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9 Silver Raghupathy Ramanathan, Ph.D. NASA-]ohnson Space Center Toxicology Group Habitability ancI Environmental Factors Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Silver is a white, lustrous, ductile, malleable metal (see Table 9-1 for a list of properties). It reacts with dilute nitric acid and hot sulfuric acid. Silver forms several inorganic and a few organic salts, including silver chloride, silver fluoride, silver iodide, silver nitrate, silver acetate, silver sulfide, silver perchiorate, silver benzoate, and silver diethy! dithiocarbamate (see Table 9-2~. OCCURENCE AND USE Silver, a transition metal, is a rare element that naturally occurs in the earth's crust, both in pure form and as an ore with lead and copper. Soil concentrations vary by geological location. Silver has also been reported in the air; in sea, well, and surface waters (originating from natural resources and from industrial waste); and in finished public drinking water supplies (Durfor and Becker 1964; Kopp and Kroner 1967~. A median concentration of silver at 2.2 micrograms per liter (vigil) (range 0.3-5 vigil) in finished water supplies has been reported in the United States (Kopp and Kroner 1967~. 324

Silver TABLE 9-1 Physical and Chemical Properties 325 Formula Ag Chemical name Silver Synonyms Argentum, shell silver, silber (German), silver colloi- dal (Stokinger 1981) CAS registry no. 7440-22-4 Molecular weight 107.87 Atomic number 47 Melting point 960.5°C Density 10.5 g/cm3 at 20°C Units 1 ppm in water = 1 mg/L in water Solubility Metallic silver is practically insoluble in hot and cold water; it is soluble in fused alkali hydroxides; most silver salts have limited solubility in water; low solu- bility depends on pH and chloride concentrations (0.1- 10 mg/L) Silver and silver salts have been extensively used in making jewelry, table silverware, coinage, solder, high capacity batteries and conductors, and dental alloys. It is used extensively in photographic processing. Silver also has some use as an antibacterial agent in water treatment (Merck 1989~. Pharmaceutical preparations used for the treatment of warts end bums con- tain silver. Silver nitrate has also been used as a prophylaxis against opthal- mia neonatorum. Silver acetate has been used in chewing gums and loz- enges as a smoking deterrent. High concentrations of silver were found in the blood and urine of subjects who consumed silver acetate lozenges (Macintire et al. 1978; East et al. 1980~. The use of silver in medical equip- ment and devices has been a major area of research in dentistry and medicine (e.g., silver amalgam vs mercury amalgam and antimicrobial efficacy and biocompatibility of silver-coated central venous catheters, prosthetic valves, and silver impregnated collagen cuffs to decrease infec- tion in tunneled catheters). Human exposure to silver usually occurs by inhalation of silver-con- taining dust in the environment or by dermal contact to jewelry or photographic materials containing silver. Silver has been the primary agent used to disinfect potable water processed from humidity condensate in the Russian Mir space station. Silver will also be used in the humidity-conden-

326 Spacecraft Water Exposure Guidelines TABLE 9-2 Physical Properties of Silver Salts Silver Silver Silver Silver Nitrate Silver Acetate Lactate Chloride Fluoride Formula AgNO3 CH3COO.Ag Ag(CH3CH AgC1 AgF (OH)COO) Molecular 169.89 166.92 214.97 143.32 126.88 weight NO Silver 63.5 64.63 54.78 74.65 85.04 (wlw) Solubility 122 g/100 1 g/100 mL at 1 g/15 mL at 1.93 mg/L 1.82 g/100 in water mL at 0°C 0°C 0°C at 25°C mL at 15°C Source: Merck 1989. sate water-processing assembly in the Russian service module (SM) to support the crew during the early phases of assembly of the International Space Station (ISS). The Russian and U.S. crew members aboard the early assembly missions ofthe ISS will consume water containing silver at about 0.5 milligrams (mg)/L. Moreover, silver will be added electrolytically in the Russian water supplies carried to the ISS via Progress resupply vehicles during the ISS assembly phase. The concentrations of silver in the archived water samples from the cold and hot water galleys of various Mir missions ranged from ~ ~g/L to 670 ~g/L, although the target concentration was 500 ~g/L. That probably indicates that the mechanism of silver addition did not work reliably, or there was a silver demand in the system after it had been added. During the Mir missions, when U.S. astronauts lived in the Mir space station for 3-6 months (mo), the fuel-cell water transferred from the shuttle was deiodinated and silver was added as silver salts to support the crew drinking water requirements. The residual iodine precipitated some of the silver, which caused very low silver concentrations in some samples. The common salts that were used to maintain silver in solution were formate and fluoride. If the crew uses water recovered from the humidity condensate, the forms of the silver salts will depend on the salts of calcium and magnesium added as mineralizing agents to improve the organoleptic properties. Because that has been proprietary, the exact forms are not known.

Silver 327 PHARMACOKINETICS AND METABOLISM The bioavailability of silver appears to depend on whether it is metallic silver or one ofthe various silver salts. The available data on the toxicity of silver focus primarily on its bioaccumulation in aquatic organisms and its potential toxicity to humans. Absorption In an occupational setting, silver can be absorbed readily through inha- lation of silver dust or dermal exposure to photographic processing chemi- cals. It also has been absorbed after ingestion of colloidal forms (Hill and Pillsbury 1939; Newton and Homes 1966; Dequidt et al. 1974, as cited in ATSDR 1990~. Data on absorption was estimated from the excretion kinetics of radio- active silver after administration by the oral route. Furchner et al. (1968) determined the body burden (by measuring whole-body radioactivity using a gamma-ray detector) and retention of silver at various times after adminis- tering doses of Wag (as the nitrate) via the intravenous and oral routes in female RF mice, male Sprague-Dawley rats, beagle dogs, and Macacca mulatto monkeys. It was reported that the body burden (based on whole- body monitoring) was higher when silver was administered intravenously rather than orally and was proportionately higher as a function of species size. One must note that the calculated doses (in milligrams per kilogram tmg/kg]), which were based on the specific activity of the radioactivity administered, varied widely from species to species. It is not known how that would have affected the relative amounts absorbed. On the basis ofthe cumulative excretion by the second day after oral ingestion, which was between 90°/O and 99°/O of the orally administered dose, the authors con- cluded that gut absorption was very low. The dog appeared to retain the greatest percentage ofthe dose, and the authors explained that the phenome- non was related to gastrointestinal transit time (S hours th] in mice and rats and about 24 h in dogs, monkeys, and humans). The much longer intestinal transit time resulted in higher absorption in dogs compared with the other species studied. By extrapolating the parabolic relationship between body weights and estimated equilibrium factors from small animals to humans, the authors estimated 4°/O retention of silver in humans. A much higher level of silver retention was estimated from a case his- tory study of silverpoisoning associated with antismoking lozenges (Respa-

