Continuing Education Activity

Cobalt toxicity is an uncommon but potentially serious condition resulting from excessive exposure to cobalt, an essential trace element and a structural component of cobalamin (vitamin B12). Although cobalt is required for normal erythropoiesis and neurologic function, elevated levels, particularly from inorganic forms, can produce multisystem toxicity. Acute exposure is rare and most often related to excessive supplementation or accidental ingestion, whereas chronic toxicity more commonly occurs through occupational exposure in mining, metal processing, battery manufacturing, or from wear and failure of metal-on-metal hip prostheses. Pathophysiological mechanisms include mitochondrial dysfunction, oxidative stress, and disruption of calcium homeostasis, which together lead to cellular injury. Clinical manifestations vary based on exposure duration and dose and may include cardiomyopathy, peripheral neuropathy, sensorineural hearing loss, visual impairment, hypothyroidism, and polycythemia. Diagnosis depends on a thorough exposure history, measurement of serum or whole-blood cobalt levels, and targeted evaluation of affected organ systems.

This activity for healthcare professionals is designed to enhance clinicians' competence in recognizing, evaluating, and managing cobalt toxicity. Participants strengthen their understanding of exposure sources, toxicokinetics, and multisystem clinical manifestations to support earlier diagnosis and intervention. The course reviews evidence-based diagnostic strategies, interpretation of cobalt levels, and management approaches, including exposure cessation, supportive care, and prosthesis revision when indicated. Emphasis is placed on coordinated care involving occupational medicine, cardiology, neurology, endocrinology, orthopedics, and toxicology. Effective interprofessional collaboration and communication are highlighted as critical to minimizing irreversible organ damage, optimizing treatment decisions, and improving patient outcomes.

Objectives:

• Identify clinical and diagnostic features of cobalt poisoning, linking findings to exposure sources to guide timely management and consultation.
• Apply best practices in cobalt toxicity management to prevent or mitigate long-term organ and neurologic complications.
• Improve patient understanding of cobalt toxicity, including exposure sources, symptoms, potential complications, and strategies to address possible long-term health effects.
• Collaborate with all members of the interprofessional team, including specialists such as emergency medicine clinicians, toxicologists, and internists, to provide efficient, comprehensive, and coordinated care for individuals experiencing cobalt toxicity.

Access free multiple choice questions on this topic.

Introduction

Cobalt (atomic symbol Co) is a gray, ductile, magnetic element with atomic number 27 and atomic weight 58.9 Da. In the environment, cobalt occurs in naturally occurring minerals and is commonly combined with elements such as copper, nickel, manganese, arsenic, sulfur, and oxygen. Cobalt’s ferromagnetic properties, as well as high melting (1495.05 °C/ 2723.1 °F) and boiling (2927 °C/5312.6 °F) points, support its widespread industrial use in manufacturing hard metals and superalloys. The alloy Alnico, a blend of iron, aluminum, nickel, and cobalt, is valued for its permanent magnetic properties. Chronic occupational exposure often occurs during the production of tungsten carbide, which is utilized for its hardness, heat resistance, and mechanical strength.[1]

Historically, cobalt chloride (CoCl₂) was used in medicine to treat anemia by promoting erythropoiesis.[2] Adverse effects, including thyroid dysfunction and goiter, led to the discontinuation of cobalt administration for this indication. Cyanocobalamin, otherwise known as vitamin B12, contains a trivalent cobalt ion (Co₃+) and is a biochemically important cobalt compound. Vitamin B12 is an essential nutrient naturally present in foods of animal origin, including dairy, eggs, fish, poultry, and meat. Deficiency may result in pernicious anemia and peripheral neuropathy.[3] Hydroxocobalamin, a metabolic precursor, is employed as an antidote for cyanide poisoning and may have therapeutic potential in vasoplegic shock.[4] Potential exposure to cobalt occurs via oral, respiratory, and dermal routes.

Etiology

Cobalt occurs in elemental, inorganic salt, and organic forms. Common sources of cobalt exposure include artist pigments (cobalt blue), dyes, porcelain, cement, rubber, superalloys, drill production, cutting tools, catalysts, orthopedic implants, dental hardware, vitamin supplementation, electroplating, outdated anemia treatments, and widia-steel production. However, exposure to pure elemental cobalt is primarily occupational and exerts toxicity via the respiratory route.[5] Inorganic salts, such as CoCl₂ and cobaltous sulfate (CoSO₄), are generally more toxic than organic cobalt. Organic cobalt exposure typically arises from ingestion of cyanocobalamin and demonstrates low toxicity due to minimal oral bioavailability.[6]

The single toxic dose of cobalt and its salts is unknown. In patients with the condition originally described as "beer drinker’s cardiomyopathy," reported cobalt intake averaged 6 to 8 mg of CoSO₄ per day over weeks to months.[7] Severe toxicity developed in several patients, including multiple fatalities. In contrast, infants treated for anemia received 40 mg of CoCl₂  per day for 3 months without clinically apparent adverse effects.[8] These observations indicate that additional factors influence the development of cobalt poisoning.[9]

Epidemiology

Historically, cobalt exposure occurred through the use of CoCl₂ to treat anemia and through the consumption of beer containing CoSO₄ as a foam stabilizer. Current sources of cobalt exposure include chemistry sets, dyes, metal mining and processing facilities, and orthopedic implants. The most significant potential source of exposure is the production of hard-metal tungsten carbide. Several epidemics of cobalt-induced goiter and cardiomyopathy were documented between 1950 and 1970.

