silver ions with sulfur. Surgical removal of the affected tissue led to resolution of all symptoms.

Cardiovascular

    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPERTENSION
    a) ANIMALS given PARENTERAL silver showed central vasomotor stimulation with a subsequent increase in blood pressure (Petering, 1976). This is an unlikely mode of exposure for humans.
    2) BRADYCARDIA
    a) Bradycardia was also seen in ANIMALS given PARENTERAL doses, most likely due to central vagal stimulation (Petering, 1976).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) STANDARD CHEST X-RAY ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) LUNG DEPOSITS/CHRONIC EXPOSURE: Silver polishers exposed to silver and polishing dust for lengthy periods may have increased densities in the lungs on x-ray. This may be due to silver deposition in the elastic membranes of the pulmonary vessels (ACGIH, 2001; McLaughlin et al, 1945).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) A workman exposed to high concentrations of heated metallic silver vapor for 4 hours developed lung damage with pulmonary edema (ACGIH, 2001).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY DEPRESSION
    a) Respiratory depression was the primary cause of death in animals given parenteral silver ions (Petering, 1976).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Peripheral neuropathies have been associated with high silver ion concentrations. In only a few cases are clear-cut associations possible.
    b) CASE REPORT: Vik et al (1985) reported a reversible neuropathy associated with a high silver ion concentration.
    c) CASE REPORT: Silver sulfadiazine (SSD) cream therapy (200 g/day) for 2 weeks in a patient with endstage renal disease resulted in an increase of serum silver concentration (maximum of 291 ng/mL) in association with a rapid deterioration of mental status. The patient died 4 months later, and the autopsy revealed profoundly elevated levels of silver in the brain tissue (617.3 and 823.7 ng/g wet tissue in the cerebrum and cerebellum, respectively) (Iwasaki et al, 1997).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CHRONIC SILVER INGESTION
    1) CASE REPORT: A 75-year-old man developed myoclonic seizures along with a progressive neurodegenerative disorder (ie, asymmetrical parkinsonism and myoclonic jerks) suggesting corticobasal degeneration. A CT of the brain showed generalized brain volume loss and mild periventricular chronic ischemic changes and a MRI of the brain showed moderate global cerebral atrophy with pronounced widening of the parietal sulci. Myoclonic seizures persisted during his hospitalization. His wife reported intermittent colloidal silver use by the patient for its antibiotic effects. He created a suspension at home that was tested and contained a silver concentration of 477 micromol/L (51.4 mg/L). His serum silver concentration was 628.3 nmol/L (67.7 mcg/L). Myoclonus was controlled with clonazepam. The patient continued to have an elevated serum silver concentration (111.4 nmol/L; reference range less than 2.8 nmol/L) 10 months after discharge, despite the recommendation to discontinue silver use (Stepien et al, 2009).
    2) CASE REPORT: A schizophrenic patient who ingested greater than 20 mg of silver daily for 40 years developed generalized seizures associated with an elevated serum silver concentration. Seizures resolved once serum silver levels decreased to normal (Ohbo et al, 1996).
    3) CASE REPORT: A 71-year-old man developed myoclonic status epilepticus and coma after the ingestion of colloidal silver (at least one ounce per day) for 4 months. High levels of silver in plasma (41.7 nmol/L; normal range: 1 to 2.3), erythrocytes (48.2 nmol/L; normal range: 4.3 to 10), CSF (2.1 nmol/L; normal: 0), and 24-hour urinary excretion (47.28 nmol/L; normal range: 0 to 0.46) were obtained. Although plasmapheresis reduced the silver levels in plasma (1.9 nmol/L), erythrocytes (2.2 nmol/L), and CSF (1.04 nmol/L), he entered a persistent vegetative state until his death 5.5 months after the onset of his seizures. EEGs showed 14- to 18-Hz electropositive central-frontal polyspikes during myoclonic jerks and alpha-theta coma followed by burst suppression. A grossly normal brain with microscopic evidence of diffuse Alzheimer type 2 astrocytosis and microglial activation was observed during autopsy (Mirsattari et al, 2004).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) BRAIN STEM DISORDER
    a) In tests where animals were given silver ions parenterally, the brain stem was first stimulated and then depressed (Petering, 1976).
    2) NEUROPATHY
