Nickel Toxicology

Etiology

Nickel carbonyl is the cause of acute toxicity seen in occupational exposures. Often described as a colorless to yellow volatile liquid, it can have a musty or sooty odor, which is difficult to detect at dangerous concentrations.[1] Ludwig Mond developed this liquid, which occurs as a reaction between nickel and carbon monoxide. This Mond process purifies nickel and allows it to be plated onto surfaces.[2] Nickel carbonyl, a byproduct, is harmful if inhaled or absorbed through the skin. 

Nickel carbonyl finds significant applications in industrial settings as a catalyst in carbonylation reactions involving plastic, petroleum, or steel plating.

Nickel is a well-known culprit for contact dermatitis and is found in various everyday items such as household products, clothing, cosmetics, medical equipment, and jewelry. When sweat interacts with nickel-containing items, soluble nickel salts are released and can be absorbed by the skin, leading to a delayed-type hypersensitivity reaction. Once sensitized, the hypersensitivity to nickel can persist indefinitely.[1]

Epidemiology

Even though nickel contact can occur through diet and natural sources such as soil and water, workplace exposure is the predominant location for significant toxicity. Occupational use can be seen with refining nickel itself, whether smelting or reclaiming. Industries include battery manufacturers, stainless steel, welders, and petroleum refining. Industrial use is seen throughout the United States, while only one active mine exists in Michigan. Historically there have been several notable toxicity cases. In 1953, nickel carbonyl inhalation occurred at a Gulf Oil Company refinery in Texas, causing two deaths.[2]

In 1987, an incident took place at an electroplating plant in Canada where twenty employees fell ill after consuming contaminated water from a fountain. The affected individuals experienced symptoms such as nausea, vomiting, and abdominal pain. Fortunately, there were no fatalities, and the reported symptoms subsided within 3 days.[3]

Nickel is recognized as one of the primary allergens that cause contact dermatitis, particularly in industrialized countries. It can be found in various household items including jewelry, cosmetics, clothing, and detergents. Women are more commonly affected by nickel sensitivity, with approximately 10% of them exhibiting a reaction. Reactions to nickel have also been associated with ear piercing.[4]

Nickel is also found in dental materials and surgical implants. The exposure leads to absorption and a hypersensitivity reaction causing the notable erythematous, vesicular, and pruritic rash.[5] This rash can remain localized near the site of allergen exposure. However, with implants or frequent exposures, the rash can become more systemic and appear in various locations.

Pathophysiology

Acute Toxicity

Toxicity from nickel can occur through various routes of exposure, including inhalation, ingestion, injection, and dermal absorption.

In the occupational setting, nickel carbonyl, a colorless liquid formed in the Mond process, poses a significant risk. Absorption of nickel carbonyl through the skin or inhalation can be lethal. It is characterized by a distinct odor described as musty and sooty. The toxic effects of nickel carbonyl are believed to occur through oxidative stress pathways.[6][7] 

The symptoms can occur immediately after exposure or be delayed. Inhalation can cause respiratory, neurologic, and hepatic dysfunction. Pulmonary findings include pneumonitis and acute lung injury. Other findings include cerebral edema, myocarditis, altered mental status, and seizures.[8] In one case report, the inhalation of nickel nanoparticles led to acute respiratory distress syndrome, where the nanoparticles were found in lung tissue macrophages.

The ingestion of nickel salts will acutely manifest toxicity. Gastrointestinal symptoms are prominent, including nausea, vomiting, diarrhea, and abdominal pain. This is believed to be caused by lipid peroxidation leading to cell membrane disruption with calcium influx and cell death.[9]

Parenteral toxicity can occur from hemodialysis if the stored water is kept in a nickel container. Their symptoms are similar to those of nickel carbonyl toxicity. 

Dermal absorption can lead to type IV skin sensitivity causing pruritis and erythematous papules.[5] Dermatitis has two phases; first, the skin is sensitized when initially exposed to nickel, and in phase two, the reexposed skin causes the allergy to manifest as a rash. 

Chronic Toxicity

Exposure can occur in the form of nickel dust or aerosols. Inhalation can result in changes in the nasopharynx and the epithelium of the respiratory tract. Chronic changes can include rhinitis, polyps, rhinitis, asthma, or pulmonary fibrosis. Of note, an increased incidence of nasal and pulmonary cancer has been observed.

Occupational exposure to nickel has been associated with an increased risk of sino-nasal cancers, including squamous cell carcinoma, anaplastic carcinoma, and adenocarcinoma. Additionally, increased handling of nickel has been linked to the development of dermatitis. These findings highlight the importance of proper safety measures and protective equipment in occupational settings where nickel exposure is expected.[7]

Toxicokinetics

Exposure can come from environmental means, including soil, volcanic dust, industrial pollution, food, and water. Household water can contain nickel from pipe corrosion. Nickel is not an essential element but is found in various foods. Per the U.S. Environmental Protection Agency, oral intake ranges from 100 to 300 mcg daily. Daily oral nickel consumption is about 20 mcg, and inhalation includes 0.4 mcg.

