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Suggested Citation:"Appendix 6: Nickel." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 6: Nickel." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 6: Nickel." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 6: Nickel." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 6: Nickel." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 6: Nickel." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 6: Nickel." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 6: Nickel." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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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

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 20°C); NiCl2 (642 g/L at 20°C) 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,

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-

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

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.

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

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

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

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

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

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,

214 Spacecraft Water Exposure Guidelines and cellular enzyme activities were determined (Dieter et al. 1988~. Mice in the 108-mg/kg/d and 150-mg/kg/d dose groups drank less water than controls; decreases in body and organ weights were seen only in mice in the 1 50-mg/kg/d dose group, with the exception of the dose-related reductions in thymus weights. Blood nickel concentrations seen at 4 wk and ~ wk were proportional to time and dose; however, those concentrations did not increase substantially in any ofthe dose groups after ~ wk. The kidney was the major organ of nickel accumulation, and minimal convoluted tubular damage was noted. There was a loss of renal tubular epithelial cells, and hyaline casts were present in the tubules of the 108-mg/kg/d dose group, suggesting protein loss, but not the 44-mg/kg/d dose group. A LOAEL of 108 mg/kg/d and a NOAEL of 44 mg/kg/d for renal effects could be identi- fied. There were dose-related decreases in bone marrow cellularity and decreases in granulocyte macrophage colony forming units (CFUs) and pluripotent stem-cell proliferative response CFUs. Inhibition of certain carbohydrate metabolism enzymes was confined to the fractionated and enriched granulocyte macrophage cell populations, suggesting that these committed stem cells were a primary target of nickel sulfate toxicity. Sev- eral immune parameters were evaluated, including spleen cellularity. An observed reduction in the lymphoproliferative response to lipopoly- saccharide (with out any change in proliferative response to the mitogen concavalin A), a measure of systemic immunotoxicity, was regarded as secondary to the primary effect of NiSO4 on the myeloid system, because it was the only significant change among a panel of seven immune parame- ters that were evaluated. Vyskocil et al. (1994) exposed male and female Wistar rats to drinking water containing nickel as NiSO4 at 100 mg/L for 6 mot The average nickel intake was calculated to be 6.9 mg/kg/d for males and 7.6 mg/kg/d for fe- males. Kidney weights were significantly increased in the exposed groups. Urinary excretion of albumin increased significantly in female rats, but the increase was marginal (due to wide data variation) in male rats. These results are indicative of adverse effects of nickel on renal function, female rats being more sensitive to the nephrotoxicity of nickel than males. No changes were noted in urine lactate dehydrogenase, N-acetyI-beta-D- glucosaminidase, or beta-2-microgiobulin (a marker for renal tubular dam- age). Male and female Wistar derived albino rats (25 per gender per group, 56-65 g body weight) were fed diets containing nickel as NiSO4 (hexahy- drate) at 0, 100, 1,000, and 2,500 ppm (0, 5, 50, and 125 mg/kg/~) for 2 y (Ambrose et al. 1976~. Significant body-weight reductions were observed

Nickel 215 in both the male and female rats fed 125 mg/kg/~. Significant increases in heart-to-body weight ratios and decreases in liver-to-body weight ratios were observed at 50 mg/kg/d and 125 mg/kg/~. No significant effects were seen in the 5-mg/kg/d group. Male and female beagle dogs (three per dose per gender, 6 mo old) maintained for 2 y on diets providing nickel as NiSO4 (hexahydrate) at 0, 100, 1,000, and 2,500 ppm (0, 3, 29, and 70 mg/kg/~) showed various hepatic, renal, and hematotoxic effects. No significant changes were noted in the 3-mg/kg/d and 29-mg/kg/d dose groups (Ambrose et al.1976~. De- pressed body-weight gain (40°/O decrease), lowered hematocrit and hemo- giobin levels, and decreased liver-to-body weight ratios and kidney-to-body weight ratios were noted only at the highest dose. Polyurea and increased liver and kidney weights were also noted at the 70-mg/kg/d dose. The authors also reported respiratory system effects in dogs at the highest dose, such as subpleural peripheral cholesterol granulomas, bronchiolectasis, emphysema, and focal cholesterol pneumonia. Microscopic examinations did not reveal any changes in the brains of the dogs for up to 2 y. The principal binding site for nickel to serum albumin is the histidine residue near the amino terminus and is the same in humans, rodents, and bovines (Hendel and Sunderman 1972~. Dogs do not have that binding locus. It has been reported that greater than 85°/O of administered nickel is found in the ultrafiItrable fraction of dog serum albumin. Because this important differ- ence determines the transport and turnover of nickel, extrapolating dog data to humans is questionable. Schroeder et al. (1974) administered nickel at 5 ppm (average daily dose of 0.41 mg/kg) in drinking water for life (18 mo) to both male and female rats. Significant reductions in body weights were noted. In addi- tion, histopathologic examinations showed an increased incidence of focal myocardial fibrosis. In a 2-y study, Ambrose et al. (1976) reported increased heart weights without any reported histologic changes of the heart tissue in rats exposed to nickel at 75 mg/kg/d and in dogs given nickel as NiSO4 in the diet at 62.5 mg/kg/~. Similarly, there were no histologic changes in the hearts of rats exposed to nickel in drinking water at 53 mg/kg/d for up to 30 wk (RTI 1988~. Reproductive Toxicity Although nickel crosses the placenta (Jasim and Tjalve 1986), no spe-

216 Spacecraft Water Exposure Guidelines cific reports are available related to adverse effects of nickel on fetal matu- ration, reproduction, or development in humans. In a 4-mo study, when male rats were intubated with NiSO4 at 25 mg/kg, several testicular chan- ges, such as interstitial cell proliferation, transparent vessel walls, and re- duced number of spermatozoa and some testicular enzymes such as steroid 3 beta-dehydrogenase, were seen (Waltschewa et al. 1972, as cited in EPA 1985~. Sobti and Gill (1989) reported increased abnormalities ofthe heads of spermatozoa 5 wk after mice were treated with a single oral dose of NiSO4, NiCI2, or nickel nitrate (Ni(NO3~2) at 28, 43, and 23 mg/kg, respectively. Ni(NO3~2 is the most potent when compared with the sulfate or the chloride salts (which were equipotent). Kakela et al. (1999) conducted a study to determine the reproductive effects of nickel in both female and male Wistar rats in which one or both genders were exposed to nickel at 10-100 ppm as NiCI2 in drinking water. In males (exposed 28 ~ or 42 ~ before copulation), NiCI2 induced shrinkage of seminiferous tubules and decreased the number of spermatogonia in the tubules. The number of pregnancies and the num- ber of pups born were reduced. There was a 50°/O reduction in the fertility index in males drinking water spiked with nickel at 30 ppm (estimated 3 mg/kg/~) for 28 d. In addition, this exposure resulted in an average of only 5.3 live born pups per delivered female in comparison to 10 per controls (females copulated with unexposed males). However, the fertility index in male rats exposed for 48 ~ was better than in those exposed for 28 d. The reason for that is unclear. In female rats exposed to nickel as NiCI2 at 10-100 ppm (1, 3, or 10 mg/kg/~) in water for 14, 28, or 100 ~ before copulation and through preg- nancy and lactation, the fertility index was unaffected. Pup mortality dur- ing lactation was high (Kakela et al. 1999~. There does not appear to be a clear trend of cause-effect relationship, and because only one dose was used, this study was not used to calculate an AC. Mice treated orally with NiCI2 (90.6 mg/kg/~) during gestation days 8-12 did not show any change in the average number of neonates per litter or weights of the neonates (Seidenberg et al. 1986~. A multigeneration study of nickel suggested that high oral exposures to nickel salt might adversely affect reproduction. NiCI2 was given in the feed to rats at 0, 22.5, 45, or 90 mg/kg/d (Ambrose et al. 1976~. A dose-related increase in the number of stillborn pups and a decrease in the number of weaning pups were seen in the F~ generation. However, the microscopic examination of testes and ovaries of rats and dogs in the 2-y Ambrose et al. study did not reveal any changes in those tissues.