328 Spacecraft Water Exposure Guidelines ton) that contain 6 mg of silver acetate (Macintire et al. 1978~. A 47-y-old woman with a 2-y history of blue-gray discoloration of neck and face (argyria) reported the onset of discoloration after the use of 32 lozenges per day for 6 mot The woman was given an oral dose of silver acetate labeled with silver tracer Wag (4.4 Loci and 10 mg of ammonium chloride, as in the Respaton formulation). Retentions of silver measured by whole-body counter at 1, 2, 8, and 30 weeks (wk) were 21%, 20%, 19%, and 18.7% of the total radioactive count measured 20 minutes (min) after the dose (nor- malized as 100%) (also see East et al. 1980~. There was almost no excre- tion after 1 day Gil. The blood level 2 h after administration was very low, and based on the whole-blood volume, the total amount in blood repre- sented only 1.~% ofthe administered dose. The effect of ammonium chio- ride in the formulation on the retention and absorption of silver in this in- stance is not known. Prior to the tracer dose, the total body burden of silver was estimated by neutron analysis to be about 6.4 ~ 0.2 grams (g). How- ever, East et al. ( 1980) reported that such high-level constant retention after an initial drop was not consistent with the biological half-life of 5 ~ for the retention of whole-body Wag and the half-lives of 30, 15, and 10 ~ in bone, liver, and kidneys, respectively, as reported by the International Com- mission on Radiological Protection. That implies that there should be insig- nificant retention at 30 wk. In addition, according to East et al. (1980), other investigations believed that the use of the lozenges did not result in any significant level of absorption of silver. That indicates that with repetitive doses, the overall body retention might be higher, perhaps due to the satura- tion ofthe only biliary excretion pathway, resulting in increased distribution to tissues and poor excretion. Hence, the high percentage of retention could be a gross overestimate of what might result from chronic small doses. This level of retention is much higher than that derived by Furchner et al. (1968) for humans. It has to be noted that a different silver salt was used in those reports. A summary of oral absorption is presented in Table 9-3. In a case of accidental inhalation exposure of one worker to dust con- taining radioactive ~ Wag from an experimental nuclear reactor, radioactiv- ity was found in the liver and feces even after 200 d (Newton and Holmes 1966~. This strongly indicates that silver could be absorbed through the lungs into the systemic circulation. Whole-body radiation monitoring dur- ing the first 155 d revealed wide areas of radioactivity, and 25% of it was located in the liver. Silver also was found in measurable concentrations in the blood of workers in a silver oxide/silver nitrate manufacturing plant, indicating exposure through inhalation (Rosenman et al. 1979~. Similarly, Armitage et al. (1996) reported that the blood silver levels ranged from 0.1 ~g/L to 23 ~g/L in 98 occupationally exposed workers

Silver 329 TABLE 9-3 Interspecies Differences in the Retention of Silver After an Oral Dosea Species Form Dose Retained Reference Mouse Silver nitrate <1% Furchner et al. 1968 Rat Silver nitrate <2% Furchneret al. 1968 Monkey Silver nitrate <5°/0 Furchner et al. 1968 Dog Silver nitrate <10% Furchneret al. 1968 Human Silver acetate 18% of initial Macintire et al. 1978; retentions East et al. 1980 aEstimated from cumulative excretion at day 2. The animal data were obtained after only tracer doses of silver nitrate. Doses were very small (mg/kg) and were different for each species. bData from one argyric human who ingested silver acetate from lozenges for over 2 y. The formulation also contained ammonium chloride. involved in bullion production, cutlery manufacture, and silver reclamation. When colloidal silver was administered to Wistar rats orally at 1.68 g/kg for 4 ~ or 0.42 g/kg for 12 4, about 2-5% ofthe dose was absorbed (Dequidt et al. l 974, as cited in ATSDR 1990~. In another study by Scott and Hamilton (1950),itwasfoundthatwhencarrier-freeradioactivesilver(<1 fig; 1 loci) was intragastrically administered to rats, 99°/O ofthe dose was eliminatedin the feces and 0.1 SILO was eliminated in the urine within 4 d. The total tissue distribution of the radioactivity was about 0.84°/O of the dose. The results indicated very little absorption. Distribution Reports strongly indicate that silver is distributed to almost all organs of the body after exposure. Rats given silver nitrate in drinking water (0.15% or 8.8 millimolar tmM] of silver) for 5 wk showed deposition of silver granules in the kidneys (Moffat and Creasey 1972; Creasey and Mof- fat 1973~. Similarly, in Sprague-Dawley rats that received silver nitrate at various concentrations (6,12, and24 mM of silver) in drinking water for 60 wk. silver accumulated in the basement membranes of the giomerulus, colon, liver, thyroid, urinary bladder, and prostatic acini (Walker 1971~. Although the rats were restored to silver-free water, the deposited silver did not diminish even 10 wk after silver salt ingestion. Maffat et al. (1973) reported that when silver nitrate was given to three rabbits and 10 rats as a

330 Spacecraft Water Exposure Guidelines 0. 15% solution (~.8 mM of silver) in drinking water, silver was found in the meduliary interstitial tissue and in the interstitial cells (which showed signs of degeneration) in both species. There was a species difference in the amount of silver deposited (heavy deposits of silver in the rat and smaller amounts in the rabbit). Matuk et al. (1981) reported retardation of growth in rats given silver nitrate at 0.25% (15 mM) in drinking water for 10 wk. When continued for an additional 12 mo, all rats died. Examination of eyes showed deposits of silver particles in Bruch's membrane the number and size ofthe particles increased with continued ingestion, but was found to be decreased in the group that was continued on silver-free water. In a study involving biologic monitoring of workers (n = 37) in one of the silver smelting and refining industries in which the exposure is entirely by inhalation, silver was found in the blood (0.011 fig per milliliter tmL]), urine (<0.005 ~g/mL), and feces (15 ~g/g). Control subjects excreted about 1.5 Gag in the feces (n = 35~. The author suggests that human fecal excre- tion of silver at exposure levels equal to the Threshold Limit Value (TLV) (0.1 mg per cubic meter tm33) would be about 1 mg of silver per day (Di- Vincenzo et al. 1985~. Rungby (1986a) studied the anatomical distribution of silver in the peripheral nervous system of rats 4 ~ after intraperitoneal (silver lactate) or oral administration (silver lactate or silver nitrate). Silver was found to be distributed throughout the peripheral nervous system in dorsal root ganglia, peripheral nerve, adrenal medulla, and enteric ganglia. The localization of silver deposits in the orally treated animals was independent of the form of the salt. In all organs, large amounts were present in connective tissue fibers and basement membranes (Rungby 1986a). In postmortem analyses for several metals in the tissues of 150 human adults who died instantaneously, silver was found to be present in all tissues (Tipton and Cook 1963) in the order of thyroid > skin > liver > adrenals > intestine > stomach and other tissues. East et al. (1980) did a detailed study on the uptake and disposition of silver in a 47-y-old woman who ingested antismoking lozenges containing 6 mg of silver acetate daily for 2.5 y and developed argyria in the process. Using radioactive tracer of silver acetate (4.5 ma; 4.43 loci), they measured silver retention. At the end of first week, 1 8°/O of the ingested radioactivity was retained, and that remained constant up to 30 wk. The blood levels and the percent of excretion in urine over the first week were very low. Silver was detected at a high concentration in a skin biopsy sample (71.3 ~ 3.7 ~g/g). Uptake by the skin was substantial. In the Newton and Holmes ( 1966) study, whole-body monitoring of a 29-y- old man who accidentally inhaled an unknown amount of dust containing

Silver 331 Wag from an experimental nuclear reactor showed that about 25% ofthe body burden of Wag (total radioactivity) was found near the liver. Excretion It was first demonstrated by Scott and Hamilton (1950) that when bile ducts were ligated in rats, the percent of silver excreted in the feces was much lower (by a factor of 10) than in control rats, although renal excretion increased, clearly demonstrating that silver is excreted primarily via the bile into feces. In a study on the mechanism of elimination of silver by the liver, Klaassen ( 1979) concluded that most of the silver excreted in feces was the result of elimination of silver through bile. When the disappearance of Wag from plasma and bile was measured 2 h after the intravenous admin- istration at 0.01, 0.03, 0.1, and 0.3 mg/kg Wag was mixed with silver nitrate) in rats, the concentration of silver in bile was 20 times greater than that in plasma. Also, the concentration in liver was much higher than that in plasma, and 25-45% of the dose was excreted in the bile within 2 h (Gregus and Klaassen 1986~. The disappearance of silver from the plasma and its excretion into the bile after intravenous administration of silver at 0.1 mg/kg in rats, rabbits, and dogs indicated marked species variations in the biliary excretion of silver. Rats excreted silver at the rate of 0.25 ~g/min/kg, while rabbits and dogs excreted at rates of 0.05 ~g/min/kg and 0.005 ~g/min/kg, respectively. The species with the slowest excretion rate had the highest liver concentration. Dogs had the highest silver levels in the liver, and rats had the lowest, indicating that the transport from liver to bile is the governing factor (Klaassen 1979~. This difference might also explain the rentention data obtained by Furchner et al. (1968) (see discussion be- low). Scott and Hamilton (1950) studied the distribution of silver after an intramuscular administration of radioactive metallic silver alone as a tracer dose and then coadministered with two doses of nickel nitrate (0.4 mg/kg/d and 4.0 mg/kg/~. They reported that when excretion in the feces was de- creased, a corresponding increase was noted in the deposition of silver in the pancreas, gastrointestinal tract, and thyroid. This increase suggested that the liver elimination pathway might be saturated. Several studies indicate that the elimination of silver follows a 2- or 3- exponential profile, one with a short half-life and others with a half-life of several days. In the Newton and Holmes (1966) study cited above, calcula- tion ofthe amount of silver excreted in the feces by a man who accidentally

