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Cobalt Toxicity
Introduction
Cobalt (Co) metal is a gray, ductile, magnetic element with an atomic number of 27 and an atomic weight of 58.9 Da. In the environment, cobalt is a component of naturally occurring minerals and is found in combination with other elements such as copper, nickel, manganese, arsenic, sulfur, and oxygen.
Due to its ferromagnetic properties, high melting point (1495.05 C), and high boiling point (2927 C), cobalt is widely used in industry to produce hard metals and superalloys. For example, the alloy Alnico is a blend of iron, aluminum, nickel, and cobalt used for its permanent magnetic properties. A common source of chronic cobalt exposure is in the production of tungsten carbide, which is used for its hardness, heat resistance, and strength.[1]
Historically, cobalt chloride (CoCl2) has been used in medicine as a treatment for anemia due to its ability to promote erythropoiesis.[2] However, due to its adverse effects of thyroid dysfunction and the development of goiters, the use of cobalt in treating anemia has fallen out of favor. A biochemically important cobalt compound is cyanocobalamin (vitamin B12) which contains a Co3+-ion.
Vitamin B12 is an essential nutrient naturally found in foods of animal origin, such as dairy, eggs, fish, poultry, and meat. Deficiencies in vitamin B12 may lead to pernicious anemia as well as peripheral neuropathy.[3] The precursor hydroxocobalamin is used as an antidote for cyanide poisoning and may have a role in treating vasoplegic shock.[4]
Potential cobalt exposure can occur via oral, respiratory, and dermal routes.
Etiology
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Etiology
Cobalt (Co) occurs in pure elemental, inorganic salts, and organic forms. Sources of common cobalt exposure include artist's pigmentation (cobalt blue), dyes, porcelain, cement, rubber, super alloys, drill production, cutting tools, catalysts, orthopedic implants, dental hardware, vitamin supplementation, electroplating, outdated treatments for anemia, and widia-steel production.[1]
Pure elemental cobalt exposure is described in the occupational setting and exerts toxicity via the respiratory route.[5] Inorganic salts, such as cobaltous chloride (CoCl2) or cobaltous sulfate (CoSO4), are generally considered to be more toxic than compared to organic cobalt. Organic cobalt exposure typically results from the ingestion of cyanocobalamin (Vitamin B12), which is considered low toxicity due to its low oral bioavailability.[6]
The single toxic dose of cobalt and its salts is not known. In the cohort of patients with "beer drinker's cardiomyopathy," it was determined that patients were taking an average of 6 to 8 mg of CoSO4 per day for weeks or months.[7] These patients went on to develop severe toxicity, with several deaths. In contrast, infants treated for anemia received 40 mg of CoCl2 per day for three months and did not develop toxicity.[8] This suggests other factors that contribute to the development of toxicity from cobalt.[9]
Epidemiology
Historically, cobalt exposure occurred through using cobalt chloride (CoClto treat anemia) and from drinking beer in which cobalt sulfate had been added as a foam stabilizer. Current sources of cobalt exposure include chemistry sets, dyes, mining, and orthopedic implants. The most significant potential source of cobalt exposure is in the production of the hard metal tungsten carbide.
