99: Nickel

Nickel is a ubiquitous metal commonly found in both home and industry. It exists in a variety of chemical forms, from naturally occurring ores to synthetically produced nickel carbonyl. Elemental nickel is a white, lustrous metal whose name is derived from the German word “kupfernickel” or “devil’s copper.” Swedish chemist Baron Axel Fredrik first identified nickel in 1751 in a mineral known as niccolite. Nickel comprises 0.008% of the Earth’s crust and is found in diverse locations, ranging from meteorites and soil to bodies of fresh and saltwater.

First produced by the Chinese, nickel has been used as a component in a variety of metal alloys for more than 1700 years. The first malleable nickel was produced by Joseph Wharton following the American Civil War. Wharton went on to sell bulk quantities of nickel to the US government for the minting of 3-cent coins, and later donated the equivalent of 3.3 million of these coins to help fund what is today known as the Wharton School of Business.⁶⁵ The modern US 5-cent piece, the “nickel,” is actually only approximately 25% nickel by weight, and all US coins except the penny are made of nickel-containing alloys.¹⁰

Nickel ores typically consist of accumulations of nickel sulfide minerals of relatively low nickel content. Although a variety of technical methods for extracting nickel from ore have been developed, one method of special note was developed in 1890 by Ludwig Mond, who is credited with the discovery of nickel carbonyl. The Mond process for the extraction of nickel involves passing carbon monoxide over smelted ore. This creates nickel carbonyl, which then decomposes at high temperatures to produce purified nickel and carbon monoxide.⁶⁵ Nickel mining ceased 30 years ago in the United States, and despite an increasing worldwide demand, as of 2011 there were still no active domestic nickel mines.¹⁰ Nickel is imported into the United States from other nickel-rich countries, such as Canada, Russia, and Australia, while domestic production of nickel in the United States is essentially limited to the recycling of nickel-containing metals.

Nickel is a siderophoric material that forms naturally occurring alloys with iron, a property that has made it useful for many centuries in the production of coins, tools, and weapons. Today, most nickel is used in the production of stainless steel, a highly corrosion-resistant alloy containing 8% to 15% nickel by weight.

Occupational exposure to nickel and nickel containing compounds occurs in a variety of industries, including nickel mining, refining, reclaiming, and smelting. Chemists, magnet makers, jewelry makers, oil hydrogenator workers, battery manufacturers, petroleum refinery workers, electroplaters, stainless steel and alloy workers, and welders are at increased risk for exposure to nickel and nickel-containing compounds. Most nonindustrial human exposures to nickel are usually from dietary and environmental sources, although cigarette smoking is an important nickel exposure and elevates urinary nickel concentrations.⁶³ In the occupational setting, nickel carbonyl is responsible for the great majority of acute nickel toxicity, while in clinical practice, the most common health issue related to nickel is the development of allergic dermatitis from jewelry and clothing, as well as cosmetics and complementary and alternative medicines.^9,19 Nickel and Toxicodendron species exposures are the most common causes of allergic contact dermatitis, with a large proportion of the population—particularly women—demonstrating nickel sensitivity.

Exposure

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.

Absorption

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

Distribution

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.

Elimination

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.

Acute

The clinical manifestations associated with acute exposure to nickel depend on the particular compound and route of exposure. Inhalation of nickel-containing aerosolized particles tends to affect the lungs and upper airways directly, whereas ingestion and intravenous administration may result in systemic toxicity, usually involving the nervous system (Table 99–1).

The most common disorder associated with exposure to nickel, by far, is an allergic dermatitis. Although acute toxicity has been reported following various routes of exposure, the most important source of acute nickel toxicity is inhalational exposure to nickel carbonyl, which is associated with pulmonary, neurologic, and hepatic dysfunction.⁶⁵

Nickel Allergy and Dermatitis.

