Organ systems affected by acute cobalt poisoning include endocrine,68 gastrointestinal,43,58 central58,139 and peripheral nervous system,139 hematologic,52,83,105,166 cardiovascular,69 and metabolic.69 Chronic inhalational exposures affect the pulmonary system26,32,46,87,88,128,147 and dermatologic system.50,134,165 Radioactive 60Co used for radiation therapy is associated with radiation burns (Chap. 134). Unlike acute toxicity, chronic cobalt exposure is not associated with an increased mortality; a cohort study evaluating more than 1100 persons with pulmonary exposures to cobalt salts and oxides over a 30-year period was unable to show an increased mortality rate.110
“Beer drinker’s cardiomyopathy.”
In 1966, a Veterans Affairs (VA) Hospital in Nebraska cared for 28 white men with a history of beer drinking who presented with tachycardia, dyspnea, metabolic acidosiswith elevated lactate concentration, and congestive heart failure.101 The mortality rate for these cases was 38%, and death occurred rapidly within 72 hours of presentation, due to severe acute metabolic acidosis and cardiac failure.101 Of the survivors, most responded immediately to supportive care and thiamine supplementation and a lack of response was found to be secondary to complications—most commonly, symptomatic pericardial effusions or embolic events.101 Epidemiologic evaluation of this case series revealed that these men habitually drank large quantities of beer.
Ultimately, 64 cases and 30 fatalities were reported from Nebraska.154 Of the reported 30 deaths, 26 decedents received autopsies. Common postmortem findings were dilated cardiomyopathy and cellular degeneration with vacuolization and edema with a lack of inflammation or fibrosis.101 When cobalt was implicated in the pathogenesis of these deaths, preserved cardiac tissue of eight decedents revealed cobalt concentrations ten times greater than that of controls.154
Within a year of the Nebraska cases, reports began to emerge from Quebec.108 Forty-eight beer drinkers (only two of whom were women) developed unexplained cardiomyopathy with a mortality rate of 46%.108 The only association between these patients was the common consumption of “brand XXX beer”.108 The producers of this beer had factories in Quebec City and Montreal. The only difference between the Nebraska brewery and the one in Quebec was that the latter added ten times the amount of CoSO4 to the beer as a foam stabilizer.106 Clinical findings in these cases included tachycardia, tachypnea, polycythemia, and low voltage electrocardiograms (ECGs).107 Cases began to appear one month after beer with the higher amount of CoSO4 was released onto the market, and no new cases were reported in Quebec after this beer with more CoSO4 was removed from the market.106
In 1972, 20 additional cases occurred in Minneapolis with similar findings of tachycardia, dyspnea, pericardial effusion, polycythemia, and metabolic acidosis with elevated lactate concentration, and there was a mortality rate of 18% acutely and 43% over a 3-year period.80 Similar to the previous cases, all were associated with the addition of CoSO4 as a foam stabilizer in beer.
Since the clinical findings resemble the cardiomyopathy associated with chronic alcoholism48 and infantile malnutrition,123 a debate persists as to whether cobalt is the sole cause of this syndrome. Cardiomyopathies due to poor protein intake, vitamin deficiency, and cobalt toxicity have similar histological findings. For example, myocardial biopsy of dogs with cobalt-induced cardiac failure revealed diffuse cytosolic vacuolization, loss of cross striations, and interstitial edema,137 all of which are similar to findings of malnutrition.48,123 However, some other findings may be specific to cobalt-associated cardiomyopathy. For example, a small retrospective analysis revealed myocyte atrophy and myofibril loss to be present in people with cobalt-associated cardiomyopathy significantly more often than in those with idiopathic dilated cardiomyopathy.24
Some animal models of cobalt cardiomyopathy were only able to reproduce pathologic and ECG findings if cobalt and ethanol8 were administered, while others required protein deficiency.132 Contrary to these studies, several murine and canine models of cobalt poisoning demonstrated cardiac lesions,62,136,137 cardiac failure65,136,137 and ECG abnormalities while receiving nutritional supplementation.63,136
Despite the implication that cobalt-induced cardiomyopathy requires malnutrition or alcoholism, a case of cardiac toxicity following acute cobalt poisoning is reported.68,69 However, it is difficult to identify other cases reported outside of the aforementioned small epidemics in beer drinkers. In a controlled study of occupationally exposed subjects evaluated with echocardiograms, significantly more cobalt exposed workers had diastolic dysfunction when compared to controls.91 However, none of these subjects under study developed congestive heart failure.91 Of the few reported cases of cardiomyopathy associated with arthroplastic cobaltism, patients are typically older than those with the “beer drinker’s cardiomyopathy” cohort and their nutritional status and ethanol use are unreported.115,121 There are rare reports of cardiomyopathy in chronically exposed workers,15,30,78 which suggests that the cardiomyopathy reported in the “beer drinkers” cohort is multifactorial and not solely due to cobalt.
