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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 11 Zinc and Zinc Salts (Inorganic) Raghupathy Ramanathan, Ph.D. NASA-Johnson Space Center Toxicology Group Houston,Texas OCCURRENCE AND USE Zinc (Zn) is a naturally occurring element found in the earth’s crust in most rock-forming minerals. It is also present in significant concentrations in soil near highways (because of emissions and tire wear) and industrial locations such as power plants and factories. In natural waters, zinc exists in several chemical forms. It usually occurs as zinc sulfide, zinc carbonate, zinc chromate, or zinc oxide (ZnO) (Merck Index 1989). Zinc compounds such as zinc chloride (ZnCl2), zinc sulfate (ZnSO4), ZnO, and zinc sulfide are found at hazardous waste sites, and the possibility that they could get into drinking water has been a concern. The acetates, chlorides, and sulfates of zinc are extensively used in the dyeing industry and in common consumer products such as ZnO skin ointments and shampoos. For chemical and physical properties, see Table 11-1. TABLE 11-1 Chemical and Physical Properties of Zinc and a Few Zinc Compoundsa Chemical Zinc Zinc Chloride Zinc Sulfate Heptahydrate Zinc Oxide Zinc Acetate Formula Zn ZnCl2 ZnSO47H2O ZnO Zn(C2H3O2)2 Molecular weight 66.38 136.29 287.54 81.4 183.46 % of zinc 100% 47.97% 40.5% 80.34% 35.64% Water solubility Insoluble 4.32 g/mL at 25 °C 1.66 g/mL Insoluble 0.43 g/mL aData from Merck Index 1989.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 The average zinc concentration in tap water across the United States is 0.245 milligrams per liter (mg/L) (NRC 1980). The highest mean value reported for tap water from galvanized pipes is about 2 mg/L (Sharrett et al. 1982). Occupational exposure to zinc by means of inhalation occurs extensively in zinc mining, smelting, welding, and the manufacturing of galvanized metals, paints, tires, and certain personal consumer products. ZnCl2 is primarily used in making batteries, zinc silicate in phosphors of cathode ray tubes, and ZnO in the rubber vulcanizing process. Exposure to zinc through drinking water can take place in areas near where these activities occur. Zinc is an essential food element. Dairy products, grains, meats, fish, and poultry are the richest sources of zinc (Tanner and Friedman 1977). The Recommended Dietary Allowance (RDA) of zinc for nonpregnant women is 12 mg per day (d), and for men it is 15 mg/d. A typical mixed diet provides at least 65-80% of the daily RDA (Bowerman and Harrill 1983). According to the Food and Drug Administration (FDA) Total Diet Study (1991-1997), the mean intake of zinc from food by males between 31 and 50 years (y) of age is 13.38 ± 0.16 mg/d (n = 1,805). Daily intake by women of that age range is 8.51 ± 0.11 mg/d (n = 1,733) (see Appendix E in IOM 2001). Zinc occurs in all living cells as a constituent of metalloenzymes involved in major metabolic pathways (NRC 1989). Zinc controls several enzymes of intermediary metabolism, DNA and RNA synthesis, gene expression, and immunocompetence. Zinc can interact with almost all hormones and plays a significant role in homeostasis of hormones such as thyroid and steroid hormones, insulin, and pituitary hormones like prolactin (Brandao-Neto et al. 1995). Summary reports on humidity condensates collected from the Mir space station and water recycled from Mir during the years 1995-1998 indicate that zinc was present at concentrations ranging from 1.26 mg/L to 5.3 mg/L in the humidity condensates and at concentrations ranging from 10.4 to 475.0 micrograms (µg) per liter in the processed (recycled) water (Pierre et al. 1999). Although the average concentrations did not exceed the U.S. Environmental Protection Agency’s (EPA’s) secondary maximum contaminant level (SMCL) of 5 mg/L, zinc was found very frequently in the recycled water. Concerns exist about potential system breakthroughs. This document will be limited to addressing the adverse effects of extraneous zinc that may leach into the drinking water through the water processing system (from distribution lines), the humidity condensate heat exchangers (through corrosion), or as a result of the failure of the ion-exchange resins to remove metal ions completely.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 PHARMACOKINETICS AND METABOLISM Absorption The existing studies strongly indicate that absorption of ingested zinc by humans varies widely depending on the type of diet and the presence of dietary components and minerals such as phytates, phosphates, sugars, amino acids, and iron, as well as other metals such as copper and cadmium. Zinc in animal products has a higher coefficient of absorption than zinc from vegetables. Phytates (IP6 or inositol hexaphosphate) and fiber present in vegetables adversely affect the availability of zinc by reducing its absorption. For example, Sandstrom et al. (1987) determined the absorption of zinc in humans from 60 g meals based on rye, barley, oatmeal, triticale (a cross between wheat and rye), and whole wheat. It was lowest (8.4 ± 1.0%) from oatmeal porridge with a phytic acid content of 600 millimicromoles (mµmoles), and relatively highest (26.8 ± 7.4%) from rye bread meal with a phytic acid content of 100 mµmoles (Sandstrom et al. 1987); thus, absorption of zinc is negatively correlated to phytic acid content. Various numbers from 20% to 40% have been used for the absorption of zinc (NRC 1989). An average zinc intake of 8.6-17.2 mg/d from various diets has been reported (Tanner and Friedman 1977; Holden et al. 1979); this is below the RDA in most cases. After short-term exposures to zinc supplements in the diet, absorption ranged widely from 8% to 81% (Aamodt et al. 1983; Reinhold et al. 1991; Sandstrom 1992). Three days after individuals ingested zinc at 0.05 mg per kilogram (kg) from bread rolls containing different concentrations of proteins, fractional zinc absorption ranged from 8% from low-protein rolls to 26% from high-protein rolls (Hunt et al. 1991), indicating that dietary protein promotes zinc absorption. The fractional absorption of zinc seems to depend on zinc dose. For example, in a group of healthy young men on a constant daily dietary intake of 15 mg/d, when various test doses of zinc were administered, fractional absorption was 81% from a 4.52 mg dose, 67% from a 6.47 mg dose, and 61% from a 24.52 mg dose (Istfan et al. 1983; also see King et al. 2000). A similar phenomenon of changes in fractional zinc absorption in response to changes in the dietary zinc concentrations have been described by several investigators (Wada et al. 1985; Taylor et al. 1991; Lee et al. 1993). Absorption of zinc also seems to depend on the zinc status of the individual. Zinc was absorbed at a higher level by zinc-deficient individuals than by zinc-sufficient individuals (Spencer et al. 1985; Johnson et al. 1988). In a 63-d study conducted with young men, Turnlund et al. (1984) reported that