Nickel dermatitis was first reported in the late 1800s in nickel-plating workers and was recognized as an allergic reaction in 1925. Since then, nickel has been recognized as a common cause of allergic contact dermatitis. Ni²⁺ is not itself antigenic but acts as a hapten, binding larger proteins and inducing conformational changes such that these become recognized as non–self-antigens.²⁸

The allergic reaction caused by contact with nickel is a type IV delayed hypersensitivity immune response that typically occurs in two phases. In the first phase, sensitization occurs when nickel enters the body. The second phase occurs when the body is re-exposed to nickel, at which time allergy manifests. The diagnosis of nickel allergy is suggested by specific historical findings listed in Table 99–2.

One population survey reported that 3% of men and 15% of women demonstrated evidence of allergy to nickel.⁴² More recent studies report even higher prevalences, ranging between 15% and 25%.³⁸ The fivefold greater prevalence of nickel allergy in women is presumably a consequence of their higher rates of body piercing and more frequent wearing of jewelry, both of which are risk factors for nickel sensitization. It is unclear if ­European nickel regulations have succeeded in reducing rates of nickel sensitivity although this has been suggested by several studies.⁷⁴

Nickel dermatitis is classified into two types: primary and secondary. The more common primary dermatitis presents as a typical eczematous reaction in the area of skin that is in contact with nickel. It is characterized initially by erythematous papules that may proceed to lichenification due to pruritus and scratching. These eruptions may mimic basal cell carcinoma.²⁵ Areas typically involved are the wrists, as a result of wearing watches and bracelets, the ears from earrings, and the periumbilical area at the site of contact with jewelry, nickel-containing buttons on jeans or nickel-containing belt buckles (Fig. 99–1). Approximately 50% of all belt buckles and 10% of buttons on blue jeans contain nickel.¹³ The most common cause for nickel dermatitis in women is direct contact from jewelry, garments, wristwatches, cosmetics, and occupational contact in the metal, hairdressing, tailoring, hotel, and restaurant industries. In men, nickel dermatitis is often occupational but may also, in some individuals, be related to jewelry, body piercing, garments, or even metal guitar strings.

The secondary form involves a more widespread dermatitis as a result of other exposures, such as ingestion or inhalation of nickel compounds, and implantation of metal medical devices, and may be regarded as a systemic contact dermatitis elicited by nickel. Secondary eruptions are typically symmetrically distributed and may localize in the elbow flexure, on the eyelids, on the sides of the neck and face, and can become widespread.

Nickel in foods, excessive skin contact, and certain orthodontic appliances with high nickel content are all linked to this eczematous eruption. Nonetheless, orthodontic exposure to nickel-containing alloys is unlikely to induce hypersensitivity reactions in patients without prior sensitization, and such reactions are still infrequent even in those sensitized.⁴⁹

Other types of medical devices containing nickel have the potential to induce either primary or local nickel dermatitis. Occlusion of a biliary stent attributed to nickel allergy has been reported.³² Much debate has arisen over the past decade regarding metallic coronary stents and the potential for nickel allergy-induced restenosis. Several studies have reported increased restenosis in nickel-allergic patients with bare-metal stainless steel³⁴ and cobalt-chromium² stents, although others have failed to find such a correlation.⁷³ Drug-eluting stents may mitigate any effect of metal allergy on rates of restenosis.⁴⁴

It is reported that the bimetallic core structure of the 1 Euro and 2 Euro coins creates an electrical potential that results in the release of nickel when in contact with sweat. While no general rise in the rate of nickel sensitivity has been confirmed, cases of dermatitis in certain high-risk patients are reported.⁵⁴

Recently, reports have emerged involving cases of contact dermatitis in users of certain types of cellular phones, with testing confirming nickel release in such phones.³⁹ Therefore, nickel should be considered a potential cause in cases of facial contact dermatitis of unknown etiology.

One study showed that following skin application nickel salts are retained in the skin for an extended period of time,³⁶ which could lead to prolonged antigen processing and consequent immune responses in dermal tissue. There may also be a genetic basis for nickel sensitization. Filaggrin gene mutations are reportedly associated with nickel contact dermatitis as a result of breakdown in nickel chelation in the stratum corneum, allowing for greater epidermal absorption of nickel.⁷² Development of an allergy, like most of toxicology, is probably dose and time related, and this is the basis of the recent EU regulations to limit consumer exposure to nickel.

