Organ systems affected by acute cobalt poisoning are the endocrine,58 GI,35,48 central48,123 and peripheral nervous,123 hematologic,44,73,91,146 cardiovascular,59 and metabolic59 systems. Chronic inhalational exposures affect the pulmonary18,23,38,77,78,112,131 and dermatologic systems.42,118,145 Radioactive 60Co used for radiation therapy has been associated with radiation burns (see Chap. 133). 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.96
"Beer Drinkers' Cardiomyopathy"
In 1966, a Veterans Affairs Hospital in Nebraska cared for 28 white men with a history of beer drinking who presented with tachycardia, dyspnea, and metabolic acidosis with elevated lactate concentration but without any finding of congestive heart failure.88 The mortality rate for these cases was 38% and death occurred rapidly within 72 hours of presentation because of severe acute metabolic acidosis and cardiac failure.88 The survivors were successfully treated with supportive care and thiamine supplementation.88 Of the survivors, most responded immediately to therapy, and a lack of response was found to be secondary to complications, most commonly, symptomatic pericardial effusions or embolic events.88 Epidemiologic evaluation of this case series revealed that these men commonly drank large quantities of beer.
Ultimately, 64 cases and 30 fatalities were reported from Nebraska.138 Of the reported 30 deaths, 26 decedents received autopsies. Common postmortem cardiac findings were dilated cardiomyopathy and cellular degeneration with vacuolization and edema with a lack of inflammation or fibrosis.88 When cobalt was implicated in the pathogenesis of these deaths, the preserved cardiac tissue of eight decedents revealed cobalt concentrations 10 times greater than those of control subjects.138
Within 1 year of the Nebraska cases, reports began to emerge from Quebec.94 Forty-eight beer drinkers (only two of whom were women) developed unexplained cardiomyopathy, with a mortality rate of 46%.94 The only association between these patients was the common consumption of a given brand of beer.94 The producers of this beer had factories in Quebec City and Montreal. The only difference between the two breweries was that the one in Quebec added 10 times the amount of CoSO4 to the beer as a foam stabilizer.92 Clinical findings in these cases included tachycardia, tachypnea, polycythemia, and low-voltage electrocardiograms (ECGs).93 Cases began to appear 1 month after the beer with the excessive cobalt was released on the market, and no new cases were reported in Quebec after the beer with the excessive cobalt concentration was removed from the market.92
In 1972, 20 additional cases occurred in Minneapolis with similar findings of tachycardia, dyspnea, pericardial effusion, polycythemia, and metabolic acidosis with elevated lactate concentration; there was a mortality rate of 18% acutely and 43% over a 3-year period.70
Because the clinical findings resemble the cardiomyopathy associated with chronic alcoholism40 and infantile malnutrition,107 a debate persists as to whether cobalt is the sole cause of this syndrome. Cardiomyopathies caused by poor protein intake and vitamin deficiency both have similar histologic findings to cobalt cardiomyopathy. For example, myocardial biopsy of dogs with cobalt-induced cardiac failure revealed diffuse cytosolic vacuolization, loss of cross striations, and interstitial edema,121 all of which are similar to findings of malnutrition.40,107 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.16
Some animal models of cobalt cardiomyopathy were only able to reproduce pathologic and ECG findings if cobalt was combined with ethanol7; others required protein deficiency.116 Contrary to these studies, several rat and canine models of cobalt poisoning and nutritional supplementation have demonstrated cardiac lesions,52,120,121 cardiac failure55,120,121 and ECG abnormalities.53,120
Despite the implication that cobalt-induced cardiomyopathy requires malnutrition or alcoholism, a case of cardiac toxicity after acute cobalt poisoning has been reported.58,59 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 compared with control subjects.80 However, none of these subjects under study developed congestive heart failure.80 There have been rare reports of cardiomyopathy in chronically exposed workers,11,21,68 which suggests that the cardiomyopathy reported in the "beer drinkers" cohort is multifactorial and not solely caused by 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.70 In patients receiving 20 to 75 mg/day of CoCl2 for various red blood cell (RBC) dysplasias, there were no reports of heart failure,70 but the "beer drinker's cardiomyopathy" group reportedly consumed only 6 to 8 mg/day of CoSO4 from drinking 24 pints of cobalt-containing beer.70,92 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.70
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 therapy also developed goiter with varying degrees of thyroid dysfunction54,74 including clinical hypothyroidism.75 In one patient, the goiter was so severe that airway obstruction developed.74
More recent occupational data suggest that inhalational exposure to cobalt metals, salts, and oxides may result in abnormalities in thyroid function studies.139 When 82 workers in a cobalt refinery were compared with gender- and age-matched control subjects, exposed workers had significantly lower T3 concentrations.139
Within the previously mentioned beer drinker's cardiomyopathy cohort, 11 of 14 decedents had abnormal thyroid histology.117 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 control subjects.117
Anemias of the newborn,19,67,109 erythrocyte hypoplasia,125 RBC aplasia,141 renal failure,48 and chronic infection114 have all been successfully treated with cobalt salts. Patients undergoing CoCl2 therapy for these diseases had increased hemoglobin,48,109 hematocrit,48,109 and RBC counts.48 Furthermore, the effects did not persist after cessation of therapy.48,109
A published series of Peruvian cobalt miners working in an open pit at an elevation of 4300 m (2.7 miles) developed clinical effects, including headache, dizziness, weakness, mental fatigue, dyspnea, insomnia, tinnitus, anorexia, cyanosis, polycythemia, and conjunctival hyperemia consistent with acute mountain sickness.65 When the study group was compared with age-, height-, and weight-matched high-altitude control subjects, the study group was noted to have higher chronic mountain sickness scores.65 The only difference detected was elevated serum cobalt concentrations in the study group.65
In addition to effects on RBCs, recent work demonstrates transient hemolysis, methemoglobinemia, and methemoglobinuria from subcutaneous CoCl2 exposure in mice.60 These findings may explain reports of dark urine after cobalt exposure in other animal models.50,133 Human cases have not been reported.