Nickel 217 Developmental Toxicity There are no reports on developmental effects of nickel in humans. In the three-generation reproduction study in rats by Ambrose et al. (1976) in which nickel was given as NiSO4 in the diet at 0, 12.5,25, or 50 mg/kg/d, no evidence of teratogenicity was seen in the offspring. A two-generation reproduction toxicity study of female Long-Evans rats given doses of nickel as NiCI2 at 0, 10, 50, or 250 ppm in drinking water (0, 1.33, 6.5, or 32.5 mg/kg) for 11 wk during mating and during two gestation and lactation periods resulted in an increased number of litters with dead pups only at the highest dose during the L1 period (NOAEL of 6.5 mg/kg). During the second generation, significant dose-related increases in the deaths of pups were seen at all doses (Smith et al.1993~. Similar results were reported in the RTI (1988) two-generation reproduction study of rats given NiCI2 in drinking water at 0, 0, 250, or 500 ppm. In the Fir generation there was a significant decrease in live pups at 500 ppm. In a study on the development of mouse embryos, intraperitoneal injection of a single dose of NiCI2 (hexa- hydrate) at 20 mg/kg in the preimplantation period resulted in a large fre- quency of both early and late resorptions, diminished body weights of the fetuses, and diminished sizes of litters (Storeng and Jonsen 1981~. Genotoxicity Bacterial mutagenicity tests have indicated that nickel is a nongenotoxic agent (Biggart and Costa 1986~. In contrast, higher organism cell tests, in vivo and in vitro, have shown that nickel (particulate and soluble com- pounds) produces a variety of genetic abnormalities: DNA strand breaks, DNA-protein cross-links, nucleotide excision, single gene mutations, insta- bility of DNA repetitive sequences, chromosome aberrations, sister chromatic exchanges, micronuclei, and cell transformation (Coogan et al. 1989; Costa 1991; Fletcher et al. 1994; Snyder 1994; Hartwig 1997; Jack- son et al. 1998~. Particulate nickel is more mutagenic (as well as carcino- genic) than are nickel compounds (Sunderman 1984~. The primary target molecules for nickel attack appear to be proteins, especially those proteins closely associated with the chromosome and with DNA repair (Lynn et al.1997~. The threshold concentration for nickel-in- duced mutagenesis is impossible to establish at present because, in most studies, the lowest concentrations used were near those that cause high cytotoxicity. For example, with a typical exposure to NiSO4 in a range of

218 Spacecraft Water Exposure Guidelines concentrations at 0.05-0.25 millimolar (mM) or 14.7-73.0 g/mL for 6-24 h, cell survival begins to plummet near the lowest concentrations and reaches near zero at the higher concentrations (Lee et al. 1993; Fletcher et al. 1994~. The high cytotoxicity of nickel probably accounts for the rela- tively low frequency of observed mutations. Nickel, like ionizing radiation, acts by increasing the levels of endoge- nous cellular hydrogen peroxide and its short-lived reactive oxygen species (i.e., OH free radicals) (Reid et al.1994; Lynn et al.1997~. Nuclear protein damage caused by nickel reduces the enzyme activity needed for DNA replication, transcription, recombination, and repair. The demonstrable inhibition of these crucial functions is undoubtedly responsible for much, if not all of nickel's mutagenic and cytotoxic effects, the latter probably due to high mutation load (Jackson et al. 1998~. Pool-Zobel et al. (1994) have found that human nasal and gastric mu- cosa cells are more susceptible (about 5 times) to the cytotoxic-genotoxic effects of NiSO4 than are cells of those tissues in rats. These data suggest that caution should be exercised in using rat data to estimate nickel risks in humans. Overall, results from genotoxicity studies are "generally consistent with animal carcinogenicity data" (Verma et al. 1999~. Carcinogenicity Carcinogenic effects of nickel have been well documented in workers exposed occupationally, particularly to nickel subsulfide dust and to nickel oxide. The respiratory system is the primary target for inhaled nickel. In serious cases, histologic changes in the lungs, which include alveolar wall damage and edema in the alveolar space, were reported. Effects included chronic bronchitis, emphysema, and reduced vital capacity. The most com- mon ailment is asthma (Shirakawa et al. 1990), which can result from pri- mary irritation or from an allergic response. Inhalation and intratracheal instillation of Ni3S2 in rats resulted in lung tumors. The results with other nickel compounds are inconclusive and appear to depend on the species. For example, although rats showed respiratory tumors when exposed to Ni3S2, mice and hamsters did not (MuhIe et al. 1992~. The National Toxi- cology Program (NTP 1996) completed three 2-y inhalation carcinogenicity studies with three nickel compounds two insoluble nickel compounds, Ni3S2 and NiO (high temperature), and one soluble nickel compound, NiSO4 in F-344 rats and B6C3F~ mice. The exposure durations were 6 in/d, 5 d/wk for 16 ~ or 13 wk. When F-344 rats were exposed to Ni3S2 at 0, 0.1, or 0.7 mg per cubic meter (m3) and B6C3F~ mice were exposed to

Nickel 219 Ni3S2 at 0, 0.4, or 0.8 mg/m3, there were dose-dependent increases in lung tumors and increased incidence of alveolar and bronchiolar adenomas and carcinomas in male and female rats. There was no evidence of a carcino- genic response in male or female mice, but there were other noncar- cinogenic effects such as chronic inflammation ofthe lungs, focal alveolar epithelial hyperplasia, macrophage hyperplasia, and lung fibrosis (NTP 1996~. After exposing rats to NiO at 0, 0.5, 1.0, or 2 mg/m3 for 2 y, carci- nomas and adenomas were seen only in rats exposed at 1.0 mg/m3 and 2.0 mg/m3, but these results were not significantly different from controls. There was no evidence of carcinogenicity in male mice; adenomas or carci- nomas were seen in female mice even at low doses, without any further increase at high doses. Noncarcinogenic effects described above were also seen. When rats were exposed to nickel as NiSO4 at 0, 0.03, 0.06, or 0.11 mg/m3 and mice were exposed at 0,0.06,0.11, or 0.22 mg/m3, there was no evidence of carcinogenic activity in either species. There were less pro- nounced noncarcinogenic effects, less than seen with other insoluble nickel compounds, in both species in both genders. There has been a lack of agreement among several organizations in the classification of nickel as a potential human carcinogen. Although NTP and IARC have classified nickel and certain nickel compounds as carcinogenic or potential carcinogens to humans (group 1), ACGIH has proposed category A4 (not classifiable as a carcinogen) for the soluble nickel salts. There are no epidemiological reports indicating cancer risk by the oral route. Shroeder et al. (1964, 1974) and Ambrose et al. (1976) could not find any increased incidence of cancer in their study when mice and rats were administered drinking water containing 0.95 mg/kg/d and 0.6 mg/kg/d, respectively, for life. Only intraperitoneal injection of nickel acetate re- sulted in lung tumors (1.5 lung tumors per mouse tPoirier et al. 1984] and 3/35 or 5/31 lung tumors in rats at 25 mg and 50 ma, respectively tPott et al. 19923) (see Table 6-4~. Similarly, lung tumors were seen when 50 intraperitoneal injections of NiSO4 at 1 mg each, twice a week, were admin- istered to female Wistar rats (Pott et al. 1992~. Several studies in rats did not show even localized tumors when NiSO4 was administered by intra- muscular injected (IARC 1990~. Nickel Sensitivity and Allergic Contact Dermatitis One of the most common effects of nickel exposure is ADC. Contact dermatitis is an allergic response to metallic nickel a sensitization risk from different types of nickel coatings and alloys. Occupational nickel ACD

