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Appendix

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1 Antimony Raghupathy Ramanathan, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas INTRODUCTION NASA is concerned about the potential for antimony contamination of wa- ter because several experimental payloads will contain science materials that use antimony alloys with dopants. Also, numerous semiconductors and electronic equipment that can be found on a spacecraft, as well as materials with flame retardants, may contain antimony. In addition, some future experiments will involve soldering. NASA is concerned because the U.S. Environmental Protec- tion Agency (EPA) maximum contamination level (MCL) for antimony is rela- tively low (6 parts per billion). OCCURRENCE AND USE Antimony is a semi-hard, silvery-white, brittle metal. It exists in the earth’s crust mostly as a sulfide, from which antimony is extracted for commer- cial use. Antimony is not usually acted upon by air and is only slightly affected by dilute acids and alkalis. It resembles arsenic, both chemically and biologi- cally, and both exist as the trivalent and the pentavalent element. When burnt, antimony becomes brilliant, producing antimony (III) oxide (Sb2O3). This prop- erty makes it a desirable compound for making firecrackers. Antimony is also used in making bullets and cable sheathing, and, when mixed with lead and zinc, it is used to prepare alloys. Antimony salts are used in pigments and abrasives, as well as for flame-proofing fabrics. Antimony is extensively used in various industries and in large quantities for several applications, such as in making paints and enameling glass (Budavari et al. 1989; ATSDR 1992). One of the most noted uses of Sb2O3 is as a flame retardant added to textiles, plastics, and 13

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14 Spacecraft Water Exposure Guidelines rubber (NRC 2000a). General physical and chemical properties of metallic an- timony and of two soluble antimony compounds are included in Table 1-1. Antimony has been used for more than 50 years in the preparation of drugs to treat cutaneous and visceral leishmaniasis, an endemic parasitic disease spread by the bite of infected blood-sucking sand flies. Pentavalent salts of an- timony (sodium stibogluconate [Pentostam] and meglumine antimonite [Glucan- time]) are used parenterally to treat schistosomiasis and leishmaniasis. Another of the most commonly used antimony-containing chemicals is a trivalent anti- monial called antimony potassium tartrate (APT), also known as tartar emetic. This compound has been used as an emetic, as well as an antischistosomal and antifilarial drug. Exposure to antimony results mostly from exposure to environmental dis- charges from the metal alloy industries and smelters. Water usually becomes contaminated with antimony as a result of exposure to sediments containing particulates from industrial pollution and as a result of runoff industrial waste from the paint, ceramics, and plastics industries. In the battery industries that use antimony in combination with lead and zinc, worker exposure to antimony oc- curs through antimony hydride (SbH3) (stibene gas), a very hazardous material that is produced when a battery overcharges and when antimony comes into contact with acid plus a reducing substance such as zinc. Stibine is used as a dopant in the microelectronics industry. In the semiconductor industries, anti- mony is used in making infrared detectors and diodes. Antimony exposure also comes from soldering, in which lead is being replaced with antimony. Several compounds of antimony are known; the most common are anti- mony pentasulfide (Sb2S5, a pentavalent compound), antimony trisulfide (Sb2S3, a trivalent compound), antimony pentoxide (Sb2O5, a pentavalent compound), APT (C8H4K2O12Sb2⋅3H2O, a trivalent compound), antimony trichloride (SbCl3, a trivalent compound), antimony trioxide (Sb2O3, a trivalent antimony com- pound), and antimony hydride (SbH3, a trivalent compound). Sodium anti- monate (NaSbO3), a pentavalent form of antimony [Sb(V)], is also widely used as a flame retardant. TABLE 1-1 Physical and Chemical Properties of Antimony and Two Soluble Antimony Compounds Antimony Potassium Antimony Parameter Metallic Antimony Tartrate⋅3H2O Trichloride C8H4K2O12Sb2⋅3H2O Chemical formula Sb SbCl3 Valence Sb(III) Sb(III) CAS no. 11071-15-1 28300-74-5 10025-91-9 Molecular weight 121.75 668 228 Solubility in water (at Insoluble 83 g/L 100 g/L room temperature) Percent Sb 100% 36% 53% Abbreviation: g/L = grams per liter.

