THE ESSENTIALITY OF NICKEL
- INTRODUCTION
- HUMAN AND MAMMALIAN STUDIES
- PLANTS AND MICROORGANISMS
- DIETARY SOURCES OF NICKEL
- SUMMARY
- REFERENCES
- Table 1 - Levels of Nickel in Foods and Estimated Daily Intake
The issue of the essentiality of nickel has changed in recent years as investigators begin to uncover the importance of a variety of trace metal compounds in the proper functioning of living systems. As shall be discussed in this review, the concept of essentiality is comprised of several factors, and consideration of these various factors in determining essentiality is complex.
Trace nutrients can be defined most simply as those materials that make up less than 0.01% of the dry weight of an organism and are required for its normal health, function and development.1 During the 1960's and 1970's, establishing the essentiality of a trace element that could not be fed at dietary concentrations low enough to cause death or to interrupt the life cycle (interference with growth, development, maturation, and the production of offspring) involved the consideration of several criteria. These criteria included the element's occurrence in the natural environment; the presence in small but physiologically important amounts in the normal diet; the presence in body tissues; the presence in the newborn and/or maternal milk; and finally deprivation of the element resulting in structural or physiological abnormalities.2 In the 1980's and 1990's however, establishing the essentiality of an element on the basis of these criteria began to receive resistance when a large number of elements were suggested as essential. This was based upon some small change in a physiological or biochemical variable in an experimental animal model supposedly fed a diet deficient in that element. If the lack of an element can not be shown to cause death or interruption of the life cycle, most scientists today do not consider an element essential unless it has a defined biochemical function for the organism of interest. As with any scientific endeavor, there is not a unanimous agreement as to what constitutes specific proof of essentiality and some scientists still favor the criteria listed above. There is, however, a growing consensus among scientific groups that evidence supporting the contention that a trace element is essential generally fits into at least one of the following four categories:
- A dietary deprivation in an animal model consistently results in a changed biological function, tissue
composition, or body structure that is preventable or reversible by an intake of a physiological amount of
the element ion question.
- The element fills the need for a known biochemical action to occur both within the animal's body as well
as in experimental external studies.
- The element is a component of known biologically important molecules in some life form.
- The element has an essential function in lower forms of life.
An element is considered to have particularly strong circumstantial and/or direct support for essentiality if it has all four types of evidence; nickel fits into this category.
In 1975, the National Academy of Sciences published a monograph on nickel in which numerous enzyme systems were studied. The conclusion of the Academy was that the nickel ion (II) under various conditions, could either activate or inhibit several enzymatic reactions which are considered to be of crucial importance in humans and other animals, and that interference with these reactions could have severe deleterious effects.3 Often, when the beneficial roles of various materials are difficult to elucidate, the essentiality can be inferred from studies that focus on the effects associated with a deficiency of the material in animal models. As an example, early research done in chicks and rats indicated both macroscopic and microscopic changes in the liver of these animals when placed on nickel deficient diets. The changes which were most consistently observed included abnormalities of the sub-cellular organelles such as rough endoplasmic reticulum and mitochondria, decreases in phospholipids, depressed hematocrits, and generally thinner, more unhealthy appearing animals.4 Many of these changes are considered to be indicative of an essential role for nickel in protein synthesis in animals. It has also been reported that nickel-deficient rats exhibit depressed growth; hemoglobin; red blood cell counts; serum concentrations of urea; ATP and glucose; liver concentrations of glucose, glycogen and triglycerides; and activity of several liver and kidney enzymes.5 In later studies, goats were selected as representative of ruminant animals that may ingest nickel through dietary uptake of plants. These animals, when kept on a six-year diet in which the animals received 100 µg Ni/kg of food compared to the control animals which received 4000 µg Ni/kg, demonstrated a significant increase in mortality of offspring born to the nickel-deficient goats.6 Similar to the rats, changes in hematocrits were also noted. Interestingly, this study produced evidence of decreased amounts of calcium and zinc in the nickel-deficient goats.7 This may suggest a role for nickel in the normal utilization of zinc. Studies in lambs produced results that were consistent with those found in other species.8