332 Spacecraft Water Exposure Guidelines inhaled an unknown amount of radioactive silver dust indicated that elimi- nation from the body followed a biphasic exponential decay curve the first phase had a half-life of 1 4, and the second terminal phase had a half-life of 43 d. Matuk (1983) reported similar results after an intraperitoneal injection of radioactive silver. There was an initial rapid loss of radioactivity from plasma, liver, end kidneys, which was followedby a slower rate of loss. The loss was somewhat linear and slower from forebrain and spleen. As shown above, silver is excreted predominantly in the feces and, to a minor extent, in the urine following an oral dose. The rate of excretion is rapid in the first week and then slows, showing biphasic elimination kinetics in humans given silver acetate orally (East et al. 1980~. Furchner et al. (1968) also reported that when radioactive silver nitrate was administered orally to mice, rats, dogs, and monkeys, 90-98°/0 of the absorbed dose was eliminated in the feces (within 2-4 d) and only minor amounts were excreted in urine. They also reported interspecies differences in the clearance of silver. A 2-exponential component described the elimi- nation data in mice and monkeys, and a 3-exponential component described the data from rats and dogs. Differences in the transit time through the gut has been offered as possible explanation (the transit time is ~ h in mice and rats and about 24 h in dogs and monkeys) (Furchner et al. 1968~. It might also be attributed to the interspecies differences in biliary excretion rate reported by Kalaasen (1979~. Metabolism Even though silver salts are not metabolized in the typical sense, silver salts that are transformed are reduced to metallic silver. It was suggested (ATSDR 1990) that the deposition of silver in tissues is the result of precip- itation of insoluble silver chlorides and silver phosphates and that those silver salts are transformed to silver sulfides by forming complexes with amino or carboxy! groups in proteins or are reduced to metallic silver by reduction with ascorbic acid (Danscher 1981~. Buckley et al. (1965) identi- fied silver particles deposited in the dermis of a woman with argyria as silver sulfide. Similarly, Berry and Galle (1982) reported that deposits of silver in the internal organs of rats were identified as silver sulfide. Silver seems to interact with other metal salts, especially with selenium in the diet (Berry and Galle 1982, as cited in ATSDR 1990~.

Silver 333 TOXICITY SU M M ARY One of the most commonly reported conditions in humans related to ingestion of silver is argyria, the blue-gray discoloring of skin resulting from the accumulation of silver in the dermis. It was mostly associated with frequent and long-term exposure, such as the use of silver amalgam, and occupational exposure to silver particles (in mines or in industries involving smelting, polishing, manufacture, and packaging of silver nitrate products). Argyria has been the result of exposure to metallic silver or silver com- pounds not only by the dermal route but also by oral and inhalation routes of exposure. Because of poor absorption of silver by all routes of expo- sures, chronic toxicities or physiologic effects at doses capable of causing argyria have not been documented. Gaul and Stand (1935) analyzed 70 cases of argyria where subjects had been exposed to silver either in a colloi- dal form or had it injected intravenously as a medication (e.g., silver arsphenamine for syphilis). Ten males and two females received a total of 31-100 intravenous injections of silver arsphenamine over a period of 2 to about 10 y. This amounted to a total exposure dose of 4-20 g of silver. No definite threshold could be identified for the incidence of argyria; some developed the condition after a total dose of 4 g of silver, while it appeared in others only after 20 g. Using a biospectrometric analysis of skin biopsies, the authors concluded that the skin discoloration was proportional to the amount of silver present. Based on the lowest level 4 g of silver arsphenamine the EPA working group on silver (EPA 1992) calculated that argyria might occur at a total body burden approximately equivalent to 1 g or above. There is no functional impairment known to be associated with argyria. In clinical studies, 30 workers (ofwhom 6 had argyria and 20 had argyrosis Preposition of silver in the eye]) who were exposed to silver and silver oxide for more than 2 y had significant blood silver levels and abnormal clinical biochemistry (Rosenman et al. 1979~. The exposed work- ers had complained of poor night vision, nausea, headache, nervousness, and tiredness. The authors reported that the presence of abdominal pain in 10 workers correlated with the level of silver in the blood. Rosenman et al. (1987) also reporteUpossible nephrotoxic effects of silver in exposedwork- ers in a precious-metal powder manufacturing plant. Workers with elevated concentrations of silver in the urine and in the blood had corneal deposits of silver and complained of poor night vision. They had significantly in- creased urinary levels of N-acetyI-beta-c'7-glucosaminidase (NAG) and a

334 Spacecraft Water Exposure Guidelines decreased creatinine clearance (clinical markers of nephrotoxicity). Because of concurrent exposure to cadmium, also a well-known nephrotoxin, the effect of silver on nephrotoxicity could not be conclusively established in this study. Acute Exposure (<1 d) Data on the toxicity of silver and its salts in humans come mainly from case reports and accidental exposures. A considerable amount of data is available from animal studies. Emphasis will be placed on oral bolus studies and drinking water studies with silver salts. Tamimi et al. (1998) deter- mined the acute and subchronic toxicity in rats and rabbits after intra- peritoneal injection and oral administration of an antismoking mouthwash containing silver nitrate at 0.5°/O (silver at 3.175 mg/mL) as an active ingre- dient. An oral LD50 (dose lethal to 50°/O of subjects) was reported at about 430 mg/kg for rats (males end females) end et about 1,300 mg/kg for rabbits (male and female). Postmortem and histopathologic examinations revealed congestion, edema, hemorrhage, and mucosal necrosis. It is not clear if other ingredients in the mouthwash might have been responsible for those effects. Death in one human was reported in an accidental ingestion of a large amount of silver nitrate. Symptoms included abdominal pain, diarrhea, vomiting, corrosion of the gastrointestinal tract, shock, and convulsions. It was estimated that silver at 143 mg/kg might be a fatal single dose for hu- mans (Hill and Pillsbury 1939; EPA 1992~. LD50 studies indicate that in general, silver salts are acutely toxic to rodents. The toxicity and mortality also was dependent on the route of administration and the chemical nature (silver acetate, lactate, nitrate, or chIoride) of the dose. There are no known reports of hepatotoxicity, nephrotoxicity, or cardiotoxicity resulting from an acute exposure. Short-Term Exposure (2-10 d) Dequidt et al. (1974, as cited in ATSDR 1990) reported deaths in rats following oral ingestion of silver colloid at 1,680 mg/kg/d for 4 d. When the silver colloid was injected intraperitoneally at 420 mg/kg, rats died within 24-48 h. Dequidt et al. also reported that nitrate is 20 times more toxic than the colloidal form when given intraperitoneally. The actual cause of death was not reported in either of the above studies.