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15 Antimony Recently, NASA has been testing the water compatibility of new water storage and transfer bags (bladder bags), which are composed of multilayer mats of a Japanese-made material called Cefral Soft. The bags will be used in the H-II transfer vehicle, an automated, uncrewed vehicle developed by the Japan Aero- space Exploration Agency (JAXA) as a cargo transportation system for the In- ternational Space Station. It was found that starting as early as 2-wk, material from the bag was leaching into the water. Analysis showed that one of the con- taminants was antimony, although the exact form of antimony in the storage and transfer bags and in the water has not been analyzed. In the initial 90-d stability test, the antimony concentration was about 8 parts per billion. As this is higher than the EPA MCL, the NASA Johnson Space Center toxicology group was charged with deriving a spacecraft water exposure guideline (SWEG) for anti- mony. According to EPA (1992), the concentration of antimony in drinking water is normally less than 5 micrograms per liter. Because a derivation of acceptable concentrations (ACs) for antimony compounds in drinking water is the main purpose of this document, descriptions of adverse effects and discussions are limited to soluble antimony compounds and studies dealing with ingestion of such compounds. Although the exact form of the soluble compound in spacecraft drinking water is not known at this time, it is not expected that insoluble forms of anti- mony will be found in the water. Hence, data from several experiments dealing with the ingestion of antimony oxides in the diet are not used to derive the AC because antimony oxide has very poor solubility (0.0014 gram per 100 millili- ters) in water. In addition, toxicity studies in which less soluble or insoluble an- timony compounds were administered are not included because use of data from such compounds could result in ACs that would underestimate the toxicity of antimony. PHARMACOKINETICS AND METABOLISM The most commonly used antimony compounds are oxides that are only minimally soluble in water. Limited data are available on the absorption, distri- bution, excretion, and elimination kinetics of soluble antimony compounds ad- ministered orally. Several studies in the literature involve the treatment of parasitic infec- tions through the administration of antimonial drugs, such as sodium stiboglu- conate and stibosamine, via intravenous (i.v.), intraperitoneal (i.p.), and intra- muscular (i.m.) routes, and these studies focused on measuring pharmacokinetic parameters to optimize the dosage for therapeutic purposes. Part of the reason these drugs must be administered parenterally is that they are poorly absorbed from the gastrointestinal (GI) tract, and doses must be high to obtain therapeuti- cally effective levels. At these doses, drugs orally administered would be very toxic to the GI tract. This includes both trivalent and pentavalent antimonial

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16 Spacecraft Water Exposure Guidelines drugs. Many of these studies involve different antimonial drugs given to patients with cutaneous leishmaniasis (see Al-Jaser et al. 1995; Nieto et al. 2003) or to animals experimentally infected with leishmania parasites. Thus, pharmacoki- netic data from these studies may not be applicable to healthy individuals. Similarly, data on antimony concentrations in blood and tissues from occupationally exposed industrial workers are the result of inhalation exposure to dust and fumes and, to a minor extent, from dermal absorption. These data are of limited use in describing the fate of antimony administered orally. Absorption Lauwers et al. (1990) estimated that absorption of the trivalent antimonial APT (tartar emetic) is 5% in humans, while APT was absorption is at about 20% in mice (Dieter et al. 1991). The existing animal studies indicate that antimony can be absorbed from the GI tract whether it is in a soluble form or a very spar- ingly soluble form. This is evident from the results of the following two studies, both of which used the soluble form of the antimony compound. Felicetti et al. (1974) studied the metabolism, differential tissue distribution, and retention ki- netics of two valence states of antimony in hamsters using radioactive APT (124Sb tartrate) after administering the dose by gavage. They also studied the absorption of antimony by delivering the dose by gastric tube. Some hamsters received the trivalent antimony and some received the pentavalent antimony. The results indicated that 7% to 15% was absorbed for both tri- and pentavalent antimony. In a study using SbCl3 in mice, Gerber et al. (1982) estimated that about 7% of the ingested antimony was absorbed. The International Commission on Radiological Protection (ICRP 1981) suggested using a 10% absorption rate for antimony tartrate and 1% for other antimony compounds (including Sb2O3) when estimating exposure from the GI tract. Distribution No data are available on the tissue distribution of antimony in humans who ingested antimony compounds orally. However, Sumino et al. (1975) col- lected autopsy data for antimony in several tissues and body fluids from unex- posed Japanese individuals. Similarly, Lauwers et al. (1990) noted that, in a pa- tient who died from accidental poisoning by ingesting antimony tartrate, the total body pool was only about 5% of the ingested dose, with the highest con- centrations in liver, gall bladder, and GI mucosa. Results are available from several animal studies in which the distribution of antimony was measured after inhalation exposure, but few studies are avail- able in which it was measured after oral ingestion. Animal studies indicate that the distribution of absorbed antimony varies with its valence state. A significant observation is that trivalent compounds seem to bind more extensively to red