    a) Although it was originally thought silver would not penetrate the blood brain barrier, a 1985 study has shown that parenterally administered silver salts accumulate in neurons and protoplasmatic glia cells of the brain and spinal cord (Rungby et al, 1985).
    b) Silver nitrate seems to have higher affinity for astroglia than silver lactate or silver proteinate (Rungby et al, 1985).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A previously healthy 17-year-old boy sustained superficial and deep dermal flame burns over 30% total body surface area (ie, legs, buttocks, and hands) while working with a highly flammable solvent. The wounds were cleaned and a silver-coated wound dressing was applied. On day 6, the patient had gradually developed grayish discoloration of his face and pale-bluish lips, appeared ill, and complained of having no appetite and being tired. He was found to have elevated AST (78 U/L), ALT (233 U/L) and gamma-galactosyl transferase (94 U/L) liver enzymes. On day 7, blood and urine silver levels were checked and found to be markedly elevated. Blood silver level was 107 mcg/kg (normal less than 0.21 mcg/kg) and silver urine level was 28 mcg/kg (normal less than 0.21 mcg/kg). The silver-coated dressing was discontinued and his skin discoloration gradually improved along with a return of normal liver function tests. He made a full recovery and was discharged 7 weeks postinjury with still markedly elevated blood silver levels. Silver was hardly detectable in blood (0.9 mcg/kg) or urine (0.4 mcg/kg) 10 months later (Trop et al, 2006).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Hepatic damage has been implicated with administration of soluble silver salts to experimental animals (Weir, 1979).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH POISONING/EXPOSURE
    a) Some texts list silver as a nephrotoxic agent. There are 2 reported cases of tubular dysfunction in silver-exposed photo developers, but these are not well documented (Rosenman et al, 1979).
    1) Rosenman et al (1987) found significantly higher urinary NAG (N-acetyl-B-D glucosaminidase) levels in exposed workers than in a control group, which correlated positively with blood silver concentrations.
    2) CASE REPORT/LACK OF EFFECT: A 58-year-old laboratory technician admitted for a right-sided intracerebral hemorrhage, severe hypertension (BP 240/140 mmHg on admission) with evidence of persistent renal dysfunction had a history of ingesting and spraying a silver colloid solution on his face for several years. A kidney biopsy showed diffuse silver deposits in the glomerular basement membranes without visible damage or proteinuria. Likewise, no cellular accumulation of silver or tissue reaction was demonstrated. No association could be found between the silver deposits observed and the patient's impaired renal function (Mayr et al, 2009).
    B) GLOMERULONEPHRITIS
    1) Glomerular lesions have not been reported in humans, but silver has been identified in the basement membrane of the glomerular capillary walls and in the mesangial regions (Aaseth et al, 1981).
    2) One study showed no silver sulfide in the basement membrane of the kidney, but instead silver selenide was present (Aaseth et al, 1981).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GLOMERULONEPHRITIS
    a) MICE: Experimentally induced glomerular lesions were seen in mice following deposition of silver in the glomerular basement membrane (Clayton & Clayton, 1994).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been a rare complication of treatment with silver sulfadiazine (Anon, 1976).
    B) HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Hemorrhage of the bone marrow, liver, and kidney was reported after injection of 50 mg of collargol (a silver salt) (Fowler & Nordberg, 1979).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) Anemia of the microcytic, hyperchromic type has been reported in animals chronically exposed to several hundred mg/kg of silver in their diet (Fowler & Nordberg, 1979).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) WITH POISONING/EXPOSURE
    a) Argyria is an unsightly blue-gray discoloration of the skin, mucous membrane, and conjunctiva, cornea, or lens due to accumulation of silver.
    1) Although argyria may be either generalized or localized to the gums, nasal septum, posterior pharynx, or eyes, localization in the skin is rare. Argyria appears not to elicit a tissue reaction (Hathaway, 1996).
    2) The pigmentation usually appears early on the face, then spreads gradually to the ears and neck, and often involves the hands in the early stages. In severe cases the skin may become almost black with a metallic luster.