The first identified cases of cardiomyopathy occurred in Nebraska in 1966, with 64 cases and 30 fatalities.[10][11] An additional 48 cases were reported in Quebec, with a mortality rate of 46%, and 20 cases in Minneapolis from 1964 to 1967, with a mortality rate of 43%.[12][13] Investigations determined that all cases were linked to beer containing added CoSO₄ as a foam stabilizer. Affected populations primarily consisted of men who consumed beer daily, often up to 24 pints per day, and were malnourished.[14]

In the general population, nutritional supplements are the most common source of cobalt exposure.[15] Environmental contamination and secondary exposure may result from inadequate disposal practices at factories handling cobalt or tungsten carbide.[16] Tungsten carbide is produced by sintering powdered cobalt and tungsten at high temperatures (1550 °C/2822?°F) in the presence of hydrogen. Airborne concentrations of cobalt and tungsten in factories can reach levels 10 times ambient concentrations.[17]

Additional occupational exposures occur during the maintenance of hard-metal blades and diamond polishing.[18][19] Inhalation of aerosolized, dissolved, and ionized cobalt generated from cutting and polishing can lead to hard metal disease (HMD). Occupational asthma is frequently associated with cobalt exposure alone or in combination with tungsten carbide.[20] The incidence of HMD is poorly defined. In a case series, 5 of 320 patients presenting to an occupational respiratory clinic over 3 years were diagnosed with HMD.[21] Other reports describe 11 of 290 exposed workers with interstitial infiltrates on chest radiography and 22 cases of cobalt-induced asthma documented over 36 years.[22][23]

Recent concern has arisen regarding the use of cobalt salts by competitive athletes for “blood doping” to enhance performance through stimulation of erythropoiesis. Potential adverse effects render this method a high-risk and suboptimal approach to performance enhancement.[24] Metal-on-metal arthroplasties, including hip and knee implants, represent a contemporary source of cobalt toxicity. Blood cobalt concentrations increase following arthroplasty implantation, and implant failure can result in substantial elevations and systemic toxicity. Patients undergoing revision of ceramic-on-ceramic arthroplasties face an increased risk of third-body wear, which may accelerate the failure of metal-on-metal implants.[25]

Pathophysiology

Similar to other transition metals, cobalt toxicity affects multiple organ systems. Acute toxicity from excessive cobalt exposure produces endocrine, cardiovascular, metabolic, central and peripheral nervous system, gastrointestinal, and hematologic effects. Chronic inhalational exposure causes pulmonary disease, including occupational asthma and HMD.[26] Divalent cobalt (Co₂+) resembles common intracellular cations such as calcium (Ca₂+) and magnesium (Mg₂+). Cobalt inhibits enzymes involved in protein and ribonucleic acid synthesis, including α-ketoglutarate dehydrogenase, α-lipoic acid, and dihydrolipoic acid.[27] Inhibition of these enzymes likely underlies cobalt-induced cardiomyopathy. CoCl₂ inhibits tyrosine iodinase. This inhibition results in decreased levels of thyroid hormones (triiodothyronine and thyroxine) and hypothyroidism.[28]

Several mechanisms may account for the erythropoietic effects of CoCl₂.[29] Cobaltous ions can bind to transferrin, impair oxygen delivery to renal cells by inducing hypoxia-inducible factor 1α, and increase iron availability for erythropoiesis. These effects lead to reticulocytosis and polycythemia.[30][31] Cobalt participates in redox cycling, generating excess free radicals that can cause tissue damage, likely contributing to pulmonary toxicity.[32] Dermatitis from cobalt likely represents a type IV hypersensitivity reaction, analogous to that caused by nickel.[33]

Histopathology

The histologic features of cobalt cardiomyopathy resemble those observed in cardiomyopathies arising from protein and thiamine deficiency.[34] In the mid-1960s, breweries began adding cobalt to beer as a foam stabilizer. Heavy beer consumers subsequently developed a distinct dilated cardiomyopathic syndrome termed "beer drinkers’ cardiomyopathy." Postmortem histology demonstrated vacuolization and cellular degeneration. Specific findings in cobalt cardiomyopathy included myocyte atrophy and myofibrillar loss.[35] Additional thyroid abnormalities in this patient cohort consisted of follicular cell changes and colloid depletion.[36]

In individuals with hard metal lung disease (HMLD), bronchoalveolar lavage revealed multinucleated giant cells and increased inflammatory cells.[37][38][39] These findings are consistent with desquamative giant cell interstitial pneumonitis (GIP). Early case series suggested that GIP is pathognomonic for HMLD.[40][41] More recent reports indicate that GIP may not be pathognomonic and that an immune-mediated etiopathogenesis could be involved.[42][43]

