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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.

Uptake and toxicity of Ni-Co mixtures in Enchytraeus crypticus were determined after 4 d, 7 d, 10 d, and 14 d exposure. Generally, body concentrations of Ni and Co increased with increasing exposure concentrations. Ni body concentration was significantly reduced in the presence of Co, whereas Ni only marginally affected Co uptake. When expressed as free ion activities, individual toxicity of Ni and Co increased with time, with median lethal concentrations (LC50) decreasing from 78.3 μM and 511 μM at 4 d to 40.4 μM and 393 μM at 14 d, respectively. When expressed as body concentrations, LC50BodyNi remained constant with time whereas LC50BodyCo increased during the first 7 d but remained stable afterwards. As identified by the MIXTOX model, interactions between Ni and Co were mainly antagonistic when based on free ion activities, however, no interaction was observed when based on body concentrations. A process-based model, incorporating exposure time to analyze the mechanisms underlying the dynamic mixture toxicity confirmed the differences in toxicokinetics of the 2 metals. The author's findings suggest that body concentrations, which incorporate bioaccumulation processes, are time-independent and can act as a more constant indicator of metal toxicity. The observed antagonism was mainly caused by competition between Co and Ni for binding sites and subsequent inhibition of Ni uptake. This competitive interaction occurred at the uptake level (toxicokinetics), but not at the target level (toxicodynamics).

Tomato (Lycopersicon esculentum) cv. Pusa ruby was grown in refined sand with complete nutrition (control) and at 0.05, 0.1, 0.2, 0.4, and 0.5 mM of cobalt sulfate. Visible effects of excess cobalt (Co) manifested on tomato at 0.5 mM Co, after 3 days of metal supply to 40 day old plants. The symptoms of excess cobalt diffused chlorosis of young leaves from base and later necrotic spots appeared on chlorotic areas. The necrotic spots enlarged in size, coalesced and in due coarse most of the entire leaf turned necrotic and withered. With excess Co, there was loss of lamina and marginal scorching of affected leaves. The affected leaves were distorted and appeared hook like with rudimentary leaflets at the top. These effects were most severe at 0.5 mM and the intensity of symptoms gradually diminished with a decrease in Co supply from 0.5 to 0.05 mM. At the latter level of Co, no visible effects could be seen except for growth depression. Excess Co restricted the biomass, concentration of phosphorus (P), sulf...

Cobalt (Co) exposure has been documented to result in increased erythropoiesis. To evaluate the potential for implant-derived Co toxicity, we examined the relationship between serum Co (sCo) and erythrocyte counts (ERY) in a metal-containing total-hip arthroplasty implant population.Retrospective review of sCo concentrations identified 77 patients with concomitant ERY. Statistical analysis was performed to determine if there was a significant difference in ERY for patients divided into clinically relevant sCo ranges. A single detailed case review of a patient with a loose mal-positioned acetabular component and significantly elevated sCo was also performed for symptoms thought to arise from Co toxicity.Statistical difference in ERY was not observed between patients with significantly elevated (10 ng/mL), elevated (4-10 ng/mL), modestly elevated (1.0-3.9 ng/mL), or normal (1.0 ng/mL) sCo. While the detailed case report was unremarkable for any of the clinical symptoms previously reported to be associated with Co toxicity and no increase in ERY was observed, this patient's sCo was 84 ng/mL.Increased erythropoiesis was not observed in patients with implant-derived increased sCo. Even with a sCo 100 × the upper-limit of normal, the patient presented did not have increased ERY nor exhibit any symptoms ascribed with Co toxicity.