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17 Antimony blood cells, whereas most of the absorbed pentavalent antimony is found in plasma (Goyer 1996; van der Voet and de Wolff 1996; Poon et al. 1998). Win- ship (1987) reported that, after oral administration (or after injection), significant concentrations of antimony could be found in liver, kidney, thyroid, adrenals, and bone. Though this may not be directly relevant to oral administration, dif- ferences in the distribution of antimony were observed between trivalent and pentavalent forms in the blood in a hamster study in which pentavalent and tri- valent antimony were administered as an aerosol inhalation (Felicetti et al. 1974). Metabolism and Excretion No direct human data on the metabolism of antimony compounds from oral doses are available. The i.p. injection of SbCl3 into adult male Sprague- Dawley rats did not result in detectable levels of any methylated antimony in the bile or urine; thus, it was concluded that, unlike arsenic, antimony is not methy- lated in vivo (Bailly et al. 1991). Antimony is excreted in the bile after conjuga- tion with glutathione (GSH), but a significant portion of antimony excreted in the bile undergoes enterohepatic circulation. It is also excreted in the urine as GSH conjugate. GSH seems to be one of the key components in the biliary ex- cretion and metabolism of antimony (Bailly et al. 1991). The evidence in hu- mans that no in vivo methylation takes place came from observation of one woman who ingested an unknown quantity of Sb2S3 and was admitted to a hos- pital within 1 h. Antimony was measured in whole blood, urine, bile, and gastric fluid for 160 h. On the basis of the type of urine analysis used, the authors con- cluded that antimony is not methylated in vivo (Bailly et al. 1991). No study of the pharmacokinetics of APT or any soluble antimony com- pounds administered orally could be located. It has been stated that in most rodents, trivalent antimony (APT) is ex- creted primarily in the feces and pentavalent antimony (from pentavalent anti- monials such as stibogluconate, also called Pentostam) is excreted primarily in the urine; in humans, both types are excreted in the urine (NRC 1980). These results were observed after i.v. injection of tri- and pentavalent antimonials, and they were based on studies by Otto et al. (1947) and Otto and Maren (1950). Similar excretion data are not available from rodents or humans who ingested APT. TOXICITY SUMMARY Numerous toxicity studies have been conducted in animals using relatively insoluble antimony oxides (Fleming 1938; Gross et al. 1955; Hext et al. 1999). The discussions and study descriptions below mostly focus on oral ingestion studies, but an abundant amount of literature on other routes of administration

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18 Spacecraft Water Exposure Guidelines provides knowledge of the target organs and the nature of the toxicities. A re- view of the literature on the toxicity of antimony compounds indicates that tox- icity depends on the chemical form of the antimony compound and its relative solubility in water, its route of administration, and whether the antimony is triva- lent or pentavalent. The literature also indicates, from various experimental and occupational exposures and from clinical observations from case histories, that trivalent compounds are more toxic than pentavalent compounds and the soluble ones are more toxic than the poorly soluble ones. In fact, the way these com- pounds are used in the medical field is also based on the valence of antimony in the compound; for example, APT can cause inflammation and severe pain and tissue necrosis and thus has been replaced with other antimonial drugs that can be administered parenterally. Exposure to SbCl3 fumes is known to cause “anti- mony spots” in the skin around the sweat and sebaceous glands. Several investi- gators have reported serious toxic effects from the injection of pentavalent anti- monial medications. Data from their studies indicate that liver, kidney, and hematologic systems may be targets for antimony toxicity. Similar effects on kidney and liver have been shown in animals after i.p. injections of trivalent antimonials such as APT (Dieter 1992). Although acute toxicity primarily in- volves the GI system, causing GI irritation, vomiting and diarrhea, and death at high doses, chronic exposures to antimony can affect liver, kidney, heart, and hematologic systems. Acute Effects The literature shows the acute oral median lethal dose (LD50) for APT ranged from 115 milligrams per kilogram of body weight (mg/kg) in rats to 600 mg/kg in mice to 115 mg/kg in rabbits (PAN Pesticide Database). According to a German document (German Association for Gas and Water installation, DVGW 1985, 1988), although the oral LD50 for APT (the soluble salt of anti- mony) for rats is 115 mg/kg, the LD50 for Sb2O3 is 20,000 mg/kg, showing a vast difference between soluble and relatively insoluble forms of antimony compounds. The LD50 in rats for APT injected i.p has been reported to be only 30 mg/kg, or about 11 mg of antimony per kg (Bradley and Frederick 1941). In rodent LD50 oral studies, fatalities resulted from myocardial edema and hypere- mia. The oxides of antimony seem to be less toxic than APT, perhaps because APT has higher solubility and thus greater bioavailability. A major form of antimony toxicity after oral ingestion involved its GI ef- fects, such as abdominal cramps, diarrhea, and vomiting due to the strong irritat- ing effect of antimony on the gastric mucosa (Elinder and Friberg 1986). The vomit, in general, contained sloughed mucosal cells and most of the antimony. A reduced respiratory rate, hemorrhagic nephritis, and hepatitis may also occur (Venugopal and Luckey 1978, van der Voet and de Wolff 1996). Using anti- mony compounds of high purity and taking care that the arsenic content re-