220 Spacecraft Water Exposure Guidelines TABLE 6-4 Carcinogenicity in Rats After Intraperitoneal Injection of Various Nickel Compounds Intraperitoneal Dose ~mg' Incidence of Tumors Substance (Number of Injections) Number Percent Nickel chloride 50 (1) 4/32 12.5% Nickel sulfate 50 (1) 6/30 20.0% Nickel acetate 25 (1) 3/35 8.6% Nickel acetate 50 (1) 5/31 16.1% Nickel carbonate 25 (1) 1/35 2.9% Nickel carbonate 50 (1) 3/33 9.1% Source: Data from Pott et al. 1992. is well known. The five most common causes of ACD in the United States are plant resins, nickel, p-phenylene diamine, rubber chemicals, and ethyI- ene diamine. Contact dermatitis, which results from dermal exposure to nickel, is the most prevalent effect of nickel in the general population. It can result from close contact with costume jewelry and clasps in clothing, eyeglass frames, and wristwatch bands. As evaluated by patch-testing, the prevalence is 7- 1 0% in women and 1-2% in men in the general population. It has been the subject of numerous studies to assess if dietary nickel or ingestion of nickel via water will perpetuate the dermatitis of nickel-sensi- tive subjects and if sensitization will occur in non-nickel-sensitive subjects. Several studies have documented that a single oral dose of nickel can result in a flare-up (aggravation) of dermatitis in nickel-sensitive individu- als individuals who had been previously sensitized by dermal contact to nickel. These studies were reviewed in Burrows (1992~. The study by Veien et al. (1985) reported that the conditions of 143 patients with vesicu- lar hand eczema (with positive patch test) disappeared in some cases and improved in many cases after 1-2 mo on a diet low in nickel, indicating that ingestion of nickel might be responsible for their condition. In a double- blind study, Christensen and Moller (1975) reported that a single oral dose of nickel at 5.6 mg produced exacerbation in nine of 12 subjects with hand eczema. The same individuals did not react to placebos, as confirmed in several later studies. Five nickel sensitive women were given NiSO4 con- taining nickel at 0.6, 1.25, or 2.5 mg in 100 mL of water after an overnight fast. Three of five at the lowest dose and five of five at the highest dose exhibited worsening of hand eczema. Erythema was noted in four of five in the highest-dose group. Thus, the lowest single dose resulting in derma-

Nickel 221 titis, including erythema on the body, worsening of hand eczema, and a flare-up at the patch-test site, was 0.6 mg/d, or 0.009 mg/kg/d for a 70-kg adult (Cronin et al. 1980~. Non-nickel-sensitive individuals were not in- cluded in the study. Some studies (Burrows et al. 1981; Gawkrodger et al. 1986) did not observe any reaction exceeding those of placebos, making it hard to interpret results on hypersensitivity. For example, Gawkrodger et al. (1986) reported that in a double-blind randomized study, when 26 sub- jects who were positive to nickel patch-tests were given either 0.4 mg or 2.5 mg of nickel sulfate (NiSO4.7H2O) as capsules (also containing lactose) on two successive days for 2 wk. the nickel-induced reactions observed after 3 ~ did not exceed those seen in placebos. However, when a dose of 5.6 mg was administered, all subjects of this group showed exacerbation of the existing condition. Some ofthe differences were also due to the conditions ofthe study and how nickel was administered, as single bolus dose or in the diet for a short-term or long-term period. An analysis by Nielsen (1992) indicates the late reactions in response to provocation in some studies were missed, leading them to conclude absence of a reaction. Although most of the studies above involved single bolus administra- tions in water, exposure to nickel via the diet caused similar reactions. Nielsen et al. (1990) fed a diet (oatmeal, soy beans, cocoa) with 5 times the normal levels of nickel (about 0.007 mg/kg/~) to 12 women who had hand eczema and known allergies to nickel for 4 d. An aggravation of hand eczema was found in six of 12 by day 4 after the start ofthe challenge, and although excess nickel was excreted by 2 ~ after the last treatment, further exacerbation of hand eczema was observed in 10 of 12 through day 11. In a double-blind randomized study in which nickel-sensitive subjects were given an oral dose of nickel at 0.5 mg (as NiSO4) two consecutive days in a week (0.007 mg/kg/~) for 4 wk. Jordan and King (1979) did not report flare-up of eczema (one in 10 was positive), suggesting that longer- term oral exposure may even serve to desensitize some individuals. Santucci et al. (1994) observed that in Bight nickel-sulfate-sensitive women given increasing daily doses of nickel (0.014-0.3 mg/kg/~) for up to 178 4, hand eczema clinically improved after 1 mo of treatment. Similarly, Gawkrodger et al. (1986) gave three different doses of nickel at 0.4, 2.5, and 5.6 mg (0.006, 0.04, and 0.09 mg/kg, assuming 60 kg as the weight of women) two times a week for 2 wk and found that six of six showed reac- tions at the highest dose. But all these studies seem to indicate oral doses of nickel do not sensitize individuals who do not have nickel ACD (Nielsen et al. 1999~. The pattern of nickel absorption and excretion did not differ from contro! non-nickel-allergic subjects.

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226 Spacecraft Water Exposure Guidelines Spaceflight Effects The physiologic and biochemical changes that occur during spaceflight (Nicogossian et al. 1994) might increase the sensitivity of astronauts to the toxic effects of nickel such as hematologic effects and reduction in water consumption. Reduced plasma volumes and changes in RBC formation (Nicogossian et al. 1994) were observed in crew members from the Skylab and Apollo missions and shuttle missions. Thus, dehydration has been a continued concern for long-duration space missions. RATIONALE The following paragraphs provide the rationales for the proposed guide- lines for nicker in NASA spacecraft drinking water for 1, 10, 100, and 1,000 ~ (see Table 6-6 for guidelines set by other organizations). The values listed (see Table 6-7) were set based on acceptable concentrations (ACs) for each duration following the methods for developing spacecraft water expo- sure guidelines (SWEGs) documented by the National Research Council (NRC 2000~. In general, we have applied a spaceflight factor of 3 for cer- tain effects, such as hematologic effects, which are known to be exacerbated by microgravity. Usually an intraspecies factor is not used because astronauts come from a healthy population, and there is no evidence of healthy people having excess susceptibility to nickel or similar compounds. Nevertheless, a re- view of the existing literature clearly shows that ingestion of nickel aggra- vates existing eczema in individuals known to be sensitive to nickel (nickel ACD). However, ingested nickel does not seem to sensitize normal individ- uals (Nielsen et al. 1999~. Though astronauts are not specifically tested for nickel sensitivity, a detailed health questionnaire including questions con- cerning allergies would reveal such sensitivity. In order to account for any potential hypersitivity to nickel, a factor of 3 has been applied to calculated ACs to at least partially protect astronauts. Several studies have clearly documented that the presence of food re- duced absorption of nickel from the gastrointestinal tract. Sunderman et al. ( 1989) indicated that 40 times more nickel was absorbed when administered in water compared with administration by food. But, in this study, nickel was administered to subjects who had fasted for 12 h before the dose and fasted for 4 more hours after the intake. The recent work by Nielsen et al. (1999) clearly indicates that, in general, there will always be food in the stomach, and drinking water will be mixed with existing food. When one