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 zinc absorption from the basal diet was 33.8% ± 2.9%, but it dropped to 17.5% ± 2.5% when 2.3 g of phytate as sodium phytate was added to the basal diet. Absorption of zinc also seems to depend on the form of the salt. For example, Galvez-Morros et al. (1992) reported that male rats absorbed 40% of labeled zinc from a diet containing zinc as ZnCl2 at 0.81 mg/kg or 8.4% from a zinc-carbonate-containing diet. Zinc uptake from inorganic salts was in the order of sulfate > acetate > chloride > citrate > phosphate (Seal and Heaton 1983). Nevertheless, the total excretion or retention was independent of the salt form. Studies using in vivo ligated intestine and 65zinc indicate that absorption was significantly greater from the duodenum than from the distal portion of the small intestine. In an experiment using an everted sac of rat duodenum and ileum, zinc absorption was shown to be pH dependent. Reducing the pH of the medium from 7.3 to 6.4 decreased absorption from the duodenal sacs. When a dose of radioactive ZnCl2 was intubated to rats maintained on a diet containing zinc at 40 mg, the maximum radioactivity attained in the whole blood was about 0.09% at 30 minutes (min), 0.045% at 1 hour (h), and 0.01% at 24 h. Liver and pancreas preferentially took up a higher percentage of radioactivity, with a peak uptake at 8 h (Methfessel and Spencer 1973). A variety of mechanisms have been proposed for the absorption of zinc. It is generally believed that zinc absorption is homeostatically controlled by the zinc content in the intestine and by circulating zinc (Davies 1980; Cousins 1985). Data also indicate that zinc uptake may be partly controlled by a carrier-mediated diffusion mechanism. Cysteine-rich intestinal protein (CRIP), a diffusible intracellular zinc carrier, binds zinc in the mucosa during absorption, a process that seems to be saturable (Hempe and Cousins 1992). Zinc transport in the intestinal lumen is also influenced by metallothionein, which can inhibit zinc absorption by competing with CRIP for zinc (Hempe and Cousins 1991, 1992). It is beyond the scope of this document to discuss the vast amount of literature on various approaches to understanding the absorption mechanism. The interaction of zinc with other metals and the influence of ligands on zinc absorption will be described later. Distribution Zinc is present in almost all tissues and body fluids in humans. In blood, zinc is present in erythrocytes (92.4% as a cofactor for carbonic
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 anhydrase isoenzymes and superoxide dismutase [SOD]), leukocytes, and platelets. Zinc is found in diffusible and nondiffusible forms in the blood (NRC 1977). About 98% of serum zinc is nondiffusible and is bound to proteins (85% to albumin, most of the remainder complexed with β2-macroglobulin [β2-MG]). Diffusible zinc in blood is associated with albumin and amino acids and not with β2-MG (EPA 1987). Circulating zinc that is tightly bound to α2-macroglobulin in the plasma is nondiffusible and not freely exchangeable with other zinc ligands in serum (Cousins 1985). The range of normal plasma zinc concentrations is 85-110 µg per deciliter (dL). Plasma proteins provide a metabolically active transport compartment for zinc in which about 70% of circulating zinc is loosely bound to albumin in the diffusible form and is freely exchangeable (Cousins 1985). Zinc is also bound to amino acids (primarily histidine and cysteine) as a diffusible form (Henkin 1974). The zinc-amino-acid complex is transported passively across tissue membranes to bind to proteins. An important binding protein in the kidney and liver is metallothionein, although other tissue-binding proteins may be present. The body of a 70 kg normal human male contains 1.4-2.3 g of zinc (see Table 11-2). High concentrations of zinc are also found in the prostate (100 µg/g wet tissue), semen (100 to 350 picograms [pg] per L) (Hidiroglou and Knipfel 1984), and retina (Bentley and Grubb 1991; Ugarte and Osborne 2001). With age, zinc concentrations increase in the liver, pancreas, and prostate and decrease in the uterus and aorta (Schroeder et al. 1967). Only 3% of zinc was transferred across the perfused placenta and seemed to involve potassium/zinc transport (Aslam and McArdle 1992). Zinc does not accumulate with continued exposure, because the body burden is controlled by homeostatic mechanisms. Studies in animals and humans have shown that the whole-body content of zinc remains constant over a 10-fold range of intakes (Johnson et al. 1993). The homeostatic mechanism acts mainly to adjust the gastrointestinal (GI) absorption and endogenous excretion (Wastney et al. 1986; Walsh et al. 1994; King et al. 2000). Increasing dietary concentrations of zinc were associated with decreasing concentrations of iron in the livers of rats (Yadrick et al. 1989). In the liver, as well as elsewhere, zinc is bound to metallothionein. The greatest concentration of zinc in the body is in the prostate, probably because this organ is rich in the zinc-containing enzyme acid phosphatase (see Klaassen 1996). About 60% of the zinc in the body is located in the skeletal muscle and 30% in the bones (Wastney et al. 1986).
