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Cobalt (Co) although, an essential element playing a key role in several physiological and biological processes, can transform into a potential toxin when present in higher amounts or in certain chemical forms. The increasing usage of transition metals in industries, agriculture, medicines and technology has led to an alarming rise in cobalt poisoning cases. Exposure to cobalt can cause several health hazards including neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, etc. Cobalt may interact with several proteins in the cellular milieu, generating reactive oxygen species (ROS) and thereby triggering apoptosis of the neural cells via DNA damage. The most common method of removal of such metals from the body is by the use of metal chelators. In this study, we report a facile strategy for the clearance of Co (II) from the physiological milieu using citrate functionalized Mn3O4 NPs (C-Mn3O4 NPs). The chelation ability of C-Mn3O4 NPs has been evaluated using steady state and pico-second resolved optical spectroscopy. Our studies reveal that C-Mn3O4 NPs form a stable complex with cobalt ions, thereby reducing the ability of Co2+ to produce reactive oxygen species (ROS) via Fenton like reaction and hence function as a novel nanotherapeutic for the detoxification of cobalt in the human system.

Symptomatic cobalt toxicity from a failed total hip replacement is a rare, but devastating complication. Potential clinical findings include cardiomyopathy, hypothyroidism, skin rash, visual and hearing impairment, polycythaemia, weakness, fatigue, cognitive impairment, and neuropathy. The case is presented of a 74 year-old man in whom, after a ceramic–ceramic replacement and two episodes of prosthetic dislocation, it was decided to replace it with a polyethylene–metal total hip arthroplasty (THA). At 6 months after the revision he developed symptoms of cobalt toxicity, confirmed by analytical determination (serum cobalt level = 651.2 μg/L). After removal of the prosthesis, the levels of chromium and cobalt in blood and urine returned to normal, with the patient currently being asymptomatic. It is recommended to use a new ceramic on ceramic bearing at revision, in order to minimise the risk of wear-related cobalt toxicity following breakage of ceramic components.

Cobalt metallosis after revision metal-on-polyethylene total hip arthroplasty for catastrophic failure of ceramic components is uncommon but a potentially devastating complication. Common findings associated with heavy metal toxicity include cardiomyopathy, hypothyroidism, skin rashes, visual disturbances, hearing changes, polycythemia, weakness, fatigue, cognitive deterioration, and neuropathy. We report a case of a 57-year-old woman who presented with complaints of progressively worsening hip pain, fatigue, memory loss, lower extremity sensory loss, persistent tachycardia, and ocular changes 5 years after synovectomy and revision of a failed ceramic-on-ceramic total hip arthroplasty to metal-on-polyethylene components. A cobalt level of 788.1 ppb and chromium level of 140 ppb were found on presentation and subsequently decreased to 468.8 ppb and 105.9 ppb, respectively, 2 weeks after revision to a ceramic-on-polyethylene total hip arthroplasty. Improvement of symptoms accompanied this decrease in cobalt and chromium levels. Revision of failed ceramic arthroplasties with later-generation ceramics to avoid this potential complication is recommended.

An acute Biotic Ligand Model (BLM) was developed to predict the effect of cobalt on the survival of the potworm Enchytraeus albidus, exposed in nutrient solutions added to acid washed, precombusted sand. The extent to which Ca2+, Mg2+ and Na+ ions and pH independently mitigate cobalt toxicity to E. albidus was examined. Higher activities of Ca2+, Mg2+ and H+ linearly increased the 14 d LC 5 0 Co 2 + (LC50 expressed as Co2+-activity) whereas Na+-activity did not. Stability constants for the binding of Co2+, Ca2+, Mg2+ and H+ to the biotic ligand (BL) were derived, i.e. log KCoBL=5.13, log KCaBL=3.83, log KMgBL=3.95 and log KHBL=6.53. It was calculated that at Co-concentrations corresponding to the 14d-LC50 value, 32% of the BL sites were occupied by cobalt. An initial validation of the applicability of this BLM in true soil exposure systems was performed by comparing observed and model-predicted 14 d LC50 s in a standard artificial soil and a standard field soil. By assuming pore water to be the only route of exposure and assuming equilibrium between pore water Co2+ and solid phase Co, which is predicted by the geochemical WHAM-Model 6, LC50 s (as mg Co kg−1 dry wt of soil) were predicted within an error of less than a factor two. Further validation in true soil exposures, combined with more detailed knowledge of Co binding to soil solid phases is needed, if this model is to be used as a tool for risk assessment and derivation of soil quality criteria for Co.

