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6 Nickel Raghupathy Ramanathan, Ph.D. NASA-Johnson Space Center Toxicology Group Habitability anc!Environmental Factors Branch Houston, Texas BACKGROUND The International Space Station (ISS) will use stainless steel plumbing systems extensively in the wastewater and processed-water distribution lines, the humidity heat exchanger, and the collection and dispenser lines. Nickel is one ofthe key components ofthese systems. The lines carry water containing various levels of iodine, which can corrode the lines, and thus nickel canbe foundintheprocessedwaters. Although the in-line conductiv- ity monitors might be able to flag such leaching, and the ion exchange resins can actively eliminate nickel, high nickel levels can foul these sys- tems. In NASA's ground-based human testing (NRC 2000, Ch. 2) for the development of ISS water-processing hardware, nickel concentrations were found in the processed water through the analysis of archived samples. Because studies in experimental animals (inhalation and injections) and epidemiological studies have shown that nickel and nickel-containing sub- stances are carcinogenic (cancers of the lung and nasal cavities), and be- cause nickel has been implicated as a cause of chronic dermatitis, it was necessary to assess if an appreciable health risk exists for the presence of nickel as soluble nickel salts in the spacecraft drinking water. Nickel also 203

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204 Spacecraft Water Exposure Guidelines TABLE 6-1 Physical and Chemical Properties of Nickel and Soluble Nickel Compounds CAS registry no. Atomic number Synonyms Oxidation states Nickel chloride (CAS registry no.) Nickel oxide (CAS registry no.) Structural formulas Water solubility 7440-02-0 28 None 1, 2, 3, and 4 77 1 8-54-9 13 13-99-1 Ni, NiCl2, NiO, NiS04, Ni(NO3)2, Ni(CH3 C02)2 Ni (insoluble); NiO (1.1 mg/L at 20C); NiCl2 (642 g/L at 20C) seems to affect the absorption of iron. The requirement for nickel as an essential trace element for humans is inconclusive. Nickel is a lustrous hard metal and exists in several salt forms, some soluble and some insoluble in water. The most common soluble forms are the chlorides, sulfates, and the nitrate. This document will discuss the health effects of nickel in drinking water; therefore, only the soluble forms will be discussed. Nickel dust or insoluble forms such as nickel sulfides will not be considered. Occurrence and Use Nickel salts are used extensively in electroplating and in the manufac- ture of alloys, catalysts, and high capacity batteries. Metallic nickel is used in the manufacture of stainless steel. Nickel is present in the earth's crust at 0.018% as the free form but predominantly as sulfides, oxides, arsenides, antimonides, and silicates in ores. Nickel is very commonly found in surface waters and groundwaters, mostly originating from industrial activities and anthropogenic discharges. In water, nickel mostly occurs as Ni2+. In an aerobic environment, at a pH below 9, nickel will form soluble compounds with hydroxides, carbonate, sulfate, and naturally occurring organic ligands. An EPA survey reported that the concentrations in surface water range from 3.9 micrograms per liter (~g/L) to 672 ~g/L,and groundwater levels ranged from 2.95 ~g/L to 440 ~g/L. Most potable waters contain <40 ~g/L of nickel (EPA 1983~. Thus,

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Nickel TABLE 6-2 Physical and Chemical Parameters of Other Nickel Compounds 205 Molecular Nickel Content Form Weight (NO) Nickel 58.69 100 Nickel chloride (monohydrate) (NiCl2) 129.60 45.29 Nickel chloride hexahydrate (NiCl2 6H2O) 238.00 25 Nickel sulfate (NiS04) 154.75 37.9 Nickel sulfate hexahydrate (NiSO4 6H2O) 262.8 22.3 Nickel acetate (Ni(CH3C00~2) 176.80 33.20 Nickel nitrate hexahydrate (Ni(NO3~2 6H2 O) 290.81 20.2 Source: Merck 1989. several surveys found that community water supplies, surface waters, drink- ing waters, and tap water samples contained nickel. Nickel may leach into drinking water from plumbing materials. It is important to note that dietary nickel forms a significant portion of the human exposure/body burden. A wide range of nickel intake through diet has been reported (IOM 2001~. According to the U.S. Food and Drug Administration total diet study of 1984, the mean adult daily nickel consumption from diet ranges from 74 fig per day (~) to 100 ~g/d (Pennington and Jones 1987~. On the contrary, a national survey from five Canadian studies during 1986-1988 reported a dietary nickel consumption of 207-406 ~g/d for adults (Dabeka and McKenzie 1995~. PHARMACOKINETICS AND METABOLISM Absorption The major route of nickel intake is ingestion, although inhalation and dermal absorption are also routes of exposure. Most ofthe data for ingestion comes from animal studies in which nickel salts were added to the diet. From the available studies it can be inferred that the bioavailability of nickel from dietary sources is different than that from drinking water sources. In general, it has been reported that in animals 1-10% of nickel administered as nickel salts either in the diet or by gavage is absorbed (Sun-

