++
Nickel occurs naturally in soil, volcanic dust, and fresh and saltwater, but it also enters the environment from the combustion of fuel oil, municipal incineration, nickel refining processes, and the production of steel and other nickel alloys that may allow aerosolized nickel to be disseminated into the environment.
++
The specific form of nickel emitted to the atmosphere depends on the source. Complex nickel oxides, nickel sulfate, and metallic nickel are associated with combustion and incineration, as well as smelting and refining processes. Consequently, ambient air concentrations of these forms of nickel tend to be higher in urban areas, and concentrations of nickel in urban household dust may be elevated under certain circumstances and thus may pose some variable exposure risk for young children who crawl or sit on floors.
++
Nickel carbonyl, Ni(CO)4, deserves special mention. This highly volatile and potentially dangerous liquid nickel compound is a product of the reaction of nickel and carbon monoxide and is commonly used in nickel refining and petroleum processing, and as a chemical reagent. Its high vapor pressure and high lipid solubility lead to rapid systemic absorption through the lungs. In the air and in the body, it decomposes into metallic nickel and carbon monoxide and its toxicity has been compared with hydrogen cyanide.35 Workers exposed to nickel carbonyl are commonly screened for low level exposure, but disasters such as the Gulf Oil Company refinery incident in 1953, and the Toa Gosei Chemical company incident in 1969, resulted in hundreds of inhalational exposures.65
++
However, non-occupational exposures to nickel are typically environmental and dietary. Ambient air nickel concentrations are typically around 10 ng/m3, while soil usually has nickel concentrations of 4 to 80 ppm, with some areas much higher. Concentrations of metallic nickel in drinking water in the United States are generally below 20 μg/L, but elevated concentrations of nickel in household and other potable and nonpotable water sources may result from corrosion and leaching of nickel alloys present in various plumbing fixtures, including valves and faucets.22 Although many water suppliers in the United States monitor nickel concentrations in their water, there is currently no US Environmental Protection Agency (EPA) regulation regarding how much nickel is permissible in drinking water.
++
Dietary intake is a recognized source of nickel exposure for humans. Foods high in nickel include nuts, legumes, cereals, licorice, and chocolate. In addition, certain homeopathic medications, ginseng products, Indian herbal teas, Nigerian herbal remedies, and Chinese herbal plants are high in nickel content, with some Nigerian herbal remedies reportedly containing up to 78 mg nickel/g substance.19 Nickel is not considered an essential element for human health and dietary recommendations for nickel have not been established. Normal consumption is between 0.3 to 0.6 mg per day, with the majority of this being unabsorbed by the gastrointestinal tract. A Danish meta analysis of 17 studies suggested that up to 1% of individuals may develop allergic contact dermatitis at the low level of oral nickel exposure represented by dietary and drinking water sources.30 Although estimates vary widely, the total body burden for a 70-kg reference human is about 10 mg of nickel, giving an average body concentration of 0.1 ppm.22 No clear biologic function has been determined for nickel in humans, but it may serve as a cofactor for various enzymes.
++
Nickel may enter the body through the skin, lungs, and gastrointestinal tract. The amount and rate of absorption is dependent on the water solubility of the nickel compound. Once in the body, nickel exists primarily as the divalent cation (Ni2+). Independent of the particular nickel compound involved in the exposure, it is nickel ion (Ni2+) that is typically measured in the serum or urine.
++
Following inhalational exposure, nickel accumulates in the lungs, but only 20% to 35% of nickel deposited in the human lung is systemically absorbed.22 The remainder of the inhaled material is swallowed, expectorated, or deposited in the upper respiratory tract. Subsequent systemic absorption from the respiratory tract is dependent on the solubility of the specific nickel compound in question. Soluble nickel salts (nickel sulfate and nickel chloride) are more easily absorbed, whereas the less-soluble oxides and sulfides of nickel are absorbed to a lesser extent.
++
Because water-soluble nickel compounds tend to be more readily absorbed from the respiratory tract when compared with poorly soluble nickel compounds, exposure to the soluble nickel chloride or nickel sulfate results in higher urinary nickel concentrations than does exposure to less-soluble nickel oxide or nickel subsulfide, while the less soluble compounds may have a longer apparent half-life. This likely at least partially represents a longer absorption phase.
++
The gastrointestinal absorption of nickel compounds varies with the particular nickel compound as well as coingestants. For example, approximately 27% of the total nickel in nickel sulfate given to humans in drinking water is absorbed, whereas only approximately 1% is absorbed when given in food. Serum nickel concentrations peak between 1.5 and 3 hours following ingestion.68 The presence of food in the gastrointestinal tract appears to reduce the absorption of nickel, and most ingested nickel remains in the gut and is excreted in the feces.
++
While systemic absorption of nickel can occur through skin contact, much of the applied nickel remains in the keratinized skin, with limited absorption by keratinocytes.37
++
In human serum, the exchangeable pool of primarily divalent nickel is bound to albumin, l-histidine, and α2-macroglobulin.47 A nonexchangeable pool of nickel that is tightly bound to a transport protein known as nickeloplasmin also exists in the serum. Nickel crosses the placenta and is present in breast milk.
++
Nickel is also concentrated in various solid organs. An autopsy study of individuals not occupationally exposed to nickel reported the highest concentrations of nickel in the lungs, followed by the thyroid, adrenals, kidneys, heart, liver, brain, spleen, and pancreas.51 Nickel concentrations in the nasal mucosa are higher in workers exposed to less-soluble nickel compounds relative to soluble nickel compounds,75 indicating that, following inhalation exposure, less-soluble nickel compounds remain deposited on the nasal mucosa.
++
In humans, most ingested nickel is excreted in the feces; however, because more than 90% of ingested nickel does not leave the gut,66 most of the nickel found in feces represents the unabsorbed fraction rather than the elimination of body nickel.68 Absorbed nickel is primarily excreted in the urine and, to a lesser degree, other bodily fluids.
++
Regardless of the route of exposure, workers occupationally exposed to nickel have increased urinary concentrations of nickel.4,26 Animal studies indicate that nickel oxide, an insoluble compound, is slowly eliminated from the lungs via macrophages and excreted in feces, while more soluble compounds, such as nickel subsulfide, were excreted primarily in the urine.7
++
In nickel workers, urinary excretion increased from the beginning to the end of the shift, indicating that a fraction of absorbed nickel is rapidly eliminated.23,75 Similarly, urinary excretion increased as the work week progressed, indicating the presence of a fraction that is excreted more slowly. In fact, after a massive inhalational welding exposure, the half-life of nickel in urine and blood followed a biphasic exponential decay pattern of excretion, and was 25 and 610 days in urine, and 30 and 240 days in blood, indicating potential saturation of elimination pathways and delayed absorption and/or redistribution of nickel.55
++
Studies of workers who unintentionally ingested water contaminated with nickel sulfate and nickel chloride reported a mean serum half-life of nickel was 60 hours, but was reportedly decreased substantially (≤ 27 hours) when the workers were treated with intravenous fluids.67
++
The available literature supports the view that systemically absorbed nickel is excreted through the kidneys, with some excretion of insoluble compounds in the feces. Due to the previously mentioned factors affecting absorption, the apparent half-life following exposure may reflect continuing absorption and will therefore depend on the route of exposure and the particular nickel species involved.