Nickel Carbonyl

Nickel carbonyl is the most harmful form of nickel and the majority of acute occupational nickel exposures involve nickel carbonyl. Nickel carbonyl is described as having a “musty” or “sooty” odor, although thresholds for detection vary considerably and potentially harmful exposures cannot be excluded simply by a reported lack of odor. Exposure to concentrations less than 100 mg/m³ is fatal in rats after 20 minutes.^33,69 Once dissociated, nickel carbonyl can be oxidized in tissues to Ni²⁺.

Nickel carbonyl exposure may cause symptoms rapidly or symptoms may be delayed. In a series of 179 exposures, approximately 40% of patients reported symptoms within 1 hour of exposure; however, it is important to note that symptoms were delayed for approximately 1 week in 20% of patients, and even patients with mild initial symptoms could develop severe delayed symptoms, although usually, within the next 2 days.⁵⁸ In patients who developed symptoms shortly following exposure, the initial manifestations involved nonspecific complaints, including respiratory tract irritation, chest pain, cough, dyspnea, frontal headache, dizziness, weakness, and nausea. Cases manifesting only these initial signs are categorized as mildly toxic.⁵⁸

Symptoms of severe acute nickel carbonyl poisoning generally develop over the course of several hours to days and may be associated with acute respiratory distress syndrome (ARDS) and interstitial pneumonitis. Myocarditis, marked by prolonged changes on electrocardiography, including ST- and T-wave changes, as well as QT prolongation, has been reported.⁵⁸ Neurologic symptoms associated with severe poisoning include altered mental status, seizures, and extreme weakness that sometimes necessitate mechanical ventilation. A moderate leukocytosis (10,000–15,000 white blood cells/mm³), nonspecific opacities on chest radiography, and elevation of aminotransferases may also occur, but these tend to resolve over the course of several weeks. Deaths from nickel carbonyl are typically caused by interstitial pneumonitis and cerebral edema occurring within 2 weeks of initial exposure.⁶⁹ Autopsy studies of those dying after nickel carbonyl exposure have shown diffuse pulmonary consolidation, organizing fibrosis, cerebral edema or hemorrhage, and cardiac dilation.⁵⁶ Survivors usually recover completely, although the development of a prolonged neurasthenic syndrome can occur and may last months in some cases.⁵⁸ Clinical features of nickel carbonyl poisoning are found in Table 99–2.

Noncarbonyl Nickel

There are few human cases of inhalational nickel poisoning. However, from the available data, the primary concerns appear to be pulmonary, neurologic and, perhaps, renal.

A case report described seizure activity in two patients following occupational inhalational exposure to non-carbonyl nickel. Both patients exhibited elevated urinary nickel concentrations, with no recurrence of seizure activity upon removal from exposure.²⁰ This complication was documented previously in rats with nickel sulfate toxicity.¹⁶ Although the mechanism for this is not quite clear, animal studies indicate that inhibition of the glutamate transporter may be involved.⁴⁰ Interstitial pneumonia is also associated with inhalational exposure while spray painting high-temperature nickel-chromium alloys.²⁷ As previously mentioned, inhalational exposure to metallic nickel particles/nanoparticles can induce ARDS, as well as acute tubular necrosis.^48,50

Parenteral Administration.

Acute parenteral toxicity from nickel-containing compounds occurred following the use of water for hemodialysis that had been heated in a nickel-plated tank.⁷⁹ The concentration of nickel in the delivered water was 0.25 mg/L, and serum concentrations exceeded 3 mg/L. Through back extrapolation, serum concentrations were estimated to have been as high as 9 mg/L. These patients developed nonspecific symptoms, including headache, nausea, and vomiting, similar to nickel carbonyl poisoning, although no respiratory complaints were reported. The effects resolved after several hours, and the patients recovered without sequelae.