Silver 335 In mice given a single intraperitoneal injection of silver lactate at 20 mg/kg, lipid peroxidation significantly increased in the liver 3, 12, and 48 h after exposure as measured by levels of malondialdehyde (Rungby 1987~. The levels were unaffected in the kidneys and the brain. The author con- cluded that silver interfered with free-radical scavenging mechanisms. A NOAEL (no-observed-adverse-effect level) for this effect could not be identified. Twenty male and 10 female mice received two intraperitoneal injections of silver lactate on successive days totaling 1 ma. Ten days after the last injection, the animals were tested for open field behavior for 3 ~ (males) or 4 ~ (females), and all silver treated mice were hypoactive (Rungby and Danscher 1984~. Hypoactivity was statistically significant in female mice 14 ~ after the injections and in male mice 11, 12, and 13 ~ after the injec- tions. Female mice accumulated silver in their brainstem, cerebral cortex, basal ganglia, anterior olfactory nucleus, and in the red and cerebeliar nu- clei. Subchronic Exposures (11-100 d) Walker (1971) reported that three of 12 Sprague-Dawley rats receiving silver nitrate in drinking water at a concentration of 24 mM (31 1 mg/kg/~) died in 2 wk. No reports on short-term adverse effects on the gastrointesti- nal tract, liver, or kidneys were found. In a 30-d subchronic study, Tamimi et al. (1998) swabbed the oral cavity of rats and rabbits with a new antismoking mouthwash containing silver nitrate at 0.5°/O at doses of 1.5, 15, and 150 mg/kg for 30 consecutive days. No differences were seen in body weight or hematologic parameters between control and treated groups. Administration of 6 mM of silver nitrate (silver at 65 mg/kg/~) in the drinking water of mice resulted in the deposition of silver granules within the gIomerular basement membrane after only 12 ~ oftreatment (Day et al. 1976~. When the silver ingestion was extended to 14 wk. larger aggregates were detected in the basement membrane. Even 21 wk after the termination of silver ingestion, the silver deposits were present. The authors reported that in their preliminary studies, when the concentration of silver was 12 mM (130 mg/kg/~), it was unacceptable to the mice, and there was a dra- matic drop in water consumption. No further details were provided. Wagner et al. (1975) did not find any growth depression or liver necro- sis when Holtzman rats (10 per group) were given silver acetate in drinking water at 7.6 mg/kg/d for 52 ~ while ingesting a diet that had the recom-

336 Spacecraft Water Exposure Guidelines mended concentrations of selenium and vitamin E. In another study by Diplock et al. (1967), no effects were seen in Holtzman rats given silver at 97 mg/kg/d as silver acetate in water for 50 ~ when the diet was complete. Liver necrosis was seen only in rats fed a vitamin-E deficient diet. Van VIeet (1976) reported that four weanling swine fed a diet contain- ing silver acetate at 0.5% for 4 wk (equivalent of 130 mg/kg/~) developed anorexia, diarrhea, and growth depression. Hepatic lesions were found in all four pigs at this dose. However, no lesions were found in pigs fed silver acetate at 0.2% (estimated dose of 52 mg/kg/~. Because the apparent NOAEL was only 2.5 times lower than the dose that killed three of four weanling swine and the dose-response was very steep, and considering the low number of subjects, the results were not considered for acceptable concentration (AC) calculations. Silver has also been reported to inhibit glutathione (GSH) peroxidase, a seleno-enzyme. Administration of silver acetate at 751 parts per million (ppm) (silver at 484 mg/L or 73 mg/kg/~) in water for 15 wk to young Holtzman rats (fed a diet adequate in vitamin E and selenium) reduced liver GSH peroxidase activity to 5% of controls. In the erythrocytes and the kidneys, the enzyme activities were reduced to 37% of controls (Wagner et al. 1975~. The same authors reported that when the rats were exposed to silver in drinking water at 76 mg/L (7.3 mg/kg/~) for 52 4, GSH peroxidase was only at 30% ofthe levels in control rats fed selenium at 0.5 ppm in the diet. These effects are probably due to the selenium deficiency caused by silver. A NOAEL could not be identified and hence could not be used to derive AC values. Chronic Exposures (>100 d) In a 37-wk study of rats given silver nitrate in drinking water at a dose of 222.2 mg/kg/d, animals showed decreased weight gain and elevated mortality starting at 23 wk (Matuk et al. 1981~. The authors also reported ocular argyria. Neurotoxicity Deposition of silver in the brains of animals and humans after short- term or long-term oral exposure through drinking water has been reported in several studies. In a 4-mo study (Rungby and Danscher 1984), adminis- tration of silver nitrate at 0.015% (estimated dose of 25 mg/kg) in drinking

Silver 337 water to 60-~-old NMRI-strain female mice (n = 20) resulted in mild hypo- activity as measured by the open field motor behavior test conducted for 4 ~ after the end of exposure. Even though the intake of water was less than in controls during the initial 3 4, it was not different for the remaining dura- tion ofthe experiment. Body-weight gain among experimental subjects was comparable to the control group. The authors suggested that hypoactivity is consistent with the intraneuronal accumulation of silver in the lysosomes of the motor nuclei of the spinal cord and brain system that they reported earlier (Rungby and Danscher 1983) and was observed by other investiga- tors (Landas et al. l 985~. It also seems to be consistent with the ataxic dis- turbances in coordination and frontally located electroencephaigram (EEG) changes seen in argyric patients (cited by Rungby and Danscher 1984~. This was the only study found on neurotoxicity determined by a test. Argyria Argyria is a consequence of chronic exposure to silver. The human data on argyric subjects came from occupational monitoring (e.g., Rosenman et al. 1979~. OIcott (1947, 1948) conducted the only experimental long-term animal study on the progression of argyria. Rats were given silver nitrate in drinking water (63.5 mg/kg/~), and the rats' eyes were observed until the respective time of sacrifice. Tissue sections were autopsied at various sacri- fice times, and the pigmentation of eyes was reported in various stages. The study continued up to 553 ~ (to a total estimated ingestion of 9.4 grams of silver as silver nitrate). The following stages were observed with respect to the intensity of pigmentation in the eyes: 21 ~ 4, slightly gray (stage 1~; 373 4, more gray than pink (stage 2~; 447 4, dark but translucent eyes (stage 3~; and 553 4, opaque eyes (stage 4~. At stage 4, the membranes were com- pletely black. No other systemic toxicity was noted at autopsy. In a study by Walker (1971), Sprague-Dawley rats were administered silver as silver nitrate at 1,290 mg/L (dose of 130 mg/kg/~) in drinking water for a total of 81 wk. Silver deposits were found in the gIomerular basemen" membranes in the kidneys at4,6,8,10, 12,25, and 60 wk. Silver deposits were also found in the colon, liver, thyroid, urinary bladder, and prostatic acini. During weeks 76 and 81, severe deterioration of clinical condition was found at this dose. However, in another group of rats given 65 mg/kg/d for 12 wk, there were no silver deposits noted end there was no reduction in water consumption. A LOAEL (Iowest-observed-adverse-effect level) of 130 mg/kg/d and a NOAEL of 65 mg/kg/d were identified.

338 Cardiovascular Effects Spacecraft Water Exposure Guidelines No reports on the cardiovascular effects of silver ingestion in humans were available. OIcott (1950) studded the effect of ingestion of silver nitrate in rats (159 rats, males and females) administered silver nitrate at 0.1% in drinking water for 218 d. Few rats were also given silver chloride in sodium thiosulfate. Despite the fact that many rats had diseased lungs, the author concluded that there was a statistically significant increase in the incidence of ventricular hypertrophy (measured as a ratio of the weight of the left ventricle to body weight) in both male and female rats with normal lungs. The exposure corresponded to 89 mg/kg/~. Alhough autopsy revealed sig- nificant pigmentation in several organs, no direct relationship between the intensity of pigmentation in the heart and the ventricular hypertrophy could be established. The author did not successfully measure changes in the blood pressure in these rats. Thus, a cardiovascular effect was not clearly documented. Factors That Influence Silver Toxicity Diplock et al. (1967) reported that vitamin E and selenium in the diet could significantly influence the toxicity of silver. When weanling Norwe- gian hooded rats fed a basal vitamin-E deficient diet were provided drinking water containing silver at 970 mg/L (as silver acetate), all rats developed liver necrosis within 2-4 wk and died. In another group, when selenium was added at 1 ppm to the vitamin-E deficient diet, and the drinking water contained silver acetate, only four of nine rats died. In another group that was fed a diet containing vitamin E and was sacrificed after 50 d of silver exposure, no river necrosis was found. Bunyan et al. (1968) reported similar observations in rats exposed to silver at 650 mg/L (as silver acetate) in drinking water. Liver necrosis was seen when the dietary selenium was reduced. Necrosis was induced at much lower doses of silver (80 mg/L). Vitamin E appeared to reverse that effect. Also, Grasso et al. (1969) re- ported that when silver (silver acetate) was fed either in the diet (at 130-1,000 ppm, or 4-33 mg/kg/d) or in drinking water (97.5 mg/kg/d) to vitamin-E deficient rats, fatal necrosis was noted. Alexander and Aaseth (1981) reported that depletion of liver GSH by diethyl maleate decreased biliary excretion of silver into the bile. Selenite also inhibited the biliary excretion of silver and increased its retention in the tissues. It was suggested that selenite formed an insoluble complex with silver that retarded biliary

