Nickel is a common metal present in the environment, and human exposure can occur through diet, the environment and materials we touch. Soluble and insoluble nickel compounds can lead to several adverse health effects, with nickel sulphate being the most potent. Workers in nickel processing industries are most frequently exposed to high levels of nickel through inhalation and skin contact, which can result in allergies, gastrointestinal and respiratory symptoms, Allergic Contact Dermatitis (ACD) and Systemic Nickel Allergy Syndrome (SNAS). Although the exact molecular pathways of nickel-induced neurotoxicity are unknown, oxidative stress and mitochondrial dysfunctions play crucial roles.
The multiple uses of nickel
Nickel has several industrial and commercial uses due to its great physicochemical properties, such as high-temperature resistance, oxidation and corrosion resistance, a melting point of 1455°C, and a boiling point of 2913°C. It exists mainly in the +2 oxidation state but can also have +3 and +4 valences. Nickel is widely used in industries like aerospace, electronics, construction, coin-making and transportation. Everyday items like jewellery, keys and paper clips also contain nickel. Nickel compounds such as nickel sulphate, nickel chloride, nickel oxide, nickel nitrate and nickel hydroxide are used in metal plating, coating plastics, producing fertilizers and manufacturing batteries. Nickel oxide is used in inorganic pigments for glazes and enamels.
Nickel sources include both natural and anthropogenic activities. Anthropogenic sources such as fuel oil burning, nickel mining, and solid waste incineration contribute significantly to atmospheric nickel concentrations, accounting for roughly 90% of total world emissions. Natural sources include wind-blown dust, woodland fires and volcanic activities. Nickel is found in air, water and soil, with higher concentrations in industrial areas. In water, nickel compounds usually exist as ions due to their solubility, and soil concentrations vary based on local geology. Dietary sources of nickel include foods like oatmeal, grains, beans, peas, soya, almonds and dark chocolate, with absorption influenced by soil concentration, pH and organic matter.
The multiple exposure routes of nickel
Humans primarily absorb nickel through the skin, ingestion via diet, and inhalation through the lungs. Nickel exposure can lead to various health problems, such as respiratory tract irritation, neurological effects, diarrhoea, headaches, lung fibrosis, kidney diseases and different types of cancers. It can also induce allergies leading to frequent adverse health effects. Prolonged contact with nickel-containing objects can cause skin rashes, dermatitis, and systemic symptoms like SNAS, which includes gastrointestinal symptoms, rhinitis, asthma, fever, joint pain and chronic fatigue. In comparison, women are more likely to develop dermatitis due to the frequent contact with nickel-containing items like jewellery, makeup, shampoos and detergents.
The adverse health effects of nickel
Nickel toxicity mechanisms involve oxidative stress, hematotoxicity, immunotoxicity and carcinogenicity. Particularly, oxidative stress from nickel exposure can damage DNA and proteins. It was demonstrated that nickel produces oxidative stress in lab-grown human lymphocytes and is considered moderately active as a reactive oxygen species when compared to other metals. Hematotoxicity can affect bone marrow cellularity and stem cell responses, as shown in studies on mice. Immunotoxicity results in allergic skin reactions and can also affect the functioning of the immune system. Nickel nanoparticles have been shown to decrease superoxide dismutase (SOD) activity and increase reactive oxygen species (ROS) levels and malondialdehyde, a lipid peroxidation marker.
Nickel compounds are classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC), with insoluble and soluble nickel compounds categorised as Group 1 carcinogens and nickel alloys as Group 2B. Nickel exposure can lead to lung and nasal cancers, with refinery workers at higher risk due to prolonged exposure to nickel particles in fumes. Nickel compounds can cause histone hyperphosphorylation, hypermethylation and hyperubiquitination, increasing the chance of inducing epigenetic effects that may lead to gene expression changes. Epigenetic regulation of gene expression involves DNA methylation, histone modification and microRNA expression, all of which can be influenced by environmental factors like nickel.
Furthermore, nickel exposure may lead to teratogenic effects, causing congenital malformations and growth retardation. Factors like the mother's diet and polluted food or water can indirectly affect the embryo, as nickel can cross the placenta and induce lipid peroxidation, decreasing placental vitality and increasing embryo toxicity. Studies on mice have shown that nickel exposure can lead to significant reproductive damage, including reduced sperm motility and increased testicular cell apoptosis. Nickel-induced apoptosis is a process of controlled cell death triggered by biochemical processes that result in distinctive cellular alterations, such as shrinking of cells, nuclear and chromosomal DNA fragmentation, chromatin condensation and RNA decay. Nickel ions can cause the release of cytochrome c from mitochondria, leading to the activation of caspases and cell death.