Nickel has also been shown to play an interactive role with other materials important to the proper biological functioning of various metabolic systems. Specifically, nickel deprivation in rats affects vitamin B-12 levels with concomitant changes in growth, kidney weight-to-body weight ratios, and plasma concentrations of copper, iron, and molybdenum. In the absence of vitamin B-12, even rats on a nickel-supplemented diet tended to exhibit changes in these parameters which would have been expected to occur in nickel-deprived animals.9
Calcium also appears to have a physiological relationship with nickel that may be mediated by specific genes. One recent article10 describes the specific induction by nickel compounds of a novel gene, Cap43, in a transformed human lung cell line. This induction occurs in a time and dose-dependent manner at varying levels of both water soluble and insoluble nickel compounds. The induction of Cap43 was detected in different cell lines and did not occur in response to other metals of similar charge and ionic radius. The Cap43 gene was found to be conserved evolutionarily and regulated similarly in different species, including rats, mice, and humans. These findings raise the possibility that Cap43 plays a role in the possible essentiality of nickel in humans. Homocysteine was also found to induce the Cap43 gene in certain cell lines. Other studies11, 12 have suggested that nickel has a function that is related to changes cause by deprivation of folic acid, pyridoxine or vitamin B12. These vitamins are involved in sulfur amino acid metabolism including synthesis of homocysteine. Together, these results suggest a possible interaction between nickel and homocysteine regarding intracellular calcium levels and neuromuscular signal pathways. Interestingly, calcium is one of the elements whose concentrations have been consistently found to be altered by nickel deprivation in muscle and bone of test animals.
In plants and microorganisms, the importance of nickel has been well documented. In many cases, nickel is needed for the proper functioning of various plant enzymes such as urease and hydrogenase. In the decreased presence of urease, due to the lack of adequate nickel, urea accumulation leads to necrosis of the plant.13 In soybeans, where hydrogenase activity was depressed due to nickel-depletion, only low levels of nitrogen-fixation occurred, which resulted in slow plant growth and decreased crop yields. Nickel depletion has also been linked to necrosis of the leaves and stems of a variety of plants, lack of grain viability, and depressed vigor of seedlings.14 Because of the broad distribution of plants that exhibit a nickel requirement, the authors of the aforementioned studies suggest that this element is an essential micronutrient for all higher plants.
In microorganisms, energy-dependent nickel transport has been demonstrated in a variety of species. Energy dependency is an important characteristic within living systems to designate the distinction between the active need for an element to complete a given metabolic pathway, in contrast to the passive surface binding of a material. In several cases this transport is a function of interactions with other energy dependent systems such as the magnesium transport systems. In addition to magnesium, nickel transport may be inhibited by cobalt, copper or zinc, thus demonstrating possible inter-dependence upon other metallic elements.15 The role of nickel in microorganisms is not just an anecdotal one or one that occurs in rare and exotic enzyme systems. Very recently, nickel was discovered as a key component of the enzyme methyl-coenzyme M reductase, which is the key enzyme in biological methane formation in certain bacteria.16 The evidence enumerated above meets the criteria for establishing that nickel is essential for higher plants in that a plant grown in a medium adequately purged of that element fails to grow normally or complete its life cycle.17
Based on intake data and extrapolation from animal experiments, a dietary requirement for humans of 25-35 µg/day has been suggested for nickel.18 With the growing awareness of the importance of micronutrients, several multi-vitamin producers now add nickel to their products in concentrations ranging from 5-6.5 µg per tablet. Diets high in chocolate, nuts, dried beans, peas, and grains could supply more than 900 µg/day, while conventional diets usually provide around 150 µg/day.19 The other routine source of nickel in the diet is found in drinking water. Generally, the levels found in drinking water from sources around the world varies from 5-20 µg/l. In surveys such as one undertaken for Health Canada, the average and total daily intake of nickel for the general population has been estimated as follows:20
| Medium | Estimated Daily Intake | Total daily Intake* |
| (µg/kg body weight/day) | (µg/day) | |
| Ambient air | 0.0003-0.007 | 0.21-0.49 |
| Water | 0.004-0.15 | 0.28-10.5 |
| Soil | 0.002-0.014 | 0.14-9.8 |
| Food | 4.4 | 308 |
*The total daily intake estimations given above are based upon a 70 kg adult. More detailed information on the nickel content in a variety of foods can be found in Table 1.