Absorption occurs through the skin, gastrointestinal tract, and lungs. Not all inhaled nickel is systemically absorbed; it can be coughed out or remain in the respiratory tract, as the solubility depends on the nickel compound. Nickel carbonyl is highly soluble and readily absorbed. Nickel salts have lower absorption and can remain in the GI tract. Their absorption is also slowed with the presence of food in the stomach.[1]

Dermal absorption is dependent on potency and skin integrity.[10] Nickel crosses the placenta and can also be found in solid organs such as the heart, lungs, and liver.[11][12] Duration of exposure and nickel solubility impacts nickel deposition in areas such as the respiratory tract.[13]

Nickel in the blood is primarily bound to albumin, with the presence of the transport protein nickeloplasmin. The distribution of nickel in the body varies depending on the route of exposure. Following exposure to nickel carbonyl, the highest concentrations of nickel are typically found in the lung, brain, kidney, liver, and adrenal glands. This distribution pattern highlights the affinity of nickel for certain organs and tissues and emphasizes the potential health risks associated with exposure to nickel compounds.[1]

Nickel is not known to exhibit cumulative toxicity, meaning it does not tend to accumulate in the body over time. Instead, it undergoes elimination primarily through urine and feces. The elimination of nickel follows first-order kinetics, which means that the rate of elimination is proportional to the concentration of nickel in the body.[8]

Multiple mechanisms have been investigated to explain the toxic effects of nickel on the human body. Research has been performed on humans and through experimental means to show the optimal amount of essential nickel to the point of toxicity. Inhalational and absorbed nickel appears to form a complex with thiol. A reaction occurs between this complex and oxygen, producing free radicals.[14] Nickel also binds to sulfhydryl proteins which reduce the levels of glutathione.[15] 

These reactions, which create reactive oxygen species, ultimately can lead to intracellular hypoxia and activates alternate specific gene expression.[6] In addition, through epigenetic alterations, nickel substitutes iron, causing alterations in DNA and histone demethylation.[16][17]

History and Physical

Acute nickel toxicity should be considered when a patient presents with any neurologic, pulmonary, or cardiac symptoms combined with known exposure. As most toxicity is due to industrial exposure, an occupational history is exceptionally important to obtain. Symptoms can include headache, vertigo, dyspnea, and chest pain. Initial symptoms can appear mild. However, delayed symptoms can get progressively more severe, causing altered mental status and a need for ventilation support. A nickel carbonyl exposure air concentration of 50 mg/m³ will produce the abovementioned symptoms.[18]

If ingestion is the route, symptoms include nausea, vomiting, diarrhea, and abdominal pain. Ingestion of 0.5 to 2.5 g could produce such symptomatology.[3] Due to the potential for nickel to leach from pipes, inquiring about the patient's home age and renovations is important. 

Chronic exposure can lead to rhinitis, bronchitis, and asthma. Increased incidents of nasal and pulmonary cancer have been reported.

Persistent exposure is also seen with contact dermatitis. The rash is typically localized to the point of nickel contact and is often described as erythematous papules with a pruritic association. Recent piercing and jewelry changes would be essential to note.

Evaluation

There are limitations in available diagnostics when evaluating nickel toxicity. Diagnosis begins with clinical suspicion obtained through detailed patient history. Acute toxicity is more commonly seen in inhalation and ingestion. Symptoms associated with respiratory impairment and gastrointestinal upset can be seen. Nickel is distributed in different organs and body fluids, but the primary analysis is through serum and urine samples.

The average serum concentration of nickel is typically around 0.3 mcg/L in individuals without excessive exposure. However, in cases of significant exposure, such as occupational or environmental exposure, serum concentrations can reach as high as 8 mcg/L. When assessing nickel exposure, urine nickel levels are also considered. A urine nickel concentration greater than 10 mg/dL may indicate excessive exposure and requires intervention or further evaluation.

Case reports have documented specific radiographic findings on chest x-rays in individuals with nickel exposure. These findings may include pleural effusion, irregular linear shadows, and nodular mottling. These radiographic changes can be suggestive of lung involvement and should raise suspicion for potential nickel toxicity. Furthermore, abnormal electrocardiogram (ECG) findings have been observed in some cases of nickel exposure. These ECG abnormalities may include sinus tachycardia (an abnormally fast heart rate originating from the sinus node) and myocardial injury, which can be reflected by ST segment and T wave changes. These cardiac manifestations indicate potential cardiovascular involvement and should be considered in the evaluation and management of individuals exposed to nickel[18] 

Patch testing is a valuable tool in the evaluation of patients with dermatitis. It is particularly useful when there is a clinical suspicion of contact dermatitis and further investigation is required to identify or confirm the causative substance. During a patch test, diluted allergens are applied to the patient's skin, usually on the back, using adhesive patches. The test allows for an extended period of contact between the allergens and the skin, typically 48 hours. After the designated time, the patches are removed, and the skin is carefully examined for allergic reactions, such as erythema, edema, or a characteristic rash.