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206 Spacecraft Water Exposure Guidelines TABLE 6-3 Nickel Levels in Various Processed Water Samples in NASA Investigations Nickel (vigil) Sample Source Minimum Maximum Frequency of Occurencea Phase II A (60 d) 1.2 265 44/81 PhaseIII (90 d) 0 328 47/58 Mir missions Mir-18-Mir-25 5.6 157 Mir water ferried 1.2 79.3 from ground 22/29 7/7 around above method quantifiable levels. Source: Data fromNASA-Johnson Space Center Water and Food Analysis Labora- tory. derman 1970~. On the basis of urine excretion data, Ho and Furst (1973) reported that female rats given nickel chloride (NiCI2) in dilute acid solution by oral intubation absorbed only 3-6% of doses at 4,16, or 64 milligrams per kilogram (mg/kg). Sunderman et al. (1989) reported that absorption of nickel from food was much lower than from water in humans (n = 8) who ingested 12,18, or 50 grams (g) of nickel as nickel sulfate (NiSO4) in food or in water (27% absorption from water and 0.7% from food). The subjects were fasted 12 hours (h) before the dose was administered, and those recieving the dose in water were fasted an additional 3 h after being dosed. The bioavailability of nickel, as measured by serum nickel levels, was simi- larly elevated in fasted subjects given NiSO4 in drinking water (peak in- crease within 3 h) but not when nickel was given in food (Solomons et al. 1982~. Food constituents such as fibers, phytate, and some metal-ion bind- ing components may bind nickel, influencing the availability. These data indicate that the presence of food significantly decreased the absorption of nickel. Absorption from solutions was higher for more soluble nickel com- pounds (Ishimatsu et al. 1995~. A detailed study by Nielsen et al. (1999) on the kinetics of nickel absorption from food end wafer and of nickel elimina- tion reported that the maximum nickel levels observed 1 h after ingestion in water were 13 times higher than those observed when nickel was given with food and water. The cumulative amount of nickel excreted increased with an increase in the interval between the meal and nickel administration

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Nickel 207 in water. From the experimental design and conclusions, it is clear that under normal circumstances, when one ingests food once every 4 h and drinks water intermittently, the existing food in the stomach will affect nickel absorption. In the same study, Nielsen et al. (1999) indicated that women absorb less nickel, and the authors propose that the difference in absorption is due to a gender-related difference in gastric emptying time, which is longer in women than in men. Nickel is believed to play a role in physiologic processes as a cofactor in the absorption of iron from the intestine. The interaction between nickel and iron occurs only under certain conditions. Nickel increased the absorp- tion of iron from the diet in iron deficient rats (female), but interaction was seen only when dietary iron was in the unavailable ferric form, whereas a mixture of ferrous and ferric sulfates (60% ferric to 40/0 ferrous) as a sup- plement to the diet did not elicit any effect (Nielsen et al. 1980~. Talikvist et al. (1994) examined nickel-iron interactions both in vivo after an oral dose and in vitro using isolated perfused jejunal and ileal segments from iron deficient and iron sufficient rats. In both cases, enhanced nickel absorp- tion from iron deficient rats was evident. Furthermore, Talikvist and Tjalve (1997) observed increased nickel uptake in several tissues of the iron-deficient rats following gastric intubation of nickel. This indicates, at least in part, that nickel is taken up by the same absorptive mechanism for iron in the intestinal epithelium. In a study using monolayers of epithelial coco-2 cells, derived from human colonic adenoma carcinoma in bicameral chambers, Talikvist and Tjalve (1998) observedthatboth transportation and accumulation of nickel (63NiCI2) were depressed when the monolayer cul- tures were loaded with iron, indicating strong interaction between nickel and iron. However, an important concern is whether increased doses of nickel (by ingestion) will affect iron status (decrease in iron absorption and tissue levels) in subjects with sufficient iron in the diet, eventually resulting in anemia. Nielsen et al. ( 1979) conducted a fully crossed two-way Pictorially designed experiment in female SD rats in which the interaction of nickel and iron was studied in rats at varying doses of nickel in the diet (0, 5, and 50 Agog) for 9 weeks (wk), and the changes in levels hematocrit and hemo- giobin levels were reported. The results showed that when iron is present at borderline deficient levels or at normal levels, nickel did not affect the above parameters. Similarly, Oosting et al. ( 1991 ) reported that the addition of 0, 3, 50, or 100 ~g/kg in the diet to rats had no major impact on iron concentrations in plasma, liver, kidneys, spleen, or femur.