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 11-2 Typical Tissue Concentrations of Zinc in Normal Human Adults Tissue Zinc (µg/g tissue) Tissue Zinc (µg/g tissue) Prostate 100 Pancreas 29 Muscle 54 Spleen 21 Kidney 55 Testes 17 Liver 55 Lung 15 Heart 33 Brain 14 Adrenals 12 Note: The total body burden (70 kg body weight assumed) of zinc is estimated to be 1.4-2.3 g. The total amount in the skin is estimated to be 0.46 g. In erythrocytes, zinc exists as a cofactor for carbonic anhydrase and SOD. Source: EPA 1990. Excretion Fecal excretion is the predominant route of elimination of zinc after an oral bolus (Davies and Nightingale 1975; Wastney et al. 1986; Reinhold et al. 1991). Only 1-2% is excreted in the urine (Wastney et al. 1986). In normal adults, daily excretion is 300-600 µ g/d. A linear excretion of zinc in the feces as a function of dose has been noted (Spencer et al. 1985). Excretion of zinc in the urine also reflects zinc intake (Wastney et al. 1986). Rats receiving zinc as ZnCl2, ZnSO4, zinc phosphate, or zinc citrate at 2.65 mg/kg/d over a 4-d period excreted 87-98% of the intake. Fecal excretion, total excretion, and retention of zinc did not differ for these various zinc forms (Seal and Heaton 1983). A small amount of zinc has also been shown to be excreted by way of bile as a complex with reduced glutathione, and the transfer from liver to bile occurs by a glutathione-dependent process (Alexander et al. 1981). Low dietary intake of zinc, starvation, and high-protein diets alter the excretion of zinc (Spencer et al. 1976); nevertheless, a homeostatic mechanism maintains the balance by a greater absorption of zinc (Henkin et al. 1975; Hunt et al. 1991). Interaction of Zinc with Other Metals Many biologic interactions between trace elements are known to occur, especially when they are present together in the diet. With zinc being an essential trace element in a wide variety of biologic systems,
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 interactions of other metals with zinc are very critical for physiologic and pathologic conditions. The trace element interaction of greatest practical significance in human nutrition is the negative effect of excess zinc on copper bioavailability (Festa et al. 1985). One of the most studied modifiers of zinc absorption is the co-absorption of copper. High concentrations of dietary zinc have an antagonistic effect on the absorption of copper, and this phenomenon has been demonstrated in humans and animals. Although dietary intakes of copper and zinc do not interfere with each other’s absorption as long their ratio is 1:5 (copper:zinc), higher zinc concentrations in the diet (as with zinc supplements) depress copper absorption, concentrations of tissue copper, and the activity of copper enzymes such as ceruloplasmin and cytochrome oxidase. In zinc-deficient animals, copper concentrations in bones and liver are increased (Roth and Kirchgessner 1977). Excess copper in the diet inhibits zinc absorption from a zinc-sufficient diet, but the effect is relatively minor compared to the effect of excess zinc on copper status (O’Dell 1989). Excess zinc stimulates an increase in the intestinal concentrations of metallothionein, which traps copper because of its high affinity to copper, leading to copper loss when the intestinal cells slough off. Hypocupremia and hypoceruloplasminemia in sickle cell anemia patients who ingest supplementary zinc are well known (Prasad et al. 1978). Similarly, L’Abbe and Fischer (1984a, b) reported that when copper status (as assessed by measuring the concentration of the copper-transport protein serum ceruloplasmin) and activity of copper-zinc SOD were determined in rats fed zinc at 15, 30, 60, 120, or 240 mg/kg in their diet for 6 weeks (wk), the number of animals with low ceruloplasmin increased with increasing doses of zinc. The control diet contained copper at 6 mg/kg and zinc at 30 mg/kg. At 120 and 240 mg/kg of zinc, copper-zinc SOD decreased significantly. The copper-zinc SOD reductions seen in animals fed a high-zinc diet were similar to those in animals fed a low-copper diet. Because the elimination of excess zinc is slow and the intestinal absorption of copper will be affected until excess zinc is eliminated, the slow elimination rate is an important aspect of zinc interactions with other trace elements. Iron and calcium are important examples of other metals that interact with zinc, because these are frequently used as dietary supplements. Iron inhibited zinc absorption when both were given in inorganic form without food (Solomons and Jacob 1981; Valberg et al. 1984). Metallothionein seems to play an integral part in these interactions. Large amounts of ingested iron (such as from iron supplements) affect the absorption of zinc (Solomons et al. 1983) and may lead to zinc deficiency, which is associated with poor growth, loss of appetite, skin lesions, lack
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 of taste and smell, delayed wound healing, delayed sexual maturation, onset of night blindness, impaired memory performance, and impaired immune response. Calcium and zinc have an antagonistic relationship. Experiments in animals indicate that if the intake of calcium is high, the absorption of zinc is decreased, and vice versa (Hanson et al. 1958; Yamaguchi et al. 1983). In vivo, it has been documented that oral administration of zinc to sickle cell anemia patients reduced the number of irreversible sickle cells (Brewer 1979). In this instance, zinc seems to interact with calcium at the red cell membrane by suppressing the calciumregulating protein calmodulin (Baudier et al. 1983), and this suppresses the formation of irreversible sickle cells. Interaction of zinc with cadmium results in an increase in the excretion of cadmium when the two elements are administered together. This has been proposed as a mechanism by which zinc protects against cadmium toxicity (Stowe 1976; NRC 1980). Because zinc and cadmium compete for a common transport mechanism, simultaneous administration of zinc and cadmium has beneficial effects on cadmium toxicity (Coogan et al. 1992). Zinc acetate has been shown to prevent cadmium carcinogenesis in the prostate and testes (Waalkes et al. 1989). Similarly, co-administration of zinc with cobalt resulted in a major reduction of cobalt-induced testis tubule damage and degeneration in mice (Anderson et al. 1993). Exposure to cadmium