To the Editor: We read with interest the documented fatality from suspected cobalt-induced cardiomyopathy in the case report, “Hip Pain and Heart Failure: The Missing Link” by Dr Gilbert and his associates, in the May 2013 issue of the Canadian Journal of Cardiology. We were intrigued by the authors’ use of dimercaprol (BAL) for cobalt chelation in this patient. Little is known about BAL’s role in suspected prosthetic hipassociated cobalt toxicity. BAL is generally used in acute arsenic, lead, and mercury poisonings although there is concern that BAL’s lipid solubility might increase metal ion flux into the brain. BAL’s role in chronic metal toxicity largely has been supplanted by unithiol and succimer. Although human experience is lacking, 1 animal study suggests that BAL is not effective for cobalt chelation. Additionally, several chelators are associated with redistribution of cobalt into the heart despite increasing urinary or fecal elimination. Perioperative chelation has been used in patients with embedded lead sources with success. However, cobalt level rebound was documented in another patient with suspected prosthetic hip-associated cobalt toxicity chelated with EDTA before hardware removal. It would be interesting to know the timing of BAL administration with regard to revision surgery in this patient and if he exhibited this phenomenon. Interestingly, the authors’ patient presented with liver failure, which has not been described previously in suspected prosthetic hip-associated cobalt toxicity. The patient’s suspected hepatotoxicity was managed with n-acetyl cysteine (NAC). NAC appears to be one of the safer and more effective cobalt chelators in an animal model of chronic cobalt poisoning. Did the patient experience any clinical improvement in cardiac function at any time after NAC therapy?

A 54-year-old male patient with bilateral metal-on-metal hip prosthesis and recently diagnosed cobalt toxicity presented with gradually worsening symptoms of heart failure. Serum cobalt (120 μg/l; normal

In a subset of high-altitude dwellers, the appropriate erythrocytotic response becomes excessive and can result in chronic mountain sickness. We studied men with (study group) and without excessive erythrocytosis (packed-cell volume >65%) living in Cerro de Pasco, Peru (altitude 4300 m), and compared them with controls living in Lima, Peru (at sea-level). Toxic serum cobalt concentrations were detected in 11 of 21 (52%) study participants with excessive erythrocytosis, but were undetectable in high altitude or sea-level controls. In the mining community of Cerro de Pasco, cobalt toxicity might be an important contributor to excessive erythrocytosis.

The mechanisms underlying cobalt toxicity in aquatic species in general and cnidarians in particular remain poorly understood. Herein we investigated cobalt toxicity in a Hydra model from morphological, histological, developmental, and molecular biological perspectives. Hydra, exposed to cobalt (0–60 mg/L), were altered in morphology, histology, and regeneration. Exposure to standardized sublethal doses of cobalt impaired feeding by affecting nematocytes, which in turn affected reproduction. At the cellular level, excessive ROS generation, as the principal mechanism of action, primarily occurred in the lysosomes, which was accompanied by the upregulation of expression of the antioxidant genes SOD, GST, GPx, and G6PD. The number of Hsp70 and FoxO transcripts also increased. Interestingly, the upregulations were higher in the 24-h than in the 48-h time-point group, indicating that ROS overwhelmed the cellular defense mechanisms at the latter time-point. Comet assay revealed DNA damage. Cell cycle analysis indicated the induction of apoptosis accompanied or not by cell cycle arrest. Immunoblot analyses revealed that cobalt treatment triggered mitochondria-mediated apoptosis as inferred from the modulation of the key proteins Bax, Bcl-2, and caspase-3. From this data, we suggest the use of Hydra as a model organism for the risk assessment of heavy metal pollution in aquatic ecosystems.

The effect of two concentrations of cobalt (Co(2+)) on photosynthetic activity and antioxidative response in Lemna minor L. were assessed 24, 48 and 72h after the start of the exposure. Higher concentration of cobalt (1mM) induced growth inhibition while lower concentration (0.01mM) increased photosynthetic pigments content. Analysis of chlorophyll a fluorescence transients revealed high sensitivity of photosystem II primary photochemistry to excess of Co(2+) especially at the higher concentration where decreased electron transport beyond primary quinone acceptor QA(-) and impaired function of oxygen evolving complex (OEC) was observed. Due to impairment of OEC, oxygen production was decreased at higher Co(2+) concentration. Activity of superoxide dismutase was mainly inhibited while lipid peroxidation increased, at both concentrations, indicating that cobalt-induced oxidative damage after short exposure and moreover, susceptibility of the membranes in the cell to cobalt toxicity. Results obtained in this study suggest possible application of used parameters as tools in assessment of early damage caused by metals.