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208 Spacecraft Water Exposure Guidelines Distribution The total amount of nickel found in the human body has been estimated to be 86 ~g/kg for a 70-kg person (Sumino et al. l 975~. Serum nickel levels peaked at 2.5 h to 3 h after ingestion of NiSO4 (Sunderman et al. 1989~. In workers who accidentally drank nickel-contaminated drinking water, the serum half-life was 60 h (Sunderman et al. 1988~. In short-term and long-term studies of animals administered various soluble nickel salts orally, nickel was found primarily in the kidneys. Whanger ~ 1973) reported that there was a dose-dependent increase in the retention of nickel from the diet when rats were fed diets containing nickel at 0,10,50, or 100 mg/kg/~. The relative tissue concentrations were kidneys > lungs > liver > heart > testes (Ambrose et al. 1976; Dieter et al. 1988; Ishimatsu et al. 1995; Whanger 1973.) Oral administration of radioactive 63Ni2+ to mice resulted in higher accumulation of 63Ni2+ in the spinal cord than in the cerebellum or frontal cortex (Borg and Tjalve 1989~. In control rats, there appeared to be a difference in the levels of nickel in bones between males and female rats 0.53 parts per million (ppm) and <0.096 ppm, respectively (Ambrose et al. 1976~. Casey and Robinson (1978) reported that the levels of nickel in the liver, heart, and muscles were similar in human fetuses and in adults. When pregnant rats were fed nickel salts at 1,000 ppm in the diet (50 ma/ kg/~), their newborn pups had a total tissue concentration of 22-30 ppm; the levels in decreasing order were bone > spleen > kidneys > heart > intestine > blood > testes, indicating transplacental transfer of nickel (Phatak and Patwar~han 1950, as cited in EPA 1995~. When NiCI2 was injected subcutaneously into lactating SD rats, a dose-dependent increase of nickel in milk was observed (Dostal et al. 1989~. When nickel at 5 ppm (0.41 mg/kg/d, soluble salt not specifiers was added in drinking water, however, the rats did not accumulate significant amounts in tissues (Schroeder et al. 1974~. Metabolism In humans and animals, serum albumin is the main carrier of nickel in the serum. In human serum, nickel was found to bind to albumin, L-his- tidine, and alpha-2-macrogIobulin (Sarkar 1984~. The low-molecular- weight complex of albumin-histidine-nickel can be transported across cellu- lar membranes. Nickel bound to the alpha-2-macrogIobulin (nickeloplas- min) pool is considered a nonexchangeable pool (Nomoto and Sunderman 1989~. Serum albumin in dogs does not have the specific Ni+2 binding site

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Nickel 209 (Glennon and Sarkar 1982), and hence, most of the nickel in dog serum is not protein-bound. It has been shown that there are large species variations in the proportions of ultraf~Itrable and protein-bound serum nickel (Hendel and Sundennan 1972~. Excretion In humans, most ingested nickel is not absorbed and is eliminated pre- dominantly in the feces. Some of the nickel absorbed from the gastrointes- tinal tract is excreted in the urine and is associated primarily with low- molecular-weight complexes that contain amino acids. In humans, nickel can also be eliminated through sweat and milk. Sunderman et al. (1989) reported that in humans who ingested 12, 1 8, or 50 fig of nickel from NiSO4 in food or water, 26% of the dose given in water was excreted in the urine and 76% was excreted in the feces by 4 d poet-treatment. Ofthe dose given via food, only 2% was excreted in the urine and almost all the rest was excreted in the feces. A 40-fold difference was seen in the absorption of nickel from drinking water and from food; absorption was higher from the drinking water. Hansen et al. (1994) reported that excretion of nickel fol- lowing a single oral dose given to women after an overnight fast was found to decrease with increasing age, suggesting that nickel absorption may decrease with age. Ho and Furst (1973) reported that 1 ~ after administra- tion of NiCI2 to rats, about 95/O was excreted in the feces and about 3-6% in the urine. Similarly, in dogs given NiSO4 in the diet for 2 years (y), only 1% to 3% of the dose was excreted in the urine (Ambrose et al. 1976~. The kinetics of 63Ni2+ metabolism was studied in rats end rabbits follow- ing an intravenous injection of 63NiCI2 to develop a compaWnental model useful in predicting nickel concentrations under various circumstances (Onkelinx et al. 1973~.63Ni2+ was rapidly cleared from plasma and serum during the first 48 h after injection and was cleared at a much slower rate from 72 h to 168 h. The model developed was tested and validated in other separate experiments in which NiCI2 was either perfused or injected daily for 14 ~ (Onkelinx et al. 1973~. TOXICITY SUMMARY Available evidence indicates that the natural concentrations of nickel present in water, soil, and food do not constitute a threat to humans (NAS 1977~. Toxicity studies have demonstrated that significant differences can