Several epidemics of "cobalt-induced goiter and cardiomyopathy" were identified between the 1950 and 1970s. The first identified cases of cardiomyopathy were in Nebraska in 1966, with 64 cases and 30 fatalities.[10][11] An additional 48 cases were identified in Quebec with a mortality rate of 46%, and another 20 cases in Minneapolis from 1964-1967 with a mortality rate of 43%.[12][13]
Researchers found that all cases were associated with beer with cobalt sulfate added as a foam stabilizer.[14] The affected populations in these cases largely consisted of men who drank beer daily, often up to 24 pints a day, and were malnourished.[14]
In the general population, the most common source of cobalt is likely to be in the form of nutritional supplements.[15] Poor disposal practices by factories dealing with cobalt or tungsten carbide can subsequently lead to environmental contamination and exposure to those in the surrounding areas.[16]
Tungsten carbide is created by sintering powdered cobalt and tungsten at high temperatures (1550 C) in the presence of hydrogen. Studies have shown that the concentration of cobalt and tungsten in the air inside factories can be ten times greater than when compared with atmospheric concentrations.[17]
Other potential occupational exposures can occur in the maintenance of hard-metal blades[18] and diamond polishing.[19] The resultant inhalation of aerosolized dissolved and ionized cobalt from cutting and polishing results in hard metal disease (HMD).[17] Occupational asthma is also commonly associated with cobalt exposure alone or in the setting of tungsten carbide.[20]
The actual incidence of HMD is not well defined. In one case series, 5 out of 320 patients presenting to an occupational respiratory clinic in over three years were diagnosed with HMD.[21] Other case series describe 11 of 290 exposed workers with interstitial infiltrates on chest radiography[22] and 22 cases of cobalt-induced asthma over 36 years.[23]
More recently, concern has been raised that competitive athletes may use cobalt salts for "blood doping" to increase athletic performance by promoting erythropoiesis. Though the potential adverse effects make it a less-than-ideal method of doping.[24]
Pathophysiology
Similarly to other transition metals, cobalt toxicity affects multiple organ systems. In acute toxicity, excessive cobalt exposure has endocrine, cardiovascular, metabolic, central and peripheral nervous system, gastrointestinal and hematologic effects. Chronic inhalational exposures result in diseases of the pulmonary system, including occupational asthma and hard metal disease.[20][25][5]
Divalent cobalt (Co2+ or cobaltous) is very similar to common intracellular cations, such as Ca2+ and Mg2+. Cobalt inhibits various enzymes responsible for protein synthesis and RNA synthesis as α-ketoglutarate dehydrogenase, α-lipoic acid, and dihydrolipoic acid.[26] This is the likely underlying pathophysiology resulting in cardiomyopathy.
CoCl2 inhibits tyrosine iodinase, which leads to decreased thyroid hormone (T3, T4) and hypothyroidism.[27]
There are multiple theories on the promotion of erythropoiesis by CoCl2.[28] Cobaltous ions may bind to transferrin resulting in impaired oxygen transport to renal cells through induction of hypoxic inducible factor-1 alpha and likely increased iron availability for erythropoiesis. This leads to the development of reticulocytosis and polycythemia.[29][30]
Lastly, cobalt can participate in redox cycling, leading to an excess of free radicals leading to tissue damage. This is the likely mechanism resulting in pulmonary toxicity.[31]
Dermatitis from cobalt is likely a type IV hypersensitivity reaction similar to nickel.[32]
Histopathology
The histologic findings of cobalt cardiomyopathy have similar features to cardiomyopathies induced by protein and thiamine deficiency.[33] In the mid-1960s, breweries began adding cobalt to beer as a foam stabilizer. Subsequently, heavy beer drinkers began to present with a distinct dilated cardiomyopathic syndrome called Beer drinkers' cardiomyopathy. Post-mortem histological features include vacuolization and cellular degeneration.[11]
More characteristic findings in cobalt cardiomyopathy included myocyte atrophy and myofibril loss.[34] Additional abnormal thyroid histology was also found in this patient cohort, including follicular cell abnormalities and colloid depletion.[35]
In patients with hard metal lung disease (HMLD), bronchoalveolar lavage findings include multinucleated giant cells and increased inflammatory cells.[36][37][38] These findings correspond to desquamative giant cell interstitial pneumonitis (GIP). Case series suggest that GIP is pathognomonic for HMLD.[39][40]
Arthroprostethic cobaltism likely results from the development of metallosis and trunnionosis. Metallosis describes the process by which metal particles from an implant deposit into the surrounding tissue due to abnormal wear.[41]
Trunnionosis is the process of metal erosion at the level of the trunnion, which is the area where the femoral head implant connects to the neck of the arthroplasty.[42] These processes indicate implant failure, placing patients at higher risk of systemic toxicity. Patients with arthroprostethic cobaltism will often have findings of aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL) or pseudotumor.[43]
