DSF is used topically to reduce dentin hypersensitivity in adults [1
] and arrest tooth decay in both adults and children [4
]. For sensitivity in adults, a single application reduces sensitivity by at least half [1
] and application 2 or 3 times per year is sufficient clinically. In applying DSF, no deleterious changes in the gingiva were noted in our earlier study nor were changes seen in this work. Direct application of various silver compounds to wounds has been associated with localized argyria [21
]. DSF should therefore be applied to teeth with care when used near areas of recent surgery, injury, or soft tissue erosion. DSF should also be used with caution in patients habitually consuming large amounts of colloidal or other compounds of silver [23
]. DSF solutions will stain countertops and irreversibly damage clothing.
Maximum serum concentrations of fluoride did not exceed concentrations adults experience when using fluoridated toothpaste [16
]. Fluoride exposure was below the EPA RfD [24
]. Thus, the study results suggest that a single diammine silver fluoride treatment poses no toxic risk.
Oral exposure to metallic silver and numerous soluble silver compounds is common [25
]. For instance, intraoral silver jewelry (piercings), and medical devices such as silver-coated intraurethral and intravascular catheters, and dental amalgam restorations can expose an individual to metallic silver. Silver and silver compounds (i.e. nitrates, chlorides, oxides, and sulfides of silver) can also be found in food and water. In its 1990 review of the toxicology of silver, ATSDR found no human studies of acute or chronic oral exposure to silver that resulted in death. Rat studies suggest the no observable adverse effect level (NOAEL) from ingested silver is greater than 181 mg/(kg day) for acute exposure of 14 continuous days (Table ), [1
]. This level is more than 75 times higher than the maximum amount of silver applied to the subject’s teeth in this study.
A recent case report [27
] provides details of a patient who consumed a cumulative dose of 200 g silver and developed argyria, but was otherwise healthy. His consumption was approximately 648 mg of colloidal silver every day for 10 months. This is a daily dose of silver that is 275 times higher than the maximum amount applied as DSF in this study. DSF is intended for professional application no more than 2–3 times per year. When used as intended, the amount of silver applied as DSF should be well below the level to exhibit a toxic effect. While considered ‘cosmetic’ rather than toxic effect by the FDA [28
], an irreversible blue or blue-gray discoloration of the skin or mucous membranes (argyria), or eyes (argyrosis) may develop with chronic exposure to silver and silver compounds. Evidence suggests silver salts (soluble silver) have a higher tendency to produce argyria than metallic silver [29
After reviewing 70 cases of argyria associated with ingestion of silver and silver compounds [30
], the EPA established a chronic oral RfD of 5 μg/(kg day), or about 350 μg for a 70 kg person [31
]. The amount of silver contained in the dose of DSF applied intraorally in this study exceeded the RfD for all subjects, with 1 subject exposed to nearly 9 times the RfD. However, the RfD represents a conservative estimate of silver that can be ingested every day of one’s entire life and presumably not result in the development of argyria or argyrosis. Allowable short-term exposure (1–10 days) of 1.142 mg of silver per liter of drinking water was proposed by the EPA in May 1989 [26
]. Based on argyria development reported by Gaul and Staud [30
], the EPA set the lifetime lowest allowable effect level (LOAEL) for silver exposure at 1 g total dose, which is well over 400 times the maximum amount of silver applied in this study.
Most case reports of argyria indicate a pattern of chronic ingestion of high concentrations of colloidal or soluble silver, with total exposure in the 1– 30 g range [32
]. Evidence from a controlled study of the use of chewing gum containing silver acetate as a smoking deterrent would suggest significantly higher concentrations of silver exposure can be tolerated daily over several months without development of argyria or argyrosis. On average, 21 participants in the study by Jensen and colleagues [33
] chewed 31.9 pieces of gum per week (4.5 pieces/day) for up to 12 weeks. Each piece of gum contained 6 mg of silver acetate (approximately 3.9 mg silver ion) and chewing for 30 minutes was reported to release about half of the silver from the gum (approximately 1.9 mg silver ion). Chewing the average number of pieces each day would have resulted in ingesting 8.6 mg silver ion per day for each day of the 12-week study. Some subjects reported chewing as many as 63 pieces of gum per week (9 sticks/day average) during the first 2 weeks of the study, giving silver exposure as high as 17.1 mg per day. Physical examinations found no signs of discoloration in the oral mucosa, teeth, skin, or eyes at any time up to 6 months after the study. Of significance, skin biopsies were assessed to be normal by hematoxylin and eosin staining, and autometallographic silver development found only a few traces of silver in the majority of skin biopsies after participation in the study. Examination of skin biopsies pre- and post-silver gum treatment, found that only a ‘few’ biopsies showed increased silver grains after completion of the silver gum treatment, compared with ‘sparse’ silver grains seen pre-treatment.
The controlled, chronic silver exposures reported by Jensen and colleagues [33
] significantly exceed the dose and number of applications associated with the therapeutic use of DSF. For example, a 70 kg person chewing the average (4.5 pieces) or highest (9 pieces) number of gum pieces per day would exceed the RfD for silver by nearly 25 to 50 times, respectively. The fact that argyria or argyrosis did not develop with these higher exposures suggests it is unlikely either condition will develop from one-time or occasional use of DSF with an exposure to silver that is 2.5 to 5 times less. Moreover, there was no staining of teeth or irritation of the oral soft tissues reported at these recurring exposure concentrations over 12 weeks.
The pharmacokinetics of serum silver in 4 of 6 subjects treated with DSF in this study suggested maximum serum concentrations of silver occurred within 1–3 h after treatment. Apparently, delayed ingestion of DSF in the other 2 participants resulted in a delayed maximum serum silver level until the end of the monitoring (4 h after DSF application) in 1 participant, and no obvious serum silver peak in the other. For future studies examining the serum pharmacokinetics of a topically-applied, aqueous compound such as DSF, we suggest utilization of a plain water ‘swish and swallow’ immediately after application to facilitate dependable clearance and ingestion of excess product from the oral cavity. With these caveats, the mean maximum serum silver level was 206 nmol/L, with no participant over 270 nmol/L. These serum silver concentrations are well below those reported to be without toxic effect in subjects chewing silver acetate-containing gum [33
]. After two weeks of gum chewing, the mean serum silver in the Jensen study was 512 nmol/L, decreasing to 406 nmol/L at week 6, and 387 nmol/L at week 12. The serum silver level was essentially maintained above 371 nmol/L for a period of at least 10 weeks without development of argyria or argyrosis. These results suggest, again, that the lower serum silver level associated with a single application of DSF at the dose used in this study should not induce a toxic effect.
This was a preliminary study and, as such, the number of subjects was limited. In addition, the follow-up period was shorter than optimal, given likely delayed clearance and ingestion of DSF from the oral cavity. As a result we were not able to calculate the Area Under the Curve (AUC) for this exposure. Despite these limitations, the data obtained are certainly useful in preliminarily assessing safety and planning future studies.