Nickel

• Enzyme cofactor
• Metabolic processes support

• Potential role in iron absorption
• Possible support for blood cell formation
• Potential role in hormone production

Standard Dosage Range: No standard supplemental dosage exists for nickel as it is not recognized as an essential nutrient requiring supplementation. Dietary intake from food and water (typically 100-300 μg/day) is generally considered adequate for any potential biological functions.

Dosing Frequency: Not applicable for supplementation purposes. Natural dietary exposure occurs daily through regular food and water consumption.

Timing Considerations: Not applicable for supplementation purposes. For individuals with nickel sensitivity attempting to reduce exposure, consuming high-nickel foods earlier in the day may allow more time for processing and excretion before sleep.

Upper Limits: The European Food Safety Authority has established a Tolerable Daily Intake (TDI) of 2.8 μg/kg body weight per day (approximately 170-200 μg/day for adults). This represents a safety threshold rather than an optimal intake level.

Minimum Effective Dose: No established minimum effective dose exists as no clear deficiency syndrome or therapeutic applications have been established in humans.

Optimal Therapeutic Range: Not applicable as no therapeutic applications have been established.

Toxic Threshold: Acute toxicity typically requires doses >10 mg. Chronic toxicity thresholds are less clear but may begin at regular exposure levels of 1-2 mg/day in sensitive individuals.

Lethal Dose: The estimated lethal dose in humans is 50-500 mg/kg body weight of soluble nickel compounds, though this is based on limited data and animal extrapolation.

General Characteristics: Nickel absorption is generally poor, with only approximately 1-10% of dietary nickel being absorbed in the gastrointestinal tract. Absorption primarily occurs in the small intestine, with some evidence suggesting the duodenum as the major site. The absorption process involves both passive diffusion and active transport mechanisms. Nickel absorption is highly variable between individuals and can be significantly affected by various dietary and physiological factors. Unlike essential minerals with homeostatic regulation, nickel absorption does not appear to be tightly regulated based on body status.

Absorption Mechanisms: Nickel absorption involves multiple mechanisms: 1) Passive diffusion of soluble nickel ions across the intestinal epithelium, particularly in the duodenum and jejunum; 2) Active transport via divalent metal transporters, including DMT1 (divalent metal transporter 1), which also transports iron and other divalent metals; 3) Paracellular transport between epithelial cells, particularly for nickel bound to small organic molecules. The relative contribution of each pathway varies depending on nickel speciation, concentration, and intestinal conditions.

Factors Enhancing Absorption: Several factors can enhance nickel absorption: 1) Fasting state significantly increases absorption, with studies showing 10-40 times higher absorption when nickel is consumed with water on an empty stomach compared to with food; 2) Soluble nickel compounds (nickel chloride, nickel sulfate) are more readily absorbed than insoluble forms; 3) Acidic conditions in the stomach increase nickel solubility and subsequent absorption; 4) Certain chelating agents or organic ligands may enhance absorption by forming soluble complexes; 5) Vitamin C may enhance absorption through reduction of nickel to more absorbable forms.

Factors Reducing Absorption: Numerous dietary factors reduce nickel absorption: 1) Food matrix significantly reduces absorption, with proteins, phytates, and fiber being particularly effective at binding nickel; 2) High dietary content of competing minerals, particularly iron, zinc, and calcium, can reduce nickel absorption through competitive inhibition of shared transport mechanisms; 3) Antacids and medications that increase gastric pH may reduce nickel solubility and absorption; 4) Tannins and polyphenols in tea, coffee, and certain foods can bind nickel and reduce its bioavailability; 5) Phosphates and oxalates may form insoluble complexes with nickel, limiting absorption.

Plasma Transport: Once absorbed, nickel is transported in the bloodstream primarily bound to serum proteins. Approximately 50-75% of serum nickel is bound to albumin, while smaller fractions bind to alpha-2-macroglobulin, transferrin, and other proteins. A small percentage (2-5%) circulates as free nickel ions or bound to low molecular weight compounds like histidine and cysteine. The protein-bound forms serve as the primary transport mechanism, while the free or loosely bound fraction is more readily available for cellular uptake and excretion.

