Nickel is widespread, and it is an essential nutrient for plants and some bacteria. Instead, nickel deficiency in humans is not known, probably because it is a ubiquitous mineral. Nickel-containing cobalt and titanium alloys have become ubiquitous in the manufacturing of neurovascular medical devices.
Approximately 10-15% of the world population suffers from nickel allergy, and, according to dermatologists, its prevalence is increasing, probably due to the increased use of fashionable piercing (Genchi et al., 2020). Exposure to nickel in the general population is low and in the range of 0.1 to 0.3 mg of nickel per day. Contact with jewelry, coins, stainless steel, and other nickel-containing items or kitchenware can lead to exposure through the skin, which can also be dissolved by sweat and penetrate the skin more easily. Although nickel absorption through the skin is minimal, it is involved in the pathogenesis of contact dermatitis caused by nickel hypersensitivity (Mushak, 1984).
Nickel absorption is influenced by its chemical form
Nickel exists in different chemical forms in nature, but it is likely the nickel ion that causes systemic toxicity. The Nickel ion and its organic compounds are absorbed via the gastrointestinal tract or the respiratory passages, whereas a negligible amount is absorbed percutaneously.
There are five stable nickel isotopes, of which scientists use two specifically for tracer studies (61Ni and 62Ni). Nickel bioavailability to organisms and related biochemical processes are strongly dependent on the chemical and physical form (species) of the element. The nickel ion’s bioavailability is influenced by its solubility in biological fluids, although the latter is usually estimated based on water solubility. Soluble nickel compounds (e.g., nickel chloride, nickel sulfate) dissociate more quickly and more easily cross biological membranes; therefore, their absorption and diffusion in the organism are easier. Less soluble nickel compounds (e.g., nickel subsulfide and nickel oxide) tend to be less easily absorbed than soluble ones. However, their contribution to total nickel exposure is not negligible since their solubility might increase in the gastric acidic environment.
The most water-soluble nickel salts are:
- nickel chloride hexahydrate (NiCl2(H2O)6; 2,500 g/L),
- nickel dinitrate hexahydrate (Ni(NO3)2(H2O)6; 2,400 g/L),
- nickel sulfate hexahydrate (NiSO4(H2O)6; 660 g/L),
- nickel sulfate heptahydrate (NiSO4(H2O)7;760 g/L) and
- nickel acetate (Ni(CH3CO2)2(H2O)4; 170 g/L).
Less-soluble nickel compounds include nickel hydroxide (Ni(OH)2; 0.13 g/L) and nickel carbonate (NiCO3; 0.09 g/L). Nickel sulfides and oxides are practically insoluble in water.
Sources of nickel exposure
People can be exposed to nickel in different ways: air inhalation, food consumption, and water drinking. Food, in particular, is the primary source of nickel exposure. A less common route of exposure is the accidental ingestion of soil or dust contaminated with nickel. Tobacco use contributes up to 0.023 mg daily nickel uptake (equivalent to smoking 40 cigarettes a day) (IPCS, 1991, WHO, 2001). Infants can ingest nickel from breast milk, which can contain up to 0.79 mcg/L of this compound (Feeley et al., 1983). Factors such as host characteristics, nutritional and physiological status, as well as the stage of development, might influence nickel absorption.
Factors that can influence nickel absorption with food and water
Both chromium and nickel are heavy metals, and they can both be absorbed and bioaccumulated by several vegetables, including food tubers, such as carrots, potatoes, and onions. Many studies showed a correlation between the content in these metals in irrigation water (or soils) and the concentration in these foods (Stasinos et al., 2014).
Nickel absorption from food and water in humans occurs via intestinal absorption (Nielsen et al., 1999). Humans absorb 15 – 50% of the nickel ingested in drinking water after an overnight fast, compared to < 15% of the nickel from food (Sunderman et al., 1989). Total daily nickel intakes are approximately 200-300 mcg. However, the amount of nickel leaking from cooking ware and kitchen utensils (as well as water piping) can be as high as 1 mg/day (Grandjean, 1984).
In 1999, Nielsen and colleagues made some studies that extended and confirmed the results previously obtained by other researchers (Sunderman et al., 1989). The latter showed that having eggs 1.5 h before ingesting a water and nickel solution caused a lower absorption rate than when eating eggs four h before nickel exposure. The smaller the amount of time between the ingestion of eggs and the ingestion of the nickel solution, the lower the absorption rate measured by nickel excretion. The comparison between the eggs eaten four hours before nickel exposure and nickel mixed with the eggs showed a 10-fold difference in nickel excretion (and therefore absorption). The protein that eggs contain could, therefore, be able to chelate nickel or reduce its absorption.
The type of food ingested and its chemical characteristics can significantly influence the rate of nickel absorption by the gastrointestinal tract. Let’s explore this topic in more detail.
Chelating substances can suppress nickel absorption when the gastrointestinal tract does not absorb them. Examples of the latter substances include disulfiram and calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA), which doctors use to treat people with nickel poisoning.