Nickel 227 TABLE 6-6 Drinking Water Levels for Nickel Set by Other Organizations Organization Standard Level EPA MCL Vacated EPA MCLG Vacated EPA 1-d HA(child) 1 mg/L EPA 10-d HA (child) 1 mg/L EPA Long-terma HA (adult) 1.7 mg/L EPA Lifetime HA 0.1 mg/L EPA RfD 0.02 mg/kg/d EPA DWEL 0.6 mg/L EPA Cancer group Db,c EPA Cancer risk NA (10-4 cancer risk) ACGIHC ~ Cancer group Category A4 (soluble nickel salts); not classifiable as a car- cinogen ATSDR MRL None sete FDA Bottled water 0.1 mg/L aThe levels that will not cause any adverse carcinogenic effects up to 7 y (10%) of an individual's lifetime. bGroup D is considered not classifiable as a carcinogen in animals or humans. CIARC has classified nickel and it's compounds as group 1 carcinogens; NTP (1996) has also concluded that nickel and its compounds can reasonably be an- ticipated to be carcinogenic. ACGIH's air standard for soluble nickel compounds is 0.1 mg/m3 (under revi- sion); OSHA's air standard is 1 mg/m3 for soluble nickel compounds; and NIOSH's recommended exposure limit (REL) is 0.015 mg/m3 for metal, soluble, . . . . . . 1nso" u ~ e, ant Inorganic mc ~e" In air. eATSDR did not establish a minimal risk level (MRL) because if a value is cal- culated it will be lower than the mean daily dietary content of nickel and salts. Abbreviations: ACGIH, American Conference of Governmental Industrial Hy- gienists; ATSDR, Agency for Toxic Substances and Disease Registry; EPA, U.S. Environmental Protection Agency; DWEL, drinking water equivalent level; MCL, maximum contaminant level; MCLG, maximum contaminant level goal (nonenforcable standard); NA, not applicable; RfD, reference dose. considers water and food ingested on a continuous basis, as in 10 4, 100 4, or 1,000 4, the difference will be insignificant. If any difference exists, it will be masked by the wide variations in adsorptions within a group.

228 Spacecraft Water Exposure Guidelines TABLE 6-7 Spacecraft Water Exposure Guidelines for Nickela b Duration Concentrations (mg/L) Toxicity End Point 1 d 1.7c led 1.7c lOOd 1.7c 1,000 d 0.3 Myelopoietic system effects and decreased immune function response Myelopoietic system effects and decreased immune function response Myelopoietic system effects and decreased immune function response Myelopoietic system effects and decreased immune function response aDieter et al. (1988) was used to derive all SWEGs. bThe values incorporate a safety factor of 3 to partially protect astronauts against the risk of an allergic response to nickel ingestion. These levels do not protect people who are already hypersensitive to nickel. CThe AC derived for 100 d was used for 1 d and 10 d without any time-extrapo- lation factors because of the importance of the effect of nickel on immunologic systems. No factors were incorporated to account for differences in absorption in the calculation of ACs for water from feed-study data. A few studies that show definite adverse effects but used only one dose and one time could not be used for AC derivation because a NOAEL could not be identified. For example, mild focal myocardial fibrosis was reported in rats exposed to nickel (form not specifiers at 5 ppm in drinking water for 18 mo (Schroeder et al. 1974), but that study could not be used to derive an AC because only one dose was used and it was conducted in a metal-free environment, which might have increased the sensitivity of these animals. (The effect was seen only on 13.3% of animals.) Similarly, Waltschewa et al. (1972, as cited in EPA 1985) reported testicular changes in male rats after 120 ~ of ingestion of NiSO4 at 25 mg/kg. That study was not used to set SWEGs because a definitive NOAEL could not be identified. Haber et al. (1998) evaluated the data with benchmark dose (BMD) response modeling and the use of biologic significance in the selection of benchmark response. The authors used oral and inhalation exposure data from several studies to calculate the BMD for nickel. They determined a BRIDLE for the oral exposure to nickel (defined by the authors as the lower bound on the dose at which increased probability of an abnormal response is equal to 10%) of 4-5 mg/kg/d on the basis of increased prenatal mortality and immunologic effects. It must be pointed out that in this paper the au-

Nickel 229 thors neither derived a reference dose (RID) nor discussed which uncer- tainty factors should be used for each of the end points. For modeling they considered the data from two subchronic studies: one by American Biogenics Corporation (1988) in which nickel chloride administered by gavage for 92 ~ resulted in decreased body weights in males, and another by Dieter et al. (1988) in which exposure of female mice to nickel sulfate in drinking water for 180 ~ resulted in a decreased lymphoproliferative response (immune system effect). They also modeled data from the chronic NiSO4 dietary toxicity study of Ambrose et al. (1976) in which decreased body weight in female rats was noted after 2 y of nickel-spiked feeding and a two-generation reproduction toxicity study by Smith et al. ( 1993) in which increased number of litters with dead pups in the first generation was seen in rats exposed to NiCI2 in drinking water. In that study the authors applied a hybrid modeling approach using the Weibull model and the power model. From the results, the authors pointed out that the differences observed in BMD obtained from different studies for the same or similar end points might be due to differences in the chemical form (NiCI2 vs NiS04) and/or to the mode of oral exposure, such as oral gavages vs diet vs drinking water. In a later publication, Haber et al. (2000) derived an RID of 0.008 mg/kg/d for noncancer effects from soluble nickel salts ingested in addition to dietary nickel. In this derivation the authors evaluated data from five studies and analyzed them for deficiencies and strengths. The five studies are as follows: Vyskocil et al. (1994), in which increased albuminuria was reported in rats exposed to nickel via drinking water for 6 mo; Ambrose et al. (1976), in which rats fed nickel for 2 y showed decreased body weights; American Biogenics Corporation ~ 1988), in which reduced body weights in males were observed when nickel was administered to rats via drinking water for 92 d; Dieter et al. (1988), in which mice that ingested NiSO4 via drinking water for 180 ~ showed thymic atrophy and decreased thymus weights; and Smith et al. (1993), the two-generation reproductive study in which increased death of pups in the second generation was observed in rats exposed to NiCI2 via drinking water at various dose levels. For R 'ID deriva- tion the authors chose the decreased giomerular function, as evidenced by increased urinary albumin, as the most appropriate and sensitive end point (in the absence of any tubular damage, as measured by urinary beta-2- microgiobulin, N-acetyI-beta-~-glucosaminidase, and lactate dehydro- genase) reported by Vyskocil et al. (1994~. In that study, female rats were more responsive than male rats, and a LOAEL of 7.6 mg/kg/d was identi- fied. ANOAEL was not available because ofthe single dose. Due to wide variability in controls and some outliers, the changes in male rats were not

230 Spacecraft Water Exposure Guidelines statistically significant. The effects were seen at the end of 6 mo, not at the end of 3 mot Using the LOAEL of 7.6 mg/kg/d from the Vyskocil et al. study for renal effects, and applying a modifying factor of 1,000 based on recommendations described in Dourson et al. ~ 1996), the authors calculated an RID as shown below. In short, the authors used a factor of 10 for human variability, a factor of 10 for interspecies extrapolation, and a combined factor of 10 for subchronic-to-chronic extrapolation, use of minimal LOAEL-to-NOAEL, and an insufficient database. Thus, the authors calcu- lated the RfD as 7.6 mg/kg/d 1,000 = 0.0076 mg/kg/~. Using EPA's nominal value of daily water consumption of 2 L/d for a 70-kg person, this value is equivalent to 0.0076 mg/kg/d x 70 kg 2 L/d = 0.266 mg/L (0.27 mg/L when rounded). This is entirely from sources of ingestion other than food, because the con- centration of nickel in the animal food was not known and was not adjusted in the LOAEL. It is documented in several studies that exposure to nickel, either in feed or in water, resulted in decreased body-weight gains, in addition to changes in organ weights in some cases. These effects have not been used to set ACs because body- and organ-weight changes are not considered adverse effects. In the following AC calculations, a value of 2 L has been assumed for crew drinking water usage per person per day, instead of a total of 2.8 L (2 L for drinking and 0.8 L for food reconstitution), because the absorp- tion of nickel from food has been reported to be very low. Ingestion for 1 d No acute animal toxicity studies at low doses were available for deter- mining a 1 -d AC for nickel in water. The short-term studies of Cronin et al. (1980) and Nielsen et al. (1990) on the worsening of hand eczema and erythema in 12 nickel-sensitive women who were challenged with a diet that included low doses of nickel could not be used because they were conducted in only nickel-sensitive subjects. Sunderman et al. (1989) reported that 7 h after drinking water with a dose of NiSO4 at 0.05 mg/kg, a human volunteer complained of transient

