Heavy Metals in the Environment - Chapter 11 pot

11 Nickel Jessica E. Sutherland and Max Costa New York University School of Medicine, Tuxedo, New York 1. CHEMISTRY Nickel (Ni) is element 28 and, along with iron (Fe) and cobalt (Co), forms the first transition series group VIIIb of the periodic table. In aqueous solutions, nickel is most often divalent and exists primarily as the hexaquonickel [Ni(H 2 O) 6 ] 2ϩ ion; other valences include Ϫ1, 0, ϩ1, ϩ3, and ϩ4 (1). In solution, Ni 2ϩ is 4- or 6- coordinated and most commonly occurs in square planar configuration and less often in tetrahedral or octahedral configurations (2). Ni 2ϩ exhibits both ‘‘hard’’ and ‘‘soft’’ acid properties (3) and thus combines with nitrogen, oxygen, and sulfur-containing ligands in addition to donors from rows IV, V, VI, and VII of the periodic table. Nickel also can combine with carbon monoxide at atmospheric pressure to form highly toxic nickel carbonyl (Ni(CO) 4 ). The acetate, nitrate, sulfate, and halogen salts of nickel are all water soluble whereas the oxides, sulfides, carbonates, phosphate, and elemental forms of nickel are insoluble in water (4). In biological systems, Ni 2ϩ coordinates with water alone or with other solu- ble ligands. Nickel ions tend to be less ‘‘soft’’ than other toxic metal ions and hence are more likely to participate in ligand exchange reactions. Such reactions often govern the movement of nickel among different biological compartments. Copyright © 2002 Marcel Dekker, Inc. Important biological ligands for nickel are proteins containing the amino acids histidine and cysteine (5). 2. NICKEL IN THE ENVIRONMENT 2.1 Air Atmospheric nickel arises primarily from anthropogenic sources such as the burn- ing of residual and fuel oil, nickel metal refining, municipal waste incineration, steel production, nickel alloy production, and coal combustion (6). These activi- ties release approximately 56 million kg of nickel into the atmosphere per year (7). Natural sources of atmospheric nickel are windblown dust, volcanoes, and wildfires, and approximately 8.5 million kg of nickel are released into the atmo- sphere from these sources each year (8). Airborne nickel is primarily aerosolic with particles of many sizes. Schroeder et al. (9) reported particulate nickel atmospheric concentrations in the United States to be 0.01–60, 0.6–78, and 1–328 ng/m 3 for remote, rural, and urban areas, respectively. The species of nickel found in the aerosols vary with the source and include nickel oxides, nickel sulfate, metallic nickel, nickel sili- cate, nickel chloride, and nickel subsulfide (6). 2.2 Water Nickel in surface water arises from runoff from soil and tailing piles, from landfill leachates, and from atmospheric deposition. Industrial and municipal wastewater is another important source of nickel in surface waters. Nriagu and Pacyna (7) estimated that anthropogenic contributions of nickel to water ranged between 33 and 194 million kg/year with a median value of 113 million kg Ni/year. Much of the nickel in surface water partitions into the sediments resulting in low surface water concentrations (6). Nickel concentrations in seawater range from 0.1 to 0.5 ppb whereas nickel levels in fresh surface waters are more variable and range from 0.5 to 600 ppb (6,10,11). Leaching of nickel from soil into groundwater accounts for much of the nickel found in groundwater and this process is acceler- ated in regions susceptible to acid precipitation. Groundwater nickel concentra- tions are generally lower than 10 ppb (12,13). 2.3 Soil On average, nickel constitutes 0.0086% of the earth’s crust (6). Soil concentra- tions of nickel vary with local geology and anthropogenic input with typical con- centrations ranging from 4 to 80 ppm (8). Major emission sources of soil nickel include coal fly ash, waste from metal manufacturing, atmospheric deposition, Copyright © 2002 Marcel Dekker, Inc. urban refuse, and sewage sludge (6). Hazardous waste sites frequently have ele- vated soil nickel concentrations (6). 