Some food constituents, such as phosphate, phytate, fibers, and other nutrients with metal-ion-binding capability, represent chelating agents that are not absorbed and that might contribute to the reduce bioavailability of the nickel absorbed with food compared to the nickel absorbed with water on an empty stomach (Solomons et al., 1982; Sunderman et al., 1989).
Chelating agents that the gastrointestinal tract absorbs can, instead, enhance nickel absorption. In potatoes, legumes, and grains, nickel is usually bound to the starch (particularly to amylose and amylopectins), an example of a chelating agent that the gastrointestinal tract absorbs (Ciesielski and Pietr, 2004).
Since the nickel ion’s solubility depends on the pH of the medium where nickel is dissolved, the ingestion of food might influence nickel absorption by stimulating acid release in the stomach. Nickel is more soluble in an alkaline environment compared to an acidic one. However, eating a diet rich in alkaline foods does not necessarily help since many of these foods, such as fruit, nuts, legumes, and vegetables, are also rich in nickel and produce an allergic reaction in subjects sensitive to nickel.
Gastric emptying patterns differ between men and women and are slower in the latter (Oester-Joergensen et al., 1991). The longer nickel remains in the stomach, the higher is the probability that it will bind to food materials that can prevent its absorption, although its absorption also becomes more protracted.
Competitive inhibitors and redox reagents
Iron – Nickel absorption may also be suppressed by competitive inhibitors and redox reagents (e.g., vitamin C, a reducing agent). Regarding the former, in both rats (Onkelinx et al., 1973) and humans (Rezuke et al., 1987), scientists showed that nickel is eliminated via biliary excretion. Studies that used isolated small intestinal segments of rats and monolayers of human intestinal Caco2 cells indicate that nickel and iron share and compete for absorptive pathways (Forth and Rummel 1971; Valberg and Flanagan 1983; Tallkvist et al. 1994; Tallkvist and Tjälve 1997 & 1998).
In 2003 Tallkvist and colleagues showed that in laboratory-cultured cells cultivated in minimum essential medium (MEM) supplemented with iron for three days, nickel absorption was 50% lower than when the cells grown in MEM only. Tallkvist et al. (2003) showed that Divalent metal transporter 1 (DMT1) expression decreases in iron-treated Caco-2 cells. The down-regulation of DMT1 correlated with reduced uptake of iron and nickel into the Caco-2 cells. Since DMT1 mRNA levels correlate with iron and nickel uptake in fully differentiated Caco-2 cells, these metals are both taken up by DMT1 in the intestinal epithelium, and adequate iron intake and status, therefore, likely limit nickel absorption. However, these are in vitro studies, and caution is needed when drawing any practical conclusion concerning humans.
These results suggest that, by assuring adequate iron intake and status, nickel absorption and toxicity should be lower. A higher intestinal nickel absorption due to low iron status may therefore potentiate nickel sensitization. However, there are only animal studies showing that iron-deficient subjects absorb more nickel than non-deficient subjects (Tallkvist et al., 1994).
Cadmium – Another heavy metal that can compete with nickel absorption is cadmium, which can delay nickel absorption. However, it also has an inhibitory effect on nickel elimination, therefore favoring nickel bioaccumulation. Nickel and cadmium bind to the same proteins in the bloodstream. The richest foods in cadmium are cereals and cereal products, some vegetables, nuts and pulses, starchy roots including potatoes, and meat and meat products. Vegetarians tend to have the highest exposure levels to cadmium due to their high consumption of cereals, nuts, oilseeds, and pulses (source: European Commission). Unfortunately, most of these foods are also rich in nickel and induce an allergic reaction in sensitive subjects.
Vitamin C – Redox reagents, such as vitamin C, are likely to reduce dietary nickel absorption (Joneja, 1995; Solomons et al., 1982). Co-ingestion or lack of these two nutrients can have a major effect on nickel absorption, even without altering the amount of nickel consumed.
Alternative ways to decrease dietary nickel absorption (and promote fecal excretion) could therefore be to recommend consumption of iron-rich foods (e.g., meat) and vitamin C-rich foods (e.g., kiwis, citrus fruit) in the same meal as nickel-rich foods (e.g., nuts, tomatoes, etc.) or to recommend vitamin C supplementation.
Nickel absorption in sensitized people
Old studies on nickel kinetics inside the human body suggested that nickel absorption might be different when comparing sensitized with non-sensitized individuals. In allergic patients, nickel could more easily bind to serum proteins and cells, particularly T-lymphocytes (Hildebrand et al., 1987), affecting nickel’s toxicokinetics.
Nickel-sensitized subjects might eliminate nickel less efficiently (Nielsen et al., 1987, 1990; Bonde et al., 1990; Grandjean et al., 1992), perhaps because it binds more readily to cells and endogenous proteins (Hildebrand et al., 1987) such as albumin, L-histidine, and α-2-macroglobulin (Sunderman, 1993).
