Nickel (Ni) is a metallic element that is naturally present in the Earth's crust. Due to unique physical and chemical properties, metallic nickel and its various compounds are widely used in modern industry.

 

It is only within recent decades that the hazards of exposure to Ni and nickel compounds have come to be recognized.

 

Since Ni has not been recognized as an essential element in humans, it is not clear how nickel compounds are metabolized. It is known, however, that exposure to nickel compounds can have adverse effects on human health. Human exposure to Ni occurs primarily via inhalation and ingestion. Significant amounts of Ni in different forms may be deposited in the human body through occupational exposure and diet over a lifetime.

Ni

Nickel

28

Atomic mass: 58.71

Despite their name,
nickels are comprised of only 25% nickel; they are actually 75% copper.

Sources of Exposure

Inhalation exposure in occupational settings is a primary route for nickel-induced toxicity and may cause toxic effects in the respiratory tract and immune system. The sources of environmental nickel contamination include the production and processing of Ni and its by-products, the recycling of nickel-containing products and nickel-containing waste disposal. The most toxic of all compounds of Ni that are encountered in industrial operations is nickel carbonyl (Ni(CO)4). Hazards from exposure may arise from a variety of operations. These include: 

 

  1. the separation of nickel from its ores; 

  2. the preparation of intermediates in organic syntheses, sometimes under extremely high pressures; 

  3. electroplating operations as a medium for depositing thin layers of metallic nickel in electronic circuits and magnetic tapes; and 

  4. inadvertent formation whenever carbon monoxide comes into contact with an active form of nickel.

 

Environmental sources of lower levels of Ni include tobacco, dental or orthopaedic implants, stainless steel kitchen utensils and inexpensive jewelry. Municipal drinking water in the United States generally contains Ni at concentrations less than 10 µg/l. 

 

Occupational exposure to Ni compounds is dependent upon industrial processing and is usually substantially higher than work-unrelated nickel exposure. The form of Ni to which workers are exposed differs in the various industries in which Ni is used and occurs through inhalation or dermal contact (inhalation is the primary route of exposure), with ingestion taking place where there are poor industrial hygiene practices.

 

Tobacco and tobacco smoke - cigarettes - are also a source of bioavailable Ni (nickel carbonyl); one cigarette may contain 2 to 6 micrograms of nickel - of which up to 20% is inhaled in the smoke. Generally, daily oral intakes of nickel are extremely variable and may range from negligible amounts tp up to 900 micrograms.

Nickel is normally present in human tissues and, under conditions of high exposure, these levels may increase significantly. In the general population, contributions to the body burden from inhalation of Ni in the air and from drinking water are generally less important than dietary intake and ingestion is considered to be the most important route of exposure. 

 

Inhaled Ni is selectively concentrated in the lung, followed by heart, diaphragm, brain, and spinal cord tissues. In general, the lung has the tendency to retain significant amounts of Ni independently of the route of exposure. The kidney, in addition to the lung, brain, pancreas, and other tissues is considered a target organ for Ni retention following high levels of Ni exposure.

Target Tissues

Biochemistry

The exposure to high doses of Ni disturbs established cellular homeostasis via changes of intracellular calcium levels and produces oxidative stress. Although nickel does not react significantly with DNA, it does interact strongly with proteins. The strength of the interaction is dependent on the identity of the amino acids present, and the greatest affinity is shown towards histidine residue. Several proteins with high affinity to nickel have been identified in recent years. They are mainly involved in Ni transport, detoxification and excretion. It is of interest to note that the metal-binding protein metallothionein does not appear to constitute a major nickel-binding component in different tissues. Serum albumin, l-histidine and α2-macroglobulin have been identified as the main binding partners of nickel in blood serum. The ability of nickel ions to interact with a number of proteins raises the possibility that nickel may significantly change intracellular homeostasis by altering protein functions and producing stress similar to unfolded protein response.

 

Nickel is a known contact carcinogen and allergen. Ironically, at the same time that Ni presumably uncouples our protective mechanism against cancer, it over-stimulates at least one immune response (cytolytic antibody production) linked to cancer-negating activities. Thus, a misdirecting or uncoupling of our normal immune surveillance for cancer, while compensating with an over-escalation of an immune response that can produce hypersensitivity and perhaps even auto-immunity, essentially describes the immunopathology of nickel poisoning.