3. HUMAN EXPOSURE 3.1 Ingestion In the general population, ingestion of nickel-containing foodstuffs represents the primary route of nickel exposure. Estimates of average daily dietary intake of nickel range from 70 µg to 300 µg (14–17). Foods that typically contain fairly high concentrations of nickel (i.e., greater than 1 ppm) include oatmeal, dry le- gumes, hazelnuts, cocoa, soybeans, and soy products (10,15). Shellfish, de- pending upon the area from which they are harvested, can also contain high con- centrations of nickel (6). Food preparation in stainless steel cookware can add up to 0.1 mg Ni to the diet per day (18). Drinking water nickel concentrations average 2 ppb and are usually less than 20 ppb (4,8). Consumption of 2 L of drinking water per day would therefore add 40 µg nickel to the daily amount of ingested nickel. In the United States, there is no Environmental Protection Agency (EPA)-mandated legal limit on the amount of nickel in drinking water but the agency has recommended a maximum contaminant level (MCL) of 0.1 mg Ni per liter of drinking water (19). Nickel levels in drinking water may be elevated due to corrosion of valves, pipes, or faucets made from nickel-containing alloys (6). 3.2 Inhalation On average, individuals in the general population inhale 0.1–1.0 µg Ni/day (20). The highest reported general population intake of nickel from air is 18 µgNi/ day (8). Exposure to nickel also occurs from tobacco smoking. Cigarettes, on aver- age, contain 1–3 µg Ni (4,6) and mainstream smoke from one cigarette contains 0–0.51 µg Ni (21). Smoking a pack of cigarettes results in an inhalation exposure to 2–12 µg Ni (8). Occupational exposure to nickel occurs via inhalation of nickel-containing aerosols, dusts, fumes, and mists. Nickel alloys and compounds have widespread industrial applications and each year, several million workers worldwide are oc- cupationally exposed to nickel (22). Nickel mining and refining, nickel alloy production, nickel electroplating and thermal spraying, welding, production of nickel-cadmium batteries, manufacture of some types of enamel or glass, and the use of nickel compounds as chemical catalysts result in occupational nickel exposure (23–25). In these industrial settings, inhalation exposure varies in terms of amount and in terms of nickel speciation, depending on the activity. The Amer- ican Conference of Governmental Industrial Hygienists (ACGIH) recently Copyright © 2002 Marcel Dekker, Inc. adopted threshold limit values (TLV) for an 8-h workday, 40-h workweek of 0.1 mg Ni/m 3 air for water-soluble nickel, 0.2 mg Ni/m 3 air for water-insoluble nickel, and 1.5 mg/m 3 for elemental/metallic nickel (26). The U.S. Occupational Safety and Health Administration (OSHA) has established permissible exposure limits (PEL) of 1 mg/m 3 as 8-h time-weighted averages for insoluble and soluble nickel compounds (27,28). 3.3 Dermal Humans are also exposed to nickel via dermal contact with stainless steel, coins, fasteners, and jewelry and by occupational exposure to dusts, aerosols, and liquid solutions containing nickel (6). Sunderman (13) reported that soaps may also contain nickel if they were hydrogenated with nickel catalysts. 3.4 Iatrogenic Nickel alloys used in surgical and dental prostheses, and clips, pins, and screws used for fractured bones release small amounts of nickel into the surrounding tissue and extracellular fluid (20,29). Nickel can also be absorbed from dialysis and intravenous solutions. Kidney dialysis solutions typically contain Յ1 µg Ni/L but have been reported to contain as much as 250 µg Ni/L (30). Intravenous solutions containing albumin have been reported to contain as much as 222 µg Ni/L (8). 