Histologic findings consist of lymphocytic invasion forming perivascular infiltrates. There can also be gross findings of synovial fluid discoloration.[44]
Toxicokinetics
Bioavailability between various forms of cobalt varies widely and mainly derives from animal studies. In humans, the distribution of cobalt is influenced by plasma proteins, such as albumin, as well as transferrin which is a protein that normally binds iron. Uptake is mediated by the P2X7 transporter and is a substrate of divalent metal transporter 1 (DMT1).[45]
Cobalt elimination is mostly in the urine, with a smaller portion in the feces. Urinary elimination is increased in acute exposures.[46] In studies of occupational exposures, elimination rates generally correlate with the exposure pattern. In a standard workweek, urinary excretion increases at the end of the week compared to the beginning of the week. Evidence suggests that urinary excretion also increases in the period immediately following cessation of exposure.[47][48]
History and Physical
Cobalt toxicity is a rare diagnosis, and clinical signs and symptoms overlap significantly with more common diseases. Clinical suspicion is required for the diagnosis of cobalt toxicity. Ingestion of cobalt salts and elemental cobalt may cause gastrointestinal (GI) distress, likely due to irritation of the GI tract itself.[49]
A complete history, including occupational, nutritional, and surgical histories, is important to help identify the potential source of cobalt exposure. In those with cobalt-induced cardiomyopathy, heart failure findings are prominent, including tachycardia, dyspnea, and signs of fluid overload.[11]
Occupations in hard metal manufacturing and diamond polishing will be at a much higher risk of developing toxicity, particularly hard metal lung disease (HMLD). These patients will present with complaints of dyspnea, cough, and wheezing.[50][51]
Arthroprosthetic-associated cobalt toxicity may present with neurologic dysfunction, including peripheral neuropathy, ocular toxicity, cognitive decline, as well as findings of hypothyroidism and cardiomyopathy.[52][53] Before the onset of severe toxicity, these patients may have general complaints of pain and swelling and difficulty walking, usually well after the initial surgery.[52]
Findings of dermatitis can also be found in patients, particularly in the occupational setting, as cobalt is a known sensitizer.[54]
Based on case reports and current evidence, cobalt does not appear to cause renal toxicity, teratogenicity, or impaired fertility.[55][56]
Evaluation
Early discussion with the Poison Control Center or a Medical Toxicologist will assist in guiding workup and management.
Body fluid testing for cobalt is not widely available, so use in the acute setting is limited. Use of adjunctive tests that may signal signs or symptoms of toxicity should be used to direct acute care, including the complete blood count (CBC), reticulocyte count, erythropoietin, and thyroid stimulating hormone levels (TSH). Patients with more severe illnesses may have findings of metabolic acidosis and elevated lactate levels. Electrocardiograms, echocardiograms, and troponin may help identify patients with cardiomyopathy.[57]
Chest radiographs and computed tomography scans will help identify patients with pulmonary disease, particularly in the context of occupational exposures, although pulmonary toxicity can be found in the setting of other routes of exposure. In the outpatient setting, pulmonary function testing may show decreased vital capacity.[58][59][60]
In patients where arthroprosthetic failure is of concern, imaging may be beneficial to identify those who are at high risk of developing toxicity. Ultrasound and magnetic resonance imaging (MRI) are more specific and sensitive studies for cobalt-containing implants.[61] It is important to note that imaging cannot diagnose cobalt toxicity but can identify local tissue reactions and implant failure.
Urine cobalt levels are most commonly used for occupational monitoring. Normal serum cobalt is reported to be 0.1 to 1.2 mcg/L. The normal reference range for urine cobalt is 0.1 to 2.2 mcg/L.[62][63] Because of the normal variation of elimination kinetics, it is important to determine the dose and length of time of exposure to properly interpret urine levels. Whole blood levels are thought to most accurately reflect the whole body burden.[9]
More recently, cardiac magnetic resonance imaging has been used to diagnose cobalt-induced cardiomyopathy in metal-on-metal hip prostheses.[64]
Treatment / Management
The mainstay of cobalt toxicity treatment is supportive. Patients presenting acutely will require aggressive decontamination and treatment. There are no specific studies on gastrointestinal (GI) decontamination in cobalt toxicity. Likely, typical decontamination methods, such as whole bowel irrigation, used in other metal toxicities are applicable for cobalt, mainly if there are radioopaque bodies on radiography. Gastric lavage may be beneficial if the ingested cobalt is a liquid. It is less likely to be beneficial if the ingested material is solid. Antiemetics should be utilized for nausea and vomiting.