 

Inhaled Ni, especially nickel carbonyl, is a respiratory carcinogen, producing squamous cell carcinomas. The exact mechanism(s) of nickel carcinogenesis is still unknown. It has been suggested that solubility and removal rates of the various Ni compounds may be directly related to their relative carcinogenic potential in the respiratory tract. Crystal structure, particle size, and surface area may also be related to carcinogenicity. Nickel can displace copper and zinc at enzyme-activator sites and thereby abnormally up- or down-regulate enzymatic processes. This then causes deregulation of metabolic and immunologic functions and potentiate carcinogenesis. 

 

At low concentrations, nickel induces heme-oxygenase activity; at high concentrations it inhibits it, thus disordering heme metabolism. In addition, nickel toxicity causes a transient reduction of cellular glutathione. Nickel induces metallothionein synthesis in liver cells causing a dysfunction in arginase and carboxylase activities. This may result in an impairment of the urea cycle. Both nickel sulfide and sulfate can disrupt immune function by depressing natural killer cell and CD4 lymphocyte populations in blood. Nickel salts at low concentrations can also suppress the natural oxidant cascade following the respiratory burst in phagocytes; hydrogen peroxide formation is reduced, and the anti-microbial oxidant defense system of leukocytes is thus weakened.

 

It has been difficult to estimate the specific risks associated with individual species of Ni due to mixed exposures within the workplace. The overall evidence from studies of Ni workers suggests that respiratory cancer risks are primarily related to exposure to less soluble forms of nickel (notably sulfidic and oxidic nickel). In addition to the lung and nasal sinus cancers, cancers of the larynx, kidney, prostate, stomach, colon, bladder, buccal cavity, and pharynx have also been reported in excess of expected numbers in nickel-exposed workers. 

Human exposure to highly nickel-polluted environments has the potential to produce a variety of pathological effects. Among them are skin allergies, lung fibrosis, cancer of the respiratory tract and iatrogenic Ni poisoning. Nickel is a ubiquitous metal frequently responsible for allergic skin reactions and has been reported to be one of the most common causes of allergic contact dermatitis, as reflected by positive dermal patch tests.

 

Nickel hypersensitivity also causes asthma, conjunctivitis, inflammatory reactions to nickel-containing prostheses and implants, and systemic reactions after parenteral administration of nickel-contaminated fluids and medications.

 

Epidemiological investigations and experimental studies have demonstrated that Ni metal dusts and some nickel compounds are extremely potent carcinogens after inhalation, but also that the carcinogenic risk is limited to conditions of occupational exposure Hence, probably the greatest danger from chronic Ni exposure is lung, nasal, or larynx cancers, and gradual poisoning from accidental or chronic low-level exposure, the risk of which is greatest for those living near metal smelting plants, solid waste incinerators, or old nickel refineries.

Signs & Symptoms

Nutrients Known to be Protective Against Nickel

Sulfur-bearing amino acids, certain algae (laminaria, fucus, chlorella), selenium, vitamin C, manganese, zinc and copper are antagonistic for reuptake and retention of Ni.

Testing for Nickel Toxicity

Urine and serum nickel concentrations may be used as biological indicators of occupational, environmental and iatrogenic exposures to Ni compounds. However, they do not give a good picture of past exposure and they cannot be used for risk assessment as current knowledge is not sufficient to relate nickel concentrations in these indicator media to specific adverse health effects. Nickel concentrations in serum mainly reflect recent exposure because of the short biological half-time in this compartment. The Ni excretion in urine may reflect more extended exposure and is more practical than serum.

Protocols for Nickel Detoxification

As with all detoxification protocols, the type, dose and duration of detoxification agents should always be individually assessed, and administered by a licensed medical practitioner. 

Nickel detoxification is like detoxification for mercury. The following may serve as a basic guideline for detoxification of excess Ni from chronic exposure. After 60 days, laboratory screening should be used to reassess protocol. Before initiating a detoxification program, a CBC with chemistry, including a thyroid panel with lipids should be performed. In addition, whole blood elements to assess the mineral status and a urine creatinine clearance should be performed every 60 days when using synthetic detoxifying agents. Administration of arginine and synthetic agents may cause a depletion of essential elements such as zinc, iron, calcium, magnesium, copper and other trace minerals. Of greatest concern is potential kidney toxicity that can occur when the body releases its nickel stores for excretion through the kidneys. Those with underlying kidney disease may not be able to undergo aggressive nickel detoxification therapy.