The effects of cobalt on the growth and nutrient balance of mung beans were investigated. Inhibition of seedling growth occurred at 5 μM Co and was associated with chlorosis of the younger leaves. Analysis of nutrient concentrations in root and leaf tissue of mung beans treated with 5 μM Co showed that none of the macronutrients and only two of the micronutrients, Mn and Fe, were significantly affected. The Mn concentration in roots was reduced by 55% and the Fe concentration in the leaves by 80%. Uptake of Fe into roots was not inhibited by Co but transport of Fe to the shoot was greatly reduced. It was shown that the effect of Co on growth was additive to that of Fe deficiency, which argues against Co-induced Fe deficiency as the primary cause of growth inhibition by Co. Rather, it was considered that the high concentrations of Co in the roots and leaves compared with essential micronutrient cations can disrupt a range of metabolic processes due to competitive interactions. Comparison of the toxic effects of Co with those of other toxic trace metals Cd, Cu, Ni and Hg showed that at an applied concentration of 5 μM, there were obvious differences in both the visual symptoms and in nutrient concentrations. The main difference between Co and the other metals was that only Co stimulated the uptake of S into the plant and its transport to the shoots, where the S concentration in the leaves was increased 2-fold. The common feature of all the trace metals examined was the strong inhibition of Fe transport to the shoot. A possible mechanism for the interaction of other trace metals with Fe transport is discussed.

Cobalt (Co) is an essential trace element well known as a constituent of vitamin B(12), but different compounds of Co are also described as highly toxic and/or radiotoxic for individuals or the environment. In nuclear power plants, (58)Co and (60)Co are radioactive isotopes of cobalt present as activation products of stable Co and Ni used in alloys. Skin exposure is a current occupational risk in the hard metal and nuclear industries. As biochemical and molecular cobalt-induced toxicological mechanisms are not fully identified, we investigated cobalt toxicity in a model human keratinocyte cell line, HaCaT. In this study, we propose a model to determine the in vitro chemical impact on cell viability of a soluble form of cobalt (CoCl(2)) with or without gamma-ray doses to mimic contamination by (60)Co, to elucidate the mechanisms of cobalt intracellular chemical and radiological toxicity. Intracellular cobalt concentration was determined after HaCaT cell contamination and chemical toxicity was evaluated in terms of cellular viability and clonogenic survival. We investigated damage to DNA in HaCaT cells by combined treatment with chemical cobalt and a moderate gamma-ray dose. Additive effects of cobalt and irradiation were demonstrated. The underlying mechanism of cobalt toxicity is not clearly established, but our results seem to indicate that the toxicity of Co(II) and of irradiation arises from production of reactive oxygen species.

The facultative anaerobic enterobacterium Escherichia coli requires the activity of nickel-containing hydrogenase for its anaerobic growth. Deficiency of the specific nickel transport system led to a hydrogenase-minus phenotype and slowed down the fermentative growth in the nik mutant. Addition of 300 pM nickel to the growth medium could restore the hydrogenase activity. This restoration resulted in the recovery of anaerobic growth. A fur- ther increase of nickel concentration inhibited growth. Thus nickel shows an antagonistic effect on the anaerobic growth of E. coli. To study the mech- anism of nickel toxicity, two classes of nickel-resistant mutants were isolated. The nkr mutant was obtained by selecting colonies grown on nickel-containing minimal plate. It acquired simultaneously the resistance to cobalt. A nonspecific magnesium transport mutant corA was isolated on cobalt-containing plate. The corA mutant was also resistant to nickel. When analyzing the influence of nickel and cobalt on the bacterial growth, we obtained two interesting observations. First, anaerobic growth was less sensitive than aerobic growth to cobalt toxicity. In contrast, nickel toxicity did not vary from the growth conditions. Second, cobalt seems to abolish the growth, while nickel appears to slow down the growth rate under the condition used. Environ Health Perspect 1 02(Suppl 3):297-300 (1 994).

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?