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210 Spacecraft Water Exposure Guidelines exist based on the chemical form of the nickel salt. That is probably be- cause the estimated absorbed fraction of each ofthe nickel compounds was increased with the increased solubility of the nickel compound (Ishmatsu et al. 1995~. Furthermore, although parenteral injections of nickel salts are very toxic, nickel salts have relatively low toxicity in various species of animals when administered orally. Soluble nickel compounds are more toxic than less soluble nickel compounds. For example, although the oral LD50s (doses lethal to 50/O of subjects) for less soluble nickel oxide (NiO) and nickel subsurface (Ni3S2) were 4 g/kg, the oral LD50 in female rats for NiSO4 was 39 mg/kg, and the LD50s for nickel acetate were 1 16 mg and 136 mg for female rats and mice, respectively (Hero et al. 1968; Mastromatteo 1986~. The available literature indicates that, following a high oral exposure to nickel in rats and mice, some of the most common effects reported are decline in body-weight gain, reduced water intake, hepatic and renal weight changes, gastrointestinal effects, adverse hematologic effects, and some central nervous system (CNS) effects at high doses. In addition to those effects, allergic reactions (hypersensitivity) to nickel have been reported in individuals with nickel allergic contact dermatitis (ACD). Acute Toxicity (1 d) Daldrup et al. (1983, as cited in ATSDR 1997) reported that a 2.5-y-old child died of cardiac arrest after ingesting an oral dose of NiSO4 crystals. The dose was calculated to be 250 mg/kg. In a study that was designed to find the absorption and elimination kinetics of nickel in humans, Sunderman et al. (1989) reported that 7 h after a single dose of nickel as NiSO4 (0.05 mg/kg) in drinking water, a male volunteer developed left hemianopsia for 2 h (Ioss of sight in the corresponding lateral half of the eye). However, when the dose was lowered in other subjects to 12 ~g/kg or 18 ~g/kg, that effect was not observed. Short-Term Toxicity (2-10 d) During a 2-y nickel-feed study in dogs, Ambrose et al. (1976) observed that during the first 3 ~ all dogs ingesting nickel at 2,500 ppm in their diet (37 mg/kg/~) vomited, indicating gastrointestinal distress. The concentra- tion of nickel in the diet was raised from 1,500 to 1,700, 2,100, and the target level of 2,500 ppm (37 mg/kg/~) at 2-wk intervals with no further