    b) This condition may mimic cyanosis (Timmins & Morgan, 1988), methemoglobinemia (Hori et al, 2002), metastatic melanoma with melanogenuria, or hemochromatosis (Marshall & Schneider, 1977).
    c) The deposited silver may be silver sulfide, silver chloride, or metallic silver from the reduction of silver salt within the tissues. Silver reduction is photoactivated, the skin acting similar to photographic film. Thus, argyria is often more serious in light-exposed areas (Marshall & Schneider, 1977).
    d) CASE REPORT: A 60-year-old man with schizoaffective disorder and noncompliance with his medications had a history of ingesting colloidal silver proteins (CSP) for about 10 years. He developed a generalized silvery sheen that was limited to his face and neck and blue-gray sclera. In addition, the pigment of the skin around the scrotum also lacked normal pigmentation due to self-injection of silver nitrate; the patient believed it would fight infection (Schrauben et al, 2012).
    e) CASE REPORT/EARLY ONSET: A 53-year-old man presented with an 8 month history of progressive, patchy gray hyperpigmentation of the face after consuming a liquid herbal preparation containing a dilute silver nitrate solution (Complete H20 Minerals Silver Concentrate, West Columbia, SC, USA). Physical exam showed that discoloration was limited to the face, and laboratory studies were normal. Biopsies of the skin revealed scattered black/brown particles in the basement membrane region of the eccrine and sebaceous glands, as well as in the hair follicles, blood vessels, and arrector pili muscles. Argyria was suspected and confirmed by electron micropsy. The patient reportedly started the supplement (15 mL every 6 hours) as a "natural antibiotic". In this case, early onset of argyria may be due to the ingestion of silver nitrate rather than colloidal silver (Bowden et al, 2011).
    f) CASE REPORT: A 59-year-old man gradually developed diffuse blue-gray discoloration of his face, and hands following the intermittent ingestion of colloidal silver used as an alternative medicine to treat cold symptoms. Skin discoloration was pronounced on areas exposed to sunlight, with no discoloration of the trunk. The patient reportedly obtained silver wire from a health food store and placed the wire in a solution of water and baking powder and ran a 27-volt current through the solution to suspend the silver in solution. He ingested this solution several times a year for 2 years; the exact of amount of silver ingested could not be determined. Although the patient was on numerous other medications, no new therapies were introduced during this period. The authors concluded that the dermal effects observed were due to silver ingestion and advised the patient to discontinue this practice (Chang et al, 2006).
    g) CASE REPORT: Slate-blue discoloration of the gingival margin of the oral cavity was noted in a 68-year-old man who used Argotone nasal drops (mild silver protein 1%, ephedrine HCl 0.9% in sodium chloride 0.5%) every night at bedtime for 35 years (Timmins & Morgan, 1988).
    h) CASE REPORT: After applying 1 to 2 10 mL bottles of a topical vasoconstrictor (Coldargan; one drop contains 0.85 mg silver protein, 0.68 mg ephedrine levulinate, 0.24 mg sodium levulinate, and 0.075 mg calcium levulinate), weekly for 4 years to treat symptoms of allergic rhinitis, a 42-year-old man developed generalized argyrosis (slate, blue-grey discoloring of the entire tegument, sclera, mucosal surfaces, and nails). Microscopy revealed brownish-black perivascular pigment deposits in muscle, nerve, sweat glands, and the dermis (Tomi et al, 2004).
    i) CASE REPORT: Multiple blue macules on the extremities developed in a 63-year-old woman from intracutaneous acupuncture needles left in the skin for more than 10 years. The needles, used for Hari therapy, consisted mainly of silver or gold (Tanita et al, 1985).
    j) CASE REPORT: A 73-year-old man who took about 55 g of silver on sugar particles for a 15-year period developed generalized argyria and blue discoloration of the fingernail lunulae (Hanada et al, 1998).
    k) CASE REPORT: A 13-year-old girl developed localized argyria and a subcutaneous lobule of the earlobes secondary to wearing silver earrings for 8 years (Morton et al, 1996).
    l) CASE REPORT: An 80-year-old man who had worked for 20 years as an antique restorer and polished silver daily, presented with localized slate-grey discoloration of the dorsum of the fingers, pressure areas and hypothenar eminence of the left hand. Skin biopsy revealed aggregates of small pigmented granules consistent with silver in the dermis (Kapur et al, 2001).