Ingestion.

Acute ingestions of contaminated water containing 1.63 g Ni²⁺/L caused nausea, vomiting, diarrhea, weakness, and headache, as well as pulmonary symptoms, including cough and dyspnea, lasting up to 48 hours.⁶⁷ Estimated ingested doses of nickel (as Ni²⁺) were 0.5 to 2.5 g and serum concentrations as high as 13.4 μg/L were reported. The death of a 2 year-old girl followed ingestion of 2.2 to 3.3 g Ni²⁺ in the form of nickel sulfate crystals. Following ingestion, this child reportedly developed depressed level of consciousness, nuchal rigidity, mydriasis, erythema, tachycardia, and ARDS.¹⁸

Dermal Absorption.

Although transdermal absorption is typically of minor clinical significance, disruption of the normal integument may allow for more efficient systemic absorption. A metal refinery worker suffered a 40% body surface area partial-thickness chemical injury resulting from exposure to a chemical mixture that included nickel carbonate and nickel sulfate.⁴⁵ Prior to the incident, this individual’s measured serum nickel concentration was 0.023 μmol/L (1.33 μg/L). On the sixth day following the injury the serum concentration was 0.490 μmol/L (28 μg/L). Two five-day courses of chelation with CaNa₂EDTA were begun for concomitant cobalt poisoning, and the patient’s serum and urine nickel concentrations were within normal limits by 21 days postexposure. He subsequently recovered without manifesting signs of nickel toxicity.

Chronic Nickel Exposure

Chronic inhalational exposure to nickel is associated with injury characterized by specific histologic changes in the nasopharynx and upper respiratory tract, including atrophy of the olfactory epithelium, rhinitis, sinusitis, nasal polyps, and septal damage.¹¹ Pulmonary effects may include asthma⁴¹ and pulmonary fibrosis.^8,24

The International Agency for Research on Cancer classifies nickel compounds as a group 1 carcinogen (carcinogenic to humans).²⁹ The potential for and mechanisms of carcinogenesis of nickel depend heavily on the specific compounds studied. Although nickel-induced carcinogenesis is fairly well established for nickel compounds, the role of metallic nickel is less clear.⁵⁹

An increased incidence of oral cancer has been associated with geographic areas containing higher concentrations of nickel in farming soil.⁶⁴ Although earlier studies of occupationally exposed workers, primarily electroplaters and refinery workers, also showed increased rates of nasal and pulmonary tumors, more recent studies of nickel-exposed workers in more modern environments with lower permissible limits of nickel exposure do not show a significantly increased risk of cancer or any cause of mortality.^60,61

Although the exact mechanism of any possible carcinogenesis remains to be firmly elucidated, studies indicate several potential mechanisms. Animal studies show a threshold dose–response curve for inflammation with soluble compounds (nickel sulfate), and similar curves describe the risks of pulmonary cancers with the less-soluble nickel oxides and nickel subsulfide.⁵⁷ Reactive oxygen species (ROS) formation occurs secondary to depletion of both glutathione and protein-bound sulfhydryl groups by nickel. Accumulation of ROS leads to lipid peroxidation and DNA damage.^62,77 Formation of ROS consequently causes depletion of ascorbic acid (vitamin C) as a free radical scavenger in conjunction with vitamin E. In vitro studies of human airway epithelial cells have shown that depletion of intracellular ascorbate due to nickel causes the induction of hypoxic stress. Such nickel-induced stress leads to the activation of hypoxia-inducible factor (HIF-1) and upregulation of hypoxia-inducible genes.⁵² Hypoxia is encountered in tumors as they outgrow their blood supply, thus selecting for cells with altered energy metabolism, changes in growth regulation, resistance to apoptosis, or both. Therefore, HIF-1 activation and the upregulation of hypoxia-inducible genes mimics intracellular permanent hypoxia and may be related to nickel-induced carcinogenesis.⁵³

Soluble compounds such as nickel sulfate cause a threshold-dependent inflammatory response and may act as promoters of malignancies without a directly genotoxic effect. Insoluble nickel oxides and nickel sulfide bind to chromatin and nucleic acids¹⁵ and also affect expression of various mRNAs.⁷⁸ Thus, under some conditions, these compounds may be carcinogenic through genetic mechanisms, epigenetic mechanisms, or both. The more potent carcinogenic effects of insoluble nickel compounds may be a consequence of their increased cellular uptake.¹⁷

Based on concerns about long-term health effects, exposure limits for various nickel compounds have been proposed (Table 99–3).