Silver 339 excretion. It is not clear if that is in any way related to the effect of selenium-containing diets in reducing the GSH peroxidase (see Wagner et al. 1975, described above). Reproductive Toxicity No human data on the reproductive toxicity of silver are available. Male rats given water containing silver chloride or silver nitrate (89 mg/kg/~) over a 2-y period did not show any change in the appearance or production of spermatozoa or any accumulation of silver. There was a transient epididymal edema and deformation (OIcott 1948~. Developmental Toxicity Only a few studies have reported developmental effects of silver or silver compounds. None ofthose pertains to ingestion. In a study of embry- onic toxicity of 54 elements including silver in chicks (Ridgway and Karnofsky 1952), there were no effects of silver. Wistar rat pups injected subcutaneously with silver lactate at doses of 0.1, 0.2, or 0.35 mg/kg/d during weeks 1,2,3, or 4 had smaller pyramidal cells within the hippocam- pus, indicative of silver toxicity (Rungby et al. 1987), but the functional implications are not clear. Rungby and Danscher ~ 1983) reported neuronal accumulation of silver in the brains of progeny from argyric rats. No effects related to developmental toxicity were found. Genotoxicity and Mutagenicity No genotoxic effects of silver in humans have been reported. Only data using in vitro bacterial and nonmammalian cell cultures were available. Using silver sulfadiazine, McCoy and Rosenkranz (1978) reported that silver was not mutagenic to different strains of Salmonella typhimurium. Using wild and recombinational repair-def~cient strains of bacteriumBacil- lus subtillis, Strain H17 (Rec+) and M45 (Rec-), and exposing them to 50 microliters (~L) of silver chloride solution of 0.05 molar (M) for 24 h (only one concentration), Nishikova (1975) concluded that silver was not mutagenic to Rec+ and Rec- strains. When induction of streptomycin re- verse mutations in E.co11ti was studied using six concentrations of silver

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342 Spacecraft Water Exposure Guidelines nitrate over 3-25 h, the mutation rate was no greater than that of controls. But in a study on the enhancement of viral transformation for the evaluation of carcinogenic or mutagenic potential of inorganic salts on the transforma- tion of Syrian hamster embryo cells by simian adenovirus SA7 (Casto et al. 1979), silver was listed as positive from 0.05 mM to 0.6 mM with out any noticeable cell killing. The exposure time was 72 h. Similarly, silver sul- fide, added at 10 g/mL for 24 h to cultured Chinese hamster ovary (CHO) cells, induced DNA strand breaks (Robison et al. 1982~. Rossman et al. (1986) reported that silver nitrate at 2.5E-07 M inhibited the growth of E. cold WP2s (lamda) but did not induce ~ prophage in these bacteria. Silver iodide in acetone solution or as a suspension was mutagenic only at cytotoxic concentrations in the Ames/microsome tests in TA1935, TA102, TA97, and TA98 (e.g., 30 ~g/mL in TA102 t-S9] and 150 ~g/mL in TA97 "induced +S93~. Elipoulos and Mourelatos (1998) reported a lack of genotoxicity of silver iodide in the sister chromatic exchange (SCE) assay in vitro, in vivo, and in the Ames/ microsome test. Silver iodide did not induce SCEs in cultured human lymphocytes (1 ~g/mL,72 h incubation) or in P388 lympocytic leukemia cells cultured in the peritoneal cavity of 8- to 10-wk-old DBA mice inj ected intraperitoneally with 100 ~g of silver iodide per gram. However, silver nitrate gave significant cytogenic effects from doses of 10 ~g/g. Carcinogenicity The possibility of silver acting as a carcinogen in mammals when in- gested or inhaled has not been studied directly. However, long-term toxicity tests examining other adverse effects in laboratory animals did not report the presence of any tumors. Long-term human occupational exposures, involving all three routes, have not been linked to carcinogenic effects. Schmach! and Steinhoff (1960) reported that subcutaneous injections of suspensions of colloidal silver (once a week for 10 mo) resulted in tumors in eight of 26 rats after 14 mot Furst and Schiauder (1977) reported that 5 mg of silver powder suspended in an inert fluid and injected once a month intramuscularly to F-344 rats produced no fibrosarcomas at the site of injec- tion. In another study, Furst (1981) observed local sarcomas after subcuta- neous implantation of silver foils. In both cases, the tumors were observed at the site of implantation and are considered examples of silver foil acting as a nonspecific irritant rather than as a specific carcinogen. Therefore, those observations are not of particular relevance to human risk from inges- tion of silver.

Silver 343 TABLE 9-5 Spacecraft Water Exposure Guidelines for Silvera Duration Concentration (mg/L) Target Toxicity 1 d 5 Decreased water consumption 10 d 5 Decreased water consumption 100 d 0.6 Hypoactivity 1,000 d 0.4 Argyriab aThe 1-d and 10-d SWEGs were based on an AC derived from Day et al. (1976); the 100-d SWEG was based on an AC derived from Rungby and Danscher (1984); and the 1,000-d SWEG was based on an AC derived from Gual and Staud (1935) and Hill and Pillsbury (1939). WHO (1984) estimated that the upper bound level of silver intake from food was 80 :g/d, which is about 1.1 :g/kg/d for humans. That amount was not taken into consideration when deriving final ACs. bSecondary SWEG. Argyria is not considered an adverse toxic effect. The 1,000-d value is similar to levels suggested by WHO (1984) for lifetime exposure. Spaceflight Effects Dehydration has been a serious concern during spaceflight, as seen in crews from Apollo, Skylab, and shuttle missions, resulting in reductions in total plasma volume and changes in RBC formation (Nicogossian et al. 1994). Silver in drinking water has been reported to cause a reduction in water consumption, which might exacerbate dehydration. RATIONALE The following paragraphs provide a rationale for proposing spacecraft water exposure guidelines (SWEGs) for silver in spacecraft drinking water for 1, 10, 100, and 1,000 d. The values (listed in Table 9-5, above) were set following the NRC guidance for developing of guideline levels for space- craft water. (See Table 9-6 for standards set by other organizations.) In determining the ACs for silver, a spaceflight factor of 3 was used when the AC was determined on the basis of reduced water consumption. A factor of 10 was applied to account for differences in absorption between rodents and humans. The estimated absorption of silver (from retention data) in mice and rats was reported to be in the range of 1-2% (Furchner et al. 1968). Silver absorption was reported at about 20% in a study of one fe- male human (Macintire et al. 1978; East et al. 1980). There were some limitations in the animal retention study and in the one human case study