    m) CASE REPORT: A 56-year-old man developed a dusky discoloration of his face and a blue to gray band of discoloration of the proximal aspect of his fingernail after using a colloidal silver product as an allergy and cold medication. Blood silver concentration was 85 mcg/L (normal less than 5 mcg/L) (Gulbranson et al, 2000).
    n) CASE REPORT: Following the ingestion of approximately 550 mg of colloidal silver over a period of 2 years, a 65-year-old developed slate-blue/gray discoloration of the lunula of the fingernails (McKenna et al, 2003).
    o) CASE REPORT: A previously healthy 17-year-old boy sustained superficial and deep dermal flame burns over 30% total body surface area (legs, buttocks, and hands) while working with a highly flammable solvent. The wounds were cleaned and a silver-coated wound dressing was applied. On day 6, the patient had gradually developed grayish discoloration of his face and pale-bluish lips, appeared ill, and complained of having no appetite and being tired. On day 7, blood and urine silver levels were checked and found to be markedly elevated. Blood silver level was 107 mcg/kg (normal less than 0.21 mcg/kg) and silver urine level was 28 mcg/kg (normal less than 0.21 mcg/kg). The silver-coated dressing was discontinued, he made a full recovery and was discharged 7 weeks post injury with still markedly elevated blood silver levels. Silver was hardly detectable in blood (0.9 mcg/kg) or urine (0.4 mcg/kg) 10 months later (Trop et al, 2006).
    B) DEPOSITION OF SILVER
    1) WITH POISONING/EXPOSURE
    a) OCCUPATIONAL EXPOSURE
    1) LOCALIZED ARGYRIA
    a) CHRONIC EXPOSURE: A 75-year-old albino man had a 30 year history of localized argyria (ie, small, round blue lesions on the forearm) after working as a silversmith during that period. He reported that he never wore gloves or a long sleeve shirt and often rested his forearms against his work surface. Biopsies of the lesions confirmed the histologic presence of silver-black granules consistent with argyria (Sendagorta et al, 2011).
    2) GENERALIZED ARGYRIA
    a) CHRONIC EXPOSURE: A 27-year-old man worked as a technician plating with aerosolized silver (composed of alcohol, acetone and silver; concentrations not specified) at a mobile telephone industry and gradually developed blue-gray discoloration of his face over 4 months. He reported no medication use. Although a protective mask was recommended during work, the patient did not wear a mask or gloves. Serum silver concentration was 15.44 mcg/dL (normal: 1.1 to 2.5 mcg/dL) and urinary silver was 243.2 mcg/L (normal 0.4 to 1.4 mcg/L). A punch biopsy of the face demonstrated silver granules in the epidermal basal layer (Cho et al, 2008).
    C) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) A contact dermatitis, sometimes referred to as fulminate itch may develop from dermal exposure to silver fulminate (ACGIH, 2001).
    D) FINDING OF WOUND HEALING
    1) WITH THERAPEUTIC USE
    a) Silver used in topical antimicrobial preparations can be absorbed through open wounds and can potentially delay healing of wounds (Hollinger, 1996) and may produce cytotoxic activity (Atiyeh et al, 2007). However, silver metabolism is modulated by induction and binding to metallothioneins which mitigates the cellular toxicity of silver and contributes to tissue repair (Lansdown, 2006).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were found in available references to assess the potential effects of exposure to this agent in humans during pregnancy.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Silver nitrate was not teratogenic in chickens, but the implications of this for the occupational setting are unclear (Ridgway & Karnofsky, 1952).
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) At the time of this review, no data were found in available references to assess the potential effects of exposure to this agent in humans during pregnancy.
    B) ANIMAL STUDIES
    1) Silver nitrate injected directly into pregnant cynomolgus macaques at a dose of 780 mg/kg induced abortion, but subsequent pregnancies in these same animals were normal (ACGIH, 2001).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS7440-22-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of silver in humans.
    3.21.4) ANIMAL STUDIES
    A) SARCOMA
    1) RATS - Fibrosarcoma developed in 30 percent of rats who had silver foil imbedded in the skin (ACGIH, 2001). Silver is considered an equivocal tumorigenic agent by RTECS criteria (RTECS , 2002).