Arthroprosthetic cobaltism likely results from the development of metallosis and trunnionosis. "Metallosis" describes the deposition of metal particles from an implant into surrounding tissue due to abnormal wear.[44] "Trunnionosis" refers to metal erosion at the trunnion, the region where the femoral head implant connects to the neck of the arthroplasty.[45] Both processes indicate implant failure and increase the risk of systemic toxicity. Arthroprosthetic cobaltism frequently presents with aseptic lymphocyte-dominated vasculitis-associated lesions or pseudotumor formation.[46] Histologic features include lymphocytic invasion forming perivascular infiltrates. Gross findings may include discoloration of synovial fluid.[47]

Toxicokinetics

The bioavailability of cobalt varies widely across forms and is primarily based on animal studies. In humans, cobalt distribution is influenced by plasma proteins such as albumin and transferrin, which normally bind iron. Cellular uptake is mediated by the P2X7 transporter and occurs via divalent metal transporter 1.[48] Cobalt localizes to multiple organs, including the kidney, liver, heart, and spleen.[49] 

Cobalt elimination occurs predominantly in the urine, with a smaller fraction excreted in the feces. Urinary elimination increases during acute exposures.[50] Elimination rates generally correlate with exposure patterns in occupational exposure studies. Urinary excretion increases at the end of a standard workweek compared to the beginning. Evidence indicates that excretion also rises immediately following cessation of exposure.[51][52]

History and Physical

Cobalt toxicity is a rare diagnosis, and clinical signs and symptoms overlap substantially with more common diseases. Clinical suspicion is required for diagnosis. Ingestion of cobalt salts or elemental cobalt can cause gastrointestinal distress, likely due to direct irritation of the gastrointestinal tract.[53] A complete history, including occupational, nutritional, and surgical information, is essential to identify potential sources of cobalt exposure. Heart failure findings are prominent in patients with cobalt-induced cardiomyopathy, including tachycardia, dyspnea, and evidence of fluid overload.

Occupational exposure in hard metal manufacturing and diamond polishing confers a markedly increased risk of toxicity, particularly HMLD. Affected individuals commonly present with dyspnea, cough, and wheezing.[54][55] Arthroprosthetic-associated cobalt toxicity may manifest with neurologic dysfunction, including peripheral neuropathy, ocular toxicity, and cognitive decline, as well as hypothyroidism and cardiomyopathy.[56] 

Patients may report pain, swelling, and difficulty walking before severe toxicity develops, often occurring well after the initial surgery.[57] Dermatitis may also occur, particularly in occupational settings, as cobalt is a known sensitizer.[58] Case reports and current evidence indicate that cobalt does not appear to cause renal toxicity, teratogenicity, or impaired fertility.[59][60]

Evaluation

Early consultation with a poison control center or a medical toxicologist can guide diagnostic workup and management. Targeted testing can help confirm exposure and assess the severity of organ involvement. Body fluid testing for cobalt is not widely available, limiting the use of this assessment method in acute settings. Adjunctive laboratory tests that may indicate toxicity should guide acute care, including a complete blood count, reticulocyte count, erythropoietin level, and thyroid-stimulating hormone level. Severe cases may demonstrate metabolic acidosis and elevated lactate concentrations. Electrocardiograms, echocardiograms, and troponin measurements can assist in identifying cardiomyopathy.[61]

Urine cobalt levels are most commonly employed for occupational monitoring. Normal serum cobalt concentrations range from 0.1 to 1.2 mcg/L. The reference range for urinary cobalt is 0.1 to 2.2 mcg/L.[62][63] Interpretation of urinary levels requires consideration of exposure dose and duration, given variability in elimination kinetics. Whole-blood cobalt levels are considered the most accurate indicator of total-body burden.

Imaging can help identify individuals at high risk of developing toxicity if concerns for arthroprosthetic failure arise. Ultrasound and magnetic resonance imaging provide greater specificity and sensitivity for cobalt-containing implants.[64] Imaging does not diagnose cobalt toxicity but can detect local tissue reactions and implant failure. 

Cardiac magnetic resonance imaging has recently been used to diagnose cobalt-induced cardiomyopathy in patients with metal-on-metal hip prostheses.[65] Chest radiography and computed tomography can identify pulmonary disease, particularly in the context of occupational exposures, although pulmonary toxicity may occur from other routes of exposure. Outpatient pulmonary function testing may reveal decreased vital capacity.[66][67][68]

Treatment / Management

Supportive care is the mainstay of treatment for cobalt toxicity. Acute presentations require prompt and aggressive decontamination and medical management. No specific studies address gastrointestinal decontamination in cobalt toxicity. Standard decontamination methods used for other metal toxicities, including whole bowel irrigation, are likely applicable, particularly when radioopaque material is visible on radiography. Gastric lavage may be beneficial for liquid ingestions but is less effective for solid forms. Antiemetics should be administered for nausea and vomiting.

Chelation therapy is poorly studied in humans, with most evidence derived from animal studies and case reports. Current data suggest that calcium disodium ethylenediaminetetraacetic acid (CaNa₂EDTA) and N-acetylcysteine (NAC) are reasonable options. Although NAC is not a conventional chelating agent, the thiol group provides a binding site for cobalt.[69][70][71] Chelation has limited utility until the cobalt source is removed, for example, by arthroplasty removal.[72] Indications for chelation therapy include evidence of end-organ toxicity, such as severe acidosis or cardiac failure.