Nickel 231 impaired vision for 2 h. This adverse effect or similar symptoms were not seen when the dose was reduced to 18 ~g/kg in four other subjects (two men and two women). As these data are from only one subject, they could not be used. Sunderman et al.'s (1988) data on the workers who drank nickel-contaminated water from a water fountain (as both NiCI2 and NiSO4 and also including boric acid) can be used after applying a factor for esti- mating a LOAEL. Because the data are from 30 subjects who were af- fected, and the concentrations were determined to be 7.1-35.7 mg/kg (the intake amount), these data could be useful in deriving a 1-d AC. Thus, a 1-d AC can be calculated for neurologic effects (giddiness, weariness, and headache) as well as for transient lowered hematocrit (hematologic effects) and transient serum bilurubin (hepatic effects). Using the LOAEL of 7.1 mg/kg/d and factors of 10 and 3, for LOAEL-to-NOAEL extrapolation and an additional safety factor for nicker sensitivity, respectively, the 1 -d AC for a 70-kg person drinking 2 L of water per day is (7.1 mg/kg/d x70 kg) (10 x2L/dX 3~=8mg/L. Ingestion for 10 d Whanger ( 1973) fed weanling rats (OSU brown rats, gender not known, 35 ~ old, body weights 90 g, six rats per group) a diet containing various levels of nickel acetate (10, 50, or 100 mg/kg/~) for 6 wk. Basal ration contained nickel at 0.21 ppm. Hemoglobin and packed cell volume (PCV) were found to be decreased significantly. These data were used to calculate the 10-d AC using both the NOAEL/LOAEL method and also using the BMD method (using the lower 95°/O confidence limit on the benchmark dose corresponding to 1% risk, BMDLo~. BMDs were obtained using the EPA's BMD software, version 1.2, and the polynomial model with the power model on "continuous data." The standard deviations required for processing continous data were derived from the least significant difference (LSD) included in the study by the author. The values from these models were averaged. A summary of these values are in Table 6-~. ACs devel- oped using data from Whanger (1973) appear in Table 6-9. For those ACs, a species extrapolation factor of 10 was used, along with a factor of 3 to account for nickel sensitivity. A spaceflight factor of 3 was used in cal- culations for the PCV and hemoglobin end points. No time-extrapolation factor was used. All ACs assume 70-kg body weight and 2 L of drinking water per day.

232 Spacecraft Water Exposure Guidelines TABLE 6-X BMD and BMDL Values Calculated from the Whanger (1973) Study (in mg/kg/~) Parameter BMDo1 BMDLo1 BMDlo BMDLlo LOAEL NOAEL PCV 37 1 1 41 19 100 50 Hemoglobin 27 14.5 47.5 35 100 50 ALP 24 18 31 23 50 10 Abbreviations: ALP, plasma alkaline phosphatase; PCV, packed cell volume. Ingestion for 100 d Waltschewa et al. (1972, as cited in EPA 1985) reported that oral intubation of NiSO4 to male rats for 120 ~ resulted in degenerative changes in liver and kidneys, but their data could not be used because only one daily dose of 25 mg/kg was given, and the initial time when the effects were seen was not indicated. A definite LOAEL or NOAEL is not clear. Similarly, the data on the effects of nickel on spermatozoa and interstitial cell prolifer- ation could not be used. The Sobti and Gill (1989) report on increased abnormalities of the heads of spermatozoa observed in mice 5 wk after treatment with a single oral dose of NiSO4, NiCI2, or Ni(NO3~2 at 2S, 43, and 23 mg/kg, respectively, could not be used because of a lack of experi- mental details. 100-d AC Based on American Biogenics Corporation (19XX) In the American Biogenics 90-d gavage study, male and female rats (30 per gender) were administered daily doses of NiCI2 at 0, 5, 35, and 100 mg/kg/~. Decreased organ weights, changes in hematologic parameters (increases in white blood cells and platelets), and CNS-related symptoms such as ataxia, lethargy, and altered breathing were some of the clinical signs oftoxicity reported. A dose of 5 mg/kg/d was identified as aNOAEL. A species extrapolation factor of 10, a spaceflight factor of 3, and a safety factor of 3 to account for nickel sensitivity were applied to the AC calcu- lation. To extrapolate the 90-d data to the 1 00-d guideline, a time-extrapo- lation factor of 100/90 also was applied. The calculation assumes a 70-kg person drinking 2 L of water per day. Thus, the 1 00-d AC calculated from the American Biogenics Corporation (1988) study is (5mg/kg/dx 70 kg) t10 x (100/90) X 2L/4X 3 x 33= 1.8mg/L.

Nickel TABLE 6-9 Summary of ACs from Whanger (1973) Calculated Using NOAELs and BMDs 233 AC (mg/L) Parameter NOAEL BMD ALP 12 21 PCV 20 4 Hemoglobin 20 6 Abbreviations: AC, acceptable concentration; ALP, plasma alkaline phosphatase; PCV, packed cell volume. 100-d AC Based on the Dieter et al. (19XX) Study Female B6C3F~ mice exposed to nickel as NiSO4 at 0, 44, 108, and 150 mg/kg/d in drinking water for 180 ~ showed a significant decline in water consumption (32-57%) in the 1 08-mg/kg/d and 1 50-mg/kg/d dose groups. Significant decreases in spleen andbone marrow cellularity, decreasedbone marrow proliferative response, dose-related decreases in the spleen lymphoproliferative response to a B-cell mitogen, and treatment-related increases in nephrosis in the 108-mg/kg/d and 150-mg/kg/d dose groups were the other significant effects. A dose of 44 mg/kg/d was considered a LOAEL from this study for effects on bone marrow cellularity and mild renal tubular damage. A summary of calculated ACs is presented in Table 6-10. For the AC calculations, a factor of 10 was used for extrapolation from a LOAEL to a NOAEL; a factor of 10 was applied for species extrapo- lation; a spaceflight factor of 3 was included to account for effects on bone marrow; and a safety factor of 3 was used to account for potential allergic reactions to nickel. Thymic atrophy accompanied by decrease in lymphocyte-rich thymic cortex was judged moderate to severe. Histopathologic observations were minor and were considered background incidences for the species of this age (Dieter et al. 1988), and hence, ACs were not calculated for some pa- rameters. The BMD analysis and LOAELs and NOAELs forthose parame- ters are available in Table 6-11. 100-d AC Using the Whanger (1973) Study The data from the 6-wk nicker diet study by Whanger (1973), described