Genotoxicity

    A) Silver compounds did not cause mutations in S typhimurium or in E coli. It was clastogenic in transformed hamster embryo cells and in cultured Chinese hamster ovary cells.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific studies are needed for most patients.
    B) Specific concentrations of silver are not readily available and are unlikely to be useful in the acute setting, but can be used to confirm exposure. A normal serum silver concentration is less than 0.05 mcg/dL.
    C) Depending on the patient's presentation and symptoms, other tests may be useful or necessary. Suicidal patients should receive an ECG, basic chemistry panel, and testing for acetaminophen and salicylates, while patients with respiratory distress may need pulse oximetry monitoring and patients with seizures require a thorough neurologic exam and a head CT or MRI.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Background serum levels vary considerably, ranging from 0.004 mcg/g in 122 blood donors to 0.03 mcg/g in 93 hospitalized patients, to 0.013 in 48 "normal" hospital workers (Clayton & Clayton, 1982).
    a) Normal serum silver levels are less than 0.05 mcg/dL (Ohbo et al, 1996).
    2) Workers (n = 98) occupationally exposed to silver had blood levels as follows (Armitage et al, 1996):
    GroupMean (mcg/L)Range (mcg/L)
    Unexposed controlsless than 0.1UD to 0.2
    Reclamation workers6.81.3 to 20
    Silver refining2.50.1 to 16
    Jewelry production1.20.2 to 2.8
    UD = undetected

    3) A patient who developed argyria and generalized seizures had an initial serum silver level of 1.2 mcg/dL after ingesting 20 mg of silver daily for 40 years. After discontinuing silver ingestion, serum silver levels decreased to 0.2 mcg/dL on the 63rd day and were undetectable on the 70th day. Seizures resolved as serum silver levels decreased to normal (Ohbo et al, 1996).

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Many methods exist to analyze silver. The two most common methods used for biological materials are emission spectrochemical and atomic absorption spectrometry (Clayton & Clayton, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients exposed to silver or silver compounds should rarely need admission to the hospital. Patients with more severe symptoms (eg, corrosive damage to mucosa membranes from silver salts or seizures may require admission to the hospital for further evaluation or observation). Most patients can be admitted to the hospital ward, but patients with severe symptoms (eg, respiratory distress requiring intubation, seizures) may require ICU care. Patients should remain in the hospital until they are stable and symptoms have clearly improved.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with mild symptoms that simply require decontamination for treatment may remain at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with significant toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with persistent or worsening symptoms should be sent to a healthcare facility for evaluation. Patients should be observed until they are stable and symptoms have clearly improved.