Although nickel is widely distributed to many body fluids and tissues, urine and blood are the most commonly analyzed samples. Urine collection should ideally use acid-washed, metal-free containers. Some authors recommend correcting urinary nickel concentration per gram of urine creatinine, but it is not clear that this offers any particular advantage in clinical decision making. The average nickel concentration in serum is 0.3 μg/L, whereas the value in urine ranges from 1 to 3 μg/L,⁷¹ although substantially higher values are reported even in non-occupationally exposed populations.^31,43 Concentrations among workers occupationally exposed to nickel may be substantially higher and serum concentrations of more than 8 μg/L have been proposed as being indicative of excessive exposure.⁴³

Nickel concentrations rise in urine, serum, and whole blood following oral administration. In these studies, serum concentrations were slightly higher than, but correlated well with whole blood. Urine and blood concentrations primarily reflect exposure occurring within the previous 48 hours,¹⁴ which is roughly the biologic half-life calculated from various field studies.⁷⁶

Urine nickel concentrations are used more commonly than blood for monitoring of workplace exposures and for prognostic and therapeutic decision making in nickel carbonyl exposures. An 8-hour collection is typically performed, and the average urinary excretion of nickel (in these nickel workers) is 2 μg/L, with an upper limit of normal of 5 μg/L. In cases of nickel carbonyl poisoning, concentrations of less than 100 μg/L in the initial 8-hour specimen may imply mild toxicity. Concentrations of 100 to 500 μg/L are classified as moderate, while concentrations higher than 500 μg/L are categorized as severe poisonings.⁶⁹ These classifications have been used in guiding treatment decisions. Urine nickel concentrations rise prior to the onset of symptoms in nickel carbonyl poisoning, making this determination a potentially useful screening tool for both workforce surveillance and the management of acute exposures.

Testing for allergic contact dermatitis due to nickel is performed using patch testing, as for other types of contact dermatitis. Strip patch testing is more sensitive than standard patch testing by 16%.²¹ Testing metal surfaces for free nickel is possible and sometimes necessary in the evaluation and treatment of nickel dermatitis. Patients with clinically important sensitivity or suspect medical histories can order an inexpensive, commercially packaged dimethylglyoxime spot test, allowing them to test metal objects for the presence of free nickel.¹³

The first step in treatment of nickel-related medical problems is eliminating the exposure, which includes detection and removal of the source. In the case of acute exposures to nickel carbonyl, removal of clothing to prevent continued exposure and thorough skin decontamination may be necessary.

Symptomatic treatment for pulmonary symptoms associated with hypoxia includes the administration of supplemental oxygen. The use of bronchodilators and corticosteroids may also be necessary for the treatment of concomitant bronchospasm. Mechanical ventilation may be required in the most severe cases.

The administration of intravenous fluids to promote diuresis reduces the half-life of orally ingested nickel chloride by approximately 50%.⁶⁷ Due to high levels of protein binding, hemodialysis does not effectively remove nickel from the serum.⁷⁹

Chelation

Because there are no controlled human trials, specific recommendations for the use of chelation to treat nickel toxicity are not currently supported by the literature. As a result, extrapolation from animal studies and case reports form the basis for most treatment regimens. Most studies and reports involving treatment have focused on workers exposed to nickel carbonyl.