Tissue Distribution: Nickel distributes widely throughout the body, with highest concentrations typically found in the lungs, kidneys, liver, and endocrine glands. Significant amounts also accumulate in bone, where it may have a biological half-life of several years. The distribution pattern reflects both current exposure and historical accumulation. In occupationally exposed individuals, lung tissue may contain particularly high concentrations. Nickel can also accumulate in the placenta and cross into fetal circulation, though concentrations in fetal tissues are typically lower than maternal levels.

Cellular Uptake: Cellular uptake of nickel occurs through multiple mechanisms: 1) Divalent metal transporters including DMT1, which also transport iron and other metals; 2) Calcium channels, which can transport nickel due to similar ionic radius; 3) Specific nickel transporters identified in certain microorganisms, though their human equivalents are not well characterized; 4) Endocytosis of protein-bound nickel, particularly via transferrin receptors. Once inside cells, nickel can bind to various proteins, incorporate into metalloenzymes, or accumulate in subcellular compartments including the nucleus.

Blood Brain Barrier Penetration: Nickel can cross the blood-brain barrier, though the process is relatively inefficient compared to essential trace elements. Transport appears to involve both transferrin receptor-mediated mechanisms and passive diffusion of free nickel ions. Brain concentrations are typically lower than those in other organs, but chronic exposure can lead to accumulation. The blood-brain barrier becomes more permeable under certain conditions including inflammation, potentially increasing CNS nickel exposure during inflammatory states.

Biotransformation: Unlike organic compounds, nickel as an element cannot be metabolized in the traditional sense of structural modification. However, it undergoes various biotransformations affecting its oxidation state, binding partners, and biological activity. The primary transformations include: 1) Redox reactions between Ni(II) and Ni(III) states, with Ni(II) being the predominant form in biological systems; 2) Exchange between protein-bound and free ionic forms; 3) Formation of various coordination complexes with biological ligands including amino acids, peptides, and proteins.

Protein Binding: Nickel forms complexes with numerous proteins and peptides in biological systems. Key binding interactions include: 1) Coordination with histidine, cysteine, and other amino acid residues in proteins; 2) Specific binding to metalloproteins including urease and glyoxalase I in certain organisms; 3) Non-specific binding to serum proteins, particularly albumin; 4) Interaction with metal-regulatory proteins including metal-responsive element-binding transcription factor-1 (MTF1). These interactions affect nickel’s biological activity, transport, and toxicity.

Detoxification Mechanisms: The body employs several mechanisms to detoxify and eliminate nickel: 1) Binding to metallothioneins, cysteine-rich proteins that sequester various metals; 2) Antioxidant systems including glutathione, superoxide dismutase, and catalase that counteract nickel-induced oxidative stress; 3) Cellular export via metal efflux transporters; 4) Sequestration in lysosomes and other subcellular compartments; 5) Renal filtration and excretion of soluble nickel compounds.

Enzymatic Interactions: Nickel interacts with various enzymes, either as a cofactor or as an inhibitor: 1) Functions as a cofactor for urease, hydrogenase, and certain other enzymes in microorganisms and plants, though its role in human enzymes remains controversial; 2) Can inhibit numerous enzymes through various mechanisms including displacement of native metal cofactors, binding to catalytic sites, or inducing conformational changes; 3) May interfere with iron-sulfur cluster assembly and function, affecting multiple metabolic pathways; 4) Can disrupt zinc finger proteins involved in DNA repair and transcriptional regulation.

Primary Excretion Routes: Nickel is primarily excreted via the kidneys, with urinary excretion accounting for approximately 70-80% of absorbed nickel. Fecal excretion represents the second major route, consisting primarily of unabsorbed dietary nickel plus a smaller component from biliary excretion and intestinal secretion. Minor excretion routes include sweat, saliva, breast milk, and hair. The relative contribution of each pathway can vary based on exposure route, nickel speciation, and individual factors including kidney function and sweat rate.