Monitoring

    A) No specific studies are needed for most patients.
    B) Specific concentrations of silver are not readily available and are unlikely to be useful in the acute setting, but can be used to confirm exposure. A normal serum silver concentration is less than 0.05 mcg/dL.
    C) Depending on the patient's presentation and symptoms, other tests may be useful or necessary. Suicidal patients should receive an ECG, basic chemistry panel, and testing for acetaminophen and salicylates, while patients with respiratory distress may need pulse oximetry monitoring and patients with seizures require a thorough neurologic exam and a head CT or MRI.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) INGESTION: GI decontamination is not indicated as absorption is minimal; toxicity has only been reported after long term chronic ingestion.
    2) DERMAL EXPOSURE: Wash exposed skin with soap and water.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) GI decontamination is not indicated as absorption is minimal; toxicity has only been reported after long term chronic ingestion.
    6.5.3) TREATMENT
    A) ARGYRIA OF SKIN
    1) NOT RECOMMENDED: Local injection of 6% sodium thiosulfate and 1% potassium ferrocyanide has been tried locally to decrease silver concentration in small areas. This treatment has not been very effective and is painful (Marshall & Schneider, 1977).
    2) Discoloration produced by argyria is permanent and treatment with chelating agents is usually ineffective.
    B) CHELATION THERAPY
    1) NOT RECOMMENDED
    a) Chelation therapy has not been successful (Aub & Fairhall, 1942). Silver deposited in the tissues is relatively inert and difficult to chelate (Aaseth et al, 1981).
    b) Ethylenediamine is said not to be effective because deposited elemental silver is difficult to chelate (Marshall & Schneider, 1977).
    c) BAL is said not to be effective because deposited elemental silver is difficult to chelate (Marshall & Schneider, 1977).
    d) D-penicillamine or N-acetyl-dl-penicillamine did not increase the urinary excretion of silver in patients with argyria (Aaseth et al, 1981). The silver-albuminate complex does release 20 to 25 percent of the silver to penicillamine in vitro, but this is not seen in vivo (Aaseth et al, 1981).
    e) DIMERCAPTOPROPANE SULFONATE/DMPS: A 60-year-old man with argyria was chelated with DMPS at a dose of 0.5 to 2.5 g/day for two 5-day periods.
    1) Maximal urinary excretion values of 50 nanomoles of silver/day were reported. The estimated total amount of urinary excreted silver during 10 days of chelation was 0.35 micromole, only 0.0066 percent of the estimated 5.3 millimole total body burden (Aaseth et al, 1986) . DMPS is not an effective chelator for silver.
    2) A 55-year-old patient was given oral DMPS and renal excretion of silver increased by 100-fold. Although DMPS was more effective than penicillamine in this case, the total amount of excreted silver was still quite small (Jekat FW, Bertram HP & Kemper FH et al, 1990).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) SUMMARY
    1) There is no evidence for enhanced elimination techniques. In one case, hemodialysis was ineffective in reducing serum silver concentrations, and plasma exchange and hemofiltration do not significantly reduce the body burden of silver. Chelation therapy has not been successful for treatment because silver is relatively inert after being deposited into tissues.
    B) HEMOFILTRATION
    1) Both plasma exchange and hemofiltration were effective in decreasing serum silver, and their effects were additive. However, hemodialysis was ineffective in reducing serum silver (Iwasaki et al, 1997). Plasma exchange and hemofiltration do not significantly reduce the body burden of silver, so these techniques are rarely if ever clinically useful.

Range Of Toxicity

Summary

    A) TOXICITY: Acute toxicity is usually low; toxicity usually occurs following chronic exposure. The estimated average daily intake (from most foods) is 0.088 mg.
    B) INGESTION: CHRONIC EXPOSURE: The minimum oral dosage necessary to cause systemic argyria has been estimated to be about 25 to 30 g over 6 months.
    C) INHALATION: LACK OF EFFECT: Exposure to silver concentrations in air of less than 0.01 mg/m(3) has not caused argyria.

Therapeutic Dose

    7.2.1) ADULT
    A) SUMMARY
    1) The estimated average daily intake (mostly from foods) is 0.088 milligram (Clayton & Clayton, 1994).