In conclusion, both direct and circumstantial evidence supports the concept of essentiality of nickel in humans, animals, plants, and microorganisms. As more data is developed to clarify the essential role of nickel, a more quantitative requirement for this micronutrient may be developed. Further research into the essential role that nickel plays in living systems will undoubtedly uncover other important functions in addition to those described within this review.
1. Taylor, A. (1996). Detection and monitoring of disorders of essential trace elements. Ann. Clin. Biochem., 33, 486-510.
2. Schwarz, K. (1977). Essentiality versus toxicity of metals. In Clinical Chemistry and Chemical Toxicology of Metals, (S.S. Brown, Ed.), pp 3-22. Elsevier/North-Holland Biomedical Press, Amsterdam.
3. National Academy of Sciences Nickel Committee on Medical and Biological Effects of Environmental Pollutants - Nickel. National Academy of Sciences, Washington, DC 1975.
4. Nielsen, F.H. and Ollerich, D.A. (1974). Nickel: a new essential trace element. Fed. Proc., 33(6), 1767-1772.
5. Schnegg, A. and Kirchgessner, M. (1978). Ni deficiency and its effects on metabolism. In Trace Element Metabolism in Man and Animals-3, (M. Kirchgessner, Ed.), pp 236-243. Technische Universitat, Munchen.
6. Anke, M., Grün, M., and Kronemann, H. (1980). Distribution of nickel in nickel- deficient goats and their offspring. In Nickel Toxicology, (S.S. Brown and , F.W. Sunderman, Jr., Eds.), Academic Press, London, UK.
7. Spears, J.W., Hatfield, E.E., Forbes, R.M. and Koenig, S.E. (1978). Studies on the role of nickel in the ruminant. J. Nutr., 108, 313-320.
8. Nielsen, F.H. (1990). New essential trace elements for the life sciences. Biol. Trace Elem. Res., 26-27, 599-611.
9. Dalton, D.A., Russell, S.A. and Evans, H.J. (1988). Nickel as a micronutrient element for plants. Biofactors, 1(1), 11-16.
10. Zhou, D., Salnikow, K. and Costa, M. (1998). Cap43, a novel gene specifically induced by Ni2 compounds. Cancer Res., 58(10), 2182-2189.
11. Uthus, E.O. and Poellot, R.A. (1996). Dietary folate affects the response of rats to nickel deprivation. Biol. Trace Elem. Res., 52(1), 23-35.
12. Shuler, T.R. and Nielsen, F.H. (1985). Interactions among nickel, methionine and pyridoxine in rats: liver content of selected trace elements. Proceedings of the North Dakota Academy of Science, 39, 39.
13. Eskew, D.L., Welch, R.M. and Cary, E.E. (1983). Nickel: an essential micronutrient for legumes and possibly all higher plants. Science, 222, 621-623.
14. Brown, P.H., Welch, R.M. and Cary, E.E. (1987). Nickel: a micronutrient essential for higher plants. Plant Physiol., 85, 801-803.
15. Hausinger, R.P. (1992) Biological Utilization of Nickel. In Nickel and Human Health: Current Perspectives, (E. Nieboer and J.O. Nriagu, Eds.). Wiley Publishers, New York.
16. Ermler, U., Grabarse, W., Shima, S., Goubeaud, M. and Thauer, R.K. (1997). Crystal Structure of Methyl-Coenzyme M Reductase. Science, 278(5342), 1457-1462.
17. Epstein, E. (1972). Mineral Nutrition of Plants: Principles and Perspectives. Wiley Publishers, New York.
18. Anke, M., Angelow, L., Müller, M. and Glei, M. (1993). Trace Elements in Food, Dietary Intake, Excretion and Requirement: Dietary trace element intake and excretion of man. Trace Elements in Man and Animals-8 (M. Anke, D. Meissner and C.F. Mills, Eds.) pp 180-188. Verlag Media, Germany
19. Pennington, J.A.T. and Jones, J.W. (1987). Molybdenum, nickel, cobalt, vanadium, and strontium in total diets. J. Am. Diet. Assoc., 87(12), 1644-1650.