Hydroxocobalamin has been shown to be a rapid and powerful antidote in acute cyanide poisoning and to prevent cyanide poisoning during sodium nitroprusside administration. This cobalt-containing compound has been shown to be devoid of significant immediate side effects during acute administration. However, its potential delayed toxicity related to cobalt accumulation in tissue remains unknown. Therefore, we evaluated the toxicity of hydroxocobalamin as compared with that of cobalt salts on rat cardiac and diaphragmatic muscles.For a 21-day period, rats were treated intraperitoneally with either hydroxocobalamin (70 mg kg-1 per day, n = 14), cobalt chloride hexahydrate (12 mg kg-1 per day, n = 14) or saline (n = 10). Hydroxocobalamin and cobalt chloride groups received equimolar doses of cobalt. We studied: (1) the mechanical properties of isolated left ventricular papillary muscles and diaphragmatic strips, (2) the cardiac and diaphragmatic cobalt tissue concentrations, and (3) the myocardial histological aspect.During the study period, no significant increase in body weight was noted in the cobalt-treated group (-4 +/- 1%), which was in contrast to the hydroxocobalamin-treated group (+21 +/- 2%) and the saline-treated group (22 +/- 2%). Compared with controls, the mechanical properties of cardiac and diaphragmatic muscles were unchanged after either hydroxocobalamin or cobalt salt treatments, and myocardial histological characteristics were similar in all groups. Conversely, large amounts of cobalt deposit were observed in the cobalt-treated group in both the diaphragm (41.90 +/- 16.30 vs 0.70 +/- 0.40 mu mol mu g-1 in the control group, P0.001) and the myocardium (16.90 +/- 6.40 vs 0.14 +/- 0.01 mu mol mu g-1 in the control group, P0.001). After hydroxocobalamin administration, cobalt concentrations were significantly lower in the diaphragm (25.10 +/- 16.50 mu mol mu g-1, P0.001 vs cobalt-treated group) and the myocardium (4.50 +/- 1.20 mu mol mu g, P0.001 vs cobalt-treated group).These results indicate that repeated administration of hydroxocobalamin was devoid of significant diaphragmatic and cardiac muscle toxicity and therefore remains a safe antidote for acute cyanide poisoning.

There is public concern over the long term systemic health effects of metal released from implanted medical devices that use metal alloys. Systemic toxic side effects have been associated with excessive metal ion release from implants into human biological specimen's circulation, in which cobalt and chromium plays an important role. Cobalt intoxication has become more frequent due to the wide use of metallic medical implants. Despite the technological improvements in replacement metallic medical implants, wear and corrosion products associated with the metal compounds of these implants may result in systemic reactions and toxicities. The current review encompasses a literature of the systemic toxicity studies concerning the effect of metallic wear debris released from wear and corrosion of specific types of implanted medical devices, resulting in a postoperative increase in metal ion levels in bodily fluids and at different organ sites. Release of metallic debris is mainly in the form of particles and ions of different valences, and oxides composed of cobalt and chromium. Toxicological, clinically significant, data regarding "potential hazards" of circulating metals after systemic chronic exposure to the metal ions from metals have been included. This review further highlights some of the clinical features of cobalt toxicity.

A 63-year-old woman was referred to the specialised knee revision clinic with ongoing knee pain after total knee replacement. She incidentally had cobalt and chromium levels measured. These were seen to be elevated. Comprehensive assessment and investigation did not identify any other source of cobalt or chromium. Aseptic loosening of the knee was diagnosed, and the knee was revised. At the time of surgery, the tissue was seen to be darkened consistent with metallosis. Multiple samples excluded infection on extended cultures. Aspirated fluid showed that periprosthetic fluid had elevated cobalt levels. The knee was successfully revised with good symptomatic outcome and significantly, over the course of several months post-revision, the cobalt and chromium levels returned to normal.

Three experiments were conducted to investigate the interaction of cobalt with sulfur-containing amino acids in the chick. Fortified corn-soybean meal diets were fed and tissue concentrations of cobalt were assessed. In Experiment 1, three levels of cobalt (0, 250, and 500 microgram/g) were fed in the presence and absence of .50% supplemental DL-methionine. Dietary additions of cobalt depressed growth rate and caused cobalt accumulation in the liver and kidney. Supplemental methionine in excess of the requirement for maximal chick weight gains partially alleviated the depression in performance and decreased cobalt accumulation in the liver and kidney. Two levels of cobalt (0 and 500 microgram/g) were fed in the presence and absence of .59% supplemental L-cysteine.HCl.H2O (isosulfurous to .50% DL-methionine) in Experiment 2. Again, cobalt depressed performance and accumulated in the liver and kidney. The surfeit of cysteine increased weight gain and decreased cobalt accumulation in the liver but not in the kidney. In Experiment 3, two levels of cobalt (0 and 250 microgram/g) were fed in the presence and absence of two levels of excess DL-methionine (.50 and 1.0%) or two levels of excess cysteine.HCl.H2O (.59 and 1.18%). Multiple linear regression analysis of gain on sulfur consumed from methionine or cysteine indicated that cysteine was almost 6 times more efficacious than methionine in alleviating cobalt toxicity. In fact, cysteine supplemented at a level of 1.18% completely alleviated the growth depression caused by 250 microgram/g cobalt. Both methionine and cysteine reduced cobalt accumulation in the liver and kidney, but the liver was affected to a greater extent than the kidney.