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Nickel 211 evidence of emesis. The final dose was 37 mg/kg/d (Ambrose et al. l 976), which was continued for the rest of the 2-y duration. Acute gastrointestinal effects were also reported by Sunderman et al. (1988~. Thirty-two workers in an electroplating factory who accidentally drank water from a water fountain contaminated with nickel suffered from acute gastrointestinal (nausea, vomiting, abdominal discomfort, diarrhea) and neurologic (headache, shortness of breath, giddiness) symptoms. The amount was determined to be 1.63 g/L as NiCI2 and NiSO4. The authors estimated that intake ranged from 0.5 g to 2.5 g in 20 workers who had these symptoms. Symptoms lasted for a few hours and up to 2 ~ in some workers. Even though boric acid was also present at 68 mg/L in the water, the authors concluded that nickel was the primary cause for the observed effects. In three of 10 workers who were hospitalized, a transient increase in serum bilirubin (indicative of hepatotoxicity), a transient increase in urine albumin (indicative of renal toxicity), and a transient increase in hematocrit were reported. Other toxic responses to short-term doses of nickel are the allergic dermatologic reactions to nickel ingestion, such as flare-up of eczema and dose-related erythema, seen only in individuals who are aireadypredisposed to nickel ACD. This is discussed in a separate section later in the docu- ment. Subchronic Toxicity (10-100 d) Weber and Reid ~ 1969) reported significant reductions in body-weight gain, decreased body weight, and signs of hepato- and renal toxicities in animals as a result of daily exposure to nickel via diet or gavage. Nickel as nickel acetate at 0,1,100, or 1,600 ppm administered in the diet to male and female mice for 4 wk resulted in decreases in body weight at 100 and 1,600 ppm in females, whereas that change was seen only at 1,600 ppm in males (Weber and Reid 1969~. Liver and heart cytochrome oxidase, liver isocitric dehydrogenase, and kidney and heart maleic dehydrogenase were also decreased. A LOAEL (Iowest-observed-adverse-effect level) of 143 mg/kg/d for reduction in body weight and reduced enzyme activities was identified. Weischer et al. (1980) reported that oral administration of nickel as NiCI2 in male rats over a period of 28 d at concentrations of 2.5, 5.0, and 10.0 ~g per milliliter (mL) in drinking water (0.38, 0.75, or 1.5 mg/kg/d) resulted in significant dose-dependent hyperglycemia, decreases in serum

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212 Spacecraft Water Exposure Guidelines urea, and significant increases in urine urea. Increased leukocytes observed at 0.75 mg/kg were not observed at lower doses. Water consumptions were significantly lower than controls at all doses. These effects were noted at extremely small doses compared with other reports; hence, this study was not considered for AC derivation because of lack of confidence in the data. In weanling rats (n = 24) fed a diet containing nickel as nickel acetate at 100, 500, or 1,000 ppm (10, 50, or 100 mg/kg/~) for 6 wk. significant reductions in weight gain in the mid-dose group and loses of weight in the 100-mg/kg group were noted (Whanger 1973). Reduced blood hemoglobin and packed cell volume (PCV) were also noted. Significant reductions in plasma alkaline phosphatase and in cytochrome oxidase activities in liver and heart were seen in the 100-mg/kg group. Significantly elevated levels of iron in many tissues, particularly in the kidneys and liver, were observed in both the 50-mg/kg group and the 100-mg/kg group. These effects were not seen in the 10-mg/kg group. The influence of nickel on tissue iron levels was not clear. In a 90-d rat gavage study (American Biogenics Corporation 1988, as cited in IRIS 1996), 30 male and female CD rats received a daily gavage dose of nickel as NiCI2 (hexahydrate) at 0, 5, 35, and 100 mg/d (1.2, 8.6, and 25 mg/kg/~. Various symptoms of toxicity, such as lethargy, ataxia, irregular breathing, hypothermia, salivation, and loose stools, were ob- served in the 10- mg/kg/d group, and increased mortality (52/60 rats in the high-dose group and 2/60 in the low-dose group) was observed during the regimen. All animals in the 100-mg/kg group and 14 of 60 in the 35-mg/kg group died. Decreased body weights, decreased food intake, and clinical signs of toxicity, including ataxia, lethargy, altered breathing, lower body temperature, and discoloration of the extremities, were observed. Kidney, liver, and spleen weights were lower in the mid-dose and high-dose groups. A dose of 1.2 mg/kg/d appeared to be a NOAEL (no-observed-adverse- effect level) in this study. Waltschewa et al. (1972, as cited in EPA 1985) reported that daily oral intubations of nickel as NiSO4 at 25 mg/kg for 4 months (mo) in male rats resulted in degenerative cellular changes in the liver and kidneys. Obone et al. (1999) reported that in adult male Sprague-Dawley rats given NiSO4 (hexahydrate) at 0/O, 0.02%, 0.05/O, and 0.1%, or 0, 44.7, 111.75, and 223.5 mg/L, respectively (estimated doses of 0,5,12.5, and 25 mg/kg/~), in their drinking water for 13 wk. both the absolute and relative liver weights in the 12.5-mg/kg and 25-mg/kg groups were significantly decreased. Total plasma proteins, plasma albumin and globulins, and plasma glutamic pyruvic transaminase activity were significantly decreased