Prevention is the primary strategy for occupational exposures. Systems-based interventions, including improved ventilation, have markedly reduced toxicity associated with industrial exposures.[73] Patients with HMLD or cobalt-induced asthma may benefit from corticosteroids in addition to removal from the exposure source.

Differential Diagnosis

Acute cobalt toxicity is rare and most commonly occurs via ingestion. Presenting symptoms generally consist of gastrointestinal distress, which has a broad differential diagnosis. Diagnosis of cobalt poisoning can be challenging without an appropriate history. Poisonings with other metals may produce similar symptoms, emphasizing the need for a detailed exposure history.

Respiratory complaints should prompt consideration of pneumoconiosis in occupational settings, such as tungsten carbide manufacturing. Cobalt toxicity or HMLD should be included among potential causes. Occupational history helps rapidly narrow the etiology. Patients presenting with polycythemia or goiter should be evaluated for possible exposure to cobalt salts. Cardiomyopathy has a wide differential diagnosis. A surgical history of hip arthroplasty should raise suspicion for cobalt toxicity. Investigation of the specific implant type can aid in diagnosis and risk assessment.

Prognosis

Acute cobalt toxicity can cause severe illness. Cardiomyopathy associated with cobalt toxicity carries a high mortality rate. Data on chelation for nonarthroplastic cobalt toxicity are limited. Case reports suggest that chelation may improve recovery from cardiomyopathy in patients with arthroplastic cobalt toxicity.[74]

Prognosis in arthroprosthetic cobalt toxicity depends on early identification and timely arthroplasty revision. Revision reduces cobalt concentrations in blood and serum and is associated with clinical improvement.[75][76] Recovery likely correlates with the duration of exposure to elevated cobalt levels. In some cases, chelation after implant removal does not result in complete recovery. Persistent symptoms may include tinnitus, hearing loss, or cardiomyopathy requiring implantation of a left ventricular assist device.[77][78] Removal of the exposure source often leads to recovery in patients with HMLD.[79][80]

Complications

Delayed identification of cobalt toxicity can result in poor recovery and substantial morbidity. Manifestations 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 as Group 2B, indicating that it is possibly carcinogenic to humans.[81] Cobalt in combination with tungsten carbide is classified as Group 2A, signifying that it is carcinogenic to humans. Human data are limited, but animal studies suggest an association with cancers, including soft tissue sarcomas and lung cancer.[82][83][84]

Deterrence and Patient Education

Cobalt toxicity most commonly occurs in the context of metal-on-metal arthroplasty or occupational exposure. Appropriate personal protective equipment and adherence to workplace safety guidelines are essential to minimize exposure to cobalt and tungsten carbide powders and debris. Reducing exposure reduces the risk of disease development. Patients with metal-on-metal hip arthroplasties should discuss concerns with their surgeon, particularly if new pain, swelling, or difficulty walking develops, as these factors increase the risk of toxicity from the implant.

Enhancing Healthcare Team Outcomes

Cobalt toxicity is a relatively rare diagnosis and can be challenging to identify in typical healthcare settings, such as emergency departments or outpatient clinics. Signs and symptoms of toxicity overlap with those of many more commonly diagnosed conditions. Primary care and emergency medicine clinicians are most likely to encounter patients with acute complaints.

Consultation with certified specialists in poison information, medical toxicologists, or clinical toxicologists at the nearest poison control center is essential for developing an optimal management plan. Expert guidance also supports education of the interprofessional team, reducing potential morbidity and mortality. Management of cobalt toxicity is primarily informed by case reports and animal studies. Epidemiologic data are available from several outbreaks and occupational exposures, particularly involving pulmonary disease such as HMLD. No randomized controlled trials exist regarding treatment.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Barceloux DG. Cobalt. J Toxicol Clin Toxicol. 1999;37(2):201-6. [PubMed: 10382556]

2.

Duckham JM, Lee HA. The treatment of refractory anaemia of chronic renal failure with cobalt chloride. Q J Med. 1976 Apr;45(178):277-94. [PubMed: 940922]

3.

Silverstein WK, Cheung MC, Lin Y. Vitamin B₁₂ deficiency. CMAJ. 2022 Jun 20;194(24):E843. [PMC free article: PMC9261952] [PubMed: 35724997]

4.

Kaiser SK, Dart RC. The Roles of Antidotes in Emergency Situations. Emerg Med Clin North Am. 2022 May;40(2):381-394. [PubMed: 35461629]

5.

Swennen B, Buchet JP, Stánescu D, Lison D, Lauwerys R. Epidemiological survey of workers exposed to cobalt oxides, cobalt salts, and cobalt metal. Br J Ind Med. 1993 Sep;50(9):835-42. [PMC free article: PMC1061317] [PubMed: 8398878]

6.