Minimum Lethal Exposure

    A) INTRAVENOUS: Acute intravenous administration of 50 mg or more of metallic silver is fatal in humans. It can lead to pulmonary edema, hemorrhage and necrosis of bone marrow, liver and kidneys (Lai Becker, MW & Ewald, 2011).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Silver exhibits low toxicity and minimal risk following clinical exposures due to inhalation, ingestion or dermal use. Chronic ingestion or inhalation of silver-containing products can produce the deposit of silver particles in the skin, eye and other organs, leading to the characteristic gray/blue (argyria) discoloration (Lansdown, 2006).
    B) RISK OF EXPOSURE
    1) CHRONIC EXPOSURE: The estimated safe exposure level to which humans may be chronically exposed to silver (the US EPA Reference Dose) is 350 mcg/day (Bingham et al, 2001a).
    2) INGESTION: The minimal oral dosage necessary to cause systemic argyria has been estimated to be about 25 to 30 g over 6 months (Gettler et al, 1927).
    a) Silver serum concentrations increased over baseline levels during 12 weeks in 21 adults using a silver acetate chewing gum as a smoking deterrent. Although the number of silver granules in skin biopsies had increased, no patient developed clinical signs of argyria (Jensen et al, 1988).
    b) When average exposures to silver have ranged from 40 to 60 mcg/m(3) with values as high as approximately 150 mcg/m(3), there have been no adverse effects including any cases of argyria (skin discoloration) (ACGIH, 1991).
    3) INHALATION: Cases of argyria or other adverse effects have not resulted from silver concentrations in air averaging 0.04 to 0.06 mg/m(3). Values as high as 0.15 mg/m(3) were reported in this study (ACGIH, 1991).
    4) TOPICAL: Application of topical silver can lead to bone marrow depression and the potential development of leukopenia or aplastic anemia (Lai Becker, MW & Ewald, 2011).
    C) CASE REPORTS
    1) INGESTION
    a) PEDIATRIC: Argyria was noted in a 14-year-old who abused a silver-containing pulveriser to treat a sore throat (Capoen et al, 1989).
    b) ADULT: A 60-year-old man with schizoaffective disorder and noncompliance with his medications had a history of ingesting colloidal silver proteins (CSP) for about 10 years. He developed a generalized silvery sheen that was limited to his face and neck and blue-gray sclera. In addition, the pigment of the skin around the scrotum also lacked normal pigmentation due to self-injection of silver nitrate; the patient believed it would fight infection (Schrauben et al, 2012).
    c) ADULT: A patient who ingested greater than 20 mg of silver daily for 40 years developed argyria and generalized seizures associated with elevated serum silver levels (Ohbo et al, 1996).
    d) ADULT: A 79-year-old man ingested sugar particles coated with silver for 15 years and subsequently reported a 3-year history of a grey-brown discoloration of his skin. The discoloration was more noticeable on the sun-exposed areas of his face, neck, and the back of his hands. Lunulae of his nail beds were blue. A skin biopsy showed pigmented granules in the basal lamina of the secretory glands and elastic fibers in the dermis. X-ray microanalysis showed a single peak for silver in these granules (Hanada et al, 1998).
    e) ADULT: Seizures developed in a schizophrenic adult after ingesting greater than 20 mg silver daily for 40 years; silver serum concentration was 12 mcg/L. Seizure activity stopped with the discontinuation of silver therapy (Lai Becker, MW & Ewald, 2011).
    2) INHALATION
    a) OCCUPATIONAL EXPOSURE: A 27-year-old man worked as a technician plating with aerosolized silver (composed of alcohol, acetone and silver; concentrations not specified) at a mobile telephone industry and gradually developed blue-gray discoloration of his face over 4 months. He reported no medication use. Although a protective mask was recommended during work, the patient did not wear a mask or gloves. Serum silver concentration was 15.44 mcg/dL (normal: 1.1 to 2.5 mcg/dL) and urinary silver was 243.2 mcg/L (normal 0.4 to 1.4 mcg/L). A punch biopsy of the face demonstrated silver granules in the epidermal basal layer (Cho et al, 2008).
    3) TOPICAL
    a) OCCUPATIONAL EXPOSURE: A 75-year-old albino man had a 30 year history of localized argyria (ie, small, round blue lesions on the forearm) after working as a silversmith during that period. He reported that he never wore gloves or a long sleeve shirt and often rested his forearms against his work surface. Biopsies of the lesions confirmed the histologic presence of silver-black granules consistent with argyria (Sendagorta et al, 2011).
    D) MEDICINAL SILVER CONTAINING PRODUCTS
    1) Below is a list of silver containing products that may be used by the topical or ophthalmic route (Lai Becker, MW & Ewald, 2011):
    1) Silver nitrate (1% AgNO3): Ophthalmic
    2) Silver nitrate (10% AgNO3): Cutaneous
    3) Silver Sulfadiazine (0.2%, 1%, micronized silver sulfadiazine): Cutaneous

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Serum silver concentrations in 21 adults using a silver acetate chewing gum as a smoking deterrent for 12 weeks ranged from not detectable to 117 micrograms/liter with a mean value of 41.7 (+/- 37.51 SD) micrograms/liter (baseline 1 to 5.5 micrograms/liter) (Jensen et al, 1988).
    b) Normal serum silver levels are less than 0.05 mcg/dl (Ohbo et al, 1996).
    c) Workers (n = 98) occupationally exposed to silver had blood levels as follows (Armitage et al, 1996):
    GROUPMEAN (mcg/L)RANGE (mcg/L)
    Unexposed controls< 0.1UD to 0.2
    Reclamation workers6.81.3 to 20
    Silver refining2.50.1 to 16
    Jewelry production1.20.2 to 2.8
    UD = undetected