Another source of criticism of the role of cobalt in the development of cardiomyopathy is the relatively low dose of cobalt needed to induce heart failure in these patients.80 In patients receiving 20 to 75 mg/d of CoCl2 for various red cell dysplasias, there were no reports of heart failure,80 whereas the “beer drinker’s cardiomyopathy” group reportedly consumed only 6 to 8 mg/d of CoSO4 while drinking 24 pints of cobalt-containing beer.80,106 All patients who developed cardiomyopathies were malnourished, which supports the theory that a multifactorial nutritional deficiency in the presence of excessive cobalt may be necessary for the development of cardiomyopathy.80
Both acute and chronic cobalt exposures are associated with thyroid hyperplasia and goiter. A series of patients with severe sickle cell anemia treated with cobalt salts developed goiter with varying degrees of thyroid dysfunction,64,84 including clinical hypothyroidism.85 In one patient, the goiter was so severe that airway obstruction developed.84
Older occupational data suggest that inhalational exposure to cobalt metals, salts, and oxides may result in abnormalities in thyroid function studies.155 When 82 workers in a cobalt refinery were compared to age- and sex-matched controls, exposed workers had significantly lower T3 concentrations.155 However, more recent studies of cobalt-exposed workers in environments that limit exposure do not demonstrate any changes in serum thyroid markers.90
Within the previously mentioned beer drinker’s cardiomyopathy cohort, 11 of 14 decedents had abnormal thyroid histology.133 Among them, the most common findings were follicular cell abnormalities and colloid depletion, which did not exist on thyroid analysis from 11 randomly selected autopsies that served as controls.133 Of the patients with arthroprosthetic cobaltism, one patient developed clinical hypothyroidism,115 and another developed subclinical hypothyroidism.121
Anemias of the newborn,28,77,125 erythrocyte hypoplasia,141 red cell aplasia,161 and kidney failure associated anemia58 have all been successfully treated with cobalt salts. Patients undergoing CoCl2 therapy for these diseases had increased hemoglobin,58,125 hematocrit,58,125 and red cell counts.58 Unfortunately, the effects did not persist after cessation of therapy.58,125
A published series of Peruvian cobalt miners working in an open pit at 4300 meters (2.7 miles) elevation developed various clinical effects, including headache, dizziness, weakness, mental fatigue, dyspnea, insomnia, tinnitus, anorexia, cyanosis, polycythemia, and conjunctival hyperemia consistent with acute mountain sickness.75 When the study group was compared to age-, height-, and weight-matched high-altitude controls, the study group was noted to have higher chronic mountain sickness scores.75 The only difference detected was elevated serum cobalt concentrations in the study group.75
In addition to effects on red cells, recent work demonstrates transient hemolysis, methemoglobinemia, and methemoglobinuria from subcutaneous CoCl2 exposure in mice.70 These findings may explain reports of dark urine following cobalt exposure in other animal models.60,149 However, similar human cases have not been reported.
Gastrointestinal distress following the ingestion of “therapeutic” doses of cobalt salts139 and elemental cobalt are reported.74 Decreased proprioception, impaired VIII cranial nerve function, and nonspecific peripheral nerve findings are reported with acute oral CoCl2 exposures.139 Patients with arthroprosthetic cobaltism are reported to have seizures, cerebellar deficits, retinopathy, hearing loss, cognitive deficits, and peripheral neuropathy; some of which had concomitant elevations of cerebrospinal fluid (CSF) cobalt concentrations.23,97,115,156,157
Both asthma and “hard metal disease” are associated with cobalt exposure. Occupational asthma is reported in hard metal workers with a prevalence of 2% to 5%26,87,88 at exposure concentrations as low as 50 μg/m3.88 As is the case with most causes of occupational asthma, cobalt hypersensitivity–induced asthma is most likely immune mediated rather than toxicologic.29,87,147 Most hard metal workers are exposed to other metals, such as tungsten (W) and nickel (Ni), in addition to Co, and these other metals may account for some of the occupational asthma that is attributed to cobalt.144,146 However, in a small but well-performed study in patients with cobalt-associated asthma, intradermal cobalt chloride (CoCl2) resulted in a positive wheal response in all subjects, and 50% of patients had a positive radioallergosorbent test (RAST) scores, which correlated to the wheal size145 and suggests Co salts can illicit an immune response independent of the other metals.