Nickel and cobalt are essential elements that become toxic at high concentrations. Little is known about nickel and cobalt toxicity in aquatic animals. This study aimed to investigate acute and chronic toxicity of nickel and cobalt in Japanese flounder (Paralichthys olivaceous), with emphasis on oxidative stress reactions, histopathological changes, and differences in gene expression. The lethal concentration for 50% mortality (LC50) in 3 and 8 cm Japanese flounder exposed to nickel for 96 h was found to be 86.2 ± 0.018 and 151.3 ± 0.039 mg/L; for cobalt exposure, LC50 was 47.5 ± 0.015 and 180.4 ± 0.034 mg/L, respectively. Chronic nickel and cobalt exposure caused different degrees of oxidative enzyme activity changes in gill, liver, and muscle tissues. Erythrocyte deformations were detected after acute or chronic exposure to nickel and cobalt. the nickel and cobalt exposure also caused pathological changes such as spherical swelling over other gill patches, rod-like proliferations in the gill patch epithelial cell layer, and disorder in hepatocyte arrangement, cell swelling, and cytoplasm loosening. RNA-Seq indicated that there were 184 upregulated and 185 downregulated genes in the liver of Japanese flounder exposed to 15 mg/L nickel for 28 d. For cobalt, 920 upregulated and 457 downregulated genes were detected. Among these differentially expressed genes, 162 were shared by both nickel and cobalt exposure. In both nickel and cobalt, pathways including fatty acid elongation, steroid biosynthesis, unsaturated fatty acid biosynthesis, fatty acid metabolism, PPAR signaling, and ferroptosis were significantly enriched. Taken together, these results aided our understanding of the toxicity of nickel and cobalt in aquatic animals.

1. 1.A study using Neurospora crassa was made of the effects of Fe deficiency and toxicities of Mn, Zn, Cu, Mo, Co, and Ni on the enzymes: cytochrome oxidase, catalase, peroxidase, and succinic dehy-drogenase; those of iron deficiency and cobalt toxicity on nitrate reductase, “glucose 6-phosphate dehydrogenase,” isocitric dehydrogenase, DPNase, and alkaline phosphatase. 2. 2. A striking similarity was noted between iron deficiency and cobalt toxicity, not only on the activity of the iron enzymes but also on the activity of other enzymes not known to involve iron directly. It is suggested that iron deficiency and cobalt toxicity produce similar effects on the over-all metabolism of this organism. 3. 3.Some form of direct competition between iron and cobalt may be responsible for some of these effects, and possible implications are discussed.

Inhalation of cobalt salts in the ‘hard metal’ industry has been shown to cause giant cell interstitial pneumonitis. Substantial ingestion of cobalt salts can produce neuro-ocular, cardiac and/or thyroid toxicity. Systemic cobalt toxicity has been encountered occasionally in recipients of cobalt-containing hip prostheses. Ingestion of copper salts causes a corrosive gastroenteritis. Chronic inhalation of copper-containing pesticides has caused pulmonary fibrosis. Lead can be absorbed following inhalation or ingestion and is toxic to most organ systems through mechanisms that involve complexing with important functional chemical groups or substitution of essential metal ions. Management involves avoidance of exposure and, in more severe cases, chelation therapy with either sodium calcium edetate or dimercaptosuccinic acid (DMSA). The central nervous system is the most susceptible target organ for mercury. Chelation therapy with 2,3-dimercapto-1-propanesulfonic acid (DMPS) can enhance mercury elimination.