Excretion Kinetics: Nickel excretion follows complex kinetics with multiple phases: 1) An initial rapid phase with half-life of 20-60 hours, representing clearance of free and loosely bound nickel; 2) An intermediate phase with half-life of 50-100 days, reflecting release from soft tissue stores; 3) A slow phase with half-life of several years, corresponding to release from bone and other long-term storage sites. Following a single exposure, approximately 50-75% of absorbed nickel is excreted within 24-48 hours, primarily in urine.

Factors Affecting Excretion: Several factors can significantly affect nickel excretion: 1) Kidney function is the primary determinant, with reduced glomerular filtration rate decreasing nickel clearance; 2) Urine pH affects nickel solubility and reabsorption in the renal tubules, with acidic urine generally enhancing excretion; 3) Hydration status influences urinary concentration and flow rate, affecting nickel clearance; 4) Chelating agents including EDTA can significantly enhance nickel excretion and are used therapeutically in cases of toxicity; 5) Competitive interactions with other metals may affect renal handling and excretion rates.

Biliary Excretion: Biliary excretion represents a minor but significant route for nickel elimination, accounting for approximately 5-10% of absorbed nickel. This process involves hepatic uptake of nickel, incorporation into bile, and excretion into the intestinal tract. Some of this biliary nickel may be reabsorbed in the intestine (enterohepatic circulation), prolonging its retention in the body. Biliary excretion appears to be more significant for certain nickel compounds and may play a greater role in detoxification of nickel-protein complexes.

Absorption Rate: Nickel absorption is relatively slow compared to many nutrients, with peak plasma concentrations typically occurring 1.5-2.5 hours after ingestion on an empty stomach and 3-6 hours when consumed with food. The absorption rate is highly dependent on solubility, with nickel salts (chloride, sulfate) being absorbed more rapidly than less soluble forms. The presence of food significantly slows absorption rate in addition to reducing total bioavailability.

Bioavailability Percentage: The bioavailability of dietary nickel is typically 1-10% of ingested dose, with significant variation based on numerous factors. When consumed with water on an empty stomach, bioavailability may increase to 20-25%. Soluble nickel compounds generally show higher bioavailability (5-10%) compared to less soluble forms (<1%). Individual variation is substantial, with some studies showing 3-5 fold differences between individuals consuming identical nickel doses.

Volume Of Distribution: Nickel shows a moderate volume of distribution of approximately 0.5-1.0 L/kg, indicating distribution beyond plasma into tissues. This relatively limited distribution reflects significant protein binding and preferential accumulation in specific tissues rather than uniform distribution throughout body water. The apparent volume of distribution may increase with chronic exposure as nickel accumulates in deeper compartments including bone.

Elimination Half Life: Nickel elimination follows multi-phasic kinetics: 1) Initial rapid phase: 20-60 hours; 2) Intermediate phase: 50-100 days; 3) Terminal phase: 1-3 years. The weighted average half-life for a single exposure is approximately 28-35 hours, though this varies based on exposure history, nickel speciation, and individual factors. Chronic exposure leads to accumulation in slow-turnover compartments, extending the effective half-life.

Chemical Form: The chemical form of nickel significantly impacts its bioavailability: 1) Soluble inorganic salts (nickel chloride, nickel sulfate) show highest bioavailability (5-10%); 2) Insoluble compounds (nickel oxide, nickel subsulfide) have very low bioavailability (<1%); 3) Organically bound nickel in foods shows intermediate and variable bioavailability (1-5%); 4) Nickel bound to proteins or incorporated into food matrices typically has reduced bioavailability compared to free nickel salts.