 

  1. Identify the source (s) of nickel in the individual’s environment and remove them or remove the individual from the sources. Check dental restorations and industrial exposure.

  2. Assess whole blood cell element analysis to determine mineral nutrient deficiency and supplement appropriately.

  3. Supplement 200 mcg of selenium daily. 

  4. Supplement buffered vitamin C (corn free source) at 2000 mg up to 5000 mg daily adjusting to bowel tolerance.

  5. Supplement vitamin E at 400 to 800 IU daily.

  6. Supplement Alpha Lipoic Acid at 250 mg twice daily.

  7. Algal cells have a remarkable ability to take up and accumulate heavy metals from their external environment. The primary ones used for toxic metal excess are Chlorella vulgaris, a green microalga, and Laminaria japonica, a brown alga. Chlorella and Laminaria japonica are both chelators, moving toxic metals out of the body, and transporters, moving metals from deeper stores to more readily removable areas. Both work in unison with each other and can remove toxic metals from the body through urinary excretion. Administer 1000 to 2000 mg of Laminaria japonica concentrate (Modifilan) daily and 1000 to 2000 mg of chlorella. Adjust dosage to bowel tolerance; may be taken for long periods of time.

  8. Cilantro works well with alga to chelate, or bind up toxic metals. The issue with cilantro taken alone is that although it chelates metals, it does not remove them in the urine. This means they can recirculate to deposit elsewhere in the body. Hence, taken with algas, metals are more effectively eliminated in the urine.

  9. Shilajit is an ancient traditional medicine (Tibetan and Ayurvedic) and has been ascribed a number of pharmacological activities and has been used for ages as a rejuvenator and for treating a number of disease conditions. It is an effective detoxifier of metals and contains over 60 minerals. Modern scientific research has systematically validated a number of properties of shilajit and has proven that shilajit is truly a panacea. It is important to purchase the highest grade of shilajit.

  10. Administer oral reduced L-glutathione at 5 to 10 mg per KG of body weight daily. Do not overdose and check for renal clearance while using GSH. Glutathione is contraindicated in insulin deficiency. 

  11. Instruct patient to drink adequate amounts of pure water (Adult’s urine volume should be about 2 liters per day).

  12. Documented IV chelation therapy for nickel poisoning (for the treatment of persons exposed to nickel carbonyl) is sodium diethylcarbodithioate (DDTC). The use of DDTC was considered beneficial in a large number of anecdotal reports of human poisoning, although there are few adequately controlled human trials to support its effectiveness and lack of toxicity. Disulfiram is another nickel-chelating agent that has been used in nickel dermatitis and also in the case of nickel carbonyl poisoning. However, due to its hepatotoxicity and possible redistribution of nickel to the brain, its use in both indications is still controversial. 

Andersen, A. 1992. Cancer among nickel refinery workers, recent follow-up in Norway. In: Book of Abstracts; Fifth International Conference on Nickel Biochemistry Toxicology and Ecologic Issues; September; Sudbury, Canada. p. 19.  

 

Anke, M, Groppel, B, Kronemann, H, and Grün, M. Nickel: an essential element. In: F.W. Sunderman Jr. (Ed.) Nickel in the human environment. Oxford University Press, Oxford; 1984: 339-365.

 

Burrows, D.; Creswell, S.; Merritt, J. D. 1981. Nickel, hands and hip prostheses. Br. J. Dermatol. 105: 437-443. 

 

Casey, C. E.; Robinson, M. F. 1978. Copper, manganese, zinc, nickel, cadmium, and lead in human foetal tissues. Br. J. Nutr. 39: 639646.  

 

Coogan, T.P, Latta, D.M, Snow, E.T, and Costa, M. Toxicity and carcinogenicity of nickel compounds. Crit. Rev. Toxicol. 1989; 19: 341-384.

 

Costa, M, Simmons-Hansen, J, Bedrossian, C.W.M., Bonura, J, and Caprioli, R.M. Phagocytosis, cellular distribution, and carcinogenic activity of particulate nickel compounds in tissue culture. Cancer Res. 1981; 41: 2868-2876.

