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This document provides information on the topic of cobalt toxicity in patients with metal-on-metal (MoM) hip implants. Cobalt toxicity can lead to various symptoms and complications, including peripheral neuropathy, hearing loss, cardiomyopathy, and hypothyroidism. The diagnosis involves elevated cobalt levels, confirmed findings consistent with cobalt toxicity, and exclusion of other causes. Treatment options include symptomatic management, chelation therapy, and revision of the MoM hip implant. Early detection is important for better outcomes. [Extracted from the article]

Frequent discharge of cobalt in ionic form (Co2+) during industrial processes is contaminating agricultural soil through the addition of industrial effluent. Cobalt is beneficial element in trace amounts but its higher concentrations in soil severely damage the growth and development of plants. In this two-year study, the pre-selected sublethal level (0.5 mM) concentration of Co2+ was applied in soil to induce toxicity on two elite maize (Zea mays L.) hybrids ('Hycorn11plus' and 'P-1429'). To encounter the toxic effects of selected sub-lethal (0.5 mM) Co2+ level (applied using CoCl2·6H2O), pre-optimized levels of three stress protective chemicals (SPCs) i.e., ascorbic acid (0.5 mM), salicylic acid (0.5 mM) and thiourea (1.0 mM) were foliar sprayed. The Co2+ and SCPs treatments were applied 10 days after seedling emergence. After ten days of treatment application, the data were recorded for the growth, nutrients and leaf water status. The shoot and root dry weights and shoot-to-root (S/R) ratio were substantially reduced by the Co2+ stress. Co2+ intoxication also enhanced the leaf water loss (LWL) while relative water contents (RWC) were reduced in Co2+ stressed plants. The Co2+ treatment reduced the intake of nitrate-N, sulfate-S, phosphate-P, K+, Ca2+, Mg2+, Zn2+, and Fe2+ contents significantly both in the shoot and root. However, from the correlation matrix, it was noted that the foliar spray of SPCs effectively alleviated the Co2+damage by preventing the influx of Co2+ ions and enhanced the growth, water and nutrient contents except for LWL. From the reduced RWC and shoot and root nutrient contents, as well as increased LWL and Co2+ contents, it is evident that Co2+ interfered with either the function or structure of water and ion-transport systems located on the plasma lemma and tonoplast of root cells. AsA was more effective among the foliar applied SPCs due to its multiple metabolic roles in plants. The foliar spray of SPCs improved the root mass and tendency to absorb essential nutrients under Co2+toxicity indicating an intimate communication between shoot and root. The use of SPCs at the selected levels is a pragmatic strategy to counteract the Co2+ damage to maize in the marginally contaminated areas. [ABSTRACT FROM AUTHOR]

Introduction: Cobalt toxicity in patients with hip arthroplasty is a rare complication, but it should be considered in those patients who, after a ceramic fracture, were implanted with a metal-on-polyethylene prosthesis. The complete removal of ceramic particles during revision surgery can be complicated. If the bearing surface is replaced with a metal-on-polyethylene prosthesis, these residual ceramic particles may wear down the chrome-cobalt head, producing localised metallosis. This can trigger blood metal ion levels to rise, causing systemic toxicity. Visual and auditory alterations, cognitive deterioration, hypothyroidism, neuropathy, cardiomyopathy, anorexia, fatigue, diabetes, polycythemia, and respiratory and cutaneous symptoms are some of the clinical manifestations of prosthetic cobaltism. Case description: A young patient presented with multiorgan failure secondary to cobalt toxicity after a ceramic fracture and revision with a metal-on-polyethylene prosthesis; his serum cobalt and chromium levels were 652 μg/L and 270 μg/L, respectively. The patient needed a heart transplant after presenting with cobalt-induced cardiogenic shock. Conclusions: In a patient with a ceramic fracture who is subjected to revision surgery with a metal-on-polyethylene bearing, it is necessary to rule out the possibility of cobalt intoxication. Serum cobalt levels > 20 μg/L are inadmissible; in these cases, surgical treatment should be considered in the short term. A wide synovectomy and replacement of components should be performed with hard friction options, preferably with a ceramic-on-ceramic prosthesis. [ABSTRACT FROM AUTHOR]

Dear Editor, We read with great interest the letter from Pelclova and Lach [[1]] on the efficacy of unithiol (2,3-dimercaptopropanesulfonate) and acetylcysteine in a patient with arthroplastic cobalt toxicity. Acetylcysteine increases cobalt urinary excretion and consistently maintains the serum cobalt concentration less than the threshold of 10 g/L, which we believe to be the goal in patients with metal-on-metal implants in order to minimise cobalt toxicity from the existing prosthesis [[3]]. The authors stated that chelation therapy, either with unithiol or acetylcysteine, is often clinically inefficient in patients with very elevated cobalt concentrations (greater than 100 g/L) as long as the damaged prosthesis remains I in situ i . [Extracted from the article]