Several drugs are proposed as potential treatments for nickel carbonyl exposures. Studies in rats with various chelators show some protection by administration of British anti-Lewisite (BAL) and d-penicillamine,⁸¹ whereas calcium disodium EDTA had no protective effect.⁸⁰ Although BAL was being used in the past,⁶⁹ the most recent literature has focused on the use of diethyldithiocarbamate (DDC; Chaps. 79 and 102).

DDC is a chelator formerly used as the color reagent for urine nickel measurements. Rats exposed to several times the LD₅₀ (median lethal dose for 50% of volunteers) for nickel carbonyl had dramatically reduced mortality when pretreated with DDC; however, the antidotal efficacy decreased with increasing delay to treatment.⁶ A proposed treatment regimen for exposed workers focused on analysis both of the exposure and of the initial 8-hour urine collection.⁶⁹ Patients with suspected severe poisonings are typically given the first gram of DDC in divided oral doses. When less-severe exposures are suspected, treatment decisions are based on the urinary nickel concentration. At concentrations below 100 μg/L, no initial therapy is recommended as delayed symptoms are unlikely to develop. At concentrations between 100 and 500 μg/L, an oral regimen consisting of 1 g DDC initially, 0.8 g at 4 hours, 0.6 g at 8 hours, and 0.4 g at 16 hours is used. DDC is continued at a dose of 0.4 g every 8 hours until there is symptomatic improvement and urine nickel concentration is normal. Severe exposures with urinary nickel concentrations more than 500 μg/L can be treated using the same regimen, although these patients frequently require closer monitoring. Critically ill patients are given parenteral DDC starting at a dose of 12.5 mg/kg. However, given the animal data that the route and timing of administration are important to survival, some authors recommend that parenteral DDC be given as soon as possible following nickel carbonyl poisoning.¹² Although typically well-tolerated, DDC is capable of inducing a disulfiram reaction (Chap. 79) if taken with alcohol, and there are concerns about using DDC when there is concurrent cadmium exposure, at least by the oral route.³ As with many chelators, there is also debate about whether the redistribution of nickel by chelating agents may be detrimental by increasing brain and organ concentrations.⁴⁶

Disulfiram is metabolized into two molecules of DDC. Given that DDC is not pharmaceutically available in the United States, there is some interest in the use of disulfiram as an antidote for nickel carbonyl. Although case reports describe successful treatment of nickel carbonyl toxicity with disulfiram,³⁵ concern exists because animal studies show that disulfiram increased nickel concentration in brain tissue.⁵ Disulfiram cannot be considered a standard of care, due to lack of convincing evidence, but would be recommended due to its theoretical efficacy. One treatment regimen was 750 mg given orally every 8 hours for 24 hours, followed by 250 mg every 8 hours.³⁵

Considering most of the literature and almost all human case reports of nickel carbonyl refer to the use of DDC, it is considered the treatment of choice for nickel toxicity. Although commonly available as a reagent, pharmaceutical-grade DDC is not produced commercially. While based on less robust evidence, given the fact that disulfiram is essentially a prodrug for the unavailable DDC, treatment of nickel carbonyl poisonings with disulfiram is recommended.

Treatments evaluated for divalent nickel exposure are d-penicillamine and N-benzyl-d-glucamine dithiocarbamate, which, while not commonly available, more effectively lowers brain nickel concentrations than does DDC, perhaps because of its lower lipid solubility.⁷⁰

Contact dermatitis from nickel is treated using standard measures, including avoidance, topical steroids, and oral antihistamines. Some patients have benefited from dietary alteration to reduce nickel intake. Although sometimes advised, there does not appear to be a role for avoiding stainless steel cookware to reduce the nickel content of food.¹

• Nickel is a ubiquitous metal today.

• Allergic dermatitis due to hypersensitivity is the most common type of nickel-related disease.

• Nickel toxicity is rare and most often related to nickel carbonyl.

• There is inadequate evidence to consider chelation for toxicity.

• Chronic, excessive exposures to nickel compounds may increase the risk of aerorespiratory cancers.

Acknowledgment

Michael I. Greenberg, MD, contributed to this chapter in previous editions.

References