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19 Antimony mained negligible, Bradley and Frederick (1941) showed that, among five anti- mony compounds administered by i.p. injection, Sb2O3 was the least toxic. Several examples of antimony poisoning have been cited in the literature, but in some cases the concentration of antimony that resulted in GI distress was not known. Dunn (1928) reported that several workers who drank lemonade contaminated with antimony tartrate that leached from an enamel bucket became very sick, and 50 to 60 of them had to be taken to the hospital. The concentra- tion of antimony was provided by the author as 0.013% or 130 mg/L. Werrin (1963) reported that 150 children who drank lemonade refrigerated for 20 h in a large agate pot experienced nausea, vomiting, and diarrhea. The symptoms were caused by antimony in the lining of the pot. Lauwers et al. (1990) reported on oral antimony intoxication in four adults who ingested cake mistakenly made with tartar emetic instead of cream of tartar. They had severe GI symptoms such as abdominal cramps, nausea, continuous vomiting, and watery diarrhea. Mod- erate leukocytosis and hemoconcentration and decreased extracellular volume were noted. The estimated dose of tartar emetic was 850 mg per person. The initial electroencephalograms of three subjects were abnormal; one person had severe GI bleeding and died from cardiac and respiratory failure (Lauwers et al. 1990). Bailly et al. (1991) reported that a 24-year-old woman suffered from epi- gastric pain and dysphagia after trying to commit suicide by ingesting an un- known quantity of Sb2S3. Flury (1927) conducted feeding experiments on rats, cats, and dogs using tartar emetic, Sb2O3, Sb2O5, and other antimonial com- pounds. Dogs were more sensitive to the emetic effect than cats; in dogs, the most toxic of these compounds as an emetic agent was APT at 4 mg of antimony per kg. Similarly, dogs were more sensitive than small rodents (rats) with re- spect to digestive upsets and diarrhea, and APT was the most toxic for these effects. GI effects resulted not only from the ingestion of antimony compounds by animals and humans, but also from inhalation exposures. Smelter workers, for example, inhaled compounds such as SbCl3 in fumes, resulting in abdominal pain, diarrhea, and vomiting (Winship 1987). Short-Term Exposure Dieter et al. (1991) conducted a toxicity and distribution study of APT in rats and mice after they were exposed via drinking water and i.p. injection. Only the drinking-water study data are included here. Toxicity and concentrations of tissue antimony were compared in F344/N rats and B6C3F1 mice (both sexes) given APT in drinking water for 14 d. For the 14-d drinking-water protocol, doses estimated from water consumption data were 0, 16, 28, 59, 94, or 168 mg/kg in rats and 0, 59, 98, 174, 273, or 407 mg/kg in mice. Antimony concen- trations in the blood, kidney, heart, liver, and spleen of rats and mice were measured at the end of the study. The animal tissues were also evaluated histopathologically. One of 10 females died in the mouse group that received the highest antimony dose

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20 Spacecraft Water Exposure Guidelines (407 mg/kg). No mortalities were noted in any other group, indicating that rats tolerated a dose of at least 168 mg/kg and mice at least 273 mg/kg. The authors noted a change in water consumption that was inversely related to increasing dose, although the authors did not provide detailed dose versus water consump- tion data. Decreases in the weight of heart, spleen, thymus, and kidney were noted in the highest dose groups; body weight also decreased in these groups. Tissue histopathology indicated that in the male and female mice of the 407- mg/kg group, treatment-related gross lesions consisted of ulceration with necro- sis and inflammation of the forestomach squamous mucosal epithelium. In both male and female mice of the highest dose group (407 mg/kg), a minimal to moderate cytoplasmic vacuolization of hepatocytes was present; the male mice had more severe changes. The hepatocytes in the centrilobular region were slightly enlarged, with a loss of cytoplasmic staining. The authors did not pro- vide any quantitative data on the severity of these histopathologic lesions. In male rats given APT, cytoplasmic protein droplets normally present in the renal tubular epithelium stained slightly more prominently than those in control rats. The increases in the antimony concentrations in blood, liver, spleen, heart, and kidneys did not exhibit a clear dose-response trend (Dieter et al. 1991; Dieter 1992). Although the data from the 16-d APT i.p. injection study are not described here, the mortality and severity of histopathologic lesions in the study indicated that liver and kidney might be the target organs for antimony toxicity, and that toxicity of antimony administered orally is much lower than toxicity from the i.p. route. Subchronic Toxicity Studies In an old study, Bradley and Frederick (1941) administered APT in the diet to rats at a dose of 8 mg/kg/d. The study also involved feeding finely granu- lated metallic antimony at 8 or 40 mg/kg/d. The rats were treated for 4 or 12 months. They included a group in which the doses were raised to 100 mg/kg/d and to 1,000 mg/kg/d. The rats maintained normal growth, but abnormal histo- pathology findings were noted on examination of the kidney, liver, small intes- tine, and spleen. Congestion and polymorphonuclear leukocyte infiltration in liver, tubular necrosis of the kidneys (in addition to glomerular nephritis), hem- orrhage of the small intestine, and congestion of the spleen were observed (Bradley and Frederick 1941). Poon et al. (1998) studied the effects of APT on rats after a 90-d exposure via drinking water. Male and female Sprague-Dawley rats (127-135 g) were exposed to a soluble trivalent antimony salt, APT, in drinking water at antimony concentrations of 0.5, 5, 50, and 500 parts per million (ppm) for 13 wk. An addi- tional 10 male and 10 female rats were included in each of the control and 500- ppm groups and were given tap water for a further 4 wk as a recovery period after the 13-wk treatment period was completed. Body weight changes, water