GI distress after the ingestion of "therapeutic" doses of cobalt salts123 as well as elemental cobalt has been reported.64 Decreased proprioception, impaired cranial nerve VIII function, and nonspecific peripheral nerve findings are reported with acute oral CoCl2 exposures.123
Two pulmonary diseases are associated with cobalt exposure: asthma and "hard metal disease." Occupational asthma is reported in hard metal workers with a prevalence of 2% to 5%18,77,78 at exposure concentrations as low as 50 μg/m3.78 As is the case with most causes of occupational asthma, cobalt hypersensitivity–induced asthma is most likely immune mediated rather than toxicologic.20,77,131 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 cases of occupational asthma that are attributed to cobalt.128,130 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 size,129 suggesting that Co salts independent of the other metals may illicit an immune response.
Cobalt-associated pulmonary toxicity was first noted in tungsten–carbide workers38,56 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 two (0.7%) had a decreased predicted total lung capacity.134
Certain individuals who are exposed to large doses of hard metal 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.108 Clinically, hard metal disease is difficult to distinguish from berylliosis, although an occupational history should be helpful.
Common findings of hard metal disease on histopathology are multinucleated giant cells and interstitial pneumonitis with bronchiolitis.8 Elevated concentrations of cobalt in lung tissue can be detected,113,132 even as long as 4 years after exposure.113 Bronchioalveolar lavage (BAL) commonly reveals multinucleated giant cells, type II alveolar cells, and alveolar macrophages in patients with interstitial lung disease.23 The finding of multinucleated giant cells from BAL washing is characteristic of hard metal disease.20,26,27,89,140
A cross-sectional study of more than 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.135 In the same study, workers with exposures recorded at greater than 100 μg/m3 had higher odds (odds ratio [OR], 5.0) of having a chest radiograph profusion score of greater than or equal to 1/0.135 This profusion score, established by the International Labor Organization (ILO) and most recently updated in 2000, is a grading system for pneumoconioses. When used to grade radiographs of asbestosis, this score correlates strongly with mortality risk,87 reduced diffusing capacity, and decreased ventilatory capacity.57,97 A score of 0/1 is suggestive but not diagnostic ("negative"), and a score of 1/0 is presumptively diagnostic but not unequivocal ("positive").6 Additional studies have similarly concluded that pulmonary disease occurs when individuals are exposed to doses cobalt approach 100 μg/m3.76 Thus, the current threshold limit value (TLV) is <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.8,56,78,135 Diamond polishers started to institute the use of high-speed grinding disks coated with abrasive microdiamonds embedded a matrix of cobalt powder.79 Several case reports illustrate that cobalt-exposed diamond polishers develop similar clinical79 and pathologic findings to hard metal disease, strengthening the link to cobalt.20,26,99 Some authors still contend that the presence of other metals8,56,78,135 and diamond dust26,49,99 are confounding factors.139 Similar to hard metal disease, most reported cases show resolution of symptoms upon removal from the exposure,26 although this is not always sufficient.99
There are very few reports of isolated cobalt exposures. In an age- and gender-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, 8 years; TWA, 125 μg/m3, 25% >500 μg/m3) and unexposed workers with any objective measured pulmonary tests.139 Neither group had any abnormality in chest radiography that would suggest pulmonary fibrosis.139 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.139 These authors concluded that cobalt contributes to the development of pulmonary disease but is not independently responsible for the development of pulmonary fibrosis.139
Despite the progressive and debilitating nature of hard metal disease, most signs and symptoms improve with cessation of exposure.86,90,147 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 most important risk factor for illness.86,119
A single report associates reversible renal tubular necrosis with the chronic administration of CoCl2 as treatment for anemia.123 Some animal models of cobalt cardiomyopathy demonstrate cellular changes in renal tissue.51 However, when 26 exposed hard metal workers were evaluated for urinary albumin, retinol binding protein (RBP), β2-microglobulin, and tubular brush border antigens, no detectable difference could be found between the study group and control subjects.45 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.71 As in hard metal disease, it is difficult to isolate cobalt as the sole contributor to the development of dermatitis. Nickel, the classic toxicant causing dermatitis, is commonly found in some of these preparations and may be implicated in the development of cutaneous sensitivity.42,118
A pregnant woman with hard metal disease was able to bring the fetus to term and deliver without complications.111 In pregnant rats, CoCl2 exposure neither results in teratogenicity nor fetotoxicity.104 Only doses that are toxic to the mother result in fetal toxicity.34
In mice, chronic exposure to cobalt results in impaired spermatogenesis and decreased fertility without affecting follicle-stimulating hormone (FSH) or luteinizing hormone (LH), but acute exposures did not demonstrate similar reproductive effects.105 Additional murine studies discuss the possible interactions between cobalt with iron and zinc, which are both essential elements for spermatogenesis.4 Despite these findings, there have been no reported human cases that associate cobalt exposure with teratogenicity or impaired fertility.
Based solely on animal experiments leading to the development of soft tissue sarcomas after the injection of CoCl2 into soft tissue resulting in soft tissue sarcomas, the International Agency for Research on Cancer (IARC) considers cobalt and cobalt-containing compounds possibly carcinogenic to humans (group 2B).14,24,36,136 There have been case reports and cohort studies suggesting that pulmonary exposure to Co2+ increases the risk for lung cancer. However, these studies were unable to control for other known carcinogens such as arsenic.24 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.95