234 Spacecraft Water Exposure Guidelines TABLE 6-10 100-d ACs Based on NOAELs and BMDLs Calculated Using Immunotoxicity and Myelotoxicity Data from Dieter et al. (1988) ACs (mg/L) LOAEL/ BMDLo~ NOAEL LOAEL NOAEL Parameter (mg/kg) (mg/kg) (mg/kg) BMDLo~ Method Spleen cellulant~ 63.8 108 150 24.8 42 Lymphoproliferative 7.9 NA 44 3.0 1.7 response to LPSa Bone marrow 9.8 cellularity Granulocyte 12 macrophage CFUs b Stem cell proliferative response CFUsb aImmune function responses were evaluated by spleen cellularity and lympho- proliferative response to T-cell and B-cell mitogens; in this case only B-cell mitogen LPS data is included. bMyelotoxic responses are represented by bone marrow cellularity and bone marrow proliferative cell response (granulocyte macrophage and stem cell proliferative response CFUs). Abbreviations: AC, acceptable concentration; BMDLo~, lower 95°/O confidence limit on the benchmark dose corresponding to a 1% risk; CFU, colony forming unit; LPS, lipopolysaccharide; NA, not available. 44 108 1 1.4 1.7 NA 44 4 1.7 44 108 3.0 17 earlier in the document in the 1 0-d AC section, was also used for deriving a 1 00-d AC by using a time-extrapolation factor to apply results from 42 to 100 d. BMD analysis data and NOAELs and LOAELs are available TABLE 6-11 Other Parameters from Dieter et al. (1988) (mg/kg) Parameter BMDlo BMDLlo BMDo1 Ratio of BMDlo to BMDLo1 BMDo1 LOAEL NOAEL Thymic atrophy 87 34 27 11 3.22 44 NA Thymus relative 21.4 13.3 5.97 3.8 3.58 44 NA organ weight Nephrosis 42 29 13 8.9 3.23 108 44 Abbreviation: NA, not available.

Nickel TABLE 6-12 Summary of 100-d ACs Calculated from NOAEL and BRIDLE Data from the Whanger (1973) Study 235 ACs (mg/L) Parameter NOAELa BMDL PCV 8.0 1.8 Hemoglobin 8.0 2.5 ALP 5.0 8.0 aBecause the BMDLo~ values are much lower than the experimentally observed NOAELs, ACs calculated based on the NOAEL are the values of choice. Abbreviations: AC, acceptable concentration; ALP, plasma alkaline phosphatase; BMDLo~, lower 95°/O confidence limit on the benchmark dose cor- responding to a 1% risk; PCV, packed cell volume. in Table 6-~. The results ofthe 100-d AC calculations are reported in Table 6-12 (above). Factors of 10, 3, and 100/42 were included for species ex- trapolation, sensitivity to nickel, and time extrapolation, respectively. A spaceflight factor of 3 was applied in the calculations for hematologic ef- fects (i.e., PCV and hemoglobin only). The calculations assumed a 70-kg person ingesting 2 L of water per day. 100-d AC Using Obone et al. (1999) Data Adult male Sprague-Dawley rats were given nickel as NiSO4 (hexa- hydrate) at 0, 44.7, 111.75, or 223.5 mg/L (0, 5, 12.5, or 25 mg/kg/~) in their drinking water for 13 wk. Several biochemical parameters were mea- sured 24 h after the final dose. Total plasma proteins, plasma albumin and globulins, and plasma glutamic pyruvic transaminase activity were all sig- nificantly decreased at 25 mg/kg/~. The significance ofthese reductions is not clear; therefore, the results for these end points were not used to derive an AC. A dose-dependent and significant decrease in urine volume (75°/O) and an increase in BUN (80%) were observed in the highest-dose group. There were no differences in BUN in the other dose groups, and there was a steep increase only at the highest dose, which was only 2 times the next lower dose. It should be pointed out that urine N-acetyI-beta-~-glucosam- inidase, gamma-glutamy~transpeptidase, and urinary protein levels were not affected by nickel ingestion. Lymphocyte subpopulations (T- and B-celIs) were suppressed at the 25-mg/kg/d dose. Although the authors concluded that the immune system was a sensitive target, followed by kidneys, the

236 Spacecraft Water Exposure Guidelines TABLE 6-13 100-d ACs For Two Parameters from the Obone et al. (1999) Study BMDLo~ NOAEL LOAEL ACs (mg/L) Parameter (mg/kg) (mg/kg) (mg/kg) NOAEL BMDL BUN 10.5 12.5 25 13 11 Urine volumea 1.12 5 12.5 aThe urine volumes in control rats were very high for a 24-h urine collection. The urine may have been mixed with water Tom the drinking-water bottle. Be- cause that will affect the BMD curve fit, and due to lack of confidence in the values, the ACs for this end point are not posted in Table 6-15. Abbreviations: AC, acceptable concentration; BMDLo~, lower 95°/O confidence limit on the benchmark dose corresponding to a 1% risk.; BUN, blood urea nitrogen. 6.5 1.45 dose-response effects on thymocyte subpopulations and spleen lymphocyte subpopulations were not clear. There was a significant decrease in the urine volume compared with controls (36.7 ~ 0.76 me/d for controls vs 9.79 0.7 me/d at the highest dose). The urine volume in controls was unusually high. The urine samples might have been diluted with water from the drinking-water bottle. Even though the authors measured water consump- tion weekly, no data was presented or discussed for any change. Only data on BUN and urine volume was used to derive an AC. One-hundred-day ACs (see Table 6-13, above) were calculated using factors of 10 for species extrapolation and 3 for nickel sensitivity. A time extrapolation factor for 90 d to 100 d also was applied. The calculations assumed a 70-kg person ingesting 2 L of water per day. 100-d AC for Nephrotoxicity Using Vyskocil et al. (1994) Data Only one dose of nickel (as nickel sulfate) at 6.9 mg/kg/d for males and at 7.6 mg/kg/d for females in drinking water was tested. The measurements were made at 3 mo and at 6 mo, and the 6-mo data show significant changes in urinary albumin excretion in and increased kidney weight in the females (females being more sensitive), so the dose in females can be considered a LOAEL for a 6-mo exposure and a NOAEL for 3 mot Because there were two durations but only one dose, a BMD calculation was not possible. Using the NOAEL of 7.6 mg/kg/d, and applying factors of 10, 3, and 1.1 1

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

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 ~ .~ ~ ~ . - =¢ ~

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.

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-

Nickel 243 take, and mutagenicity of particulate and soluble nickel compounds. Environ. Health Perspect. 102(Suppl. 3~:69-79. Gawkrodger, D.J., S.W. Cook, G.S. Fell et al.1986. Nickel dermatitis: The reaction to oralnickel challenge. Br. J. Dermatol. 115:33-38. Glennon, J.D., B. Sarkar.1982. The non-specificity of dog serum albumin and the N-terminal model peptide glycylglycyl-L-tyrosine N-methylamide for nickel is due to the lack of histidine in the third position. Biochem. J. 203 :25-31. Haber, L.T., B.C. Allen, and C.A. Kimmel. 1998. Non-cancer risk assessment for nickel compounds: Issues associated with dose-response modeling of inhala- tion and oral exposures. Toxicol. Sci. 43~2~:213-29. Haber, L.T., G.L. Diamond, Q. Zhao, L. Endreich, and M.L. Dourson.2000. Haz- ard identification and dose response of ingested nickel-soluble salts. Regul. Toxicol. Pharmacol. 31:231-241. Haro, R.T., A. Furst, H.L. Falk.1968. Studies on the acute toxicity of nickelocene. Proc. West. Pharmacol. Soc. 11 :39-42. Hindsen, M., O.B. Christensen, H. Moller. 1994. Nickel levels in serum and urine in five different groups of eczema patients following oral ingestion of nickel. Acta Derm. Venereol. 74: 176- 178. Hendel, R.C., and F.W. Sunderman Jr.1972. Species variations in the proportions of ultrafiltrable end protein-bound serum nickel. Res. Commun. Chem. Pathol. Pharmacol. 4:141-146. Ho, W., A. Furst. 1973. Nickel excretion of rats following a single treatment. Proc. West. Pharmacol. Soc. 16:245-248. Hopfer, S.M., and F.W. Sunderman Jr.1988. Hypothermia and deranged circadian rhythm of core body temperature in nickel chloride-treated rats. Res. Commun. Chem. Pathol. Pharmacol. 62:495-505. Horak, E., and F.W. Sunderman Jr.1973. Fecal nickel excretion by healthy adults. Clin. Chem. 19:429-430. IARC (International Agency for Research on Cancer).1990. Pp.318-411 in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 49. Lyons, France: IARC. IOM (Institute of Medicine). 2001. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: Na- tional Academy Press. IRIS (Integrated Risk Information System).1996. Nickel, soluble salts. Integrated Risk Information System, U.S. Environmental Protection Agency, Washington, DC [Online]. Available: http://www.epa.gov/iris/subst/0271.htm. Ishimatsu, S., T. Kawamoto, K. Matsuno,and Y. Kodama. 1995. Distribution of various nickel compounds in rat organs after oral administration. Biol. Trace Elem. Res. 49~1~:43-52. Jackson, A.L., R. Chen, and L.A. Loeb.1998. Induction of microsatellite instabil- ityby oxidative DNA damage. Proc. Natl. Acad. Sci. USA 95: 12468-12473. Jasim, S., and H. Tjalve.1986. Effect of sodium pyridimethione on the uptake and