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21 Antimony and food consumption, hematologic analysis, urine analysis, serum clinical chemistry (concentration of inorganic phosphate, glucose, cholesterol, creatinine, total protein, and activity of hepatotoxicity marker enzymes, such as aspartate aminotransferase, alkaline phosphatase, sorbitol dehydrogenase, creatinine kinase, and hepatic enzymes), and tissue histopathology were all de- termined. In addition, serum thyroxin and thyroid hormone binding ratio were determined. The authors determined the calculated mean intake doses of anti- mony as 0.06, 0.56, 5.58, and 42.17 mg/kg/d for males and 0.06, 0.64, 6.13, and 45.609 mg/kg/d for females, determined on the basis of water consumption. Poon et al. reported no overt clinical signs of toxicity. They provided no further explanation of what they meant by clinical signs of toxicity in the paper. The animals in the 500-ppm group consumed 30% less water than the controls, but water consumption returned to normal during the recovery period when APT was discontinued. Food consumption was also reduced 12% in the high-dose group. Starting at 6 wk, a significant depression in weight gain was observed in the males. This was noted in females starting at 12 wk. One male in the 5-ppm group and three in the 500-ppm group had gross hematuria; one male receiving this dose had a cirrhotic liver. A dose-related decrease in serum glucose in the females starting at 5 ppm, decreased creatinine and alkaline phosphatase in both male and female rats at 500 ppm, and decreased serum protein in females were noted. No treatment-related changes in serum aspartate aminotransferase or sor- bitol dehydrogenase activities were noted. Male rats from the 500-ppm dose group had decreased red blood cell and platelet counts and a slightly increased mean corpuscular volume. No treatment-related changes in total thyroid hor- mone, thyroxin, were reported. However, in the female rats, the thyroid hormone binding ratio (a measure of the level of thyroid hormone binding protein, a globulin) increased significantly at 50 and 500 ppm. In addition, in the 500-ppm groups, mild histologic changes were observed in the thyroid, such as reduced follicle size, increased epithelial height, and nu- clear vesiculation. Some of these did not return to normal during the recovery period. The relationship between the observed increase in the thyroid hormone binding ratio found in the serum of 50- and 500-ppm rats and the observed his- tologic changes in the thyroid is not clear. Collapsed thyroid follicles, not ob- served during the treatment period, were seen at the end of the recovery period. The authors declared that changes seen in the thyroid glands were adaptive and did not show a strong dose-response level (Poon et al. 1998). Poon et al. (1998) reported that in the liver of all male and female rats in the study, the severity of anisokaryosis (inequality in the size of the nuclei of cells) approached moderate in the groups receiving higher doses and was persis- tent even 2 wk after cessation of treatment. Similarly, the hyperchromicity of the nuclei was more pronounced at high doses. In the cytoplasm of hepatocytes, increased portal density and increased perivenous homogeneity were dose re- lated. However, two serum hepatotoxicity marker enzymes, aspartate ami- notransferase and sorbitol dehydrogenase, remained unaltered in males and fe- males even in the 500-ppm APT group.