Dietary Factors: Numerous dietary components affect nickel bioavailability: 1) Phytates in whole grains, legumes, and nuts bind nickel and reduce absorption; 2) Dietary fiber, particularly insoluble fiber, can bind nickel and reduce bioavailability; 3) Ascorbic acid (vitamin C) may enhance nickel absorption through reduction to more absorbable forms; 4) Protein content of meals generally reduces nickel absorption through binding and complex formation; 5) Tannins and polyphenols in tea, coffee, and certain fruits form insoluble complexes with nickel, reducing absorption.

Physiological Factors: Individual physiological factors significantly influence nickel bioavailability: 1) Gastric acidity enhances nickel solubility and absorption, with reduced stomach acid (due to aging, medications, or medical conditions) potentially decreasing bioavailability; 2) Intestinal transit time affects exposure duration and absorption opportunity, with faster transit generally reducing bioavailability; 3) Age-related changes in digestive function and intestinal permeability may alter nickel absorption, though specific patterns are not well established; 4) Pregnancy may increase nickel absorption due to upregulation of metal transporters and altered gastrointestinal function.

Pathological Conditions: Various health conditions can affect nickel bioavailability: 1) Inflammatory bowel diseases may increase nickel absorption due to compromised intestinal barrier function; 2) Hemochromatosis and iron overload conditions may decrease nickel absorption through competitive inhibition of shared transport mechanisms; 3) Kidney disease reduces nickel excretion, potentially leading to accumulation despite unchanged absorption; 4) Malabsorption syndromes generally reduce nickel absorption along with other nutrients.

Overall Safety Rating: Low to Moderate – Nickel has a narrow therapeutic window with significant safety concerns at supplemental doses

Safety Context: Nickel is an ultra-trace mineral that is present in the human body in extremely small amounts. While it may have some biological functions, nickel is primarily considered a potential toxin rather than a beneficial supplement. The margin between adequate dietary intake and potentially harmful levels is narrow. Most people obtain sufficient nickel through their diet, and supplementation is generally unnecessary and potentially harmful. Safety concerns are particularly significant for individuals with nickel sensitivity or allergy, which affects approximately 10-20% of the population.

Regulatory Status:

• Not approved as a standalone dietary supplement with specific health claims. No established RDA or AI (Adequate Intake) values.
• No specific regulations for nickel as a supplement. The EFSA has established a Tolerable Daily Intake (TDI) of 2.8 μg/kg body weight per day.
• Not approved as a supplement with health claims. Considered a contaminant rather than a nutrient in most contexts.
• Not approved as a supplement with health claims. No established recommended intake levels.

Population Differences: Significant population differences exist in nickel sensitivity and metabolism. Women are more likely to experience nickel allergy than men (approximately 2:1 ratio). Individuals with compromised kidney function may have reduced ability to excrete nickel, increasing risk of accumulation. Those with existing nickel allergy or sensitivity (10-20% of the general population) should strictly avoid nickel supplements.

Common Side Effects:

Rare Side Effects:

Theoretical Concerns:

Absolute Contraindications:

Relative Contraindications:

Special Populations:

Significant Interactions:

Moderate Interactions:

Minor Interactions:

Common Allergens:

• High – nickel is one of the most common contact allergens worldwide, affecting approximately 10-20% of the general population. While contact allergy is most common, systemic reactions to oral nickel can occur in sensitized individuals.
• Potential cross-reactivity with other metals, particularly cobalt and palladium. Approximately 20-30% of nickel-allergic individuals may also react to cobalt. Cross-reactivity appears to be due to similarities in electron configuration and binding properties.
• Nickel supplements may contain various excipients, fillers, or coating materials that could cause allergic reactions in sensitive individuals. Common problematic excipients include certain dyes, preservatives, and binding agents.