344 Spacecraft Water Exposure Guidelines TABLE 9-6 Drinking Water Silver Standards Set by Other Organizations Organization Standard Concentration(mg/L) EPAa MCL None MCLG None SMCL (final) 0.1 1-10 d HA (child) 0.2 Long-term HA 0.2 RfD 0.005 DWEL 0.2 Lifetime 0.1 Cancer group Group D Cancer risk NA ATSDRb 1-14 d MRL None set 15-365 d MRL None set >365 MRL None set aThere are no federally regulated standards for silver in drinking water. Only guideline levels are stated. The long-term HA refers to levels that will not cause any adverse noncarcinogenic effects up to 7 y (10% of lifetime). The RfD is an estimate of a daily exposure that is likely to be without appreciable risk of dele- terious effect over a human lifetime. The DWEL assumes that water contributes to 100% of the exposure. Group D classification means not classifiable as a car- cinogen to animals or humans (EPA 1996~. bATSDR did not set MRLs because "sufficient data do not exist to identify a tar- get organ or establish an MRL for acute duration or intermediate duration. Gen- eral lack of quantitative information concerning this effect in humans or animals precludes the derivation of an MRL for chronic-duration exposure" (ATSDR 1990~. Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry; DWEL, drinking water equivalent level; EPA, U.S. Environmental Protection Agency; HA, health advisory; MCL, maximum contaminant level; MCLG, max- imum contaminant level goal; MRL, minimal risk level; RfD, reference dose; SMCL, secondary maximum contaminant level. mentioned above. The doses in the animal study (Furchner et al. 1968) were extremely small and very different from each other. In the human study (Macintire et al. 1978) the subject already had significant body burden of silver, the test dose preparation had ammonium chloride as one ofthe com- ponents, and acetate was the salt form of silver. Due to these uncertainties,

Silver 345 it was decided to use a factor of 10 to account for the differences between rodents and humans. No additional factors were applied for differences in uptake of silver from water or from food due to lack of data. ACs were calculated assuming a total intake of 2.8 L of water per day. That includes an average of 0.8 L of water used for reconstitution of food and 2 L for drinking. Ingestion for 1 d A 1-d AC was not calculated because there are no data to support a 1-d value. Although a few animal studies in which rodents were exposed to silver (as salts) via drinking water showed decreases in water consumption for the first 3 4, water consumption returned to normal in the days follow- ing. The initial phenomenon may have been due to taste aversion. The 1 0-d value will be applied to protect against any 1-d effects. Ingestion for 10 d Water Consumption Silver nitrate at 12 mM (dose of 130 mg/kg/~) in drinking water was unacceptable to mice, and water consumption dropped dramatically (Day et al. 1976~. As early as 12 4, there was uniform deposition of silver within the gIomerular membrane after exposure to 6 mM silver nitrate (calculated dose of 65 mg/kg/~), although there was no effect on water consumption. Hence, 65 mg/kg/d is considered a NOAEL for changes in water consump- tion. Factors of 10, 10, and 3 were applied for species extrapolation, differ- ences in absorption between rodents and humans, and spaceflight effects, respectively. Thus, the 10-d AC for decreased water consumption was derived as 10-d AC = (65 mg/kg/d x 70 kg) (10 x 10 x 2.S L/d x 3~; 10-d AC = 5.4 mg/L (rounded to 5 mg/L). In Sprague-Dawley rats exposed to silver (as silver nitrate) in drinking water at 6, 12, or 24 mM (65, 130, or 260 mg/kg/d), the only effect ob- served was a decline in the amount of drinking water consumed in the 260 mg/kg group (Walker 1971~. That was found as early as 1 wk. The mid- dle-dose group exhibited only silver deposits in the kidneys without any

346 Spacecraft Water Exposure Guidelines effects on the volume of ingested drinking water. Hence, for the 10-d AC, a dose of 130 mg/kg/d was used as the NOAEL for effects on water con- sumption. A factor of 10/7 was included for time extrapolation. The 10-d AC for decline in water consumption was derived as 10-d AC = (130 mg/kg/d x 70 kg) (10 10-dAC=7.5mg/L. Nephrotoxicity x 10 x 2.8 L/d x 3 x 10/7~; No human experimental data are available to establish an AC for this parameter. The industrial worker exposure survey reported by Rosenman et al. (1987), although strongly indicative of nephrotoxic effects of silver, is heavily masked by the presence of cadmium, a known nephrotoxin in the workplace. Hence, an AC for nephrotoxicity was not established. Ingestion for 100 d Cardiovascular Effects There are no human data to indicate that silver causes any cardiovascu- lar effects. In OIcott's (1950) study, rats administered silver nitrate in drink- ing water for 21 ~ ~ at a dose of 89 mg/kg/d developed left ventricular hy- pertrophy. Thickening of the renal gIomerular membrane was also noted. Although a large number of animals were used in that investigation, the way the effect was reported (as the weight of the left ventricle per 100 g body weight) was not reliable enough to derive a 100-d AC for cardiovascular effects. Neurotoxicity Rungby and Danscher (1984) reported that 60-~-old NMRI-strain fe- male mice (n = 20) receiving silver nitrate at 0.015% in drinking water (silver at 0.095 mg/mL) for 125 ~ were hypoactive, as measured by open cage field behavior for 4 ~ after the end of exposure. The authors suggested that that effect might have been due to intraneuronal accumulation of silver in motor-control nuclei ofthe brain stem. An estimated dose of 25 mg/kg/d can be considered a LOAEL for that effect. There were no dose-response

Silver 347 or time-response data. A NOAEL was not identified. A factor of 10 was applied to calculate a NOAEL from the LOAEL; a factor of 10 was applied for species extrapolation; and a factor of 10 was applied for the differences in absorption between rodents and humans. No time factor was used be- cause an AC derived from a 125-d study will be protective for a 100-d duration. A 100-d AC for neurotoxic effects can be calculated as 100-d AC = (25 mg/kg/d x 70 kg) (10 x 100-d AC = 0.6 mg/L (rounded). Water Consumption _ , _ 10 x 10 x 2.8L/d); Day et al. ~ 1976) reported that water consumption dramatical ly dropped in mice administered silver nitrate at 130 mg/kg/d in drinking water. But, in another batch of mice exposed to half that dose in drinking water and studied for 12 d to 14 wk. no reduction in water consumption was observed. Hence, 65 mg/kg/d appears to be a NOAEL for decreased water intake. Factors of 10, 10, 3, and 100/98 were applied for species extrapolation, differences in absorption between rodents and humans, spaceflight effects, and time extrapolation, respectively. A 100-d AC for decreased water consumption can be derived as 100-d AC = (65 mg/kg/d x 70 kg) (10 x 2.8 L/d x 100/98 x 3 x 10); 100-d AC = 5.0 mg/L (rounded). Ingestion for 1,000 d The deposition of silver in kidneys as a consequence of argyria has been reported to be associated with arteriosclerotic changes, and the deposition of silver in the eyes has been associated with poor night vision (NRC 1977). Deposition in various tissues, including basement membranes of kidneys, brain, and spinal cord, has been associated with changes in neuronal func- tions, such as loss of coordination and convulsions (Reinhardt 1971; Rosenman et al.1979), EEG changes, and signs of cerebellarataxia (Aaseth et al.1981). Because these case report studies did not provide enough con- trolled data to derive an AC, and correlations are only suggestive, argyria was considered an aesthetic effect. To be conservative, an AC was derived for this end point using the following sets of data.