Cobalt-associated pulmonary toxicity was first noted in tungsten-carbide workers46,66 and was subsequently referred to as “hard metal disease.” Exposures result from the process by which tungsten-carbide is sintered with cobalt. Signs and symptoms of hard metal disease may include upper respiratory tract irritation, exertional dyspnea, severe dry cough, wheezing, and interstitial lung disease ranging from alveolitis to progressive fibrosis. The prevalence of hard metal disease is largely unknown. In one study, 11 of 290 (3.8%) exposed workers were diagnosed with interstitial infiltrates on chest radiographs, but only 2 (0.7%) had a decrease in predicted total lung capacity.150
Certain individuals who are exposed to large doses of hard metals for prolonged periods never develop disease, which suggests that a susceptible population exists. A glutamate substitution for lysine in position 69 of the β unit HLA-DP has a strong association with hard metal disease, similar to chronic beryllium disease.124 Clinically, hard metal disease is difficult to distinguish from berylliosis, although an occupational history should be helpful.
Histopathologic findings of hard metal disease include multinucleated giant cells and interstitial pneumonitis with bronchiolitis.9 Elevated concentrations of cobalt in lung tissue can be detected,129,148 even as long as 4 years after exposure.129 In patients with interstitial lung disease, bronchioalveolar lavage (BAL) commonly reveals multinucleated giant cells, type II alveolar cells, and alveolar macrophages.32 The finding of multinucleated giant cells from BAL washing is characteristic of hard metal disease.29,35,36,102,159
A cross-sectional study of more than a 1000 tungsten carbide–exposed workers found an increased odds ratio of 2.1 for having a work-related wheeze when exposed to greater than 50 μg/m3 of Co.151 In the same study, workers with exposures recorded at greater than 100 μg/m3 had higher odds (OR 5.0) of having a chest radiograph profusion score of greater than or equal to 1/0.151 This profusion score, established by the United Nations agency, the International Labor Organization (ILO), is a grading system for pneumoconioses. When used to grade radiographs of asbestosis, this score correlates strongly with mortality risk,100 reduced diffusing capacity, and decreased ventilatory capacity.67,111 A score of 0/1 is suggestive but not diagnostic (“negative”), and a score of 1/0 is presumptively diagnostic but not unequivocal (“positive”).5 Additional studies have similarly concluded that pulmonary disease occurs when individuals are exposed to concentrations of cobalt that approach 100 μg/m3.86 Thus, with a margin of safety, the current threshold limit value is less than 50 μg/m3.
Until 1984, all reported cases of hard metal disease were associated with the combination of cobalt and other metals, such as nickel, cadmium and tungsten.9,66,88,151 When diamond polishers initiated the use of high-speed grinding disks coated with abrasive microdiamonds embedded in a matrix of cobalt powder, case reports ensued demonstrating similar clinical89 and pathologic findings to hard metal disease, strengthening the association with cobalt.29,35,113 Some authors still contend that the presence of other metals9,66,88,151 and diamond dust35,59,113 are confounding factors.155 Like hard metal disease, most reported cases show resolution of symptoms upon removal from the exposure,35 although this is not always sufficient.113
There are very few reports of isolated cobalt exposures. In an age-and sex-matched study of 82 workers with respiratory exposures to cobalt oxides, cobalt salts, cobalt metal, and no other metal, researchers were unable to detect a difference between exposed (mean of 8 years, time weighted average = 125 μg/m3, 25% >500 μg/m3) and unexposed workers with any objective measured pulmonary tests.155 Neither group had any abnormality in chest radiography that would suggest pulmonary fibrosis.155 The only significant pulmonary differences detected were a higher reported rate of dyspnea both on exertion and at rest and the presence of wheezing in the exposed group.155 These authors concluded that cobalt contributes to the development of pulmonary disease but is not independently responsible for the development of pulmonary fibrosis.155
Despite the progressive and debilitating nature of hard metal disease, most signs and symptoms improve with cessation of exposure.98,103,168 Moreover, the length and dose of exposure do not appear to correlate with the presence or severity of illness suggesting that individual susceptibility is the key determinant for developing illness.98,135
It has been known for some time that metal-on-metal alloy orthopedic implants result in elevation of the associated metals in blood, urine, and hair.27 Serum concentrations of cobalt become elevated 3 weeks after surgery and remain elevated through a 5-year study period, which contradicts earlier theories of elevated concentrations being related to the life of the implant.20 Despite the elevation of both chromium and cobalt in measured samples, it appears that the constellation of findings is more consistent with cobalt rather than chromium.1 However, chromium’s toxicity may present in a more delayed fashioned relative to cobalt.1 Reported cases of toxicity can follow revisions, dislocations, or first-time arthroplasties of cobalt-containing prosthetics.97,156,157 Since these findings have been reported, the association of having a cobalt-containing prosthetic, an elevated marker of cobalt burden, and findings of end-organ toxicity has been coined “arthroprosthetic cobaltism.”