The nervous system is one of the main targets of nickel toxicity; it accumulates in the brain. However, nickel has also been found in the lungs, thyroid, adrenal gland, and bones (Rezuke et al., 1987). The relative order of bioaccumulation of nickel in different organs of rats when treated at 0.1% nickel sulfate (223.5 mg Ni/L) was: kidneys > testes > lung and brain > spleen > heart and liver (Obone et al., 1999).
The rate of nickel accumulation in the human body is a function of time, absorption medium (food, water, etc.), tissue distribution, and excretion. However, nickel usually does not accumulate in tissues due to efficient excretion but, because of this, the kidneys are the primary target organs of nickel retention. The rate of nickel accumulation into the organism also depends on genetic factors, such as specific polymorphisms in genes coding for proteins involved in metal transport (Ng et al., 2015).
Assessment of nickel exposure and absorption
In general, nickel concentrations in body fluids are generally proportional to exposure levels; the absence of increased values usually indicates non-significant exposure. The presence of increased values should be a signal to reduce exposure.
Most of the absorbed nickel is excreted by the kidneys in the urine as low-molecular-weight complexes. Urine represents the main excretion route of nickel, irrespectively of the way of exposure (Christensen and Lagesson, 1981; Angerer and Lehnert, 1990). Therefore, nickel urine excretion is often considered a measure of nickel absorption. The higher urine excretion is, the more nickel was absorbed and eliminated by the organisms. Urine analysis is also the most practical way to biological monitor nickel exposure and the most commonly used in nickel kinetics studies.
Small nickel amounts are also excreted through bile, sweat, hair, saliva, and mother’s milk (Sunderman et al., 1991; Grandjean et al., 1988).
The serum is usually not used in studies on nickel exposure because it has the disadvantage of requiring venipuncture with a plastic cannula to avoid nickel contamination from stainless steel needles. The reference values for serum nickel concentrations are only slightly above the detection limit of current analytical methods in persons without occupational exposure (Sunderman et al., 1986; 1988; 1989; Grandjean et al., 1988).
Fecal excretion primarily reflects the nickel that is not absorbed from the diet and passes through the gut (Sunderman et al., 1986; Horak & Sunderman, 1973). Therefore, feces are the most reliable specimen for the biological monitoring of dietary nickel intake, irrespectively of the amount absorbed which can vary among individuals (Sunderman et al., 1986; Sunderman et al., 1989; Horak & Sunderman, 1973; Hassler et al., 1983). However, scientists rarely collect feces during nickel exposure studies because of the disadvantages of their analysis. The latter include the burden of collecting the feces for 3 – 5 d, of pooling and homogenizing the specimens, digesting the samples with concentrated acids, and the extraction of nickel into an organic solvent before analysis by atomic absorption spectrometry.
Nickel concentration in body fluids is not an indicator of specific health risks, except in the case of exposure to nickel carbonyl [Ni(CO)4], for which urine nickel concentrations indicate the severity of the poisoning. Nickel carbonyl is used in nickel coat steel and other metals and to make a very pure nickel. This chemical form is considered one of the most dangerous in nickel chemistry because of its high absorption rates via inhalation and skin. However, the exposure routes to this compound are mostly occupational (via inhalation), and nickel carbonyl is progressively falling out of use because of its health hazards.
In case of exposure to less soluble nickel compounds (e.g., nickel subsulfide, nickel oxide), increased concentrations of nickel in body fluids indicate significant nickel absorption and signal the necessity to reduce exposure. The absence of increased values does not necessarily imply no health risks associated with exposures are possible (e.g., cancers of the lung and nasal cavities).
Conclusions and general recommendations to reduce nickel absorption
Unfortunately, the few human studies on nickel absorption and toxicokinetic have all been published many years ago, and there haven’t been many signs of progress during the past few decades. The only toxicokinetic model in the literature for human exposure to Ni through the oral pathway is that of Sunderman et al. (1989), following controlled oral exposure to Ni ions. Indeed, the most recent evaluation of the evidence in this field by the European Food Safety Authority (EFSA) (EFSA Contam Panel, 2020) cited the same old studies cited in this post, i.e., those published by Sunderman and other researchers in the ’80s and ’90s. A better understanding of nickel metabolism would help better understand its toxicity.
Nickel allergy remains a neglected health topic and an unsolved rebus for many. Consuming fewer foods potentially rich in nickel can help, but most of these, such as nuts and legumes, are also recommended by official dietary guidelines.
At the moment, the only reasonable way to reduce exposure is to limit the consumption of nickel-rich foods, especially grains and legumes, since the starch they contain can chelate nickel and favor its absorption. The inclusion of vitamin C-rich and iron-rich foods in the diet (or the use of supplements) might reduce the absorption of nickel from other foods.
Finally, an alkaline environment can reduce nickel absorption in both humans and plants; therefore, plants that tend to absorb nickel more than others (i.e., legumes, tomatoes, etc.) should be cultivated on alkaline soils to minimize their nickel content.
Get in touch with me if you think we could collaborate on a research project on nickel absorption or if you are thinking of launching a new line of low-nickel foods.
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