Devi S, Pasanna RM, Shamshuddin Z, Bhat K, Sivadas A, Mandal AK, Kurpad AV. Measuring vitamin B-12 bioavailability with [13C]-cyanocobalamin in humans. Am J Clin Nutr. 2020 Dec 10;112(6):1504-1515. [PubMed: 32844171]

7.

Kesteloot H, Roelandt J, Willems J, Claes JH, Joossens JV. An enquiry into the role of cobalt in the heart disease of chronic beer drinkers. Circulation. 1968 May;37(5):854-64. [PubMed: 5646867]

8.

ROHN RJ, BOND WH. Observations on some hematological effects of cobalt-iron mixtures. J Lancet. 1953 Aug;73(8):317-24. [PubMed: 13096934]

9.

Catalani S, Leone R, Rizzetti MC, Padovani A, Apostoli P. The role of albumin in human toxicology of cobalt: contribution from a clinical case. ISRN Hematol. 2011;2011:690620. [PMC free article: PMC3198613] [PubMed: 22084701]

10.

LITTLE JA, SUNICO R. Cobalt-induced goiter with cardiomegaly and congestive failure. J Pediatr. 1958 Mar;52(3):284-8. [PubMed: 13526084]

11.

McDermott PH, Delaney RL, Egan JD, Sullivan JF. Myocardosis and cardiac failure in men. JAMA. 1966 Oct 17;198(3):253-6. [PubMed: 4223885]

12.

Morin YL, Foley AR, Martineau G, Roussel J. Quebec beer-drinkers' cardiomyopathy: forty-eight cases. Can Med Assoc J. 1967 Oct 07;97(15):881-3. [PMC free article: PMC1923396] [PubMed: 6051256]

13.

Alexander CS. Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty-eight cases. Am J Med. 1972 Oct;53(4):395-417. [PubMed: 4263183]

14.

Morin Y, Daniel P. Quebec beer-drinkers' cardiomyopathy: etiological considerations. Can Med Assoc J. 1967 Oct 07;97(15):926-8. [PMC free article: PMC1923410] [PubMed: 6051264]

15.

Tvermoes BE, Unice KM, Paustenbach DJ, Finley BL, Otani JM, Galbraith DA. Effects and blood concentrations of cobalt after ingestion of 1 mg/d by human volunteers for 90 d. Am J Clin Nutr. 2014 Mar;99(3):632-46. [PubMed: 24500148]

16.

Abraham JL, Hunt A. Environmental contamination by cobalt in the vicinity of a cemented tungsten carbide tool grinding plant. Environ Res. 1995 Apr;69(1):67-74. [PubMed: 7588496]

17.

FAIRHALL LT, KEENAN RG, BRINTON HP. Cobalt and the dust environment of the cemented tungsten carbide industry. Public Health Rep (1896). 1949 Apr 15;64(15):485-90. [PubMed: 18114620]

18.

Linnainmaa M, Kangas J, Kalliokoski P. Exposure to airborne metals in the manufacture and maintenance of hard metal and stellite blades. Am Ind Hyg Assoc J. 1996 Feb;57(2):196-201. [PubMed: 8615327]

19.

Demedts M, Gyselen A. [The cobalt lung in diamond cutters: a new disease]. Verh K Acad Geneeskd Belg. 1989;51(6):559-81. [PubMed: 2561412]

20.

Kusaka Y, Iki M, Kumagai S, Goto S. Epidemiological study of hard metal asthma. Occup Environ Med. 1996 Mar;53(3):188-93. [PMC free article: PMC1128442] [PubMed: 8704860]

21.

Mizutani RF, Terra-Filho M, Lima E, Freitas CS, Chate RC, Kairalla RA, Carvalho-Oliveira R, Santos UP. Hard metal lung disease: a case series. J Bras Pneumol. 2016 Nov-Dec;42(6):447-452. [PMC free article: PMC5344095] [PubMed: 28117477]

22.

Sprince NL, Chamberlin RI, Hales CA, Weber AL, Kazemi H. Respiratory disease in tungsten carbide production workers. Chest. 1984 Oct;86(4):549-57. [PubMed: 6434250]

23.

Sauni R, Linna A, Oksa P, Nordman H, Tuppurainen M, Uitti J. Cobalt asthma--a case series from a cobalt plant. Occup Med (Lond). 2010 Jun;60(4):301-6. [PubMed: 20308255]

24.

Ebert B, Jelkmann W. Intolerability of cobalt salt as erythropoietic agent. Drug Test Anal. 2014 Mar;6(3):185-9. [PubMed: 24039233]

25.

Cowie RM, Jennings LM. Third body damage and wear in arthroplasty bearing materials: A review of laboratory methods. Biomater Biosyst. 2021 Dec;4:100028. [PMC free article: PMC9934499] [PubMed: 36824573]

26.

Rivolta G, Nicoli E, Ferretti G, Tomasini M. Hard metal lung disorders: analysis of a group of exposed workers. Sci Total Environ. 1994 Jun 30;150(1-3):161-5. [PubMed: 7939591]

27.

de Moraes S, Mariano M. Biochemical aspects of cobalt intoxication. Cobalt ion action on oxygen uptake. Med Pharmacol Exp Int J Exp Med. 1967;16(5):441-7. [PubMed: 6072255]

28.