4. ESSENTIALITY 4.1 Plants and Microorganisms There are six known nickel metalloenzymes. In two of these enzymes, urease and bacterial glyoxalase I (GlxI), catalysis does not depend upon the redox chem- istry of nickel at the active site. In the other enzymes [nickel superoxide dismutase (NiSOD), hydrogenase, carbon monoxide dehydrogenase (CodH), and methyl coenzyme M reductase (MCR)], the redox chemistry of nickel plays a key role. Urease, found in plants and microorganisms, hydrolyzes urea to form am- monia and carbamate, which degrades further to form a second ammonia mole- cule and carbon dioxide (31). Two nickel atoms are present at each active site (32). Glyoxalase I from Escherichia coli participates in the detoxification of α- keto aldehydes to 2-hydroxycarboxylic acids. E. coli Glx I is a homodimer with a single Ni 2ϩ ion per dimer (33). Bacterial nickel superoxide dismutase was isolated in 1996 (34). The gene for this enzyme, sodN, is upregulated by Ni 2ϩ . Posttranslational modification of the enzyme is also regulated by Ni 2ϩ (35). Like other cellular superoxide dismu- tases, NiSOD catalyzes the dismutation of superoxide to peroxide and molecular Copyright © 2002 Marcel Dekker, Inc. oxygen. In the reaction, Ni (III) is reduced to Ni (II) by superoxide and then reoxidized (33). Two types of bacterial hydrogenases contain nickel in their catalytic sites. These enzymes catalyze the interconversion of dihydrogen to/from hydrogen ions (32). Bacterial carbon monoxide dehydrogenase catalyzes the interconversion of carbon monoxide and carbon dioxide (33). In acetogenic and methanogenic bacte- ria, CodH also has acetyl-CoA synthase (ACS) activity (32). The site of CO binding and oxidation contains a nickel center with S-donor ligands linked to an iron/sulfur (Fe 4 S 4 ) cluster (33). Methyl-coM reductase catalyzes the final step of methanogenesis in bacte- ria (i.e., the reduction of methyl-coenzyme M by coenzyme B to methane) (36). Nickel porphinoid (coenzyme F430) is the prosthetic group of MCR. Recently, Dai and colleagues (37) reported that E2 and E2 1 enzymes share the same protein component but catalyze two different oxidation products of the acireductone intermediate in the methionine salvage pathway in bacteria. E2 ac- tivity is gained after addition of Ni 2ϩ or Co 2ϩ to the apoenzyme whereas E2′ activity was detected after addition of Fe 2ϩ . Production of each in intact E. coli was regulated by metal availability. Further work is needed to elucidate whether these metals constitute part of the active site or merely affect its structure, re- sulting in the two different reaction products. Peptide deformylase (PDF) catalyzes the hydrolysis of N-formylmethionine from polypeptides in bacteria. When isolated in the presence of Ni 2ϩ , PDF is bound to nickel and is highly active compared to its unbound state in which Zn is bound instead. It is not clear, however, whether nickel is the native metal used by PDF (33). Organisms that employ nickel for enzymatic catalysis have evolved a num- ber of nickel-binding proteins for acquisition, transport, storage, and enzyme as- sembly (33). It was recently shown that expression one of these transport systems (nickel-specific ABC transport system) in E. coli is repressed by nickel-respon- sive regulator when high extracellular concentrations of nickel exist. This pre- vents transport of potentially toxic amounts of nickel into the cell (38). In humans, Heliobacter pylori, the bacterium that causes peptic ulcer disease, relies upon urease to produce enough ammonia to neutralize gastric acid and hence allow bacterial colonization of the gastric mucosa. This bacterium needs to scavenge Ni 2ϩ ions from gastric mucosal cells and has a specialized high-affinity nickel transporter (NixA) for this purpose (39). 