Cobalt ions can enhance the generation of reactive oxygen species (ROS), which may be the reason for cobalt toxicity. This study aimed to determine whether Co(2+) toxicity in goldfish is related to induced oxidative stress in gills, heart and spleen, and to assess responses of antioxidant systems. Exposure of goldfish to 50, 100 and 150 mg L(-1) of Co(2+) for 96 h elevated total hemoglobin in blood by 23, 44 and 78%, respectively. In gills, cobalt exposure enhanced lipid peroxide levels and activities of primary antioxidant enzymes; superoxide dismutase (SOD) rose by 125% and glutathione peroxidase (GPx) increased by 53-296%. Glutathione-S-transferase (GST) activity also increased by 117-157% and glucose-6-phosphate dehydrogenase (G6PDH) enhanced by 46-96%. Heart showed limited effects of fish exposure to 50 or 100 mg L(-1) of Co(2+), but the exposure to 150 mg L(-1) of Co(2+) elevated concentrations of lipid peroxides by 123% and activities of GPx by 98% and SOD by 208%. The most substantial effects of goldfish exposure to Co(2+) were observed in spleen: a decrease in total protein concentration by 44-60% and high molecular mass thiols by 59-82%, reduced activities of catalase by 24-58% and GR by 25-68%, whereas the level of low molecular mass thiols increased by 153-279% and activities of GPx, GST, G6PDH were enhanced by 114-120%, 192-769%, and 256-581%, respectively. The data show that fish exposure to 50-150 mg L(-1) of Co(2+) elevates blood hemoglobin level, mimicking effects of hypoxia, and causes the activation of defense systems against ROS.

Exposure to cobalt can give rise to adverse health effects related to various organs or tissues, such as the respiratory organs, the skin, the hematopoietic tissues, the myocardium, the thyroid gland, as well as teratogenic and carcinogenic effects. In occupational and environmental health, it is important to identify effects that occur at relatively low exposure, i.e. the critical effects which are crucial for preventive action. The limited database available on cobalt toxicity makes it difficult to select critical effects. For dermal exposures, allergic dermatitis may be regarded as such an effect, even if this is a reversible condition and dose-response relationships need to be defined. For inhalation exposures, effects on the respiratory tract can be considered as critical effects. Evidence of cobalt carcinogenicity in humans is inadequate and cannot be evaluated quantitatively but an extra safety factor to be added on exposures estimated from other effects may well be needed. Risks for development of pneumoconiosis are likely to be dependent on physical and chemical characteristics of airborne cobalt containing particles, but such information is lacking in most studies. It has been recognised for many years that there is an excess risk of pneumoconiosis when exposure to cobalt containing dust exceeds 100 micrograms/m3. Recently considerably lower concentrations occurring in the cobalt diamond industry have given rise to such effects. Irritation of mucous membranes may occur at 5-10 micrograms/m3.

Cobalt toxicity was evaluated in the dominant lethal assay (DLA) to determine whether the detrimental effects of cobalt on spermatozoa would have an impact on offspring. Male B 6 C 3 F 1 mice were treated with cobaltons chloride (400 ppm Co) for 10 weeks and mated. Neither the stage nor rate of development in vitro of 2-cell embryos to blastocyst from cobalt-treated males was affected. There was an increase in preimplantation losses and a decrease in total and live births, but no change in postimplantation losses from litters at day 19 of gestation. Fertility of the males was maintained during the 10-week cobalt treatment period, decreased during the DLA, and recovered over the next 6 weeks. Sperm parameters at the end of DLA and the recovery period showed that cobalt decreased all parameters measured at 12 weeks, but these parameters, except concentration, recovered to control levels by 18 weeks. Tissue concentrations of cobalt measured by atomic absorption analysis were increased in liver, kidney, testis, and epididymis after 12 weeks of cobalt treatment. We conclude that cobalt affected preimplantation losses in the DLA by compromising the fertility of treated males.