244 Spacecraft Water Exposure Guidelines distribution of nickel, cadmium and zinc in pregnant and non-pregnant mice. Toxicology 38: 327-350 Jordan Jr., W.P.,and S.E. King. 1979. Nickel feeding in nickel-sensitive patients with hand eczema. J. Am. Acad. Dermatol. 1 :506-508. Kakela, R., A. Kakela, and H. Hyvarinen. 1999. Effects of nickel chloride on reproduction of the rat and possible antagonistic role of selenium. Comp Biochem Physiol. Pharmacol. Toxicol. Endocrinol. 123:27-37. Kodell, R.L., and R.W. West. 1993. Upper confidence limits on excess risk for quantitative responses. Risk Anal. 13~2~: 177-82. Lee, Y.W., C. Pons, D.M. Tummolo, C.B. Klein, T.G. Rossman, andN.T. Christie. 1993. Mutagenicity of soluble and insoluble nickel compounds at the apt locus in G12 Chinese hamster cells. Environ. Mol. Mutagen. 21 :365-371. Lynn, S., F.H. Yew, K.S. Chen, and K.Y. Jan. 1997. Reactive oxygen species are involved in nickel inhibition of DNA repair. Environ. Mol. Mutagen. 29: 208-216. La Bella, F.S., R. Dullar, P. Lemon et al. 1973. Prolactin secretion is specifically inhibited by nicker. Nature245:330-332. Mastromatteo, E. 1986. Yant memorial lecture. Nickel. Am. Ind. Hyg. Assoc. J. 47:589-601. Menne, T.1994. Quantitative aspects of nickel dermatitis: Sensitization and elicit- ing threshold concentrations. Sci. Total Environ. 148:275-281. Mantovani, A. 1993. Reproductive risks from contaminants in drinking water. Ann. Ist. Super. Sanita 29~2~:317-26. Muhle, H., B. Bellmann, S. Takenaka, R. Fuhst, U. Mohr, and F. Pott. 1992. Chronic effects of intratracheally instilled nickel-containing particles in ham- sters. In Nickel and Human Health, Current Perspectives. E. Nieboer and J.O. Nriagu, eds. New York, NY: John Wiley and Sons Inc. Nation, J.R., M.F. Hare, D.M. Baker, D.E. Clark, and A.E. Bourgeois. 1985. Di- etary administration of nickel: Effects on behavior and metallothionein levels. Physiol. Behav. 34:349-53. Nielsen, F.H., T.R. Shuler, T.J. Zimmerman, M.E. Collings, andE.O. Uthus. 1979. Interaction between nickel and iron in the rat. Biol. Trace Elem. Res. 1 :325- 335. Nielsen, F.H., T.R. Shuler, T.G. McLeod et al. l 984. Nickel influences iron metab- olism through physiologic, pharmacologic and toxicologic mechanisms in the rat. J. Nutr. 114: 1280-1288. Nielsen, G.D., L.V. Jepson, and P.J. Jorgensen. 1990. Nickel-sensitive patients with vesicular hand eczema: Oral challenge with a diet high in nickel. Br. J. Dermatol. 122:299-308. Nielsen, G.D., U. Sodserberg, P.J. Jorgensen, D.M. Templeton, S.N. Rasmussen, K.E. Andersen, and P. Granjean. 1999. Absorption and retention of nickel from drinking water in relation to food intake and nickel sensitivity. Toxicol. Appl. Pharmacol. 154:67-75. Nicogossian, A.E., C.F. Sawin, C.L. Huntoon.1994. Overall physiologic response

Nickel 245 to space flight. In Space Physiology and Medicine, 3rd Ed., A.E. Nicogossian, C.L. Huntoon, and S.L.Pool, eds. Philadelphia, PA: Lea and Febiger. Nomoto, S., M.I. Decsy, J.R. Murphy, and F.W. Sunderman Jr. 1973. Isolation of 63Ni-labeled nickeloplasmin from rabbit serum. Biochem. Med. 8: 171 -81. NRC (National Research Council).1977. Drinking Water and Health. Washington DC: National Academy Press. Pp 285-289 NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NTP (National Toxicology Program).1996. NTP technical report on the toxicology and carcinogeneis studies of nickel sulfate (CAS No. 10101-97-0) in F344/N rats and B6C3F1 mice (inhalation studies). NTP-TRS number 454. National Toxicology Program, Research Triangle Park, NC. Obone, E., S.K. Chakrabarti, C. Bai, M.A. Malick, L. Lamontagne, and K. S. Subramanian. 1999. Toxicity and bioaccumulation of nickel sulfate in Sprague-Dawley rats following 13 weeks of subchronic exposure. J. Toxicol. Environ. Health 57(Part A):379-401. Onkelinx, C., J. Becker, F.W. Sunderman Jr.1973. Compartmental analysis of the metabolism of 63Ni(II) in rats and rabbits. Res. Commun. Chem. Pathol. Pharmacol. 6:663-76. Oosting, J.S., A.G. Lemmens, G.J. Van den Berg, and A.C. Beynen. 1991. Iron, copper, and zinc status in rats fed supplemental nickel. Biol. Trace Elem. Res. 31 :63-70. Pennington, J.A., and J.W. Jones. 1987. Molybdenum, nickel, cobalt, vanadium, and strontium in total diets. J. Am. Diet. Assoc. 8 7( 1 2~: 1 644- 1 650. Phatak, S.S., and V.N. Patwardhan. 1950. Toxicity of nickel. J. Sci. Ind. Res. 9B(3~:70-76. Poirier, L.A., J.C. Theiss, L.J. Arnold, and M.B. Shimkin. 1984. Inhibition by magnesium and calcium acetates of lead subacetate- and nickel acetate-induced lung tumors in strain A mice. Cancer Res. 44~4~:1520-1522. Pool-Zobel, B.L., N. Lotzmann, M. Knoll, F. Kuchenmeister, R. Lambertz, U. Leucht, H-G. Schroeder, and P. Schmezer. 1994. Detection of genotoxic ef- fects in human gastric and nasal mucosa cells isolated from biopsy samples. Environ. Mol. Mutagen. 24:23-45. Pott, F., R.M. Rippe, M. Roller, M. Csicsaky, M. Rosenbruch, and F. Huth. 1992. Carcinogenicity studies on nickel compounds and nickel alloys after intraperitoneal injection in rats. In Nickel and Human Health, Current Perspec- tives. E. Nieboer and A. Altio, eds. New York, NY: John Wiley and Sons. Reid, T.M., D.I. Feig and L.A. Loeb.1994. Mutagenesis by metal-induced oxygen radicals. Environ. Health Perspect. 102(Suppl. 3~:57-61. Robinson, S.H., and M. Costa. 1982. The induction of DNA strand breakage by nickel compounds in cultured Chinese hamster ovary cells. Cancer Lett. 15:35-40. RTI (Research Triangle Institute). 1986. Two-generation reproduction and fertility study of nickel chloride administered to CD rats in the drinking water. Interim report. Ninety-day toxicity study of nickel chloride administered to CD rats in