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Nickel 213 in the highest-dose group. In the splenic lymphocyte subpopulations (T- celis and B-celis), the ratio of CD4 to CDS cells was suppressed signif~- cantly in the highest-dose group (223.5 mg/L). There were also significant decreases (about 20%) in B-celis. A significant decrease in urine volume and an increase in blood urea nitrogen (BUN) were observed at the highest dose. Other nephrotoxic indices, such as excretion of urinary protein, N- acetyI-beta-D-glucosaminidase, and gamma-glutamy! transpepeptidase, were unaltered. Biochemical analysis of bronchoalveolar ravage fluid and lung tissue showed some lung damage. The 1988 American Biogenics Corporation study reported changes in heart weight in rats exposed to nickel as NiCI2 at 8.6 mg/kg/d by the oral route for 91 d. One study indicated that nickel ingestion could be neuro- toxic. Nation et al. (1985) fed adult male rats food containing nickel as NiCI2 at 0, 10, or 20 mg/kg/d for a total of 75 d. Fourteen days after the exposure started the animals were trained over 61 ~ to get their food from a lever-press operand machine. Rats receiving 20 mg/kg/d lever-pressed at a significantly lower rate than the 1 0-mg/kg/d group and the control group, thus showing behavioral effects. A dose of 10 mg/kg/d (as NiCI2) seems to be a NOAEL, and 20 mg/kg/d a LOAEL, for 75 d. Chronic Toxicity (>100 d) Male albino rats (n = 10, body weight = 80 g, strain not specified) re- ceived drinking water containing nickel as NiCI2 at 225 mg/L for 4 mo (estimated dose of about 32 mg/kg/~) (CIary 1975~. Significant reductions inbody weights, serum lipids, serum cholesterol, urinary calcium, end urine outputs compared with controls were reported in this study. Many of the biochemical changes were secondary to loss in body weight. Water intake was not measured, and the authors assumed that decreased urine output (50/O decrease) by the end of 4 mo might be due to decreased water intake. A 50/O decrease in urine output is a serious adverse effect, and there is no dose-response data to identify a NOAEL. Because there are other drinking water studies using nickel that provide dose-response data that can be used for AC development, this study was not considered for AC derivation. Dieter et al. (1988) conducted a study to evaluate tissue disposition, myelopoietic responses, and immunologic responses in female B6C3F, mice after long-term exposure to nickel as NiSO4 in drinking water at 0, 1, 5, or 10 g/L (0, 44, 108, 150 mg/kg/~) for 180 d. Water consumption, con- centration of nickel in blood and tissue, body and organ weights, histo- pathology, immune responses, bone marrow cellularity and proliferation,

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Nickel 237 for species extrapolation, nickel sensitivity, and time extrapolation from 90 ~ to 100 4, respectively, the 100-d AC for potential nephrotoxic effects (increased albuminuria) was calculated as follows: (7.6 mg/kg/d x 70 kg) t10 x 2 L/d x 3 x (100/90~] = ~ mg/L. As usual, the calculation assumes a 70-kg person ingesting 2 L of wafer per day. 100-d AC for Behavioral Effects Adult male rats were fed NiCI2 at 0, 10, or 20 mg/kg/d via a 10 g daily food ration. Following 14 ~ of exposure, animals were trained over a period of 61 ~ to lever-press for food on a VI-2 operant training schedule while continuing to ingest the indicated daily doses of nickel (Nation et al. 1985~. Rats in the 20-mg/kg/d group lever-pressed at a significantly lower rate than those in the 10-mg/kg/d and control groups, thus indicating behavioral effects. A LOAEL of 20 mg/kg/d and a NOAEL of 10 mg/kg/d were identi- fied. As the authors presented the data in a graphic form, numerical data for BMD calculation were not available. Applying a factor of 10 for species extrapolation, a factor of 3 for nickel sensitivity, and a factor of 1.333 for time extrapolation from 75 ~ to 100 4, the 100-d AC for behavioral effect was calculated as follows: (10 mg/kg/d x 70 kg) (10 x 2 L/d x 3 x 1.333) = 9 mg/L. Ingestion for 1,000 d A 13% increase in focal myocardial fibrosis was observed in a life-term study of rats ingesting nickel at 5 ppm as NiCI2 in drinking water for 18 mo (Schroeder et al. 1974~. However, the experiments were done in a metal-free environment, which may have made the animals more sensitive. These data could not be used due to the lack of dose- and time-response data. Two 2-y drinking water studies were considered for calculating the 1,000-d ACs. They are two-generation and three-generation reproductive and developmental studies using NiCl2 andNiSO4 in drinking water, respec- tively. Microscopic examination of ovaries and testes of rats and dogs that