KRISS JP, CARNES WH, GROSS RT. Hypothyroidism and thyroid hyperplasia in patients treated with cobalt. J Am Med Assoc. 1955 Jan 08;157(2):117-21. [PubMed: 13211322]

29.

GARDNER FH. The use of cobaltous chloride in the anemia associated with chronic renal disease. J Lab Clin Med. 1953 Jan;41(1):56-64. [PubMed: 13023095]

30.

Yang L, Wang D, Wang XT, Lu YP, Zhu L. The roles of hypoxia-inducible Factor-1 and iron regulatory protein 1 in iron uptake induced by acute hypoxia. Biochem Biophys Res Commun. 2018 Dec 09;507(1-4):128-135. [PubMed: 30415773]

31.

Fried W, Kilbridge T. Effect of testosterone and of cobalt on erythropoietin production by anephric rats. J Lab Clin Med. 1969 Oct;74(4):623-9. [PubMed: 5821519]

32.

Nemery B, Lewis CP, Demedts M. Cobalt and possible oxidant-mediated toxicity. Sci Total Environ. 1994 Jun 30;150(1-3):57-64. [PubMed: 7939609]

33.

Minang JT, Areström I, Troye-Blomberg M, Lundeberg L, Ahlborg N. Nickel, cobalt, chromium, palladium and gold induce a mixed Th1- and Th2-type cytokine response in vitro in subjects with contact allergy to the respective metals. Clin Exp Immunol. 2006 Dec;146(3):417-26. [PMC free article: PMC1810408] [PubMed: 17100760]

34.

Packer M. Cobalt Cardiomyopathy: A Critical Reappraisal in Light of a Recent Resurgence. Circ Heart Fail. 2016 Dec;9(12) [PubMed: 27852654]

35.

Centeno JA, Pestaner JP, Mullick FG, Virmani R. An analytical comparison of cobalt cardiomyopathy and idiopathic dilated cardiomyopathy. Biol Trace Elem Res. 1996 Oct-Nov;55(1-2):21-30. [PubMed: 8971351]

36.

Roy PE, Bonenfant JL, Turcot L. Thyroid changes in cases of Quebec beer drinkers myocardosis. Am J Clin Pathol. 1968 Aug;50(2):234-9. [PubMed: 5673088]

37.

Forni A. Bronchoalveolar lavage in the diagnosis of hard metal disease. Sci Total Environ. 1994 Jun 30;150(1-3):69-76. [PubMed: 7939611]

38.

Cugell DW, Morgan WK, Perkins DG, Rubin A. The respiratory effects of cobalt. Arch Intern Med. 1990 Jan;150(1):177-83. [PubMed: 2297286]

39.

Demedts M, Gheysens B, Nagels J, Verbeken E, Lauweryns J, van den Eeckhout A, Lahaye D, Gyselen A. Cobalt lung in diamond polishers. Am Rev Respir Dis. 1984 Jul;130(1):130-5. [PubMed: 6742597]

40.

Dai JH, Miao LY, Xiao YL, Meng FQ, Cai HR. [Giant cell interstitial pneumonia associated with hard metals: a case report and review of the literature]. Zhonghua Jie He He Hu Xi Za Zhi. 2009 Jul;32(7):493-6. [PubMed: 19954001]

41.

Naqvi AH, Hunt A, Burnett BR, Abraham JL. Pathologic spectrum and lung dust burden in giant cell interstitial pneumonia (hard metal disease/cobalt pneumonitis): review of 100 cases. Arch Environ Occup Health. 2008 Summer;63(2):51-70. [PubMed: 18628077]

42.

Moriyama H, Takada T, Aoki A, Shima K, Kikuchi T. Is giant cell interstitial pneumonia pathognomonic for hard metal lung diseases?-pathological and elemental analyses of 84 cases. Histopathology. 2025 Dec;87(6):923-932. [PubMed: 40815182]

43.

Fortarezza F, Perilli M, Della Barbera M, Pezzuto F, Faccioli E, Cocconcelli E, Cozzi E, Somigliana AB, Bonvicini B, Rea F, Basso C, Rizzo S, Calabrese F. Giant cell interstitial pneumonia: case series with comprehensive ultrastructural analyses of "not only" hard metal pneumoconiosis. Histopathology. 2025 Feb;86(3):450-459. [PubMed: 39438781]

44.

Ude CC, Esdaille CJ, Ogueri KS, Ho-Man K, Laurencin SJ, Nair LS, Laurencin CT. The Mechanism of Metallosis After Total Hip Arthroplasty. Regen Eng Transl Med. 2021 Sep;7(3):247-261. [PMC free article: PMC9075182] [PubMed: 35530571]

45.

Dutta A, Nutt J, Slater G, Ahmed S. Review: Trunnionosis leading to modular femoral head dissociation. J Orthop. 2021 Jan-Feb;23:199-202. [PMC free article: PMC7856321] [PubMed: 33551613]

46.