affects the distribution of zinc, leading to preferential accumulation of zinc in liver and kidney and negatively affecting zinc concentrations in other tissues. Because cadmium and zinc additively increase metallothionein induction, they may adversely affect the absorption of other metals. TOXICITY SUMMARY Zinc plays an important role in growth and many physiologic functions. It is an essential nutrient, and the RDA values (the estimated amount of zinc required to maintain tissue and the growth and metabolism of the individual) range from 12 mg/d for nonlactating and nonpregnant women to 15 mg/d for adult men. Consumption of concentrations of zinc below the RDA has been reported to lead to loss of appetite, loss of taste and sense of smell, and slow healing of skin sores. Retarded growth and development of reproductive organs and retarded development of offspring have been noted in humans. Zinc is present in blood plasma, erythrocytes, leukocytes, and platelets but is chiefly localized within erythrocytes (where 87% of it is in carbonic anhydrase, the major
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 binding site) (Ohno et al. 1985). A vast amount of data pertaining to zinc toxicity is available, and a significant portion of the data is from human case reports and human subject experiments, mainly from zinc-supplementation studies. A significant amount of data pertaining to the oral administration of zinc to rodents is also available. Most studies have addressed changes in hematologic parameters and changes in serum high-density lipoprotein (HDL) cholesterol. A review of the literature clearly indicates that ingestion of a large amount of soluble zinc compound by humans or animals for an intermediate-to-long duration results in a variety of adverse effects in the GI, hematologic, immunologic, and nervous systems. Some of the key effects reported are decreases in serum HDL cholesterol, hematocrit, hemoglobin, and serum ferritin concentrations, as well as an impact on copper balance, anemia, and lesions in the adrenals, pituitary, and pancreas. Severe GI distress and bleeding were found only in acute cases exposed to high doses of zinc. These effects were not seen with small doses in the long-duration experiments. Occasional renal and reproductive toxicity has also been observed. Acute Exposures Callender and Gentzkow (1937) reported that 80% of the two army companies experienced diarrhea and GI distress after drinking limeade prepared in galvanized trash cans. The average dose of zinc ingested was estimated to be about 7 mg/kg. Within 24-48 h after ingesting zinc-contaminated food (2.4-6.8 mg/kg) from galvanized containers, 300-350 persons developed intestinal symptoms such as severe diarrhea with abdominal cramping. About 50% had gross blood in the feces (Brown et al. 1964). In another episode, individuals who had consumed zinc-contaminated alcoholic fruit punch developed a hot taste and dryness in the mouth, nausea, vomiting, and diarrhea between 20 and 90 min post-ingestion. The symptoms resolved in 24 h. In the postacute phase, the individuals reported general discomfort and muscular pain. The estimated dose was 4.6-9.2 mg/kg (Brown et al. 1964). Several studies have reported that zinc ingestion causes GI distress. An individual who had drunk 3 ounces of liquid ZnCl2 (dose not known) immediately suffered throat pain, burning and pain in the mouth, and vomiting. Later, acute symptoms of pancreatitis were noted (Chobanian 1981). A schoolgirl suffered abdominal cramps and diarrhea after she ingested a zinc-sulfate-containing capsule (ZnSO4 at 440 mg/d) prescribed for acne. She suf-
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 fered from epigastric discomfort and fainting and also showed serious signs of intestinal bleeding (Moore 1978). The acute oral LD50 (the dose lethal to 50% of test subjects) value for ZnSO4 in rats was reported by Fabrizio (1974) to be 920 mg/kg; acute oral LD50 values for ZnCl2 in rats, mice, and guinea pigs are 350, 502, and 200 mg/kg, respectively (Calvery 1942; see also EPA 1990). In a study by Domingo et al. (1988), four zinc compounds (acetate, nitrate, chloride, and sulfate) were administered as a single gavage dose to rats and mice. The LD50 values are summarized in Table 11-3. The majority of deaths occurred during the first 2 d (Domingo et al. 1988). In general, mice seem to be more sensitive than rats to the lethal effects of zinc. In rats and mice, zinc acetate was the most lethal compound tested. The adrenal cortex is rich in zinc. In animals, zinc deficiency increased plasma 11-hydroxy steroids, and excess zinc decreased the same steroids (Quarterman and Humphries 1979). To understand the effect of excess zinc on adrenal function in humans, 13 subjects (males and females, 20-27 y old) were orally administered zinc (as the sulfate hepta hydrate) at 0.25, 37.5, and 50 mg after a 12-h fast. Plasma cortisol was measured in serial blood samples collected from these subjects for up to 240 min. Each individual served as his or her own control. An acute inhibition of cortisol secretion was observed (Brandao-Neto et al. 1990). Hypothalamus and hypophysis are rich in zinc, and in earlier studies designed to understand the role of zinc in functions mediated by these areas, it had been shown that in vitro addition of zinc to bovine pituitary extracts inhibited the secretion of newly synthesized prolactin (Login et al. 1983; Judd et al. 1984). For this reason, Brandao-Neto et al. (1995) wanted to evaluate the adverse effects of excess zinc on the regulation of prolactin in humans. They reported an inhibition of basal prolactin secretion in 17 normal adult men and women given oral doses of zinc as the sulfate at 0, 25, 37.5, and 50 mg. Serum prolactin was measured at sev- TABLE 11-3 LD50 for Rats and Mice of Four Zinc Compounds Compound Rat LD50 (mg/kg/d) Mouse LD50 (mg/kg/d) Zinc acetate 237 86 Zinc chloride 528 605 Zinc nitrate 293 204 Zinc sulfate 623 337 Source: Domingo et al. 1988. Reprinted with permission; copyright 1988, American Academy of Veterinary and Comparative Toxicology.