    d) A patient, who developed argyria and generalized seizures had an initial serum silver level of 1.2 mcg/dL after ingesting 20 mg of silver daily for 40 years. After discontinuing silver ingestion, serum silver levels decreased to 0.2 mcg/dL on the 63rd day and were undetectable on the 70th day. Seizures resolved as serum silver levels decreased to normal (Ohbo et al, 1996).
    2) AUTOPSY ORGAN LEVELS
    a) Tissue levels in unexposed persons and from a patient who died following ingestion of a solution containing 30.7 percent silver (Lech, 1997) -
    OrganSilver Poisoning Fatality (mg/gram)Unexposed Persons (mg/gram)
    Stomach0.96< 0.1
    Small Intestines0.85< 0.08
    Liver1.49< 0.07
    Kidney1.55< 0.06
    Spleen0.900.23
    Heart0.960.26
    Lung0.910.004 - 0.15
    Brain1.990.004 - 0.04

Workplace Standards

    A) ACGIH TLV Values for CAS7440-22-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Silver, metal, dust and fume
    a) TLV:
    1) TLV-TWA: 0.1 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: Not Listed
    3) Definitions: Not Listed
    c) TLV Basis - Critical Effect(s): Argyria
    d) Molecular Weight: 107.87
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:
    b) Adopted Value
    1) Silver, soluble compounds, as Ag
    a) TLV:
    1) TLV-TWA: 0.01 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: Not Listed
    3) Definitions: Not Listed
    c) TLV Basis - Critical Effect(s): Argyria
    d) Molecular Weight: Varies
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS7440-22-4 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Silver (metal dust and soluble compounds, as Ag)
    2) REL:
    a) TWA: 0.01 mg/m(3)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH:
    a) IDLH: 10 mg Ag/m3
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS7440-22-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Silver, metal, dust and fume
    2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Silver, soluble compounds, as Ag
    3) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Silver
    a) D : Not classifiable as to human carcinogenicity.
    4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    5) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Silver (metal dust and soluble compounds, as Ag)
    6) MAK (DFG, 2002): Not Listed
    7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS7440-22-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Silver, metal and soluble compounds (as Ag)
    2) Table Z-1 for Silver, metal and soluble compounds (as Ag):
    a) 8-hour TWA:
    1) ppm:
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 0.01
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: ITI, 1995 Lewis, 2000 RTECS, 2002
    1) LD50- (ORAL)MOUSE:
    a) 100 mg/kg (Lewis, 2000; ITI, 1995)
    2) TCLo- (INHALATION)HUMAN:
    a) 1 mg/m(3) -- skin effects (Lewis, 2000; ITI, 1995)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Silver has no known biological function in humans. It is one of the most physically and physiologically cumulative of the elements (Clayton & Clayton, 1982). It has a strong affinity for sulfhydryl groups and proteins, a fact that most likely accounts for its germicidal properties.
    B) Silver may also bind to chloride ions, and imidazole, phosphate, and carboxyl groups. This strong reactivity means there is little silver in ionized form available for entry into the blood stream (Petering, 1976).

Toxicologic Mechanism

    A) Systemic silver toxicity rarely occurs other than argyria due to rapid binding to various proteins and precipitation of silver chloride. Tissue damage occurs only when this binding ability is overwhelmed by a massive dose.
    1) Slow administration allows more binding time and distribution, resulting in less tissue damage (Marshall & Schneider, 1977).

Physicochemical

Physical Characteristics

    A) Silver is a soft and malleable lustrous, white metal. A naturally occurring element, silver has an atomic number of 47 and is present in the earth's crust at 0.1 ppm. It does not oxidize readily, but forms a black sulfide tarnish by reacting with sulfur in air (Budavari, 2000; Lewis, 2000).
    B) The only metal more malleable and ductile than silver is gold. Silver is also an excellent conductor of electricity and heat (Budavari, 2000).

Molecular Weight

    A) 107.868

Other

    A) ODOR THRESHOLD
    1) Silver is odorless (Bingham et al, 2001a).

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