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34 Spacecraft Water Exposure Guidelines gue-Dawley rats (127-135 g), 15 animals per group, were exposed to APT in drinking water at concentrations of 0.5, 5, 50, and 500 ppm antimony for 13 wk. The animals in the 500-ppm group (the highest-dose group) consumed 35% less water than the controls. So, the authors calculated the mean intake doses of an- timony as 0.06, 0.56, 5.58, and 42.17 mg/kg/d for males and 0.06, 0.64, 6.13, and 45.7 mg/kg/d for females based on water consumption. Poon et al. (1998) reported that gross hematuria was seen in three males from the 500-ppm group. Also in the 500-ppm male rats, a decrease in red blood cells and an increase in mean corpuscular volume were noted, indicating hema- tologic effects, but the NOAEL of these effects was 50 ppm. A statistically sig- nificant decrease in the platelet counts of 500-ppm-dosed males was also noted. These effects were not seen in the female rats, however, there was a dose-related decrease in serum glucose starting at 5 ppm, which was only seen in the female rats. Histologic changes were scored as 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe, and the authors presented average severity scores. Mild his- tologic changes were seen in the thyroid, liver, pituitary glands, spleen, and thymus in 500-ppm dose groups. The authors declared that the changes in the thyroids were adaptive and mild, lacked a strong dose-response relationship, and did not appear to affect thyroid function, even though the changes persisted after the 4-wk recovery period. Poon et al. (1998) proposed a LOAEL of 5 ppm (equivalent to an anti- mony intake of 0.6 mg/kg/d) and a NOAEL of 0.5 ppm (equivalent to 0.06 mg/kg/d) based only on glucose changes in the female rats. The authors consid- ered the change in glucose a credible adverse effect because similar reductions in glucose were reported in the 30-d i.m. injection study by al-Khawajah et al. (1992) and in the chronic drinking-water study by Schroeder et al. (1970). NASA first evaluated this for AC derivation. The changes in glucose showed a very poor dose-response profile, including the fact that the decrease was seen only for concentrations up to 50 ppm and the response leveled off between 50 and 500 ppm, which cannot be explained. NASA gathered that Poon et al. (1998) measured glucose in nonfasting animals for 4 h each morning over the course of several days and that, each day, animals from the different dose groups were measured in the same order, from controls to the highest-dose group. As a result, the glucose levels in the animals would be falling throughout the morn- ing, which would cause a trend for animals in higher dose groups to have lower glucose levels than controls and animals in lower dose groups. Hence, these changes were considered not to be compound related and it was decided not to use these data for AC derivation. The data were also criticized by Lynch et al. (1999) because no changes in glucose levels were seen in the Dieter et al. (1991) study in which APT was in- jected by the i.p. route and APT administered through this route was much more toxic. The liver histopathology data from the Poon et al. (1998) study was evalu- ated next. The authors reported their histopathology findings with a qualitative

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Antimony 35 scale by which 0 = no changes, 1 = minimal changes, 2 = mild changes, 3 = moderate changes, and 4 = severe changes. Their assessment of the liver consid- ered nuclear anisokaryosis and hyperchromicity, and their cytoplasmic evalua- tion considered what they described as “increased portal density,” “increased perivenous homogeneity,” and fibrosis. The authors did not include photos to illustrate the nuclear lesions or cytoplasmic lesions other than fibrosis. In no case did they provide an illustration of the basis for ascertaining the scale of severity of the lesions. From a personal communication from the authors, we understand that the pathologist who interpreted the slides was aware of the dose group from which the slides were derived. Upon review of the liver histopathology data, the expert pathologist of the National Research Council (NRC) Spacecraft Exposure Guidelines (SEG) com- mittee stated that in assessing human hepatic pathology, nuclear anisokaryosis and hyperchromicity would rarely be mentioned in the absence of other substan- tial hepatic pathology. It is also not clear what the authors meant by “increased portal density” and “increased perivenous homogeneity.” These are not standard descriptors of hepatic pathology, and how they relate to more conventional terms of hepatic pathology is not clear. Fibrosis is a standard term and the one liver illustration reveals fibrosis. Although the data show progressive and dose-related increases in aniso- karyosis, hyperchromicity, “increased portal density,” and “increased perivenous homogeneity,” it is surprising that for doses ranging from 0.5 to 500 ppm there are only limited differences in all the parameters examined. In no case did any of the more obvious signs of hepatic toxicity appear, even as the dose of anti- mony was increased 1,000-fold, with the single exception of one liver with fi- brosis at the highest dose. The fact that the pathology review of the samples was not blinded and that no illustrations of the appearance of the lesions or the measures of the severity scale were included in the report makes one skeptical about the meaningfulness of the hepatic morphology aspect of the study in general. Thus, it is difficult to accept these findings as evidence of a substantial structural effect of antimony on the liver that would be interpreted as toxicity or other pathology. The NRC COT/SEG therefore recommended to NASA that the data on changes in serum glucose levels and changes in liver histopathology not be used in the derivations of AC. Next, the hematology data reported by Poon et al. (1998) were considered. Giving 500 ppm APT in drinking water to male rats resulted in a statistically significant reduction in the number of red blood cells, a reduction in mean cor- puscular volume (average volume of a red blood cell), and a reduction in platelet counts. These end points are also critical because three male rats from the 500- ppm dose group had hematuria. A NOAEL of 50 ppm APT (or antimony at 5.58 mg/kg/d) for hematologic effects could be identified. The dose-response data were processed by the benchmark dose (BMD) method, using the EPA BMD software (version 1.3.2) with the models for continuous data. There are four models for the continuous type in the EPA software, and BMD computation

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36 Spacecraft Water Exposure Guidelines could be carried out only for the polynomial model and the power model. One standard deviation change in mean response was used as the benchmark re- sponse. The statistician from the NRC SEG committee recommended that NASA use the data from the power model, which would provide a more appro- priate model fit of the response. Figure 1-1 shows the BMD plots of two dose- response models for changes in red blood cells due to antimony ingestion. The results are summarized in Table 1-5. FIGURE 1-1 BMD model curves for changes in red blood cells due to ingestion of an- timony. Source: Data from Poon et al. 1998.