Background Cobalt has a rare occurrence in nature, but may accumulate in cells to toxic levels. In the present study, we have investigated how the transcription factor Yap1 mediates tolerance to cobalt toxicity. Methods Fluorescence microscopy was used to address how cobalt activates Yap1. Using microarray analysis, we compared the transcriptional profile of a strain lacking Yap1 to that of its parental strain. To evaluate the extent of the oxidative damage caused by cobalt, GSH was quantified by HPLC and protein carbonylation levels were assessed. Results Cobalt activates Yap1 under aerobiosis and anaerobiosis growth conditions. This metal generates a severe oxidative damage in the absence of Yap1. However, when challenged with high concentrations of cobalt, yap1 mutant cells accumulate lower levels of this metal. Accordingly, microarray analysis revealed that the expression of the high affinity phosphate transporter, PHO84 , a well-known cobalt transporter, is compromised in the yap1 mutant. Moreover, we show that Yap1 is a repressor of the low affinity iron transporter, FET4 , which is also known to transport cobalt. Conclusions Cobalt activates Yap1 that alleviates the oxidative damage caused by this metal. Yap1 partially controls cobalt cellular uptake via the regulation of PHO84 . Although FET4 repression by Yap1 has no effect on cobalt uptake, it may be its first line of defense against other toxic metals. General significance Our results emphasize the important role of Yap1 in mediating cobalt-induced oxidative damages and reveal new routes for cell protection provided by this regulator.

The myocardial cobalt concentration in a patient who died 3 months after treatment with cobalt was 25-80 times greater than the concentration in control samples. Blood cobalt concentrations in maintenance hemodialysis patients who had been treated 13-20 months previously with cobaltous chloride were significantly higher than those in maintenance hemodialysis patients who had not received cobalt. Prospective studies of blood cobalt concentrations in maintenance hemodialysis patients and normal subjects after the administration of cobaltous chloride were carried out. It was found that prolonged elevation of blood cobalt concentrations occurred in both normals and maintenance hemodialysis patients, but that the blood cobalt concentrations were much higher in the dialysis patients. The urinary excretion of cobalt following the administration of a single dose of cobaltous chloride was studied in two normal subjects. Cobalt metabolism and toxicity are discussed. In view of the limited therapeutic gains to be expected and because of the lack of information regarding the long term significance of elevated blood cobalt concentrations, it is concluded that cobalt should not be used in the treatment of the anemia of patients with sever renal failure.

The significance of cobalt as a cause of symptoms after McKee hip arthroplasty is discussed. Seven patients are described in whom such arthroplasties. became unsatisfactory after periods varying from nine months to four years. Six of these patients were cobalt-positive but nickel- and chrome-negative on patch testing. Macroscopic and histological necrosis of bone, muscle and joint capsule around the prostheses was found in five patients whose hips were explored. The symptoms were progressive pain, a feeling of instability, and in two cases spontaneous dislocation. Radiological features included acetabular fracture, bone resorption, loosening and dislocation of the prosthesis. Increased cobalt concentrations (determined by atomic absorption spectrophotometry) in the urine of four patients and in a variety of tissues in one patient are presented. Patch testing is recommended in the investigation of patients with troublesome McKee hip arthroplasties

1. Increasing concentrations of cobalt in the medium result in increased production of an iron-binding compound and a corresponding fall in catalase activity of Neurospora crassa. 2. Cobalt rapidly depletes the medium of iron by enhancing the rate of iron uptake by the mycelium. 3. With toxic amounts of cobalt there is a fall in bound 59 Fe and haem 59 Fe as well as a decreased incorporation of [2- 14 C]glycine into the mycelial haem fraction. The production of the iron-binding compound precedes the fall in the iron-dependent systems mentioned. 4. The 59 Fe bound to the iron-binding compound acts as a better iron source for haem synthesis in cell-free extracts as compared with 59 FeSO 4 . 5. Cobalt inhibits iron incorporation into protoporphyrin in cell-free extracts but is not itself incorporated to an appreciable extent.