Chelation therapy is not well studied in humans, with the majority of data comprising animal studies and case reports. Current evidence suggests that calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) and N-acetylcysteine (NAC) are likely reasonable choices for chelation. Although NAC is not a typical choice for chelation, the thiol group on the molecule serves as a binding site for cobalt.[65][66][67] (B3)
Chelation likely has little role in treatment until the cobalt source is removed, including the removal of arthroplasty.[68] Indications for chelation include end-organ toxicity, such as severe acidosis or cardiac failure.(B3)
Prevention is the primary method for occupational exposure. Systems-based interventions, such as improved ventilator systems, have significantly decreased toxicity associated with exposures.[69] Patients with hard metal lung disease or cobalt-induced asthma may respond to corticosteroids in addition to removal from the exposure source.[59]
Differential Diagnosis
Acute cobalt toxicity is rare and will most likely occur via ingestion. As with most heavy metals, the presenting symptoms usually consist of GI distress, which possesses a significant differential. Without appropriate history, diagnosis of cobalt poisoning may be difficult. Additionally, poisonings with other metals can also result in similar symptoms, which highlights the importance of a detailed history.
In the appropriate work setting, such as tungsten carbide manufacturing, a patient presenting for evaluation of respiratory complaints, pneumoconiosis should be high on the differential. On the list of potential causes, cobalt or hard metal disease should be included. The occupational history will help to quickly narrow the potential etiology. In a patient presenting with polycythemia or goiter, exposure to cobalt salts should be considered.
Cardiomyopathy has a broad differential, but a surgical history of hip arthroplasty should raise suspicion of potential cobalt toxicity. Further investigation into the type of implant the patient has should be performed to aid in diagnostics.
Prognosis
Acute cobalt toxicity can cause severe illness. Patients who have cardiomyopathy have an associated high mortality rate. There is little data on chelation in the treatment of non-arthroplastic cobalt toxicity. Chelation is likely to improve recovery from cardiomyopathy based on case reports in patients with arthroplastic cobalt toxicity.[70]
The prognosis of arthroprosthetic cobalt toxicity is dependent on early identification and subsequent arthroplasty revision. Arthroplasty revision effectively decreases cobalt concentrations in blood and serum and is associated with clinical recovery.[71][72]
The recovery degree likely depends on the duration of exposure to elevated levels. In some cases, patients are given chelation after removal and do not have complete recovery. Persistent symptoms range from tinnitus and hearing loss to a cardiomyopathy requiring left-ventricular assist device implantation.[68][73][74]
Patients with hard metal lung disease often recover once the exposure source is removed.[75][76][58][59]
Complications
Delayed identification of cobalt toxicity may result in poor recovery and significant morbidity. These include cardiomyopathy, peripheral neuropathy, vision loss, and chronic respiratory disease. Cobalt metal without tungsten carbide is classified by the International Agency for Research on Cancer (IARC) as Group 2B (possibly carcinogenic to humans).[77]
Cobalt in the setting of tungsten carbide is classified as Group 2A (probably carcinogenic to humans).[77] Human data is limited but based on animal studies; associated cancers include soft tissue sarcomas and lung cancer.[78][79][80]
Deterrence and Patient Education
Cobalt toxicity most commonly will be in the setting of a metal-on-metal arthroplasty or the occupational environment. It is essential to wear appropriate personal protective equipment and follow workplace guidelines to minimize exposure to cobalt and tungsten carbide powders and debris.
Decreasing exposure will ultimately reduce the risk of the development of disease. If you have a metal-on-metal hip arthroplasty, be sure to discuss concerns with your surgeon, particularly if you begin to have new pain, swelling, or difficulty walking, as this may put you at a higher risk of developing toxicity from the implant.
Enhancing Healthcare Team Outcomes
Cobalt toxicity is a relatively rare diagnosis and may be challenging to identify in the typical clinical setting, such as the emergency room or outpatient clinic. The signs and symptoms associated with toxicity are seen in many more commonly diagnosed diseases.
Primary care or emergency medicine clinicians are more likely to interact with patients presenting with acute complaints. Consultation with certified specialists in poison information (CSPI), medical toxicologists, or clinical toxicologists at the nearest poison control center is key in creating the best management plan for a patient as well as educating the rest of the interprofessional team about diagnosis and management, helping decrease potential patient morbidity and mortality.
The management of cobalt toxicity is based on case reports and animal studies. There is epidemiologic data on several outbreaks of toxicity as well as in the occupational setting, mainly in the context of pulmonary exposures (i.e., hard metal lung disease). There are no randomized control trials concerning treatment.
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