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 eral intervals over 2 h. However, in later studies from the same labortory (Castro et al. 1999, 2002), the authors concluded that in humans, supplementation of oral zinc at 25 mg/d for 3 months (mo) did not change the basal secretion of prolactin. A 2-y-old child who ingested ZnCl2 solution (zinc at 1,000 mg/kg) developed lethargy (Potter 1981). A 17-y-old male ingested about 85 tablets, each with 4 g of zinc gluconate (elemental zinc at 570 mg). He experienced severe nausea and vomiting within 30 min of the ingestion but had no further serious effects such as diarrhea, gastric erosion, esophageal burns, shock, neurologic dysfunction, symptoms of anemia, or hepatic inflammation. His serum zinc concentration was 4.97 mg/dL about 5 h after ingestion (Lewis and Kokan 1998). Short-Term Exposures (2-10 d) A 16-y-old boy who ingested 12 g of elemental zinc over a 2-d period (zinc at 86 mg/kg/d) experienced light-headedness, lethargy, staggering gait, and difficulty writing legibly but no apparent GI disturbances (Murphy 1970). Anemia secondary to GI hemorrhage was seen in a case report study of acute exposure to zinc as ZnSO4 at 2.6 mg/kg/d (Moore 1978) given for 1 wk as a medically prescribed treatment for acne. In rats administered oral doses of zinc at 0.1, 1, or 10 mg/100 g of body weight (zinc at 1, 10, or 100 mg/kg) for 3 d, a significant decrease in femoral calcium was seen with the 100 mg/kg dose (Yamaguchi et al. 1983). These effects were seen as early as 1 d. In addition, a significant decrease in acid phosphatase in the femoral epiphysis was seen in the zinc-treated group. The result that zinc causes a decrease in bone calcium may be very important because it indicates that zinc may trigger bone resorption. This observation is relevant to space missions for which bone resorption has been a concern. In rats administered zinc as ZnO in their diet at 487 mg/kg/d for 10 d, minor neuron degeneration and proliferation of oligodendroglia and increased amounts of secretory material in the neurosecretory nuclei of the hypothalamus were observed, indicating possible effects of zinc on the central nervous system (Kozik et al. 1980, 1981). Subchronic Exposures (10-100 d) Hooper et al. (1980) conducted a study in which 12 healthy nonobese adult males aged 23-35 y old received oral pharmacologic doses of zinc as ZnSO4 at 160 mg/d in capsules (zinc at 2.46 mg/kg/d) for 5 wk. A
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Toxicity End Point Exposure (mg/kg/d) Species Principal Study UFs AC (mg/L)a To NOAEL Species Time Extrapolation Factor Spaceflight Factor 1 d 10 d 100 d 1,000 d Effects on immunologic status and copper status NOAEL, 0.43 Human Bonham et al. 2003a,b 10/√19 1 1 1 — — 5 — Hypertrophy of adrenal cortex and pancreatic cells LOAEL, 70 Mouse Aughey et al. 1977 10 10 5.55 1 — — — 3 Reduction in hemoglobin and in serum copper concentrations (hypocupremia) LOAEL, 175 Rabbit, male Bentley and Grubb 1991 10 10 6.5 3 — — — 2 SWEG 11 11 2 2 aThe AC values for water are in addition to the daily contribution of dietary zinc.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 REFERENCES Aamondt, R.L., W.F. Rumble, and R.I. Henkin. 1983. Zinc absorption in humans: Effects of age, sex, and food. Pp. 61-82 in The Nutritional Bioavailability of Zinc, G. Inglett, ed. Washington, DC: The American Chemical Society. Alexander, J., J. Aaseth, and T. Refsvik. 1981. Excretion of zinc in rat bile—A role of glutathione. Acta Pharmacol. Toxicol. 49:190-194. Amacher, D.E., and S.C. Paillet. 1980. Induction of trifluorothymidine-resistant mutants by metal ions in L5178Y/TK+/ cells. Mutat. Res. 78:279-288. Anderson, M.B., K. Lepak, V. Farinas, and W.J. George. 1993. Protective action of zinc against cobalt-induced testicular damage in the mouse. Reprod. Toxicol. 7:49-54. Aslam, N., and H.J. McArdle. 1992. Mechanism of zinc uptake by microvilli isolated from human term placenta. J. Cell Physiol. 151:533-538. ATSDR (Agency for Toxic Substances and Disease Registry). 1994. Toxicology Profile for Zinc (Update). Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services, Atlanta, GA. Aughey, E., L. Grant, B.L. Furman, and W.F. Dryden. 1977. The effects of oral zinc supplementation in the mouse. J. Comp. Pathol. 87:1-14. Banu, B.S, K.D. Devi, M. Mahboob, and K. Jamil. 2001. In vivo genotoxic effect of Zn sulfate in mouse peripheral blood leukocytes using Comet assay. Drug Chem. Toxicol. 24:63-73. Baudier, J., K. Haglid, J. Haiech, and D. Gerard. 1983. Zinc ion binding to human brain calcium binding proteins, calmodulin and S100b protein. Biochem. Biophys. Res. Commun. 114:1138-1146. Bentley, P.J., and B.R.Grubb. 1991. Effects of a zinc-deficient diet on tissue zinc concentrations in rabbits. J. Anim. Sci. 69:4876-4882. Black, M., D.M. Medeiros, E. Brunett, and R. Welke. 1988. Zinc supplements and serum lipids in young adult white males. Am. J. Clin. Nutr. 47:970-975. Bonham, M., J.M. O’Connor, H.D. Alexander, J. Coulter, P.M. Walsh, L.B. McAnena, C.S. Downes, B.M. Hannigan, and J.J. Strain. 2003a. Zinc supplementation has no effect on circulating levels of peripheral blood leucocytes and lymphocyte subsets in healthy adult men. Br. J. Nutr. 89:695-703. Bonham, M., J.M. O’Connor, L.B. McAnena, P.M. Walsh, C.S. Downes, B.M. Hannigan, and J.J. Strain. 2003b. Zinc supplementation has no effect on lipoprotein metabolism, hemostasis, and putative indices of Cu status in healthy men. Biol. Trace Elem. Res. 93:75-86. Bowerman, S.J., and I. Harrill. 1983. Nutrient consumption of individuals taking or not taking nutrient supplements. J. Am. Diet Assoc. 83:298-302, 305. Brandao-Neto, J., B.B. de Mendonca, T. Shuhama, J.S. Marchini, W.P. Pimenta, and M.T. Tornero. 1990. Zinc acutely and temporarily inhibits adrenal cortisol secretion in humans. A preliminary report. Biol. Trace Elem. Res. 24:83-89.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Brandao-Neto, J., G. Madureira, B.B. Mendonca, W. Bloise, and A.V. Castro. 1995. Encdocrine interaction between zinc and prolactin. An interpretive review. Biol. Trace Elem. Res. 49(2-3):139-149. Brewer, G.J. 1979. Detours on the road to successful treatment of sickle cell anemia. Perspect. Biol. Med. 22:250-272. Broun, E.R., A. Greist, G. Tricot, and R. Hoffman. 1990. Excessive zinc ingestion. A reversible cause of sideroblastic anemia and bone marrow depression. JAMA 264:1441-1443. Brown, M.A., J.V. Thom, G.L. Orth, P. Cova, and J. Juarez. 1964. Food poisoning involving zinc contamination. Arch. Environ. Health 34:657-660. Callender, G.R., and C.J. Gentzkow. 