4.2 Animals Nickel is believed to be an essential element for rats (40,41), chicks (42), swine (43), goats, and sheep (44). The reported symptoms of nickel deficiency in these animals included depressed growth; depressed hematocrit; low plasma glucose; Copyright © 2002 Marcel Dekker, Inc. impaired reproductive performance; hepatic abnormalities including altered lipid metabolism; decreased ruminal urease activity; altered copper, iron, zinc, and calcium metabolism; and altered cobalamin (vitamin B 12 ) function (45). However most of these symptoms varied considerably among studies; therefore, reaching a consensus regarding the nutritive roles of nickel in animals is difficult. More- over, interpretation of animal studies may be confounded by possible pharmaco- logical actions of the high amounts of nickel added to control or ‘‘nickel-ade- quate’’ diets in some of the experiments (46,47). Nevertheless, Reeves (48) rec- ommended addition of 500 mg Ni (as NiCO 3 )/kg diet to purified laboratory animal diets. To date, there is no evidence that nickel is essential in humans nor has a nickel-deficient state in humans been identified. There are no established nutri- tional standards for nickel; however, an ‘‘acceptable daily dietary intake’’ of 100–300 µg has been proposed (49). 5. METABOLISM 5.1 Cellular Uptake Cellular uptake of nickel into cells is modulated by nickel’s solubility. Experi- ments with cultured cells have indicated that insoluble nickel compounds are taken up by cells to a greater extent than are soluble nickel compounds (50). Uptake of soluble nickel from serum into tissues is believed to be governed by ligand exchange reactions. A proposed model suggests that l-histidine removes nickel from serum albumin and mediates its entry into cells. Active transport and diffusion probably function in movement of soluble nickel across plasma membranes but the actual mechanisms are not well understood. Soluble nickel and magnesium may share a common transport system (51). Uptake of ionic nickel may be low owing to competition with Mg 2ϩ ions normally present in millimolar amounts (52). Some soluble nickel probably also enters cells via cal- cium channels (53,54). There is also evidence that nickel and iron may also share common cellular uptake mechanisms with nickel effectively competing with iron for low-affinity transport in cultured rabbit or rat reticulocytes (55,56). Iron-defi- cient rats, given intraperitoneal (i.p.) injections of 4 µg 63 Ni/kg body weight, accumulated more 63 Ni in tissues than did iron-sufficient rats (57). Nickel binds to the iron transport protein transferrin (58) and it is possible that some nickel enters cells on transferrin. Tandon et al. (59) reported that dietary iron deficiency had no effect on tissue disposition of nickel in rats following an intraperitoneal injection of 120 µmol NiCl 2 -6H 2 O/kg body weight. Tissue disposition following injection of such a high dose of nickel may not have accurately reflected physio- logical conditions. Cellular uptake of soluble nickel is also temperature-dependent. Abbrachio Copyright © 2002 Marcel Dekker, Inc. et al. (60) reported that uptake of nickel following treatment of Chinese hamster ovary (CHO) cells with NiCl 2 at 4°C was decreased 50% compared to cells main- tained at 37°C. Similarly, uptake of soluble nickel by cultured rat primary hepato- cytes was decreased by 20% compared to uptake at 37°C (54), suggesting that nickel transport, at least in part, may be mediated by membrane carriers. In contrast, insoluble nickel compounds enter the cell via phagocytosis (61–63). This process is influenced by crystalline structure, surface charge, and particle size (64–66). Although the mechanisms are unclear, cellular nickel accu- mulation following exposure to insoluble nickel is reduced in the presence of extracellular magnesium (50,67). 5.2 Absorption 5.2.1 Inhalation In general, inhaled nickel-containing particles with diameters greater than 2 µm settle in the upper respiratory tract whereas particles smaller than 2 µm lodge in the lower respiratory tract and in lung tissue. In humans, absorption of respired nickel has been estimated by measuring urinary nickel levels following inhalation exposure. It has been estimated that approximately 35% of the nickel present in the respiratory tract of humans is absorbed into the bloodstream (6). It has been proposed that soluble nickel compounds (e.g., nickel sulfate, nickel chloride) are absorbed to a greater extent (as estimated from urinary nickel) than insoluble compounds (e.g., nickel subsulfide, nickel oxide) (68,69). However, greater ele- vations in urinary nickel following