 

Drake, H.L. Biological transport of nickel. in: J.R Lancaster (Ed.) The bioinorganic chemistry of nickel. VCH, Weinheim; 1988: 111-139.

 

Dunnick, J. K.; Benson, J. M.; Hobbs, C. H.; Hahn, F. F.; Cheng, Y. S.; Eidson, A. F. 1988. Comparative toxicology of nickel oxide, nickel sulfate hexahydrate, and nickel subsulfide after 12 days of inhalation exposure to F344/N rats and B6C3F1 mice. Toxicol. 50: 145156.  

 

Dunnick, J. K.; Elwell, M. R.; Benson, J. M.; Hobbs, C. H.; Hahn, F. F.; Haley, P. J.; Cheng, Y. S.; Edison, A. F. 1989. Lung toxicity after 13-week inhalation exposure to nickel oxide, nickel subsulfide or nickel sulfate hexahydrate in F344/N rats and B6C3F1 mice. Fund. Appl. Toxicol. 12: 584594.  

 

Dunnick, J. K.; Elwell, M. R.; Radovsky, A. E.; Benson, J. M.; Hahn, F. F.; Nikula, K. J.; Barr, E. B., and Hobbs, C. H. Comparative carcinogenic effects of nickel subsulfide, nickel oxide, or nickel sulfate hexahydrate chronic exposures in the lung. Cancer Res. 55:5251-5256, (1995).  

 

Durham, NC: Nickel Producers Environmental Research Association; NiPERA Contract No. 89-09.  

 

Eck, P. and Wilson, L., Toxic Metals in Human Health and Disease, Eck Institute of Applied Nutrition and Bioenergetics, Ltd., Phoenix, AZ, 1.

 

Edoute, Y.; Vanhoutte, P. M.; Rubanyi, G. 1992. Mechanisms of nickel-induced coronary vasoconstriction in isolated perfused rat hearts. In: Nieboer, E., Advances in Environmental Sciences and Technology, Vol. 25, Nickel and Human Health: Current Perspectives, New York, 1992, pp. 587-602.

 

Haley, P. J.; Shopp, G. M.; Benson, J. M.; Cheng, Y. S.; Bice, D. E.; Luster, M. I.; Dunnick, J. K.; Hobbs, C. H. 1990. The immunotoxicity of three nickel compounds following 13 week inhalation exposure in the mouse. Fund. Appl. Toxicol. 15: 476487.

 

Malo, J.-L, Cartier, A, and Doepner, M. Occupational asthma caused by nickel sulfate. J. Allergy Clin. Immunol. 1982; 69: 55-59.

 

Nriagu, J. O., eds. Nickel and Human Health: Current Perspectives: Proceedings of the Fourth International Conference on Nickel Metabolism and Toxicology; September 1988; Helsinki, Finland. New York, New York: John Wiley & Sons, Inc. pp. 587-602.  

 

POISINDEX System, Thomson MICROMEDEX Health Care Series (monograph on CD-ROM), Vol. 122, 2004.

 

Ragsdale, S.W. Nickel biochemistry. Curr. Opin. Chem. Biol. 1998; 2: 208-215.

 

Redmond, C. K.; Arena, V. C.; Costantino, J. P.; Trauth, J. M.; Bass, G.; LeGasse, A. A. 1993. High nickel alloys workers study update: Final Report. 

 

Sunderman, F.W and Kincaid, J.F. Nickel poisoning: II. Studies on patients suffering from acute exposure to vapors of nickel carbonyl. JAMA. 1954; 155: 889-894.

 

Sunderman, F. W. Efficacy of sodium diethyldithiocarbamate (dithiocarb) in acute nickel carbonyl poisoning. Annals of Clinical & Laboratory Science 9.1 (1979): 1-10.

 

Sunderman, F.W Jr., Hopfer, S.M, and Sweeney, K.R. Nickel absorption and kinetics in human volunteers. Proc. Soc. Exp. Biol. Med. 1989; 191: 5-11.

 

Watt, R.K and Ludden, P.W. Nickel-binding proteins. Cell. Mol. Life Sci. 1999; 56: 604-6.

 

Young R.A. Toxicity Profiles. Toxicity summary for nickel and nickel compounds. 1995. Website: http://risk.lsd. ornl.gov/tox/profiles/nickel (accessed 03.03.2005).

References

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