Allergic Reaction Characteristics:

• Contact dermatitis is the most common manifestation, characterized by redness, itching, swelling, and vesicle formation. Systemic reactions to oral nickel may include widespread dermatitis, urticaria, gastrointestinal symptoms (nausea, vomiting, diarrhea), headache, fatigue, and in severe cases, respiratory symptoms or anaphylaxis.
• Contact reactions typically develop within 24-48 hours of exposure. Systemic reactions to oral nickel may occur more rapidly, sometimes within hours of ingestion, particularly in highly sensitized individuals.
• Female gender (approximately 2:1 female to male ratio for nickel allergy), history of atopic conditions (eczema, asthma, allergic rhinitis), genetic predisposition, previous dermal sensitization (e.g., from jewelry, watches, or other nickel-containing items), occupational exposure to nickel.

Hypoallergenic Formulations:

• No truly hypoallergenic nickel formulations exist, as the element itself is the primary allergen. For individuals requiring trace nickel for research or specific medical purposes, certain chelated forms may be less allergenic, but evidence is limited.
• If nickel administration is absolutely necessary in sensitive individuals (which is rare), consider forms with minimal free nickel ions, administration routes that bypass initial immune contact, or desensitization protocols under medical supervision.
• Higher purity formulations with minimal contaminants may reduce risk of additional reactions, but will not eliminate the allergenic potential of nickel itself.

Acute Toxicity:

• Oral LD50 in rats: 350-500 mg/kg for nickel chloride; 600-800 mg/kg for nickel sulfate. Human toxicity occurs at much lower doses, with significant adverse effects possible at 7-10 mg/kg.
• Single doses above 1 mg in humans may cause significant gastrointestinal distress. The tolerable upper intake level is set at 1 mg/day for adults, though sensitive individuals may react to much lower doses.
• Acute nickel poisoning manifests primarily as gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), followed by neurological effects (headache, dizziness, visual disturbances), cardiovascular effects (tachycardia, hypotension), and in severe cases, metabolic acidosis, acute kidney injury, and hepatotoxicity.

Chronic Toxicity:

• Chronic exposure to elevated nickel levels has been associated with increased oxidative stress, inflammation, and tissue damage in multiple organ systems. Animal studies show dose-dependent effects on liver, kidney, and reproductive function with chronic exposure.
• Primary target organs include the skin (dermatitis, eczema), respiratory system (rhinitis, asthma, reduced lung function), kidneys (tubular damage, reduced filtration), liver (elevated enzymes, steatosis), and immune system (altered cytokine production, hypersensitivity).
• Certain nickel compounds are classified as Group 1 carcinogens (carcinogenic to humans) by IARC, particularly for respiratory cancers following inhalation exposure. The carcinogenic potential of oral nickel at supplement doses is less clear but remains a concern for long-term exposure.
• Nickel compounds have demonstrated mutagenic potential in various test systems, including bacterial and mammalian cell assays. Mechanisms include DNA damage through reactive oxygen species, direct DNA binding, inhibition of DNA repair enzymes, and epigenetic alterations.

Reproductive Toxicity:

• Animal studies show that high-dose nickel exposure can reduce fertility in both males and females. Effects include altered hormone levels, reduced sperm quality, and disrupted estrous cycling. Human data is limited but suggests potential concerns at high exposure levels.
• Nickel crosses the placental barrier and has demonstrated embryotoxic and teratogenic effects in animal studies at doses that cause maternal toxicity. Effects include increased resorptions, reduced fetal weight, and skeletal abnormalities. Human data is limited but warrants caution.
• Nickel is excreted in breast milk, with levels correlating with maternal exposure. Safety during lactation has not been established, and supplementation should be avoided.

Genotoxicity:

• Nickel compounds can cause DNA damage through multiple mechanisms: generation of reactive oxygen species, direct binding to DNA causing conformational changes, inhibition of DNA repair enzymes, and disruption of epigenetic regulation including DNA methylation and histone modifications.
• Various nickel compounds have been shown to induce chromosomal aberrations, micronuclei formation, and sister chromatid exchanges in both in vitro and in vivo test systems.
• Nickel exposure has been associated with significant epigenetic alterations, including changes in DNA methylation patterns, histone modifications, and microRNA expression. These changes may contribute to long-term health effects including carcinogenesis.