Objectives Recently, high failure rates of metal-on-metal (MOM) hip implants have raised concerns of cobalt toxicity. Adverse reactions occur to cobalt nanoparticles (CoNPs) and cobalt ions (Co2+) during wear of MOM hip implants, but the toxic mechanism is not clear. Methods To evaluate the protective effect of zinc ions (Zn2+), Balb/3T3 mouse fibroblast cells were pretreated with 50 μM Zn2+ for four hours. The cells were then exposed to different concentrations of CoNPs and Co2+ for four hours, 24 hours and 48 hours. The cell viabilities, reactive oxygen species (ROS) levels, and inflammatory cytokines were measured. Results CoNPs and Co2+ can induce the increase of ROS and inflammatory cytokines, such as tumour necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). However, Zn pretreatment can significantly prevent cytotoxicity induced by CoNPs and Co2+, decrease ROS production, and decrease levels of inflammatory cytokines in Balb/3T3 mouse fibroblast cells. Conclusion These results suggest that Zn pretreatment can provide protection against inflammation and cytotoxicity induced by CoNPs and Co2+ in Balb/3T3 cells. Cite this article: Y. Liu, H. Zhu, H. Hong, W. Wang, F. Liu. Can zinc protect cells from the cytotoxic effects of cobalt ions and nanoparticles derived from metal-on-metal joint arthroplasties? Bone Joint Res 2017;6:649–655. DOI: 10.1302/2046-3758.612.BJR-2016-0137.R2.

Cobalt is known to produce a variety of symptoms in patients who accumulate a toxic amount in their blood. Cobalt poisoning can arise from metal implants due to wear and tear on the metal implant surfaces, but implant deterioration has not yet been reported to cause muscle spasticity. A 45-year-old male patient with a medical history of multiple sclerosis (MS) and bilateral hip arthroplasty presented with spasticity that persisted despite administration of anti-spasmodic medication and intrathecal baclofen. Concerns of high cobalt levels, confirmed via blood testing, led to revisions of both of his hip prosthesis, which alleviated his muscle spasms. To our knowledge, this is the first reported case of muscle spasticity associated with increased blood cobalt levels. Reduction in the patient's spasticity was associated with prosthesis revision and subsequent reduction in blood cobalt, suggesting that cobalt was involved in the pathogenesis or at minimum worsening of his spasticity given his concurrent MS. Review of the literature suggests that increased levels of cobalt can interfere with metabolism in neurons and damage muscle fibers, providing possible pathological mechanisms for the patient's spasticity.

This is one of the first documented cases of metal-on-metal (MoM) total hip arthroplasty cobalt cardiac toxicity that has led to patient death. A 69-year-old female presented to our institution with cardiac failure secondary to cobalt toxicity resulting from bilateral MoM total hip arthroplasty. Her presenting metal ion levels were a cobalt level of 199 ppb and a chromium level of 77 ppb. She underwent bilateral femoral revisions to remove the source of cobalt. On postoperative day 7, the patient sustained a cerebral infarct and eventually expired because of the insult. This case represents one of the first documented fatalities related to MoM cobalt cardiac toxicity.

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

Background: It is often difficult to establish clinical relevance of metal exposure in cobalt-allergic patients. Dermatologists and patients may incorrectly assume that many metallic items release cobalt at levels that may cause cobalt dermatitis. Cobalt-allergic patients may be unaware that they are exposed to cobalt from handling work items, causing hand dermatitis. Objectives: To present early findings with a newly developed cobalt spot test. Methods and Results: A cobalt spot test based on disodium-1-nitroso-2-naphthol-3,6-disulfonate was able to identify cobalt release at 8.3 ppm. The test may also be used as a gel test if combined with an agar preparation. We found no false-positive reactions when testing metals and alloys known not to contain cobalt. However, one cobalt-containing alloy, which elicited cobalt dermatitis in cobalt-allergic patients, was negative upon cobalt gel testing. Conclusions: The cobalt test detects amounts of cobalt release that approximate the elicitation concentration seen in cobalt-allergic patients. It may serve as a useful tool in dermatology offices and workplaces.