inhalation of soluble nickel may reflect more rapid clearance of this form rather than greater absorption per se. Accordingly, urinary nickel concentrations may not be reliable indicators of exposure to insolu- ble nickel via inhalation (70,71). Uptake of inhaled nickel into the brain from the nasal epithelium via olfac- tory neurons may represent another route of exposure to inhaled nickel (72). In rats and pike, intranasal instillation of 63 Ni 2ϩ resulted in migration along the olfac- tory neurons and entry into the cerebrum (72–74). The significance of this expo- sure route in terms of overall nickel uptake is unknown because of a lack of data regarding the proportion of inhaled nickel in the nasal epithelium that is taken up by the olfactory pathways. However, it is interesting to note that impairment of olfactory sensation has been observed in workers in nickel refineries and in rats exposed to soluble nickel (72). 5.2.2 Ingestion Nickel absorption from the gastrointestinal tract is higher when the nickel is pres- ent in drinking water as opposed to food. Humans given 12, 18, and 50 µg/kg body weight absorbed 27 Ϯ 17% of the nickel sulfate present in drinking water as compared to only 0.7 Ϯ 0.4% when it was in food (75). Solomons et al. (76) Copyright © 2002 Marcel Dekker, Inc. and Nielsen et al. (77) reported a similar decrease in the bioavailability of nickel in food as compared to drinking water. These studies estimated absorption via balance studies where nickel concentrations in urine and feces were measured for up to 4 days following ingestion. Unfortunately, high doses of nickel were administered to produce detectable changes in nickel concentrations in urine and blood. Recently, nickel metabolism studies have been conducted in humans with stable isotope tracers ( 61 Ni and 62 Ni) (77–79). Nickel absorption in these studies ranged from 11 to 33%. In all of these tracer studies, the nickel isotope was administered in water; it is important to remember that nickel is much more bioavailable in water than when ingested in foodstuffs. The mechanisms of intestinal nickel absorption have been studied using everted gut sacs (80), perfused rat jejunal and ileal segments (81–83), and Caco- 2 cell monolayers (84). Absorption of nickel in the gut is believed to involve both active and passive transcellular processes; the role of paracellular transport in nickel absorption is not clearly defined (82,83). Nickel and iron may share some absorptive mechanisms (57,84,85). How- ever, from a nutritional standpoint, iron absorption is likely to be nonaffected by poorly bioavailable dietary nickel. Supplementation of diets with 3–100 mg Ni/ kg diet did not affect iron status in rats (86). Cobalt may also compete with nickel and iron for uptake in the gut (87). Stangl et al. (88) reported that cattle deficient in vitamin B 12 accumulated significantly more iron and nickel in liver than vita- min B 12 -sufficient animals, which suggests increased absorption and/or increased hepatic uptake of nickel by the cobalt-deficient cattle. There may be homeostatic regulation of nickel absorption from the gut. The rates of nickel uptake in everted jejunal sacs obtained from nickel-depleted rat pups were significantly greater than those in obtained from nickel-adequate pups (80). Homeostatic regulation of uptake is a hallmark of many essential trace metals (e.g., zinc, iron, copper, and manganese). Demonstration of this phenome- non in vivo for nickel is currently lacking but would do much to bolster arguments for nickel’s essentiality. 5.2.3 Dermal Soluble nickel salts are absorbed through the skin to a greater extent than insolu- ble compounds. Nickel chloride applied to excised human skin was absorbed approximately 50 times faster than nickel sulfate (89). However, dermal absorp- tion was low; approximately 0.2% of the nickel chloride penetrated the skin sam- ple in the 144 h immediately following application. Absorption of nickel chloride approximated 3.5% in occluded skin. Following dermal application, nickel is retained in the skin for extended periods (90). This is important toxicologically Copyright © 2002 Marcel Dekker, Inc. because retention of nickel in the skin leads to nickel sensitivity and contact dermatitis. 