1937. Acute poisoning by the zinc and antimony content of limeade prepared in a galvanized iron can. Mil. Surg. 80:67-71. Calvery, O. 1942. Trace elements in foods. Food Res. 7:313-331. Castro, A.V., B.B. Mendonca, W. Bloise, T. Shuhama, and J. Brandao-Neto. 1999. Effect of zinc administration on thyrotropin releasing hormone-stimulated prolactinemia in healthy men. Biometals 12:347-352. Castro, A.V., J. Caramori, P. Barretti, E.E. Baptistelli, A. Brandao, E.M. Barim, C.R. Padovani, F.F. Aragon, and J. Brandao-Neto. 2002. Prolactin and zinc in dialysis patients. Biol. Trace Elem. Res. 88:1-7. Chandra, R.K. 1984. Excessive intake of zinc impairs immune responses. JAMA 252:1443-1446. Chandra, R.K. 1991. 1990 McCollum Award Lecture: Nutrition and immunity: lessons from the past and new insights into the future. Am. J. Clin. Nutr. 53(5):1087-1101. Chobanian, S.J. 1981. Accidental ingestion of liquid Zn chloride: local and systemic effects. Ann. Emerg. Med. 10:227-233. Coogan, T.P., R.M. Bare, and M.P. Waalkes. 1992. Cadmium-induced DNA strand damage in cultured liver cells: reduction in cadmium genotoxicity following zinc pretreatment. Toxicol. Appl. Pharmacol. 113:227-233. Cousins, R.J. 1985. Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol. Rev. 65:238-309. Davies, N.T. 1980. Studies on the absorption of zinc by rat intestine. Br. J. Nutr. 43:189-203. Davies, N.T., and R. Nightengale. 1975. Effect of phytate on zinc absorption and faecal zinc excretion and carcass retention of zinc, iron, copper and manganese. Proc. Nutr. Soc. 34:8A-9A. Deknudt, G., and M. Deminatti. 1978. Chromosome studies in human lymphocytes after in vitro exposure to metal salts. Toxicology 10:67-75. Deknudt, G., and G.B. Gerber. 1979. Chromosomal aberrations in bone-marrow cells of mice given a normal or a calcium-deficient diet supplemented with various heavy metals. Mutat. Res. 68:163-168.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Domingo, J.L., J.M. Llobet, J.L. Paternain, and J. Corbella. 1988. Acute zinc intoxication: Comparison of the antidotal efficacy of several chelating agents. Vet. Hum. Toxicol. 30:224-228. EPA (U.S. Environmental Protection Agency). 1990. Health Advisory for Zinc. U.S. Environmental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency). 1992. Zn chloride. Health Advisory Office of Water, U.S. Environmental Protection Agency, Washington, DC. Evenson, D.P., R.J. Emerick, L.K. Jost, H. Kayongo-Male, and S.R. Stewart. 1993. Zinc-silicon interactions influencing sperm chromatin integrity and testicular cell development in the rat as measured by flow cytometry. J. Anim. Sci. 71:955-962. Fabrizio, D. 1974. Mutagenic Evaluation of compound FDA-71-79, Zinc Sulfate. PB-245451. Prepared for FDA. National Technical Information Service, U.S. Department of Commerce, Springfield, VA. Festa, M.D., H.L. Anderson, R.P. Dowdy, and M.R. Ellersieck. 1985. Effect of zinc intake on copper excretion and retention in men. Am. J. Clin. Nutr. 41:285-292. Fischer, P.W., A. Giroux, and M.R. L'Abbe. 1984. Effect of zinc supplementation on copper status in adult man. Am. J. Clin. Nutr. 40:743-746. Freeland-Graves, J.H., B.J. Friedman, W.H. Han, R.L. Shorey, and R. Young. 1982. Effect of zinc supplementation on plasma high-density lipoprotein cholesterol and zinc. Am. J. Clin. Nutr. 35:988-992. Galvez-Morros, M., O. Garcia-Martinez, A.J.A. Wright, and S. Southon. 1992. Bioavailability in the rat of zinc and iron from basic salts. Food Chem. 43(5):377-381 Gyorffy, E.J., and H. Chan. 1992. Copper deficiency and microcytic anemia resulting from prolonged ingestion of over-the-counter zinc. Am. J. Gastroenterol. 87:1054-1055. Hanson, L.J., D.K. Sorensen, and H.C. Kernkamp. 1958. Essential fatty acid deficiency; its role in parakeratosis. Am. J. Vet. Res. 19:921-930. Hempe, J.M., and R.J. Cousins. 1991. Cysteine-rich intestinal protein binds zinc during transmucosal zinc transport. Proc. Natl. Acad. Sci. 88:9671-9674. Hempe, J.M., and R.J. Cousins. 1992. Cysteine-rich intestinal protein and intestinal metallothionein: an inverse relationship as a conceptual model for zinc absorption in rats. J. Nutr. 122:89-95. Henkin, R.I. 1974. Metal-albumin-amino acid interactions: chemical and physiological interrelationships. Adv. Exp. Med. Biol. 48:299-328. Henkin, R.I., B.M. Patten, P.K. Re, and D.A. Bronzert. 1975. A syndrome of acute zinc loss. Cerebellar dysfunction, mental changes, anorexia, and taste and smell dysfunction. Arch. Neurol. 32:745-751. Hidiroglou, M., and J.E. Knipfel. 1984. Zinc in mammalian sperm: a review. J. Dairy Sci. 67:1147-1156. Hoffman, H.N., II, R.L. Phyliky, and C.R. Fleming. 1988. Zinc-induced copper deficiency. Gastroenterology 94:508-512.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Holden, J.M., W.R. Wolf, and W. Mertz. 1979. Zinc and copper in self-selected diets. J. Am. Diet Assoc. 75:23-28. Hoogenraad, T.U., A.W. Dekker, and C.J. van den Hamer. 1985. Copper responsive anemia, induced by oral zinc therapy in a patient with acrodermatitis enteropathica. Sci. Total Environ. 42:37-43. Hooper, P.L., L. Visconti, P.J. Garry, and G.E. Johnson. 1980. Zinc lowers highdensity lipoprotein-cholesterol levels. JAMA 244:1960-1961. Hunt, J.R., G. Lykken, and L.K. Mullen. 1991. Moderate and high amounts of protein from casein enhance human absorption of zinc from whole wheat or white rolls. Nutri. Res. 11:413-418. Huntoon, C.L., P.A. Whitson, and C.F. Sams. 1994. Hematologic and immunologic functions. Pp. 351-362 in Space Physiology and Medicine, 3rd Ed., A.E. Nicogossian, C.L. Huntoon, and S.L. Pool, eds. Philadelphia, PA: Lea and Febiger. IOM (Institute of Medicine). 2001. Zinc. In Dietary Reference Intakes: Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. Istfan, N.W., M. Janghorbani, and V.R. Young. 1983. Absorption of stable 70Zn in healthy young men in relation to zinc intake. Am. J. Clin. Nutr. 38:187-194. Johnson, P.E., C.D. Hunt, D.B. Milne, and L.K. Mullen. 1993. Homeostatic control of zinc metabolism in men: zinc excretion and balance in men fed diets low in zinc. Am. J. Clin. Nutr. 57:557-565. Johnson, P.E., J.R. Hunt, and N.V. Ralston. 1988. The effect of past and current dietary Zn intake on Zn absorption and endogenous excretion in the rat. J. Nutr. 118:1205-1209. Judd, A.M., R.M. Macleod, and I.S. Login. 1984. Zinc acutely, selectively and reversibly inhibits pituitary prolactin secretion. Brain Res. 294:190-192. Ketcheson, M.R., G.P. Barron, and D.H. Cox. 1969. Relationship of maternal dietary zinc during gestation and lactation to development and zinc, iron and copper content of the postnatal rat. J. Nutr. 98:303-311. King, J.C., D.M. Shames, and L.R. Woodhouse. 