One commonly used patch test is the dimethylglyoxime spot test, which can be obtained over the counter. This test specifically aids in the identification of nickel allergy by applying dimethylglyoxime to the skin and observing the development of a pink coloration as a positive reaction. Patch testing plays a crucial role in diagnosing contact dermatitis, guiding appropriate treatment, and helping patients avoid exposure to allergens

Treatment / Management

The initial treatment approach for nickel toxicity involves decontamination and removal from the exposed environment. This includes removing contaminated clothing, jewelry, and any visible skin contaminants. Symptomatic relief is a crucial aspect of management, which may involve using bronchodilators, supplemental oxygen, and steroids. These interventions aim to alleviate symptoms and support respiratory function. Prompt and appropriate management is essential to mitigate the adverse effects of nickel toxicity and improve patient outcomes.[18] (B3)

In cases of elevated urine nickel concentrations, diuresis can be considered a treatment option to reduce the half-life of nickel in the serum. A case analysis involving patients who ingested nickel and had initial urine concentrations greater than 1.5 mg/L showed that diuresis was employed as part of their treatment.[3] Due to its high protein binding, hemodialysis does not remove nickel from circulation. Therefore, diuresis may be a viable approach to enhance the elimination of nickel in cases of toxicity.

While current literature does not support the use of chelation therapy in nickel toxicity, there have been suggestions, and case reports exploring its potential. In acute nickel carbonyl poisoning cases, diethyldithiocarbamate (DDC) has been considered an antidote. For critically ill patients, DDC can be administered parenterally at a dose of 12.5 mg/kg IV and should be initiated early in the course of poisoning. In cases where urine nickel levels are equal to or greater than 10 mg/dL, oral dosing of DDC at 1 g can be considered. However, it is essential to note that further research is needed to establish the efficacy and safety of chelation therapy in nickel toxicity.

When DDC availability is limited, contacting local poison control can guide alternative treatment options. One such option is the use of disulfiram, which can be considered if DDC is not available. Disulfiram is metabolized in the body to form two molecules of DDC. It is important to note that data on chelation therapy for nickel toxicity is limited, and further research is needed to establish its effectiveness and safety.[19][20][21] (B3)

In a separate case report, a patient developed delayed pneumonitis following exposure to nickel carbonyl. The patient showed a positive response to treatment with disulfiram. It is important to note that this is an isolated case, and further research is needed to establish the efficacy and safety of disulfiram in treating nickel carbonyl-induced pneumonitis.[22][20][22](B3)

The treatment of nickel dermatitis focuses on symptom management. In addition to avoiding nickel-containing objects, topical corticosteroids and moisturizers/emollients can be utilized. These topical agents help alleviate inflammation and soothe the skin. Implementing preventive measures such as using protective creams, gloves, and other protective equipment can act as a barrier to reduce exposure to nickel and prevent the onset or exacerbation of dermatitis.[23] Healthcare providers must educate patients about these treatment options and preventive strategies to optimize patient outcomes and improve their quality of life.

Differential Diagnosis

Whether through inhalation or ingestion, the acute presentation of nickel toxicity may resemble other respiratory and gastrointestinal conditions. Obtaining a thorough and detailed patient history is crucial, including information about possible exposures, occupation, family history, and the timing of symptoms. It is important to consider a broad range of differential diagnoses, including but not limited to: 

Prognosis

The outcomes of acute nickel toxicity can vary depending on the levels and duration of exposure. The course of toxicity can range from self-limited with symptomatic management in an outpatient setting to requiring hospitalization with close monitoring. In the case of nickel carbonyl exposure, symptoms can onset within an hour of exposure and progress to severe delayed symptoms within the next 48 hours. Over a period of 1 to 2 weeks, pulmonary fibrosis, consolidation, and cerebral edema may develop.[24][25] It is important to be aware of these potential complications and provide appropriate medical care and monitoring based on the severity and progression of symptoms in patients with acute nickel toxicity.

While patients with acute nickel toxicity can recover, some may experience long-term effects such as neurasthenic syndrome.[18] Ingestion of nickel has been reported to result in fatalities, including at least one case involving a young child.[26][6] The symptoms and course of nickel toxicity are influenced by the amount of nickel ingested. The severity of symptoms and prognosis are generally correlated with the extent of exposure.

Following dermal sensitization to nickel, the hypersensitivity response is typically long-lasting and can persist indefinitely. Once an individual becomes sensitized to nickel, subsequent exposures to even trace amounts of nickel can trigger an allergic reaction. However, it is important to note that the intensity of the reaction may vary depending on the frequency and duration of exposure. Extended periods between exposures can potentially lead to a diminished allergic response, but complete resolution of the hypersensitivity is uncommon.[1]

Complications

Acute nickel inhalation sequelae include pneumonitis, myocarditis, altered mental status, and profound weakness. Symptoms may remain for several months after the initial evaluation and management. Chronic inhalational exposure can lead to cancer within the respiratory tract, emphysema, and pulmonary eosinophilia, requiring further management and monitoring. 

In 1990, the International Agency for Research on Cancer (IARC) classified all nickel compounds, except metallic nickel, as carcinogenic to humans.[8]