20. Canadian Environmental Protection Act. Priority Substances List Assessment Report. Nickel and its Compounds. (1994).
Table 1
Levels of Nickel in Foods and Estimated Daily Intake
| Composites | Nickel(µg/g)20 | Estimated Nickel Intake (µg/kg bw./day)a For 70 kg adult |
| 20 years (70 kg) |
||
| MILK AND DAIRY PRODUCTS | ||
| MILK, WHOLE | 0.009 | 0.018 |
| MILK, 2% B.F. | 0.002 | 0.0017 |
| MILK, SKIM | 0.010 | 0.0044 |
| EVAPORATED MILK, CANNED | 0.006 | 0.00098 |
| CREAM | 0.002 | 0.00029 |
| ICE CREAM, MIXED | 0.323 | 0.059 |
| YOGURT, MIXED | 0.014 | 0.00031 |
| YOGURT, PLAIN | 0.009 | 0.00020 |
| CHEESE | 0.066 | 0.0079 |
| CHEESE, COTTAGE | 0.019 | 0.0015 |
| CHEESE, PROCESSED CHEDDAR | 0.100 | 0.0054 |
| BUTTER | 0.017 | 0.0033 |
| MEAT AND POULTRY | ||
| BEEF STEAK, COOKED | 1.097 | 0.27 |
| ROAST BEEF | 0.047 | 0.018 |
| GROUND BEEF, COOKED | 2.521 | 0.78 |
| PORK, COOKED | 0.702 | 0.23 |
| PORK, CURED | 1.009 | 0.11 |
| VEAL, COOKED | 0.067 | 0.0021 |
| POULTRY, COOKED | 0.283 | 0.086 |
| EGGS | 0.007 | 0.0032 |
| MEAT ORGAN | 0.023 | 0.00092 |
| COLD CUTS & LUNCHEON MEATS | 0.062 | 0.0082 |
| LUNCHEON MEATS. CANNED | 0.044 | 0.0013 |
| FISH | ||
| MARINE FISH, COOKED | 0.211 | 0.020 |
| FRESHWATER FISH. COOKED | 0.047 | 0.00085 |
| FISH, CANNED | 0.101 | 0.0059 |
| SHELLFISH, FRESH OR FROZEN | 0.118 | 0.0033 |
| SOUPS | ||
| SOUPS, MEAT, CANNED | 0.689 | 0.54 |
| SOUPS, PEA, CANNED | 0.214 | 0.093 |
| SOUPS, TOMATO, CANNED | 0.198 | 0.020 |
| SOUPS, DEHYDRATED | 0.064 | 0.0070 |
| BAKERY GOODS AND CEREALS | ||
| WHITE BREAD, ALL | 0.053 | 0.051 |
| BREAD, WHOLE WHEAT AND RYE | 0.087 | 0.025 |
| BREAD, ROLLS AND BISCUITS | 0.243 | 0.035 |
| FLOUR, WHEAT | 0.135 | 0.013 |
| CAKE, WHITE, YELLOW, CHOCOLATE | 0.261 | 0.076 |
| COOKIES, ALL | 1.273 | 0.28 |
| DANISH AND DONUTS | 0.178 | 0.014 |
| CRACKERS | 0.441 | 0.022 |
| WAFFLES AND PANCAKES | 0.162 | 0.0047 |
| COOKED WHEAT CEREAL | 0.023 | 0.0021 |
| OATMEAL CEREAL | 0.248 | 0.058 |
| OATMEAL CEREAL, DRY | 0.964 | 0.23 |
| CORN CEREAL | 0.199 | 0.0052 |
| WHEAT AND BRAN CEREALS | 0.324 | 0.011 |
| RICE CEREAL, COOKED | 0.083 | 0.018 |
| PIE, APPLE | 0.096 | 0.0127 |
| PIE, OTHERS, MIX | 0.104 | 0.017 |
| PIZZA | 0.105 | 0.0026 |
| PASTA, CANNED | 0.081 | 0.018 |
| PASTA, PLAIN, COOKED | 0.012 | 0.0023 |
| VEGETABLES | ||
| CORN, RAW AND CANNED, COOKED | 0.053 | 0.0062 |
| POTATOES, BAKED | 0.059 | 0.0041 |
| POTATOES, BOILED, SKINS | 0.982 | 0.076 |
| POTATOES, PEELED, BOILED | 0.042 | 0.049 |
| FRENCH FRIES | 0.456 | 0.13 |