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238 Spacecraft Water Exposure Guidelines received NiSO4 and NiCI2 by the oral route for 2 y did not indicate any abnormality (Ambrose et al.1976; American Biogenics Corporation 1988~. NASA has not considered using developmental toxicity data for determin- ing SWEGs. The only other long-term study, a 2-y feeding study in rats and dogs, is that of Ambrose et al. (1976~. Rats of both genders (25 per gender per group) were given NiSO4(hexahydrate) at 0,100,1,000, and2,500 ppm (0, 5, 50, and 125 mg/kg/~. Although significant depression in growth, de- creases in body weights, and decreases in liver- and heart-to-body weight ratios were noted at the 1,000-ppm and 2,500-ppm doses, no such effects were noted at the 100-ppm dose. A parallel study in dogs indicated that at higher doses hemoglobin and hematocrit values tended to be lower, and the dogs showed lung and bone marrow lesions. NASA has not used the dog data, because nickel is not bound to albumin in dogs the way it is in humans and rodents. The pharmacokinetics, and hence the toxicologic mechanisms, may be different in dogs. 1,000-d ACs Based on Dieter et al.'s (19XX) lX0-d Study Dieter et al.'s (1988) 180-d drinking water study was used after apply- ing a time factor. In that study, female B6C3F~ mice were given NiSO4 at 0, 44, 108, and 150 mg/kg/d in drinking water for 180 d. Significant changes in the immune system, decreases in water consumption, decreases in bone marrow cellularity, mild renal tubular damage, and thymic atrophy were significant toxic effects noted at the two highest doses. A 1,000-d AC was calculated using a time-extrapolation factor of 5.555 (1,000/180~. Factors of 10 and 3 were applied for species extrapolation and nickel sensi- tivity, respectively. A spaceflight factor of 3 was added to the calculations for hematologic end points. A LOAEL-to-NOAEL factor of 10 was in- cluded in calculations that used the LOAEL. The calculations assumed a 70-kg person ingesting 2 L of water per day. (See Table 6-15 for ACs.) The most sensitive parameters seem to be the lymphoproliferative re- sponse and the granulocyte macrophage colony forming response both end points give a 1,000-d AC of 0.3 mg/L.

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240 5 A V V Cal Cal o Cat to to to to o to ~ 2= O == Cal o . En Cal .O Via O O Cal .~ o . - X Ed Do ~ . ~ O ~ ~ ~ =^ ~t ~ ~ ~ =^ ~ o O~ ~ ~ O ~ O ~ ho = Cal Cal ~ ~ C) cx3 cat at a ~ 5 ~ ~ ~ ~ lo.- ~ o Cal vO - ~ c~ . ~ ~ ^ .~o ~ ~ ~ ~o s~ ~ c) . c) o o=> c) ~ v = ~ ~ (~, ~ ^ ~_1-g ~ v ~ ~ p ~ o ~ . o ~ ~ ~ s^ ~ o =~ s~ ~ . ~ o , o ~ o c~ ~ c~ ~ o o c) s~ ~ ~o o c~ c) . c~ ~ E~ ~ vl . ~ ~ . o = c~ . ~ ~o o ~ o ~ ~ o .. o ~ .~ ~ ~ . - = ~

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Nickel TABLE 6-15 1,000-d ACs Calculated for Various End Points Using Data from the Dieter et al. (1988) Study 241 BMDLo~ NOAEL LOAEL ACs (mg/L) Parameter (mg/kg) (mg/kg) (mg/kg) BMDLo~ NOAEL Spleen cellularity 63.8 108 150 4.5 7.5 Lymphoproliferative 7.9 NA 44 0.55 0.3 response to LPS Bone marrow 9.8 44 108 0.7 3.08 cellularity Granulocyte 12 NA 44 0.8 0.3 macrophage CFUs Stem cell proliferation 7.6 44 108 0.5 3 CFUs Abbreviations: AC, acceptable concentration; BMDLo~, the lower 95/O confidence limit on the benchmark dose corresponding to a 1% risk; CFU, colony forming unit; LPS, lipopolysaccharide. REFERENCES Ambrose, A.M., P.S. Larson, J.F. Borzelleca et al.1976. Long-term toxicological assessment of nickel in rats and dogs. J. Food Sci. Technol. 13:181-187. American Biogenics Corporation. 1988. Ninety-day gavage study in albino rats using nickel. Final report to U. S. Environmental Protection Agency. Ameri- can Biogenics Corporation, Decatur, IL. ATSDR (Agency for Toxic Substances and Disease Registry).1997. Toxicological Profile for Nickel (Update). U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA. Biggart, N.W., and M. Costa. 1986. Assessment of the uptake and mutagenicity of nickel chloride in Salmonella tester strains. Mutat. Res. 175:209-215. Borg, K., H. Tjalve. 1989. Uptake of 63Ni in the central and peripheral nervous system of mice after oral administration. Effect oftreatment with halogenated 8-hydroxyquinolines. Toxicology 54:59-68. Burrows, D., S. Creswell, and J.D. Merrett.1981. Nickel, hands, and hip prosthe- sis. Br. J. Dermatol. 105:437-444. Burrows D.1992. Is systemic nickel important? J. Am. Acad. Dermatol.26~4~:632- 635. Casey, C.E., M.F. Robinson.1978. Copper, manganese, zinc, nickel, cadmium and lead in human fetal tissues. Br. J. Nutr. 39:639-634. Clary, J.J. 1975. Nickel induced metabolic changes in the rat and the guinea pig. Toxicol. Appl. Pharmacol. 31 :55-65.