Watters TS, Cardona DM, Menon KS, Vinson EN, Bolognesi MP, Dodd LG. Aseptic lymphocyte-dominated vasculitis-associated lesion: a clinicopathologic review of an underrecognized cause of prosthetic failure. Am J Clin Pathol. 2010 Dec;134(6):886-93. [PubMed: 21088151]

47.

Gilbert CJ, Cheung A, Butany J, Zywiel MG, Syed K, McDonald M, Wong F, Overgaard C. Hip pain and heart failure: the missing link. Can J Cardiol. 2013 May;29(5):639.e1-2. [PubMed: 23313008]

48.

Catalani S, Rizzetti MC, Padovani A, Apostoli P. Neurotoxicity of cobalt. Hum Exp Toxicol. 2012 May;31(5):421-37. [PubMed: 21729976]

49.

Zhong Q, Pan X, Chen Y, Lian Q, Gao J, Xu Y, Wang J, Shi Z, Cheng H. Prosthetic Metals: Release, Metabolism and Toxicity. Int J Nanomedicine. 2024;19:5245-5267. [PMC free article: PMC11162637] [PubMed: 38855732]

50.

Kent NL, McCance RA. The absorption and excretion of ;minor' elements by man: Cobalt, nickel, tin and manganese. Biochem J. 1941 Sep;35(8-9):877-83. [PMC free article: PMC1265580] [PubMed: 16747455]

51.

Mosconi G, Bacis M, Vitali MT, Leghissa P, Sabbioni E. Cobalt excretion in urine: results of a study on workers producing diamond grinding tools and on a control group. Sci Total Environ. 1994 Jun 30;150(1-3):133-9. [PubMed: 7939586]

52.

Apostoli P, Porru S, Alessio L. Urinary cobalt excretion in short time occupational exposure to cobalt powders. Sci Total Environ. 1994 Jun 30;150(1-3):129-32. [PubMed: 7939585]

53.

Schirrmacher UO. Case of cobalt poisoning. Br Med J. 1967 Mar 04;1(5539):544-5. [PMC free article: PMC1841345] [PubMed: 6017158]

54.

Linna A, Oksa P, Palmroos P, Roto P, Laippala P, Uitti J. Respiratory health of cobalt production workers. Am J Ind Med. 2003 Aug;44(2):124-32. [PubMed: 12874844]

55.

HARDING HE. Notes on the toxicology of cobalt metal. Br J Ind Med. 1950 Apr;7(2):76-8. [PMC free article: PMC1036305] [PubMed: 15414282]

56.

Bradberry SM, Wilkinson JM, Ferner RE. Systemic toxicity related to metal hip prostheses. Clin Toxicol (Phila). 2014 Sep-Oct;52(8):837-47. [PubMed: 25132471]

57.

Apostoli P, Catalani S, Zaghini A, Mariotti A, Poliani PL, Vielmi V, Semeraro F, Duse S, Porzionato A, Macchi V, Padovani A, Rizzetti MC, De Caro R. High doses of cobalt induce optic and auditory neuropathy. Exp Toxicol Pathol. 2013 Sep;65(6):719-27. [PubMed: 23069009]

58.

Kieć-Swierczyńska M. Occupational dermatoses and allergy to metals in Polish construction workers manufacturing prefabricated building units. Contact Dermatitis. 1990 Jul;23(1):27-32. [PubMed: 2144804]

59.

Fritzsche J, Borisch C, Schaefer C. Case report: High chromium and cobalt levels in a pregnant patient with bilateral metal-on-metal hip arthroplasties. Clin Orthop Relat Res. 2012 Aug;470(8):2325-31. [PMC free article: PMC3392404] [PubMed: 22692823]

60.

Vendittoli PA, Lavigne M, Roy AG. How do serum cobalt and chromium levels change after metal-on-metal hip resurfacing? Clin Orthop Relat Res. 2006 Oct;451:292-3; author reply 293. [PubMed: 16906090]

61.

D'Adda F, Borleri D, Migliori M, Mosconi G, Medolago G, Virotta G, Colombo F, Seghizzi P. Cardiac function study in hard metal workers. Sci Total Environ. 1994 Jun 30;150(1-3):179-86. [PubMed: 7939594]

62.

Alexandersson R. Blood and urinary concentrations as estimators of cobalt exposure. Arch Environ Health. 1988 Jul-Aug;43(4):299-303. [PubMed: 3415357]

63.

Iyengar V, Woittiez J. Trace elements in human clinical specimens: evaluation of literature data to identify reference values. Clin Chem. 1988 Mar;34(3):474-81. [PubMed: 3280162]

64.

Kwon YM, Della Valle CJ, Lombardi AV, Garbuz DS, Berry DJ, Jacobs JJ. Risk Stratification Algorithm for Management of Head-Neck Taper Tribocorrosion in Patients with Metal-on-Polyethylene Total Hip Arthroplasty: Consensus Statement of the American Association of Hip and Knee Surgeons, the American Academy of Orthopaedic Surgeons, and The Hip Society. J Bone Joint Surg Am. 2021 Mar 03;103(5):e18. [PubMed: 33411461]

65.