2000. Zinc homeostasis in humans. J. Nutr. 130:1360S-1366S. Klaassen, C. 1996. Toxic effects of metals. Pp. 720-721 in Casarette and Doull's Toxicology, The Basic Science of Poison, C. Klaassen, M. Amdur, and J. Doull, eds. New York, NY: McGraw-Hill Publishers. Kowalska-Wochna, E., F. Moniuszko-Jakoniuk, E. Kulikowska, and K. Miniuk. 1988. The effects of orally applied aqueous solutions of lead and zinc on chromosome aberrations and induction of sister chromatid exchanges in the rat Rattus-SP. Genet. Pol. 29:181-190. Kozik, M.B., G. Gramza, and M. Pietrzak. 1981. Neurosecretion of the hypothalamo-hypophyseal system after intragastric administration of zinc oxide. Folia Histochem. Cytochem. (Krakow) 19:115-122.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Kozik, M.B., L. Maziarz, and A. Godlewski. 1980. Morphological and histochemical changes occurring in the brain of rats fed large doses of zinc oxide. Folia Histochem. Cytochem. (Krakow) 18:201-206. Krebs, J.M., V.S. Schneider, A.D. LeBlanc, M.C. Kuo, E. Spector, and H.W. Lane. 1993. Zinc and copper balances in healthy adult males during and after 17 wk of bed rest. Am. J. Clin. Nutr. 58:897-901. Kumar, S. 1976. Effect of zinc supplementation on rats during pregnancy. Nutr. Rep. Int. 13:33-36. Kurokawa, Y., M. Matsushima, T. Imazawa, N. Takamura, M. Takahashi, and Y. Hayashi. 1985. Promoting effects of metal compounds on rat renal tumorigenesis. J. Am. Coll. Toxicol. 4:321-330. L’Abbe, M.R., and P.W. Fischer. 1984a. The effects of dietary zinc on the activity of copper-requiring metalloenzymes in the rat. J. Nutr. 114:823-828. L’Abbe, M.R., and P.W. Fischer. 1984b. The effects of high dietary zinc and copper deficiency on the activity of copper-requiring metalloenzymes in the growing rat. J. Nutr. 114:813-822. Lee, D.Y., A.S. Prasad, C. Hydrick-Adair, G. Brewer, and P.E. Johnson. 1993. Homeostasis of zinc in marginal human zinc deficiency: role of absorption and endogenous excretion of zinc. J. Lab. Clin. Med. 122(5):549-56. Lewis, M.R., and L. Kokan. 1998. Zinc gluconate: acute ingestion. J. Toxicol. Clin Toxicol. 36:99-101. Llobet, J.M., J.L. Domingo, M.T. Colomina, E. Mayayo, and J. Corbella. 1988. Subchronic oral toxicity of zinc in rats. Bull. Environ. Contam. Toxicol. 41:36-43. Login, I.S., M.O. Thorner, and R.M. MacLeod. 1983. Zinc may have a physiological role in regulating pituitary prolactin secretion. Neuroendocrinology 37:317-320. Mahomed, K., D.K. James, J. Golding, and R. McCabe. 1989. Zinc supplementation during pregnancy: a double blind randomized controlled trial. Br. Med. J. 299:826-830. Maita, K., M. Hirano, K. Mitsumori, T. Takahashi, and Y. Shirasu. 1981. Subacute toxicity studies with Zn sulfate in mice and rats. J. Pest. Sci. 6:327-336. Merck Index. 1989. An Encyclopedia of Chemicals, Drugs, and Biologicals, 11th Ed. S. Budavari, M.J. O’Neil, and A. Smith, eds. Whitehouse Station, NJ: Merck & Co. Methfessel, A.H., and H. Spencer. 1973. Zinc metabolism in the rat. I. Intestinal absorption of zinc. J. Appl. Physiol. 34:58-62. Moore, R. 1978. Bleeding gastric erosion after oral zinc sulphate. Br. Med. J. 1(6115):754. Mulhern, S.A., W.B. Stroube, Jr., and R.M. Jacobs. 1986. Alopecia induced in young mice by exposure to excess dietary zinc. Experientia 42, 551-553. Murphy, J.V. 1970. Intoxication following ingestion of elemental zinc. JAMA 212:2119-2120. Nishioka, H. 1975. Mutagenic activities of metal compounds in bacteria. Mutat. Res. 31:185-189.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 NRC (National Research Council). 1977. Inorganic Solutes. Pp. 205-488 in Drinking Water and Health. Washington, DC: National Academy Press. NRC (National Research Council). 1980a. The contribution of drinking water to mineral nutrition in humans. Pp. 315-321 in Drinking Water and Health. Washington, DC: National Academy Press. NRC (National Research Council). 1980b. The contribution of drinking water to mineral nutrition in humans. Pp. 265-404 in Drinking Water and Health. Washington, DC: National Academy Press. NRC (National Research Council). 1989. Recommended Dietary Allowances, pp. 195-246. Washington, DC: National Academy Press. NRC (National Research Council). 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants. Washington, DC: National Academy Press. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. O’Dell, B.L. 1989. Mineral interactions relevant to nutrient requirements. J. Nutr. 119:1832-1838. Ohno, H., R. Doi, K. Yamamura, K. Yamashita, S. Iizuka, and N. Taniguchi. 1985. A study of zinc distribution in erythrocytes of normal humans. Blut 50:113-116. Pal, N., and B. Pal. 1987. Zinc feeding and conception in the rats. Int. J. Vitam. Nutr. Res. 57:437-440. Patterson, W.P., M. Winkelmann, and M.C. Perry. 1985. Zinc-induced copper deficiency: megamineral sideroblastic anemia. Ann. Intern. Med. 103:385-386. Pierre, L., R.L. Sauer, Y.E. Sinyak, V.M. Skuratov, N.N. Pratasov, and L.S. Bobe. 1999. Chemical Analysis of Potable Water and Humidity Condensate: Phase One Final Results and Lessons Learned. SAE Technical Paper Series no. 1999-01-2028. 29th International Conference on Environmental Systems, Denver, CO, July 12-15. Porea, T.J., J.W. Belmont, and D.H. Mahoney, Jr. 2000. Zinc-induced anemia and neutropenia in an adolescent. J. Pediatr. 136:688-690. Porter, K.G., D. McMaster, M.E. Elmes, and A.H. Love. 1977. Anaemia and low serum-copper during zinc therapy. Lancet 2:774. Potter, J.L. 1981. Acute Zn chloride ingestion in a young child. Ann. Emerg. Med. 10:267-269. Prasad, A.S. 1978. Hypocupremia induced by zinc therapy in adults. J. Am. Med. Assoc. 240:2166-2168. Prasad, A.S. 1988. Clinical spectrum and diagnostic aspects of human zinc deficiency. In Essential and Toxic Trace Elements in Human Health and Disease, A.S. Prasad, ed. New York, NY: Alan R. Liss Inc. Prasad, A.S., J.G. Brewer, E.B. Schoomaker, and P. Rabbani. 1978. Hypocupremia induced by zinc therapy in adults. J. Am. Med. Assoc. 240(20):2166-2168.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Quarterman, J., and W.R. Humphries. 1979. Effect of zinc deficiency and zinc supplementation on adrenals, plasma steroids and thymus in rats. Life Sci. 24:177-183. Reinhold, J.G., B. Faradji, P. Abadi, and F. Ismail-Beigi. 