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Antimony 37 TABLE 1-5 Summary of BMDs for Hematologic Effects of Antimony BMD BMDL (mg/kg/d) (mg/kg/d) Parameter Model Red blood cells Polynomial 41.77 35.65 Power 41.29 29.12 Mean corpuscular volume Polynomial 42.66 26.75 Power 42.10 29.55 Platelets Polynomial 49.35 12.95 Power 43.10 30.98 Note: Only male rat data included; female rat data were not statistically significant. Abbreviations: BMD, benchmark dose; BMDL, 95% lower confidence limit of BMD. The 100-d AC can be calculated using the statistically significant decrease in the amount of red blood cells as a critical end point in male rats ingesting 500 ppm of APT via drinking water (Poon et al. 1998). Using the BMD method, a BMD lower confidence limit (BMDL) for antimony of 29 mg/kg/d was ob- tained. The 100-d AC can thus be calculated as follows: 100-d AC(hematologic effects) = [29 mg /kg/d(BMDL) × 70 kg(adult body weight) × 1/10(species) × 1/3(spaceflight) × 90 d/100 d(time extrapolation)] ÷ 2.8 L/d(water ingestion/d) = 21.75 mg/L, rounded to 22 mg/L. Thus, the 100-d AC for hematologic effects is 22 mg/L. As the 100-d AC value of 22 mg/L is higher than the value of 4.0 mg/L derived for GI effects for 1- and 10-d ACs, to be protective of GI effects, the 1- and 10-d AC was adopted as the 100-d AC. Thus, the 100-d AC for GI effects is 4 mg/L. As has been discussed under the 1-d AC, this concentration is far below the threshold emetic level when water is consumed in separate boluses, and thus the 1-d value can be used for 100 d. 1,000-Day AC for Antimony Ingestion In the literature, no human subject study data are available that can be used to derive a 1,000-d AC. Only one laboratory has conducted lifetime chronic animal studies in which antimony was administered orally (Schroeder et al. 1968, Kanisawa and Schroeder 1969, Schroeder et al. 1970). It was conducted in the late 1960s and early 1970s on rats and mice. As NRC guidelines have not recommended the use of survival rate, growth rate, and organ weight changes for deriving ACs, the data from these studies could not be considered. In the lifetime (from weaning until natural death) mouse study by Kani- sawa and Schroeder (1969), groups of male and female Swiss CD-1 mice were

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38 Spacecraft Water Exposure Guidelines given 5 ppm of antimony as APT in drinking water. With the intent of avoiding any influence on the results by the coexistence of other trace metals, the diet was rye, dried skim milk, and corn oil, which are normally low in trace elements, even though some trace elements are nutritionally important. Considering a nominal body weight of 30 g and water intake of 5 mL/d, the dose rate for anti- mony in water can be estimated to be 0.83 mg/kg/d. In the 1969 mouse study, sections of only a few tissues (liver, lung, adrenals, and mammary glands) were used and gross observations on tumors were made. The lesions were graded only as pretumorous, benign, and malignant. Not all tissues were included in the histopathology. The authors concluded from this study that antimony was not tumorigenic when given in drinking water. The numbers of epithelial tumors, nonepithelial tumors, and carcinomas found in the treated mice were not signifi- cantly different from those in the controls. No data suggested overt toxicity from antimony at this dose. In the 1968 mouse study (Schroeder et al. 1968) in which male and female CD-1 mice were exposed to 5 ppm of antimony in water as APT, growth rate, survival rate, tissue antimony levels, incidence of spontaneous tumors, and other physiological changes such as incidence and severity of hepatic fatty degenera- tion were reported. There was no evidence of increased fatty degeneration over the controls. Antimony was found to be not tumorigenic at this concentration. In the study of Schroeder et al. (1970), antimony was administered at a single concentration, 5 ppm, as APT in drinking water to groups of 50 male and female Long-Evans rats from weaning until natural death, and the antimony dose was estimated to be 0.43 mg/kg/d. Glucose and cholesterol were measured on days 718 and 698 for control males and females, respectively, and on days 853 and 859 for treated males and females; thus, control and treated groups were not evaluated at the same age. Nonfasting glucose levels of treated males and females were reported to be significantly lower than those of the controls. How- ever, the nonfasting glucose levels were lower than the fasting glucose levels; thus, the results are of questionable significance. The authors reported no treatment-related increase in tumor incidence, noted only as grossly visible tumors at necropsy. Such limited information pre- cludes consideration of these data for AC derivation. Most importantly, Schroeder et al. (1970) stated that male and female rats in control and treated groups had a high incidence of death due to an epidemic of virulent pneumonia that struck the rat colony during the 4 years of the ex- periment. Lynch et al. (1999), who critically evaluated all published subchronic and chronic studies that used APT by the oral route, concluded that the Schroe- der et al. (1970) study on antimony had numerous shortcomings, such as virulent pneumonia in the rat colony and the use of animals that survived for the comple- tion of the study, lack of detailed histopathology of tissues examined before de- claring that APT is not carcinogenic, biochemical measurements on controls and treated groups done with groups at different ages, and glucose being higher in fasted than in nonfasted animals. Thus, the data from this study were inappropri- ate for use in determining regulatory levels of water quality for antimony. In