Samar HY, Doyle M, Williams RB, Yamrozik JA, Bunker M, Biederman RWW, Shah MB. Novel Use of Cardiac Magnetic Resonance Imaging for the Diagnosis of Cobalt Cardiomyopathy. JACC Cardiovasc Imaging. 2015 Oct;8(10):1231-1232. [PubMed: 25797125]

66.

Du X, Liu J, Wang Y, Jin M, Ye Q. Cobalt-related interstitial lung disease or hard metal lung disease: A case series of Chinese workers. Toxicol Ind Health. 2021 May;37(5):280-288. [PubMed: 34078186]

67.

Adams TN, Butt YM, Batra K, Glazer CS. Cobalt related interstitial lung disease. Respir Med. 2017 Aug;129:91-97. [PubMed: 28732841]

68.

Ratto D, Balmes J, Boylen T, Sharma OP. Pregnancy in a woman with severe pulmonary fibrosis secondary to hard metal disease. Chest. 1988 Mar;93(3):663-5. [PubMed: 3342680]

69.

Giampreti A, Lonati D, Locatelli CA. Chelation in suspected prosthetic hip-associated cobalt toxicity. Can J Cardiol. 2014 Apr;30(4):465.e13. [PubMed: 24518658]

70.

Llobet JM, Domingo JL, Corbella J. Comparative effects of repeated parenteral administration of several chelators on the distribution and excretion of cobalt. Res Commun Chem Pathol Pharmacol. 1988 May;60(2):225-33. [PubMed: 2839877]

71.

Domingo JL, Llobet JM, Corbella J. The effects of EDTA in acute cobalt intoxication in rats. Toxicol Eur Res. 1983 Nov;5(6):251-5. [PubMed: 6426088]

72.

Rizzetti MC, Liberini P, Zarattini G, Catalani S, Pazzaglia U, Apostoli P, Padovani A. Loss of sight and sound. Could it be the hip? Lancet. 2009 Mar 21;373(9668):1052. [PubMed: 19304018]

73.

Cereda C, Redaelli ML, Canesi M, Carniti A, Bianchi S. Widia tool grinding: the importance of primary prevention measures in reducing occupational exposure to cobalt. Sci Total Environ. 1994 Jun 30;150(1-3):249-51. [PubMed: 7939604]

74.

Pelclova D, Sklensky M, Janicek P, Lach K. Severe cobalt intoxication following hip replacement revision: clinical features and outcome. Clin Toxicol (Phila). 2012 Apr;50(4):262-5. [PubMed: 22455358]

75.

Leikin JB, Karydes HC, Whiteley PM, Wills BK, Cumpston KL, Jacobs JJ. Outpatient toxicology clinic experience of patients with hip implants. Clin Toxicol (Phila). 2013 May;51(4):230-6. [PubMed: 23421810]

76.

Tower SS. Arthroprosthetic cobaltism: neurological and cardiac manifestations in two patients with metal-on-metal arthroplasty: a case report. J Bone Joint Surg Am. 2010 Dec 01;92(17):2847-51. [PubMed: 21037026]

77.

Charette RS, Neuwirth AL, Nelson CL. Arthroprosthetic cobaltism associated with cardiomyopathy. Arthroplast Today. 2017 Dec;3(4):225-228. [PMC free article: PMC5712038] [PubMed: 29204485]

78.

Oldenburg M, Wegner R, Baur X. Severe cobalt intoxication due to prosthesis wear in repeated total hip arthroplasty. J Arthroplasty. 2009 Aug;24(5):825.e15-20. [PubMed: 18835128]

79.

Mariano A, Sartorelli P, Innocenti A. Evolution of hard metal pulmonary fibrosis in two artisan grinders of woodworking tools. Sci Total Environ. 1994 Jun 30;150(1-3):219-21. [PubMed: 7939600]

80.

MILLER CW, DAVIS MW, GOLDMAN A, WYATT JP. Pneumoconiosis in the tungsten-carbide tool industry; report of three cases. AMA Arch Ind Hyg Occup Med. 1953 Nov;8(5):453-65. [PubMed: 13091448]

81.

Sprince NL, Oliver LC, Eisen EA, Greene RE, Chamberlin RI. Cobalt exposure and lung disease in tungsten carbide production. A cross-sectional study of current workers. Am Rev Respir Dis. 1988 Nov;138(5):1220-6. [PubMed: 3264482]

82.

Correction to: Inhalation toxicity and carcinogenicity studies of cobalt sulfate. Toxicol Sci. 2022 Jul 28;188(2):276. [PubMed: 35726922]

83.

Bucher JR, Hailey JR, Roycroft JR, Haseman JK, Sills RC, Grumbein SL, Mellick PW, Chou BJ. Inhalation toxicity and carcinogenicity studies of cobalt sulfate. Toxicol Sci. 1999 May;49(1):56-67. [PubMed: 10367342]

84.

Suh M, Thompson CM, Brorby GP, Mittal L, Proctor DM. Inhalation cancer risk assessment of cobalt metal. Regul Toxicol Pharmacol. 2016 Aug;79:74-82. [PubMed: 27177823]

Disclosure: Richard Chen declares no relevant financial relationships with ineligible companies.

Disclosure: Vincent Lee declares no relevant financial relationships with ineligible companies.