Of the reported cases, some of arthroplasties have had excessive wear115 or have been placed following a ceramic arthroplasty resulting in metallosis.100 In one case, a patient developed hypothyroidism, seizures, peripheral neuropathy, and cardiomyopathy.115 Unfortunately, the diagnosis was not established initially, and the hip revision resulted in improvement of serum cobalt concentrations and thyroid markers but the patient had permanent neurologic sequelae.115 Furthermore, one patient with cobaltism with evidence of cardiac tamponade, hypothyroidism, hearing loss, and polycythemia underwent implant removal and chelation with 2,3-dimercaptoproprane-1-sulfonate, which resulted in decreased blood cobalt concentrations but permanent hearing loss.121 However, other case reports of metallosis from cobalt arthroplasties suggest clinical manifestations of cobaltism improve following revision.156,157 It appears that lumbar metal-on-metal total disk replacements are associated with smaller elevations in serum cobalt concentrations when compared to hip resurfacing or total hip arthroplasties,19 but there are no reported cases of clinical cobaltism with lumbar implants. Finally, within this cohort, retinal effects have been noted in at least two case reports.10,11 The pathophysiology of these cases is poorly understood and confounded by comorbidities typical in this cohort of patients.
A single report associates reversible acute kidney injury with the chronic administration of CoCl2 as treatment for anemia.139 Some animal models of cobalt cardiomyopathy demonstrate cellular changes in renal tissue.61 However, when 26 exposed hard metal workers were evaluated for urinary albumin, retinol binding protein, β2-microglobulin, and tubular brush border antigens no detectable differences could be found between the study group and controls.54 Additionally, patients with cobalt-containing total hip arthroplasties were followed over 2 years with elevated serum cobalt concentrations without any significant effect on serum creatinine over this study period.14 Based on these few reports, it appears that acute and chronic exposure to cobalt has little effect on the kidneys.
In a study of 1782 construction workers, 23.6% developed dermatitis and 11.2% developed oil acne while using cobalt-containing cement, fly ash, or asbestos.81 As in hard metal disease, it is difficult to isolate cobalt as the sole contributor to the development of dermatitis. Nickel (Chap. 99) is the classic toxicant causing dermatitis. Commonly found in some of these construction occupations, it may be implicated in the development of cutaneous manifestations.50,134 However, consumer products such as piercings, tattoo ink, plastics, clothing dye, makeup, and dental treatments are implicated in cobalt-induced allergic contact dermatitis.53 Furthermore, in vitro studies demonstrate that cobalt can induce production of both Th1- and Th2-type cytokines in peripheral blood mononuclear cells—the same pathway implicated in nickel contact dermatitis.104 Thus, it appears that cobalt can independently induce a hypersensitivity reaction independent of the presence of nickel.
In pregnant rats, CoCl2 exposure neither results in teratogenicity nor fetal toxicity.119 In a case report of a pregnant woman with hard metal disease, the woman was able to bring the pregnancy to term and deliver without complication.127 In another case report, a woman with a cobalt-containing hip arthroplasty had repeated joint aspirations, dislocations, and revisions before and during her pregnancy.56 Cobalt concentrations of this mother were 138 to 143 μg/L throughout the pregnancy, cord blood concentration was 75 μg/L, and infant blood concentration at 8 weeks was 13 μg/L. Despite these elevated concentrations, there was no clinical evidence of toxicity.56 It is hypothesized that only exposures toxic to the mother result in fetal toxicity.42
In mice, chronic exposure to cobalt results in impaired spermatogenesis and decreased fertility without affecting follicular stimulating hormone or leuteinizing hormone, whereas acute exposures did not demonstrate similar reproductive effects.120 Additional murine studies discuss the possible interactions between cobalt with iron and zinc, which are both essential elements for spermatogenesis.6 Despite these findings, there are no reported human cases that associate cobalt exposure with teratogenicity or impaired fertility.
Animal experiments with injection of CoCl2 into soft tissue resulted in soft tissue sarcomas, leading the International Agency for Research on Cancer (IARC) to consider cobalt metal without tungsten carbide and cobalt sulfate and other soluble cobalt (II) salts possibly carcinogenic to humans (group 2B).18,33,44, 152,167 It was suggested that cobalt metal associated with tungsten carbide was probably carcinogenic to humans (group 2A).167 There are case reports and cohort studies that suggest that pulmonary exposure to Co2+ increases the risk of lung cancer. However, these studies were unable to control for other known carcinogens such as arsenic.33 In the largest cohort study to date, which followed more than 1100 workers for more than 38 years, there was no increase in the prevalence of lung cancer.109