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Antimony 39 concurrence with this summary criticism, the data from the Schroeder et al. (1970) study were considered not acceptable to NASA for AC derivations. It must be pointed out that EPA derived an RfD for antimony with the data from the Schroeder et al. study, using longevity, blood glucose, and cholesterol, but EPA declared that its confidence in the RfD was low. Confidence in the chosen study was rated as low because only one species was used, only one dose was used, no NOAEL was determined, and gross pathology and histopathology were not well described. Confidence in the database was low because of a lack of adequate oral exposure investigations. In spite of criticisms and limitations ex- pressed by authors such as Lynch et al. (1999) on the principal study used by EPA, the organization has not revised the MCLs for antimony to date. In the absence of any other chronic toxicity study on soluble antimony compounds by the oral route, 1,000-d AC will use the observations of hema- tologic effects reported by Poon et al. (1998) from the subchronic antimony tar- trate drinking-water study. The 100-d AC derived from the BMDL of the dose- response curve for changes in red blood cells (with spaceflight factor applied) will be extrapolated with a time factor of 10 to derive a 1,000-d AC. This may be somewhat conservative, considering that the slope of the dose-response curve for hematologic changes seen in the Poon et al. study is rather low. The 1,000-d AC for antimony can be calculated as follows: 1,000-d AC(hematologic effects) = 22 mg/L(100-d AC) × 1/10(time factor) = 2.2 mg/L, rounded to 2.0 mg/L. Thus, the 1,000-d AC for antimony based on hematologic effects is 2.0 mg/L. Drinking water ACs for antimony for 1-, 10-, 100-, and 1,000-d and the SWEGs for these durations have been summarized in Table 1-6. RECOMMENDATIONS FOR ADDITIONAL RESEARCH Oral toxicity for only one soluble compound, APT, has been extensively reported in the literature, mainly for reasons of it having been used as an emetic agent. However, there are no oral toxicity data on even short-term durations for compounds such as SbCl3 and SbCl5, which are used in the dyeing industry, and antimony acetate, which is used in the synthetic fiber industry.

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40 TABLE 1-6 Summary of Acceptable Concentrations and Spacecraft Water Exposure Guidelines for Antimony Uncertainty Factors Acceptable Concentrations, mg/L Toxicity End Point NOAEL/ Reference LOAEL to Species Time Safety and Chemical LOAEL Species Study NOAEL Factor Factor Factor 1d 10 d 100 d 1,000 d Induction of LOAEL = Human 10 1 1 3a 4.0 — — — Dunn 1928 vomiting: emetic 130 mg/L (beverage) stimulus (antimony mixture) Reduction in water NOAEL = Rat 1 10 1 3b — 8 — — Dieter et al. intake 10 mg/kg 1991 Hepatotoxicity NOAEL = Rat 1 10 1 1 — 145.0 — — Dieter et al. 58 mg/kg 1991 Hematotoxicity BMDL Rat NA 10 100 d/ 3 — — 22 — Poon et al. (reduction in 29 mg/kg 90 d 1998 RBCs) Hematotoxicity BMDL Rat NA 10 1,000 d/ 3 — — — 2 Poon et al. (reduction in 29 mg/kg 90 d 1998 RBCs) 4.0c 4.0d SWEG 4.0 2.0 a As the adverse effect seen was so serious that recovery took a few days, this factor was added to reduce the LOAEL. b Spaceflight factor to prevent astronauts from drinking less water. c The lowest concentration in the column under 10-d AC (8 mg/L) is higher than the levels that will cause gastrointestinal effects; thus, the lower 1-d AC value was adopted per recommendation of the committee. d 22 mg/L will not protect against gastrointestinal effects. Therefore, the 1-d AC of 4 mg/L is adopted. Abbreviations: BMDL, 95% lower confidence limit on the benchmark dose; LOAEL, lowest-observed-adverse-effect level; NA, not applicable; NOAEL, no-observed-adverse-effect level; RBC, red blood cell; —, not derived for this duration.

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