| POTATO CHIPS | 0.342 | 0.0064 |
| CABBAGE, COOKED AND COLESLAW | 0.027 | 0.0040 |
| CELERY | 0.058 | 0.0069 |
| PEPPERS, GREEN AND RED | 0.105 | 0.0019 |
| LETTUCE | 0.097 | 0.018 |
| CAULIFLOWER, RAW AND COOKED | 0.069 | 0.0014 |
| BROCCOLI, RAW AND COOKED | 0.081 | 0.0025 |
| BEANS, RAW AND CANNED, COOKED | 0.222 | 0.022 |
| PEAS, RAW AND CANNED, COOKED | 0.225 | 0.030 |
| CARROTS, COOKED, CANNED | 0.006 | 0.000051 |
| CARROTS, RAW | 0.056 | 0.011 |
| ONION, COOKED | 0.044 | 0.0039 |
| ONION, RAW | 0.060 | 0.0053 |
| TURNIPS, RUTABAGAS | 0.069 | 0.0056 |
| TOMATOES, RAW AND COOKED | 0.036 | 0.0092 |
| TOMATO JUICE, CANNED | 0.067 | 0.0096 |
| TOMATOES/SAUCE, CANNED & KETCHUP | 0.410 | 0.037 |
| MUSHROOMS, RAW | 0.045 | 0.000090 |
| MUSHROOMS, CANNED | 0.152 | 0.0032 |
| CUCUMBERS, RAW, PICKLED | 0.187 | 0.030 |
| FRUIT AND FRUIT JUICES | ||
| CITRUS FRUIT, RAW | 0.062 | 0.029 |
| CITRUS FRUIT, CANNED | 0.054 | 0.00012 |
| CITRUS JUICE | 0.015 | 0.0075 |
| CITRUS JUICE, CANNED | 0.012 | 0.0023 |
| APPLES | 0.042 | 0.012 |
| APPLE JUICE, CANNED | 0.0023 | |
| APPLE SAUCE | 0.038 | 0.0032 |
| BANANAS | 0.078 | 0.014 |
| GRAPES | 0.010 | 0.00042 |
| GRAPE JUICE, BOTTLED | 0.00052 | |
| PEACHES, CANNED AND RAW | 0.109 | 0.016 |
| PEARS, RAW, CANNED | 0.133 | 0.015 |
| PLUMS, PRUNES, DRIED, CANNED | 0.284 | 0.019 |
| CHERRIES, RAW AND CANNED | 0.42 | 0.012 |
| MELONS | 0.063 | 0.0089 |
| STRAWBERRIES | 0.090 | 0.010 |
| BLUEBERRIES | 0.133 | 0.0038 |
| PINEAPPLE, CANNED | 0.049 | 0.0015 |
| PINEAPPLE, RAW | 0.162 | 0.00019 |
| FATS AND OILS | ||
| COOKING FATS & SALAD OILS | 0.045 | 0.0032 |
| MARGARINE | 0.185 | 0.016 |
| PEANUT BUTTER & PEANUTS | 1.467 | 0.074 |
| SUGAR AND CANDIES | ||
| SUGAR | 0.003 | 0.00082 |
| SYRUP | 0.082 | 0.0058 |
| JAMS | 0.082 | 0.0072 |
| HONEY | 0.012 | 0.00037 |
| PUDDINGS, CHOCOLATE FROM POWDER | 0.185 | 0.023 |
| CANDY, CHOCOLATE | 0.577 | 0.030 |
| CANDY, OTHERS | 0.058 | 0.0037 |
| BEVERAGES | ||
| COFFEE | 0.015 | 0.075 |
| TEA | 0.052 | 0.26 |
| SOFT DRINKS | 0.0016 | |
| WINES | 0.028 | 0.0094 |
| BEER, BOTTLES AND CANS | 0.004 | 0.0069 |
| MISCELLANEOUS | ||
| BRAN MUFFINS, PLAIN | 0.185 | 0.0041 |
| BAKED BEANS | 0.178 | 0.021 |
| RAISINS | 0.074 | 0.00066 |
| WIENERS | 0.049 | 0.0017 |
| IN DESSERT | 0.006 | 0.00067 |
| BEETS, RAW AND CANNED, COOKED | 0.213 | 0.0055 |
| TOTAL | 4.40 | |
a = Estimates based on the concentrations of nickel in the various food types (NNW, 1992) multiplied by the age-specific food intakes from the Nutrition Canada Survey (END, 1992).
