In great enough quantities, silver manifests cardiovascular, hepatic, and hematopoietic toxicity. Acutely, administration of 50 mg or more of metallic silver IV in humans is fatal, leading to pulmonary edema; hemorrhage; and necrosis of bone marrow, liver, and kidneys.1,14 The mechanism for this acute toxicity was studied only in the water flea (Daphnia magna) in which silver blocks Na+-K+-adenosine triphosphate (ATPase) activity.3 Toxicity in animals is listed by system in Table 99–2.
Silver is neither classified as a human carcinogen nor found to be mutagenic, and no data link therapeutic use of silver to human cancer.13 Although animal studies show that silver implanted subcutaneously may lead to local sarcoma formation, this reaction has been deemed uninterpretable in regard to carcinogenicity as implantation of other insoluble solids, such as plastic and smooth ivory, produce similar results.13 Colloidal silver injected into rats induces growths at injection sites, but intramuscular injections of silver powder have not induced cancer.18 Local inflammatory responses notwithstanding, silver is considered an inert substance and not a human carcinogen.
The most significant effect of silver overexposure in humans is argyria, a permanent bluish-gray discoloration of skin resulting from silver throughout the integument. (See Fig. 99–1)
Long-term exposure to AgNO3 in the workplace led to this patient's characteristic pigment changes of argyria. A normally pigmented arm is across the patient's chest. (Image contributed by New York University Department of Dermatology).
Cases of argyria have been reported in the medical literature since at least the early 19th century. One of the most famous cases of argyria is that of the Barnum and Bailey Circus' "Blue Man" who died at New York's Bellevue hospital in 1923 and was described on autopsy as follows: "The color of the skin was of an unusually deep blue and from a distance appeared almost black. This deep color was almost uniform throughout the entire body, although it was more intense over the exposed skin areas."21 An American woman who developed argyria as a teenager during the 1950s from use of a nasal CSP for allergies, has described her story on the Internet to warn others of the effects of prolonged contact with or ingestion of silver salts.23 Her appearance was documented as an Image in Clinical Medicine in the New England Journal of Medicine.5
Generalized argyria may result from either simple mechanical impregnation of the skin by silver particles or inhalational and oral absorption of particulate silver. Local routes of silver absorption may be through the conjunctiva or oral mucous membranes after long-term topical treatment with silver salts. In 2002, a 42-year-old European man developed argyria after weekly application for 4 years of a topical nasal vasoconstrictor (Coldargan, manufactured by Siegfried, Sweden) available in Austria. The patient used this product to treat his rhinitis medicamentosa; each drop of medication contained 0.85 mg of silver protein.46 More directly, colloidal silver protein ingestion for "health supplementation" leads to body burdens of silver that may produce argyria. Argyria was reported in a 33-year-old woman who had ingested 48 mg/d of elemental silver (from silver nitrate capsules) during alternating 2-week periods over 1 year to treat chronic GI symptoms.4 Her serum silver concentrations remained at 500 μg/L for 3 months after discontinuation of the capsules, indicating significant silver deposition in tissues.
Mechanical impregnation of silver produces localized argyria or argyrosis (deposition into eyes) after repeated contact with metallic silver or silver salts.25 Localized argyria is reported from both implanted acupuncture needles and short-contact acupuncture, when particle deposition may occur from silver needles used repeatedly during brief therapeutic sessions.26 Silver sulfadiazine use produces localized argyria in and around wound scars.17 Localized argyria of the tongue and gingiva is described in patients with silver dental amalgams.24,39 These patients may also have elevated tissue concentrations of silver, but there are no known cases of significant absorption resulting in generalized argyria.12 Even long-standing wearing of silver earrings has resulted in local contact argyria.29,45,47 Corneal argyrosis was frequently reported from prolonged use of colloidal silver disinfectant eyedrops, but because these drops are no longer used, the condition has become an occupational disease caused by both inadequate eye protection and workers rubbing their eyes with hands contaminated by silver particles.40,42,54
Histopathology of Argyria
There are no pathologic changes or inflammatory reactions visible at a histologic level from silver deposition or impregnation. Rather, the skin discoloration of argyria comes from the silver itself and from the induction of increased melanin production. Silver granules are initially found within fibroblasts and macrophages and then extracellularly along the basement membrane of blood vessels, sweat glands, and dermoepidermal junction and beside erector pili muscles (see Chap. 29). Patients with argyria commonly manifest increased pigmentation over sun-exposed skin. Although the mechanism for this process is not yet fully understood, it has been proposed that silver-complexed proteins are reduced to their elemental form via photoactivation from sunlight, similar to photographic image development. Silver plus light then further stimulates melanogenesis, increasing melanin in light-exposed areas and enhancing this cycle.
Argyria develops in stages, beginning with an initial gray-brown staining of gingiva, progressing to hyperpigmentation and bluish-gray discoloration in sun-exposed areas. Later, nail beds, sclerae and mucous membranes become hyperpigmented; on autopsy, viscera are noted to be blue. Confirmation of the diagnosis of argyria is through skin biopsy, showing brown-black clusters of silver granules.
Argyria occurs at exposure doses much lower than those associated with acutely toxic effects of silver; the degree of discoloration is directly proportional to the amount of silver absorbed or ingested.20 The threshold dose for silver accumulation and retention resulting in generalized argyria varies considerably. Discoloration has been reported in some patients from as little as a cumulative 1 g of metallic silver administered IV (from 4 g of silver arsphenamine used to treat syphilis over a 2-year period in the early 1900s), but others have tolerated infusions containing up to 5 g of elemental silver over 9 months before a clinical change was noted.20