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Silver 349 There have been several reports of argyria in humans as a result of treatment using medications containing silver (Gaul and Stand 1935), after large doses of lozenges containing silver (East et al. l 980), and after ingest- ing capsules containing silver nitrate for 15 y (Blumberg and Carey 1934~. Although these are human cases, there has been a lot of uncertainty about the exposure levels. In the latter two cases, there had been only one subject. The Gaul and Stand (1935) study is a report of 70 cases of generalized argyria in individuals who received several intravenous injections of silver arsphenamine for syphilis. The disadvantage of that study was that argyria developed at different total doses, indicating that some individuals were a lot more sensitive than others. A total dose of 4 g of silver arsphenamine (or 1 g of silver ions) over 1 y could cause argyria (Gaul and Stand 1935; Hill and Pillsbury 1939~. Extrapolating intravenous exposure to an oral bolus, using a mean absorption in humans of 10%, that dose would be 10,000 mg over 365 ~ (accumulated dose over a year). One gram of silver by intrave- nous injection would correspond to lo gby oral dose (based on the assumed 10% absorption). That would correspond to 27.4 mg/d (10,000 mg/365 d), giving a dose of 0.39 mg/kg/d for a 70-kg person. Using that as a LOAEL for argyria, a 1,000-d AC was calculated. Factors of 10 and 1,000/356 were applied for deriving a NOAEL from the LOAEL and for time extrapolation, respectively. The AC was calculated as follows: 1,000-d AC = (0.39 mg/kg/d x 70 kg) (10 x 2.8 x 1,000/365~; 1,000-d AC = 0.36 mg/L (rounded to 0.4 mg/L). NASA also calculated a 1,000-d AC from the only long-term animal study found in the literature. OIcott (1947) described different levels of discoloration of eyes in 139 albino rats after administering a solution of silver nitrate (1:1,000) equivalent to 63 mg/kg/~. Slight gray color in the eyes was seen after 21 ~ ~ of exposure to silver. The 63 mg/kg/d value was considered a LOAEL because the coloration was only slight (according to gradation of colors specified by the authors of the studies). Eye discolor- ation has been reported in studies in Wistar rats (Rungby 1986b) and in human cases involving use of eye drops or make-up containing silver (Greene and Su 1987~. Workers exposed to silver for over 2 y had corneal deposits of silver, and some complained of poor night vision (Rosenman et al. 1979~. Factors of 10, 10, 10, and 1,000/21 ~ were applied for species extrapolation, differences in absorption between rodents end humane, deriv-

350 Spacecraft Water Exposure Guidelines ing a NOAEL from a LOAEL, and time extrapolation, respectively. A 1,000-d secondary AC for this aesthetic effect was calculated as 1,000-d AC = (63 mglkg/d x 70 kg) (10 x 10 x 10 x 2.8 L/d x 1,000/218~; 1,000-d AC = 0.4 mg/L (rounded). REFERENCES Alexander, J., and J. Aaseth. 1981. Hepatobiliary transport and organ distribution of silver in the rat as influenced by selenite. Toxicology 21~3~:179-86. Aaseth, J., A. Olsen, J. Halse et al. 1981. Argyria-tissue deposition of silver as selenide. Scand. J. Clin. Lab. Invest. 41:247-251 Armitage, S.A., M.A. White, and H.K. Wilson. 1996. The determination of silver in whole blood and its application to biological monitoring of occupationally exposed groups. Ann. Occup. Hyg. 40:331-338 ATSDR (Agency for Toxic Substances and Disease Registry).1990. Toxicological profile for silver. ATSDRITP-90-24. Agency for Toxic Substances and Disease Registry, U.S. Public Health Service, U.S. Department of Health and Human Services, Washington, DC. Berry, J.P., and P. Galle. 1982. Selenium and kidney deposits in experimental argyria. Electron microscopy and microanalysis. Pathol. Biol. (Paris) 30~3~: 136-40. Buckley, W.R., C.F. Oster, and D.W. Fassett.1965. Localized argyria II: chemical nature of silver containing particles. Acta Dermatol. 92:697-705 Blumberg, H., and T.N. Carey.1934. Detection of unsuspected and obscure argyria by the spectrographic demonstration of high brood Ag. JAMA 103: 1521-1524. Bunyan, J., A.T. Diplock, M.A. Cawthorne, and J. Green. 1968. Vitamin E and stress. Nutritional effects of dietary stress with silver in vitamin E deficient chicks and rats. Br. J. Nutr. 22: 165-182. Casto, B.C., J. Meyers, and A. DiPaolo. 1979. Enhancement of viral transforma- tions for the evaluations of the carcinogenic or mutagenic potential of inor- ganic metal salts. Cancer Res. 39: 193-198 Creasey, M., and D.B. Moffat. 1973. The deposition of ingested silver in the rat kidney at different ages. Experentia 29:326-327. Danscher, G.1981. Light and electron microscopic localization of silver in biologi- cal tissue. Histochemistry 71: 177- 186. Day, W.A., J.S. Hunt, and A.R. McGiven. 1976. Silver deposition in mouse glomeruli. Pathology 8:201-204. Dequidt, J., P. Vasseur, and J. Gromez-Potentier.1974. Experimental toxicological study of some silver derivatives [in French]. Bull. Soc. Pharm. Lille 1 :23-35.

Silver 351 Diplock, A.T., J. Green, J. Bunyan, D. McHale, and I.R. Muthy. 1967. Vitamin E and stress. The metabolism of D-alpha tocopherol in the rat under dietary stress with Ag. Br. J. Nutr. 21:115-125. Di Vincenzo, G.D., C. J. Giordano, and L.S. Schrieves.1985. Biologic monitoring of workers exposed to Ag. Int. Arch. Occup. Environ. Health 56:207-215. Durfor, C.N., and E. Becker. 1964. Public water supplies of the 100 largest cities in the United States, 1962. U.S. Geological Survey Paper 1812. Washington, DC: U.S. Government Printing Office. East, B.W., K. Boddy, E.D. Williams, D. MacIntyre, and A.L.C. McLay. 1980. Silver retention, total body silver and tissue silver concentrations in argyria associated with exposure to an anti-smoking remedy containing silver acetate. Clin. Exp. Dermatol. 5:305-311. Eliopoulos, P., and D. Mourelatos. 1998. Lack of genotoxicity of silver iodide in the SCE assay in vitro, in vivo, and in the Ames/microsome test. Teratog. Carcinog. Mutagen. 18:303-8. EPA (U. S. Environmental Protection Agency).1980. Ambient water criteria for Ag. EPA 440/5-80-071. Office of Environmental Criteria and Assessmen, U.S. Environmental Protection Agency, Cincinnati, OH. EPA (U.S. Environmental Protection Agency). 1981. EPA working group. An exposure and risk assessment for silver. EPA-440-4-81-017. U.S. Environ- mental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency).1992. Drinking Water Health Advi- sory for Silver. NTIS/PB92-135516. U.S. Environmental Protection Agency, Washington, DC. Furchner, J.E., G.A. Drake, and C.R. Richmond. 1966. Retention of 110Ag by mice. U.S. Atomic Energy Commission, Science Laboratory, University of California, Los Alamos. Furchner, J.E., C.R. Richmond, and G.A. Drake. 1968. Comparative metabolism of radionuclides in mammals. IV. Retention of 110Ag in the mouse, rat, mon- key and dog. Health Phys. 15:505-514. Furst, A., and M.C. Schlauder.1977. Inactivity oftwo noble metals as carcinogens. J. Environ. Pathol. Toxicol. 1:51-57. Furst A. 1981. Bioassay of metals for carcinogenesis: Whole animals. Environ. Health Perspect. 40:83-91. Gammill, J.C., B. Wheeler, E.L. Carothers, and P.F. Hahn. 1950. Distribution of radioactive silver colloids in tissues of rodents following injection by various routes. Proc. Soc. Exp. Biol. Med. 74:691-695. Ganther, H.E.1980. Interactions of vitamin E and selenium with mercury and Ag. Ann. NY Acad. Sci. 355:212-225. Gaul, L.E., andA.H. Staud.1935. Clinical Spectroscopy. Seventy cases of general- ized argyrosis following organic and colloidal silver medication, including a biospectrometric analysis often cases. JAMA 104:1387-1390