246 Spacecraft Water Exposure Guidelines the drinking water. Report to Office of Solid Waste, U.S. Environmental Pro- tection Agency, Washington, DC, by Research Triangle Institute, Research Triangle Park, NC. RTI (Research Triangle Institute).1988a. Two-generation reproduction and fertility study of nickel chloride administered to CD rats in the drinking water: Fertility and reproductive performance of the Fo generation. Final study report (II of III). Report to Office of Solid Waste, U.S. Environmental Protection Agency, Washington, DC, by Research Triangle Institute, Research Triangle Park, NC. RTI (Research Triangle Institute).1988b. Two-generation reproduction and fertility study of nickel chloride administered to CD rats in the drinking water: Fertility and reproductive performance of the Fit generation. Final study report (III of III). Report to Office of Solid Waste, U.S. Environmental Protection Agency, by Research Triangle Institute, Research Triangle Park, NC. Sarkar, B.1984. Nickel metabolism. Pp.367-384 in IARC Publication # 53. Lyon, France: International Agency for Research on Cancer (IARC). Santucci, B., F. Manna, A. Cristaudo, C. Cannistraci, andM. Picardo.1988. Nickel sensitivity: Effects of prolonged oral intake ofthe element. Contact Dermatitis 19:202-205. Santucci, B., F. Manna, C. Cannistraci, A. Cristaudo, R. Capparella, A. Bolasco, and M. Picardo. 1994. Serum and urine concentrations in nickel-sensitive patients after prolonged oraladministration. Contact Dermatitis 30~2~:97-101. Schafer, S.G., and W. Forth.1983. The influence oftin, nickel, and cadmium on the intestinal absorption of iron. Ecotoxicol. Environ. Saf. 7:87-95. Schroeder, H.A., J.J. Balassa, W.H. Vintin Jr. 1964. Chromium, lead, cadmium, nickel, and titanium in mice. Effect on mortality, tumors, and tissue levels. J. Nutr. 83:239-250. Schroeder, H.A., M. Mitchner, and A.P. Nasaon.1974. Life-term effects of nickel in rats: Survival, tumors, interactions with trace elements and tissue levels. J. Nutr. 104:239-243. Seidenberg, J.M., D.G. Anderson, and Becker. 1986. Validation of an in vivo de- velopmental toxicity screen in the mouse. Teratog. Carcinog. Mutagen. 6: 361-74. Shirakawa, T., Y. Kusaka, N. Fujimura, M. Kato, S. Heki, and K. Morimoto.1990. Hard metal asthma: Cross immunological and respiratory reactivity between cobalt and nickel? Thorax 45~4~:267-71. Smith, M.K., J.A. George, J.A. Stober, and H.A. Feng. 1993. Perinatal toxicity associated with nickel chloride exposure. Environ. Res. 61 :200-211. Sobti, R.C., end R.K. Gill.1989. Incidence of micronuclei and abnormalities in the head of spermatozoa caused by the salts of a heavy metal nickel. Cytologia (Tokyo) 54:249-254. Solomons, N.W., F. Viteri, T.R. Shuler, and F.H. Nielsen.1982. Bioavailability of nickel in man: Effects of foods and chemically defined dietary constituents on the absorption of inorganic nickel. J. Nutr. 112~1~:39-50. Storeng, R., and J. Jonsen. 1981. Nickel toxicity in early embryognesis in mice. Toxicology 20:45-51.

Nickel 247 Sumino, K., K. Hayakawa, T. Shibata et al. 1975. Heavy metals in normal Japa- nese tissues. Amounts of 15 heavy metals in 30 subjects. Arch. Environ. Health 30:487-494. Sunderman Jr., F.W. 1984. Nickel in the Human Environment. IARC Scientific Publications #53. Lyon, France: International Agency for Research on Cancer (IARC). Sunderman Jr., F.W. 1986. Sources of exposure and biological effects of nickel. Vol. 8. Some metals: As, Be, Cd,Cr, Ni, Pb, Se,Zn. In IARC Scientific Publications #71. Lyon, France: International Agency for Research on Cancer (IARC). Sunderman Jr, F.W., B. Dingle, S.M. Hopfer, and T. Smith. 1988. Acute nickel toxicity in electroplating workers who accidentally ingested a solution of nickel sulfate and nickel chloride. Am. J. Ind. Med. 14:257-266. Sunderman Jr., F.W., S.M. Hopfer, K.R. Sweeney, A.H. Marcus, B.M. Most, and J. Creason. 1989. Nickel absorption and kinetics in human volunteers. Proc. Soc. Exp. Biol. Med. 191:5-11. Synder, R.D. 1994. Effects of metal treatment on DNA repair in polyamine-de- pleted HeLa cells with special reference to nickel. Environ. Health Perspect. 162(Suppl. 3~:51-55. Tallkvist, J., A.M. Wing, and H. Tjalve. 1994. Enhanced intestinal nickel absorp- tion in iron-deficient rats. Pharmacol. Toxicol. 75:244-249. Tallkvist, J., and H. Tjalve.1997. Effect of dietary iron-deficiency on the disposi- tion of nickel in rats. Toxicol Lett. 92: 131-138. Tallkvist, J., and H. Tjalve.1998. Transport of nickel across monolayers of human intestinal Caco-2 cells. Toxicol. Appl. Pharmacol. 151:117-122. Veien, N.K., T. Hattel, O. Justesen, and A. Norholm. 1987. Oral challenge with nickel and cobalt in patients with positive patch tests to nickel and/or cobalt. Acta Derm. Venereol. 67:321-325. Verma, A., S. Ohshima, J. Ramnath, K.N. Thakore, and J.R. Landolph. 1999. Pre- dictions and correlations of carcinogenic potentials of nickel compounds by short-term in vitro assays using C3H IOT1/2 mouse embryo cells. Environ- mental Mutagen Society 30th annual meeting. Washington, DC. March 27-April 1, 1999. Environ. Mol. Mutagen. 33(Suppl. 30~:66. Vyskocil, A., C. Viau, and M. Cizkova. 1994. Chronic nephrotoxicity of soluble nickel in rats. Hum. Exp. Toxicol. 13 :257-261. Waltschewa, W., M. Slatewa, and I. Michailow. 1972. Testicular changes due to long-term administration of nickel sulfate in rats [in German]. Exp. Pathol. (Jena) 6:116-120. Weischer, C.H., W. Kodel, and D. Hochrainer.1980. Effects of NiC12 end NiO in Wistar rats after oral uptake and inhalation exposure respectively. Zentrabl. Bakteriol. Mikrobiol. Hyg. [B] 171 :336-351. Weber, C.W., and B.L. Reid. 1969. Nickel toxicity in young growing mice. J. Anim. Sci. 28:620-623. Whanger, P.D. 1973. Effects of dietary nickel on enzyme activities and mineral content in rats. Toxicol. Appl. Pharmacol. 25:323-331.

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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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