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242 Spacecraft Water Exposure Guidelines Christensen, O.B., and H. Moller.1975. Nickel allergy and hand eczema. Contact Dermatitis 1~3~:129-35. Christensen, O.B., and H. Molter. 1975. External and internal exposure to the antigen in the hand eczema of nickel allergy. Contact Dermatitis 1 :136-141. Christensen, O.B., and V. Langesson. 1981. Nickel concentration of blood and urine after oral administration. Ann. Clin. Lab. Sci. 11: 119- 125. Christensen, O.B., C. Lindstrom, H. Lolberg, and H. Mohler.1981. Micromorph- ology and specificity of orally induced flare-up reactions in nickel-sensitive patients. Acta Derm. Venereol. 61 :505-510. Cronin, E., A. Di Michiel, and S.S. Brown. 1980. Oral Nickel challenge in nickel-sensitive women with hand eczema. Pp.149- 152 in Nickel Toxicology, S.S. Brown and F.W. Sunderman Jr., eds. New York, NY: Academic Press. Coogan, T.P., D.M. Latta, E.T. Snow, and M. Costa.1989. Toxicity and carcinoge- nicity of nickel compounds. CRC Crit. Rev. Toxicol. 19:341-384 Costa, M. 1991. Molecular mechanisms of nickel carcinogenesis. Annul Rev. Pharmacol. Toxicol. 31: 321 -337. Dabeka, R.W., and A.D. McKenzie. 1995. Survey of lead, cadmium, fluoride, nickel, and cobalt in food composites and estimation of dietary intakes ofthese elements by Canadians in 1986-1988. J. AOAC Int. 78~4~:897-909. Daldrup, T., K. Haarhoff, S. Szathmary. 1983. Fatal nickel sulfate poisoning [in German]. Beitr. Gerichtl. Med. 41:141-4. Dally, H., and A. Hartwig, (1997~. Induction and repair inhibition of oxidative DNA damage by nickel(II) and cadmium(II) in mammalian cells. Carcinogenesis 18: 1021 - 1026. Dieter, M.P., C.W. Jameson, A.N. Tucker, M.I. Luster, J.E. French, H.L. Hong, and G.A. Boorman. 1988. Evaluation oftissue disposition, myelopoietic and im- munologic responses in mice after long-term exposure to nickel sulfate in the drinking water. J. Toxicol. Environ. Health 24:356-372. Dostal, L.A., S.M. Hopfer, S.M. Lin, and F.W. Sunderman Jr. 1989. Effects of nickel chloride on lactating rats and their suckling pups, and the transfer of nickel through rat milk. Toxicol. Appl. Pharmacol. 101~2~:220-31 EPA (U.S. Environmental Protection Agency).1983. Nickel occurrence in drink- ing water, food and air. Office of Water, U.S. Environmental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency).1985. Drinking water criteria docu- ment for nickel. NTIS PB86-117801. Environmental Criteria and Assessment Office, U.S. Environmental Protection Agency, Cincinnati, OH. EPA (U.S. Environmental Protection Agency). 1995. Nickel. Drinking Water Health Advisory. Office of Water, U.S. Environmental Protection Agency, Washington, DC. EPA (U. S. Environmental Protection Agency). 1996. Drinking water regulations and health advisories. EPA 822-R-96-001. Of fice of Water, U.S. Environmen- tal Protection Agency, Washington, DC. Fletcher, G.G., F.E. Rossetto, J.D. Turnbull, and E. Nieboer. 1994. Toxicity, up-

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