352 Spacecraft Water Exposure Guidelines Grasso, P., R. Abraham, R. Hendy, A.T. Diplock, L. Goldberg, and J. Green.1969. The role of dietary silver in the production of liver necrosis in vitamin E-deficient rats. Exp. Mol. Pathol. 11:186-199. Greene, R.M., and W.P. Su. 1987. Argyria. Am. Fam. Physician 36:151-154 Gregus, Z., and C.D. Klaassen.1986. Disposition of metals in rats: A comparative study of fecal, urinary and biliary excretion and tissue distribution of eighteen metals. Toxicol. Appl. Pharmacol. 85:24-38. Hill, W.R., and D.M. Pillsbury.1939. Argyria. The Pharmacology of Silver. Balti- more, MD: Williams and Wilkins Company. Jackson, W.F., and B.R. Duling.1983. Toxic effects of Ag-Ag chloride electrodes on vascular smooth muscles. Circ. Res. 53~1~:105-108. Klaassen, C.D.1979. Biliary excretion of silver in the rat, rabbit and dog. Toxicol. Appl. Pharmacol. 50:49-55. Kopp, J.F., and R.C. Kroner. 1967. Trace metals in waters ofthe United States. A five-year summary of trace metals in rivers and lakes of the United States (October 1,1962 to September 30, 1967~. U. S . Department of Interior, Federal Water Pollution Control Administration, Division of Pollution Surveillance. Cincinnati, OH. Landas, S., J. Fischer, L.D. Wilkin, L.D. Mitchell, A.K. Johnson, J.W. Turner, M. Theriac, andK.C. Moore.1985. Demonstration ofregionalblood-brain barrier permeability in human brain. Neurosci. Lett. 57~3~:251-256. Macintire, D., A.L.C. Mclay, B.W. East, E.D. Williams, and K. Boddy. 1978. Silver poisoning associated with an antismoking lozenge. Br. Med. J. 2: 1749-1750. Matuk, Y., M. Ghosh, and C. McCulloch. 1981. Distribution of silver in the eyes and plasma proteins of the albino rat. Can. J. Ophthalmol. 16:145-150. Matuk, Y. 1983. Distribution of radioactive silver in the subcellular fractions of various tissues ofthe rat and its binding to low molecular weighs proteins. Can. J. Physiol. Pharmacol. 61:1391-1395. McCoy, E.C., and H.S. Rosenkranz. 1978. Silver sulfadiazine: Lack of mutagenic activity. Chemotherapy 24:87-91. Merck. 1989. The Merck Index, 11th Ed. Rahyway, NJ: Merck and Co. Moffat, D.B., and M. Creasey. 1972. The distribution of ingested silver in the kidney of the rat and of the rabbit. Acta Anat (Baser) 83 :346-55. Newton, D., and A. Holmes . 1966. A case of accidental inhalation of zinc-65 and 110Ag. Radiat. Res. 29:403-412. Nicogossian, A.E., C.F. Sawin, C.L. Huntoon. 1994. Overall physiological re- sponse to space flight. Chapter 11 in Space Physiology and Medicine, 3rd Ed., A.E. Nicogossian, CL Huntoon, and S.L. Pool, eds. Philadelphia, PA: Lea and Febiger. Nishioka, H.1975. Mutagenic activity of metal compounds in bacteria. Mutat. Res. 31 :185-189.

Silver 353 NRC (National Research Council).1977. Drinking Water and Health. Washington, DC: National Academy Press. Olcott, C.T. 1947. Experimental argyrosis. III. Pigmentation of the eyes of rats following ingestion of silver during long periods of time. Am. J. Pathol. 23: 783-789. Olcott, C.T.1948. Experimental argyrosis. IV. Morphologic changes in the experi- mental animal. Am. J. Pathol. 24:813-833. Olcott, C.T. 1950. Experimental argyrosis. V. Hypertrophy ofthe left ventricle of the heart in rats ingesting silver salts. Arch. Pathol. 49:138-149. Reinhardt, G., Geldmacher-von Mallinck, H. Kittel, O. Opitz. 1971. Acute fatal poisoning with silver nitrate following an abortion attempt [in German]. Arch. Kriminol. 148~3~:69-78. Ridgeway, L.P., and D.A. Karnofsky. 1952. The effects of metals on the chick embryo: Toxicity end production of abnormalities in development. Ann. N. Y. Acad. Sci. 55:203-206. Robison, S.H., O. Cantoni, and M. Costa. 1982. Strand breakage and decreased molecular weight of DNA induced by specific metal compounds. Carcino- genesis 3:657-62. Robkin, M.A ., D.R . Swanson, and T.H. Shepard. 1973. Trace metal concentra- tions in human fetal livers. Trans. Am. Nucl. Soc. 17:97. Rosenman, K.D., A. Moss, and S. Kon. 1979. Argyria. Clinical implications of exposure to silver nitrate and silver oxide. J. Occup. Med 21 :430-435. Rosenman, K.D., N. Seixas, and I. Jacobs. 1987. Potential nephrotoxic effects of exposure to silver. Br. J. Ind. Med. 44:267-72 Rossman, T.G., and M. Molina.1986. The genetic toxicology of metal compounds: l l .Enhancement of ultraviolet light-induced mutagenesis in Escherichia cold WP2. Environ. Mutagen. 8:263-271. Rungby, J., and G. Danscher. 1983. Localization of exogenous silver in brain and spinal cord of silver exposed rats. Acta Neuropathol. (Berl) 60:92-98. Rungby, J., and G. Danscher. 1984. Hypoactivity in silver exposed mice. Acta Pharmacol. Toxicol. (Copenh) 55:398-401. Rungby J.1986a. Exogenous silver in dorsal root ganglia, peripheral nerve, enteric ganglia, and adrenal medulla. Acta Neuropathol. (Berl) 69~1-2~:45-53. Rungby, J.1986b. Experimental argyrosis: Ultrastructural localization of silver in rat eye. Exp. Mol. Pathol. 45:22-30. Rungby, J.1987. Silver induced lipid peroxidation in mice: Interactions of selenium end Nicker. Toxicology45:135-142. Rungby, J., L. Slomianka, G. Danscher, A.H. Andersen, and M.J. West. 1987. A quantitative evaluation ofthe neurotoxic effect of silver on the volumes ofthe components of the developing rat hippocampus. Toxicology 43 :261-268. Schmachl, D., and D. Steinhoff. 1960. Experimental carcinogenesis in rats with colloidal silver and gold solutions [in German]. Z. Krebsforsch. 63:586-591.

354 Spacecraft Water Exposure Guidelines Scott, K.G., and J.G. Hamilton. 1950. The metabolism of silver in the rat with radio-silver used as an indicator. Publ. Pharmacol. 2:241-262. Stokinger, H.E.1981. The metals: Ag. Pp.1881-1894 inPatty's Industrial Hygiene and Toxicology, 3rd Ed., Vol. 2A, G.D. Clayton and F.E. Clayton, eds. New York, NY: John Wiley and Sons. Tichy, P., J. Rosina, K. Blaha Jr., and M. Cikrt. 1986. Biliary excretion of 110Ag and its kinetics in the isolated perfused liver in rats. J. Hyg. Epidemiol. Microbiol. Immunol. 30:145-148. Tamimi, S.O., S.M. Zmeili, M.N. Gharaibeh, M.S. Shubair, andA.S. Salhab.1998. Toxicity of a new antismoking mouthwash 881010 in rats and rabbits. J. Toxicol. Environ. Health 53~1~:47-60. Van Vleet, J.F.1976. Induction of lesions of selenium-vitamin E deficiency in pigs fed Ag. Am. J. Vet. Res. 37:1415-1420. Wagner, P.A., W.G. Hoekstro, and H.E. Ganther.1975. Alleviation of silver toxic- ity by selenite in the rat in relation to tissue glutathione peroxidase. Proc. Soc. Exp. Biol. Med. 148:1106-1110. Walker, F. 1971. Experimental argyria: A model for basement membrane studies. Br. J. Exp. Pathol. 52:589-593. WHO(WorldHealthOrganization).1984.Pp.141-144inGuidelinesforDrinking Water Quality, Volume 2. Geneva: WHO.

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To protect space crews from contaminants in potable and hygiene water, NASA requested that the National Research Council (NRC) provide guidance on how to develop water exposure guidelines and subsequently review NASA’s development of exposure guidelines for specific chemicals.

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