1991. The Journal of Nutrition, Volume 106:1976: Decreased absorption of calcium, magnesium, zinc and phosphorus by humans due to increased fiber and phosphorus consumption as wheat bread. Nutr. Rev. 49:204-206. Roth, H.P., and M. Kirchgessner. 1977. Content of zinc, copper, iron, manganese and calcium in bone and liver of rats during zinc depletion and repletion [in German] Zentralbl. Veterinarmed. A 24:177-188. Samman, S., and D.C. Roberts. 1988. The effect of zinc supplements on lipoproteins and copper status. Atherosclerosis 70:247-252. Sandstrom, B. 1992. Dose dependence of zinc and manganese absorption in man. Proc. Nutr. Soc. 51:211-218. Sandstrom, B., A. Almgren, B. Kivisto, and A. Cederblad. 1987. Zinc absorption in humans from meals based on rye, barley, oatmeal, triticale and whole wheat. J. Nutr. 117:1898-1902. Schiffer, R.B., F.W. Sunderman, Jr., R.B. Baggs, and J.A. Moynihan. 1991. The effects of exposure to dietary nickel and zinc upon humoral and cellular immunity in SJL mice. J. Neuroimmunol. 34:229-239. Schlicker, S.A., and D.H. Cox. 71968. Maternal dietary zinc, and development and zinc, iron, and copper content of the rat fetus. J. Nutr. 95:287-294. Schroeder, H.A., A.P. Nason, I.H. Tipton, and J.J. Balassa. 1967. Essential trace metals in man: zinc. Relation to environmental cadmium. J. Chronic Dis. 20:179-210. Seal, C.J., and F.W. Heaton. 1983. Chemical factors affecting the intestinal absorption of zinc in vitro and in vivo. Br. J. Nutr. 50:317-324. Shankar, A.H., and A.S. Prasad. 1998. Zinc and immune function: the biological basis of altered resistance to infection. Am. J. Clin. Nutr. 68:447S-463S. Sharrett, A.R., A.P. Carter, R.M. Orheim, and M. Feinleib. 1982. Daily intake of lead, cadmium, copper, and zinc from drinking water: The Seattle Study of Trace Metal Exposure. Environ. Res. 28:456-475. Simon, S.R., R.F. Branda, B.F. Tindle, and S.L. Burns. 1988. Copper deficiency and sideroblastic anemia associated with zinc ingestion. Am. J. Hematol. 28:181-183. Smith, S., and E. Larsen. 1946. Zinc Toxicity in Rats. Antogonistic effects of copper and liver. J. Biol. Chem. 163:29-38. Solomons, N.W., and R.A. Jacob. 1981. Studies on the bioavailability of zinc in humans: effects of heme and nonheme iron on the absorption of zinc. Am. J. Clin. Nutr. 34:475-482. Solomons, N.W., O. Pineda, F. Viteri, and H.H. Sandstead. 1983. Studies on the bioavailability of zinc in humans: mechanism of the intestinal interaction of nonheme iron and zinc. J. Nutr. 113:337-349. Spencer, H., L. Kramer, and D. Osis. 1985. Zinc metabolism in man. J. Environ. Pathol. Toxicol. Oncol. 5:265-278.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Spencer, H., D. Osis., and L. Kramer. 1976. Intake, excretion, and retention of zinc in man. In Trace Elements in Human Health and Disease. Vol. 1. Zinc and Copper, A.S. Prasad, ed. New York, NY: Academy Press. Stowe, H.D. 1976. Biliary excretion of cadmium by rats: effects of zinc, cadmium, and selenium pretreatments. J. Toxicol. Environ. Health 2:45-53. Sutton, W.R., and V.E. Nelson. 1937. Studies on Zinc. Proc. Soc. Exp. Biol. Med. 36:211-213. Tanner, J.T., and M.H. Friendman. 1977. Neutron activation analysis for trace elements in foods. J. Radioanal. Chem. 37:529. Taylor, C.M., J.R. Bacon, P.J. Aggett, and I. Bremner. 1991. Homeostatic regulation of zinc absorption and endogenous losses in zinc-deprived men. Am. J. Clin. Nutr. 53(3):755-763. Thompson, E.D., J.A. McDermott, T.B. Zerkle, J.A. Skare, B.L. Evans, and D.B. Cody. 1989. Genotoxicity of zinc in 4 short-term mutagenicity assays. Mutat. Res. 223:267-272. Turnlund, J.R., J.C. King, W.R. Keyes, B. Gong, and M.C. Michel. 1984. A stable isotope study of zinc absorption in young men: effects of phytate and alpha-cellulose. Am. J. Clin. Nutr. 40:1071-1077. Ugarte, M., and N.N. Osborne 2001. Zinc in the retina. Prog Neurobiol. 64(3): 219-249. Valberg, L.S., P.R. Flanagan, and M.J. Chamberlain. 1984. Effects of iron, tin, and copper on zinc absorption in humans. Am. J. Clin. Nutr. 40:536-541. Vilkina, G., M. Pomerantzeva, and L. Ramaya. 1978. Lack of mutagenic activity of cadmium and zinc salts in somatic and germ mouse cells. Genetica (The Hague) 14:2212-2214. Volpe, S.L., J.C. King, and S.P. Coburn. 2000. MicroNutrients. Chapter 10 in Trace Elements and B Vitamins. Pp. 213-232 in Nutrition in Spaceflight and Weightlessness Models, H.W. Lane, and D.A. Schoeller, eds. Washington, DC: CRC Press LLC. Waalkes, M.P., S. Rehm, C.W. Riggs, R.M. Bare, D.E. Devor, L.A. Poirier, M.L. Wenk, and J.R. Henneman. 1989. Cadmium carcinogenesis in male Wistar [Crl:(WI)BR] rats: dose-response analysis of effects of zinc on tumor induction in the prostate, in the testes, and at the injection site. Cancer Res. 49:4282-4288. Wada, L., J.R. Turnlund, J.C. King. 1985. Zinc utilization in young men fed adequate and low zinc intakes. J. Nutr. 115(10):1345-1354. Walsh, C.T., H.H. Sandstead, A.S. Prasad, P.M. Newberne, and P.J. Fraker. 1994. Zinc: health effects and research priorities for the 1990s. Environ. Health Perspect. 102(Suppl 2):5-46. Walters, M., and F.J. Roe. 1965. A study of the effects of zinc and tin administered orally to mice over a prolonged period. Food Cosmet. Toxicol. 3:271-276. Wastney, M.E., R.L. Aamodt, W.F. Rumble, and R.I. Henkin. 1986. Kinetic analysis of zinc metabolism and its regulation in normal humans. Am. J. Physiol. 251:R398-408.
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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Whitson, P., M. Pietrzak, and C. Sams. 1999. Space flight and the risk of renal stones. J. Gravit. Physiol. 6:87-88. Yadrick, M.K., M.A. Kenney, and E.A. Winterfeldt. 1989. Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult females. Am. J. Clin. Nutr. 49:145-150. Yamada, G., K. Sugimura, S. Nakamura, M.O. Yamada, Y. Tohno, I. Maruyama, I. Kitajima, and T. Minami. 1997. Trace element composition and histological analysis of rat bones from the space shuttle. Life Sci. 60:635-642. Yamaguchi, M., K. Takahashi, and S. Okada. 1983. Zinc-induced hypocalcemia and bone resorption in rats. Toxicol. Appl. Pharmacol. 67:224-228. Yamaguchi, M., T. Sakurai, J. Ohtaki, and T. Hoshi. 1991. Simulated weightlessness and bone metabolism: Evidence for direct gravitational effect and its related insulin action. Res. Exp. Med. (Berl.) 191:273-280. Zaporowska, H., and W. Wasilewski. 1992. Combined effect of vanadium and zinc on certain selected haematological indices in rats. Comp. Biochem. Physiol. C 103:143-147.
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