5.3 Tissue Disposition In the bloodstream, nickel binds to albumin, transferrin, l-histidine, and α-2- macroglobulin (also sometimes called nickeloplasmin) (91). The primary binding site of nickel to albumin is a histidine residue at the third position from the amino terminus of the protein (92). Neighboring residues (aspartate and alanine) are also involved in nickel complexation (93) forming a square planar N-terminal complex of nickel and albumin (94). Copper also binds to this site with an affinity one order of magnitude higher than nickel (93). Bal et al. (94) reported that human, bovine, and porcine albumins contained a second binding site for Ni(II), which also binds Cu(II), Zn(II), and Cd(II) with similar affinity but is not believed to be an important Cu(II) binding site under physiological conditions. In humans, approximately 76% of plasma nickel is bound to high-molecular-weight proteins (91). Nickel bound to α-2-macroglobulin is not readily exchangeable and hence this protein is not believed to be an important nickel transport protein (95). In humans, serum and whole blood nickel concentrations in unexposed individuals range from 0.1 to 1 µg Ni/L (75,96–99). Plasma or serum concentra- tions of nickel in occupationally exposed workers range from 1 to 12 µgNi/L (96,100–102). Average serum nickel concentrations of 6–7 µg Ni/L have been reported in hemodialysis patients (99,103). Workers who accidentally ingested 0.5–2.5 g of nickel in drinking water had serum nickel concentrations of 13– 1340 µg Ni/L (104). Numerous animal studies have indicated that the kidney and lung are the primary organs in which nickel accumulates following injection, intratracheal, or oral administration of soluble nickel compounds. Smaller amounts of nickel accumulate in liver, other soft tissues, and bone (2,105–107). Nickel measurements made in human autopsy samples revealed that nickel was ubiquitously distributed in the body with highest concentrations present in lung (108) or bone (109). Whole-body nickel levels were found to be less than 600 mg Ni/kg dry tissue (91). In most studies, lung nickel concentrations in- creased with age (108,110–112) but Raithel et al. (113) and Fortoul et al. (114) found no such relationship. Lung nickel concentrations varied with topography within the lung and were generally highest in the upper lung regions (113,115,116). 5.4 Excretion Animal studies reveal that most nickel absorbed from soluble forms, regardless oftherouteofexposure,isexcretedinurine(Table1).Smalleramountsofnickel Copyright © 2002 Marcel Dekker, Inc. T ABLE 1 Urinary and Fecal Excretion of Administered Nickel Nickel Animal Route of Period after Percentage of Ni Percentage of Ni compound species exposure dosing (h) dose in urine dose in feces Ref. 63 NiCl 2 Rat i.v. 72 61 5.9 541 63 NiCl 2 Rat i.v. 72 78 15 119 63 Ni & 62 Ni Rat i.v. 80 60 5.4 79 63 NiCl 2 Rat i.v. 96 100 0 542 63 NiCl 2 Rat i.p. 144 80 6 543 63 NiCl 2 Rat i.t. 72 75 NA 544 63 NiCl 2 Rat i.t. 72 63 5 545 63 NiCl 2 Rat i.t. 72 78.5 NA 546 63 NiCl 2 Rat i.t. 96 54–82 13–31 127 63 NiO Rat i.t. 72 16 17 545 63 Ni 3 S 2 Mouse i.t. 72 33 57 130 Copyright © 2002 Marcel Dekker, Inc. [...]... breaks Vicininal thiol-containing molecules generated H 2 O 2 in solution whereas mono-thiol-containing molecules did not suggesting that the DNA strand breaks induced by vicinal thiols and Ni were mediated by H 2 O 2 molecules This result could have important implications in occupational health settings because many of these vicininal thiol-containing molecules are used as chelating agents in metal-intoxicated... events within the nucleus Vicinal-thiol-containing molecules [i.e., meso-2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropane-1-sulfonate, and 2,3 dimercaptopropanol] greatly enhanced NiCl 2-induced DNA strand breaks in a human