The manifestations of nickel exposure
High quantities of nickel have been found in blood, urine and bodily tissues, particularly in the lungs, as a result of occupational exposure for several million employees globally. Boiling water in kitchen kettles with nickel-plated components can cause nickel to leach into the water. The reason for this widespread contamination of this metal is because nickel nanoparticles are used in various applications, such as lubricant additives, magnetic materials, biological therapies and catalysts. Acute nickel exposure can manifest as respiratory tract irritation, neurological effects, diarrhoea and headaches. Chronic exposure can accumulate nickel in the body and have several harmful impacts on human health, including contact dermatitis, gastrointestinal manifestations, lung fibrosis, kidney and cardiovascular problems and respiratory tract cancer.
Nickel allergy is the most frequent adverse health impact of nickel exposure. When nickel-containing jewellery or other tools come into direct contact with the skin for an extended time, a person may develop nickel sensitivity. Subsequent interaction with nickel can trigger an allergic reaction, such as an itchy skin rash at the contact site. In some hypersensitive individuals, dermatitis can develop and manifest elsewhere other than the original reaction site. The mechanism by which nickel causes skin allergies involves nickel penetrating the skin, activating epithelial cells to produce cytokines or chemokines, and initiating complex immune responses. Nickel can bind to proteins in the intestine, forming antigenic complexes responsible for allergic reactions, leading to SNAS, which presents with gastrointestinal symptoms, rhinitis, asthma, fever, joint pain and chronic fatigue.
Nickel exposure can lead to chronic inflammatory lung diseases, such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) and asthma. Studies have ranked nickel sulphate as one of the most potent nickel compounds to cause allergic asthma among workers in plating industries. Histopathological changes in the nasal mucosa due to nickel exposure can serve as biomarkers for the development of nasal carcinoma. Epithelial-mesenchymal transition (EMT), a physiological process crucial for differentiation, development and wound healing, can be induced by nickel exposure, leading to pathological diseases like cancer and fibrosis.
Cardiovascular diseases resulting from nickel exposure involve increased oxidative stress, endothelial cell dysfunction and leukocyte recruitment in the vasculature, leading to vascular inflammation, dysfunction and accelerated atherosclerosis. Advanced atherosclerosis reduces coronary blood flow, increasing the risk of dysrhythmia and myocardial ischemia, thus raising mortality risk.
Nickel reducing strategies
Strategies to reduce nickel contamination include phytoremediation, phytomining, iron supplementation, vitamin C supplementation and daily measures to decrease contact with nickel-containing materials. Phytoremediation uses plants to absorb and remove pollutants from soil and water, while phytomining involves harvesting plants that accumulate contaminants. Iron supplementation can reduce nickel absorption in individuals with iron deficiency anaemia (IDA), as IDA increases nickel absorption due to higher levels of divalent metal transporter (DMT) proteins. Vitamin C supplementation enhances iron bioavailability, decreasing nickel absorption. Daily measures to reduce nickel exposure include using nickel-free jewellery, covering electronic devices and replacing metal items with plastic ones.
The EU Nickel Directive aims to decrease the harmful effects of constant nickel exposure by restricting the amount of nickel that may be emitted from jewellery and other products intended to come into continuous contact with the skin. These restrictions, called migration limits, are 0.2 µg/cm²/week for pierced ears and other pierced body parts and 0.5 µg/cm²/week for other goods designed to have direct, ongoing skin contact.
Conclusion
In conclusion, nickel exposure poses significant environmental health risks, leading to various diseases. Nickel can be consumed, inhaled or absorbed through the skin due to its widespread use in products and industries, as well as its prevalence in soil, water and food. This leads to several health effects, ranging from respiratory and neurological disorders to skin irritability and cancer. Prolonged exposure to nickel increases the risk of respiratory illnesses, such as sinus, nasal and lung cancer. Moreover, nickel exposure has been linked to skin conditions, reproductive toxicity and kidney impairment. To mitigate the risks of nickel exposure, it is crucial to implement appropriate measures to control and monitor its release into the environment. These measures include regulating industrial processes, reducing emissions and providing protective equipment for workers. Effectively, individuals can reduce their exposure to nickel by avoiding sources of pollution and maintaining good personal hygiene. By implementing measures to control nickel exposure, we can reduce the incidence of diseases associated with this metal and promote a healthier environment for all.
Renald Blundell is a biochemist and biotechnologist with a special interest in Natural and Alternative Medicine. He is a professor at the Faculty of Medicine and Surgery, University of Malta.
Emily Gatt is currently a medical student at the University of Malta.