Although generally rare in natural aquatic systems, cobalt concentrations can be elevated through ore and coal mining operations and discharges of certain textile dyes. The U.S. Environmental Protection Agency does not have an ambient water quality criterion for cobalt due to a lack of toxicological data. The present study determined whether freshwater acute and chronic cobalt toxicity were dependent on dilution water hardness. We specifically examined the relative toxicity of cobalt at high water hardness (≥ 200 mg/l as CaCO3) because cobalt often occurs in carbonate ores. Acute and chronic toxicity tests using both Ceriodaphnia dubia and Pimephales promelas were performed using four different synthetic waters: 50,200. 400, and 800 mg/l hardness as CaCO3. Diluent hardness appeared to have no effect on measured cobalt concentrations. Dissolved cobalt in water samples during testing was similar to the corresponding total recoverable cobalt in this study suggesting that most of the cobalt was in a soluble and presumably bioavailable form. LC50 values for P. promelas could not be calculated owing to their low sensitivity to high cobalt concentrations (≥ 5 mg/l) over a 48 h period. Regression analysis of P. promelas acute NOEC values and test water hardness indicated an R2 = 0.94 suggesting a direct relationship between water hardness and acute toxicity to cobalt for this species. C. dubia acute tests indicated water hardness effects after 48 h of exposure and non-linear dose responses in hard water (≥ 200 mg/l). Regression analysis of C. dubia 24 h LC50 values and test water hardness indicated an R2 = 0.91. For both cases, a simple power function gave the best regression fit. C. dubia appeared to be more sensitive than P. promelas at hardness ≥ 200 mg/l but the reverse was true in soft water ( ≤ 50 mg/l). The 7 d P. promelas chronic NOEC increased from 1232 μg/l cobalt (50 mg/l hardness) to ≥ 3833 μg/l (800 mg/l hardness). Effects were on fish survival and not growth. Regression analysis yielded an R2 = 0.97 based on the fish survival NOECs and the natural log of hardness. C. dubia chronic tests were inconclusive due to poor survival and reproduction in the synthetic waters. Available data suggest that within 50–200 mg/l water hardness, cobalt acute toxicily is inversely related to water hardness. Tentative cobalt acute criteria, based on power functions, are 288 μg/l and 873 μg/l for soft and hard water, respectively. Available chronic toxicity data suggest that daphnids are more sensitive to cobalt than other genera. Chronic endpoints for both P. promelus and D. magna were similar in soft and hard water (≤ 400 mg/l hardness) suggesting that chronic toxicity is not hardness-dependent over this range. However, chronic cndpoints at 800 mg/l hardness were 3.1 and ≥ 12 times higher than endpoints observed under soft water conditions for P. promelas and C. dubia respectively suggesting that very hard waters may significantly reduce chronic toxicity potential of cobalt.

Workers exposed to cobalt by inhalation are at risk from interstitial lung disease (hard metal disease) and occupational asthma. Exposed groups include tungsten carbide (TC) producers, diamond polishers, grinders and sharpeners of TC tools, and metal coaters using powdered hard metal. Cobalt, the binding agent for TC, is believed to be the casual agent. Information available to date suggests that cobalt in the absence of tungsten or TC can cause interstitial lung disease (ILD) and occupational asthma, while tungsten or TC does not. Questions for further investigation are whether cobalt toxicity is enhanced in the presence of TC or other metals and whether pure cobalt in the absence of any other metals can cause ILD. Prevalence and exposure-response information is available for ILD in workers exposed to cobalt. The prevalence of interstitial lung disease among studies on TC production workers range from 0 to 13%. Because of subject selection for active employed workers, these are probably underestimates of the true prevalence in the industry. Our study of 1039 US TC workers showed that 2.6% had abnormal chest radiographs ( profusion ≥ 1 0 ). We found that the relative odds of an abnormal chest radiograph were increased fivefold when lifetime average cobalt levels exceeded 100 μg/m3, among those with at least 10 years latency. On the other hand, we found three workers with ILD whose exposures had never exceeded 50 μg/m3 and whose latencies where less than 10 years. This study and supporting data from the literature suggests that a subgroup of workers exposed to cobalt is at risk for hard metal disease. Among the subgroup at risk, individual susceptibility to cobalt varies. This may explain why some exposed workers will develop hard metal disease after brief, low cobalt exposures (below the current US standard of 50 μg/m3), while others will develop the disease only after higher cobalt exposures of longer duration.

An experiment was conducted with young, male, crossbred chicks to investigate the interaction between dietary cobalt, methionine and experimental Eimeria acervulina infection (duodenal coccidiosis). Coccidiosis and dietary cobalt (250 mg/kg) depressed weight gain and efficiency of feed utilization; cobalt toxicity, however, was exacerbated by the coccidial infection, resulting in a depression in performance greater than could be accounted for by the independent additive effect of each entity. Dietary cobalt increased the cobalt concentration of the liver, kidney and gallbladder (with bile); experimental coccidiosis in the absence of excess dietary methionine resulted in a twofold increase in cobalt deposition in the liver and gallbladder. Excess supplemental methionine partially alleviated the decrease in chick performance and the increase in tissue cobalt content caused by dietary cobalt in both healthy and infected chicks, but with a slightly greater efficacy in the coccidiosis-infected chicks.