leukemia cell line (335) Conversely, mono-thiol-containing molecules (i.e., d-penicillamide, glutathione, β-mercaptoethanol, and diethyl dithiocarbomate) reduced NiCl 2induced... lesions; therefore, the increased presence of oxidized bases and single-strand breaks was attributed to defective repair Nickel (II) decreased the repair of N-methyl-Nnitrosurea (MNU)-induced O 6-methylguanine in a dose-dependent manner (starting at 50 µM) in Chinese hamster ovary cells stably transfected with human O 6-methylguanine-DNA methyltransferase (MGMT) cDNA (377) Activity of MGMT was diminished in. .. of hypoxia-responsive genes (430) It is difficult to reconcile the above model with the abundant evidence that nickel exposure results in increased ROS levels in cells, induces HIF-1α protein (431), and induces HIF-1-regulated genes Even if the presumptive nickel-substituted heme-containing oxidase is dysfunctional and does not produce ROS, other nickel-induced oxygen radicals present in the cell would... radiation in Chinese hamster V79 cells and enhanced the cytotoxicity of cis-diamminedichloroplatinum and these effects were ascribed to inhibition of DNA repair (365) Addition of nickel to UV-treated CHO cells inhibited ligation of DNA single-strand breaks and increased cytotoxicity but did not inhibit repair of MMS-induced single-strand breaks or in uence cytotoxicity (375) Nickel blocked removal of UV-induced... were kinetically labile (306) Further investigations with cultured cells demonstrated that cross-linking between the amino acids cysteine and histidine and DNA in the presence of nickel was greatly enhanced by the addition of hydrogen peroxide (H 2 O 2) (312) In addition, nickel bound to the DNA–amino acid complexes was readily removed by EDTA washing whereas 40–50% of the histidine or cysteine remained... designed using nickel- and histidine-tagged proteins to cross-link proteins of interest for analysis of multiprotein complexes (324) Levine et al (316) demonstrated that in the presence of Ni(II), sulfite, and ambient oxygen, spontaneous N-terminal oxidation occurred, producing a free carbonyl on the N-terminal αcarbon and suggested that this method may prove useful for artificially producing site-specific... antigen (LFA-1), a ligand for ICAM-1, in the skin of nickel-sensitive individuals Nickel also caused increased expression of the in ammatory cytokines, IL-1, and tumor necrosis factor-alpha in cultured keratinocytes (194,195,198) Expression of adhesion molecules in vascular endothelium, important for leukocyte recruitment during in ammation, is also upregulated by nickel Expression of ICAM-1, vascular... combination in a subsequent experiment (337) caused a high number of single-strand breaks in double-stranded plasmid DNA The difference might be explained by the increased sensitivity of detection in the latter assay Nickel-peptide-catalyzed DNA strand scission has been used as a research tool Footer et al (338) used a peptide nucleic acid (PNA) featuring a tripeptide consisting of glycine-glycine-histidine... complexed with the DNA (312) Moreover, in this study, the amino acid-DNA complexes were stable in the presence of SDS This suggests that Copyright © 2002 Marcel Dekker, Inc nickel did not directly participate in formation of the amino acid–DNA complexes but rather catalyzed the covalent cross-linking via oxidative means Mechanistically, the interactions between nickel ions and proteins or amino acids are . nickeloplasmin) (91). The primary binding site of nickel to albumin is a histidine residue at the third position from the amino terminus of the protein (92). Neighboring residues (aspartate and alanine). nickel in the skin leads to nickel sensitivity and contact dermatitis. 5.3 Tissue Disposition In the bloodstream, nickel binds to albumin, transferrin, l-histidine, and -2 - macroglobulin (also. are proteins containing the amino acids histidine and cysteine (5). 2. NICKEL IN THE ENVIRONMENT 2.1 Air Atmospheric nickel arises primarily from anthropogenic sources such as the burn- ing of