Common Contaminants:

• Nickel supplements may contain other heavy metal contaminants including lead, cadmium, arsenic, and mercury. These contaminants may contribute to toxicity and should be strictly limited according to established safety standards.
• Depending on manufacturing processes, residual chemicals including solvents, acids, or bases may be present. These should be monitored and controlled according to good manufacturing practices.
• As with any supplement, microbial contamination is possible during processing, packaging, or storage. Proper quality control measures should ensure compliance with established microbial limits.

Quality Indicators:

• Nickel compounds vary in appearance depending on the specific form. Nickel chloride typically appears as green to yellow crystals, while nickel sulfate forms blue-green crystals. Unusual coloration may indicate impurities or degradation.
• Solubility varies by compound: nickel chloride and sulfate are highly water-soluble, while nickel oxide is poorly soluble. Unexpected solubility characteristics may indicate quality issues.
• Specific analytical techniques including atomic absorption spectroscopy, ICP-MS, or ICP-OES should be used to verify nickel content and purity. Established pharmacopeial methods provide standardized approaches for quality assessment.

Adulteration Concerns:

• Deliberate adulteration of nickel supplements is uncommon due to their limited market presence. However, mislabeling of nickel content or form is possible and could pose safety risks.
• Sophisticated analytical techniques including ICP-MS, X-ray diffraction, and spectroscopic methods can identify and quantify specific nickel compounds and potential adulterants.
• Third-party testing and certification can help ensure product quality and safety. Look for certifications from recognized organizations that verify content, purity, and absence of significant contaminants.

Recommended Monitoring:

• Routine monitoring is not typically necessary for dietary nickel exposure. For those taking supplements (which is generally not recommended), periodic assessment for allergic reactions and symptoms of toxicity is advisable.
• Those with known nickel sensitivity, kidney disease, or occupational exposure should undergo more comprehensive monitoring including periodic assessment of kidney function, liver enzymes, and dermatological evaluation.
• For significant exposure: complete blood count, kidney function tests (BUN, creatinine, GFR), liver function tests (ALT, AST, ALP), urinary nickel levels, and dermatological assessment.

Warning Signs:

• Skin reactions (rash, itching, eczema), gastrointestinal symptoms (nausea, abdominal discomfort), headache, fatigue, and metallic taste may indicate adverse reactions to nickel exposure.
• Severe allergic reactions, persistent or widespread dermatitis, significant gastrointestinal distress, respiratory symptoms, or abnormal laboratory values (particularly kidney or liver function) warrant immediate discontinuation and medical evaluation.
• For those with occupational exposure or on nickel-containing supplements: baseline evaluation followed by monitoring every 3-6 months or as clinically indicated.

Long Term Safety:

• Nickel can accumulate in tissues with chronic exposure, potentially leading to long-term health effects including sensitization, organ damage, and increased cancer risk. The relationship between cumulative dose and specific health outcomes remains an area of ongoing research.
• Urinary nickel levels reflect recent exposure, while nickel in hair or nails may indicate longer-term exposure. Tissue biopsy (rarely performed) can assess organ-specific accumulation.
• Following significant nickel exposure, monitoring should continue for at least 6-12 months, with particular attention to kidney function, respiratory health, and dermatological conditions.

Natural Sources

Commercial Production

Quality Assessment

Market Considerations

Supplement Specific Considerations

Overall Evidence Rating: Low – Limited evidence for essential role in humans; more substantial evidence for potential toxicity

Strongest Evidence Areas: Role in certain microorganisms, plants, and some animal species, Toxicological effects at higher exposure levels, Mechanisms of nickel allergy and hypersensitivity

Weakest Evidence Areas: Essential role in human nutrition, Beneficial effects of supplementation, Optimal intake levels for potential biological functions

Research Trajectory: Research has primarily focused on nickel toxicity, occupational exposure, and allergy mechanisms rather than potential nutritional roles. Recent interest in low-dose biological effects has emerged, but remains preliminary.