The purpose of this study was to investigate the sublethal Co toxicity on rainbow trout (Oncorhynchus mykiss). Trout were exposed to Co and selected parameters were evaluated at intervals of 1, 15 and 30 days. Fish exposed to higher levels of Co grew slower than fish exposed to lower levels of Co. Weight gain, specific growth rate (SGR) decreased linearly with the increase of cobalt in the water. The body condition factor (CF) of fish reared in water with low cobalt concentration decreased substantially but this decrease was not significant for fish exposed to higher cobalt concentration. The values of the feed conversion ratio (FCR) increased in fish exposed to higher levels of Co. Co significantly changed the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and decreased at day 30, and in both cases this decrease was more remarkable at day 15 so that the level of AST and ALT reached the control value at day 30. The alkaline phosphatase (ALP) level also showed a remarkable 15-day decline. There was a significant increase in glucose (G) concentration in both Co-exposed groups on day 15. However, serum cholesterol (Chl) was significantly reduced on day 15 and increased on day 30; there were no significant differences in both exposed Co-groups. The triglyceride (TG) level also decreased substantially. There was no regular pattern of total protein (TP) in the serum, so that no significant differences were found in the level of TP between low and high-exposed fish. In summary, this study suggests that exposure of essential trace elements such as cobalt may change growth and biochemical parameters, and that measurement of these parameters may be used in toxicological studies to determine the general health status of fish. [ABSTRACT FROM AUTHOR]

We conclude that treatment with either unithiol or acetylcysteine is inefficient in patients with very elevated serum cobalt concentrations, especially greater than 100 µg/L, as long as the damaged prosthesis remains I in situ i . Dear Editor, Previously [[1]] we reported a 56-year-old man with severe cobalt poisoning from a damaged metal-on-ceramic hip prosthesis. However, her serum cobalt concentration reached 221 µg/L in February 2022 on the day of the surgery, which subsequently decreased to 51 µg/L 11 days after surgery, 10 µg/L 2.5 months after surgery, and 3 µg/L 6 months after surgery, all without further treatment. [Extracted from the article]

This case illustrates the potential for systemic cobalt toxicity in non-metal-on-metal bearings and its potentially devastating consequences. We present a 71-year-old male with grinding sensations in his right hip following ceramic-on-ceramic total hip arthroplasty (THA). After diagnosing a fractured ceramic liner, the hip prosthesis was revised into a metal-on-polyethylene bearing. At one year postoperatively, X-rays and MARS-MRI showed a fixed reversed hybrid THA, with periarticular densities, flattening of the femoral head component, and a pattern of periarticular metal wear debris and pseudotumor formation. Before revision could take place, the patient was admitted with the clinical picture of systemic cobalt toxicity, supported by excessively high serum cobalt and chromium levels, and ultimately died. At autopsy dilated cardiomyopathy as cause of death was hypothesized. A third body wear reaction between ceramic remnants and the metal femoral head very likely led to excessive metal wear, which contributed systemic cobalt toxicity leading to neurotoxicity and heart failure. This case emphasizes that fractured ceramic-on-ceramic bearings should be revised to ceramic-on-ceramic or ceramic-on-polyethylene bearings, but not to metal-on-polyethylene bearings. We aim to increase awareness among orthopedic surgeons for clinical clues for systemic cobalt intoxication, even when there is no metal-on-metal bearing surface. [ABSTRACT FROM AUTHOR]

Context:Post-arthroplasty metallosis, which refers to metallic corrosion and deposition of metallic debris in the periprosthetic soft tissues of the body, is an uncommon complication. Systemic cobalt toxicity post-arthroplasty is extremely rare. The few known fatal cases of cobalt toxicity appear to be a result of replacing shattered ceramic heads with metal-on-metal or metal-on-polyethylene implants. Friction between residual shards of ceramic and cobalt–chromium implants allows release of cobalt into the synovial fluid and bloodstream, resulting in elevated whole blood cobalt levels and potential toxicity. Case details:This is a single patient chart review of a 60-year-old woman with prior ceramic-on-ceramic right total hip arthroplasty complicated by fractured ceramic components and metallosis of the joint. She underwent synovectomy and revision to a metal-on-polyethylene articulation. Ten months post-revision, she presented to the emergency department (ED) with right hip pain, dyspnea, worsening hearing loss, metallic dysgeusia, and weight loss. Chest CTA revealed bilateral pulmonary emboli (PE), and echocardiogram revealed new cardiomyopathy with global left ventricular hypokinesis with an ejection fraction (EF) of 35–40% inconsistent with heart strain from PE. Whole blood cobalt level obtained two days into her admission was 424.3 mcg/L and 24-h urine cobalt level was 4830.5 mcg/L. Although the patient initially clinically improved with regard to her PE and was discharged to home on hospital day 5, she returned 10 days later with a right hip dislocation and underwent closed reduction of the hip. The patient subsequently decompensated, developing cardiogenic shock, and respiratory failure. She went into pulseless electrical activity (PEA) and expired. Autopsy revealed an extensive metallic effusion surrounding the right hip prosthesis that tested positive for cobalt (41,000 mcg/L). There was also cobalt in the heart muscle tissue (2.5 mcg/g). A whole blood cobalt level obtained two days before she expired was 641.6 mcg/L. Discussion:This is a case of fatal cobalt-induced cardiomyopathy in a patient whose ceramic components of a total hip arthroplasty fractured causing metallosis with worsening cobalt toxicity. We recommend that when a fractured device is revised with a prosthesis with cobalt–chromium components, whole blood and urine cobalt measurements should be obtained and periodically monitored to evaluate for rising concentrations. Providers should be aware of clinical signs and symptoms of cobalt toxicity in patients who have prostheses with cobalt–chromium components. If suspected, toxicology and orthopedics should be involved for possible chelation and removal of the prosthesis. [ABSTRACT FROM PUBLISHER]

Case: We present a case of systemic cobalt toxicity secondary to third-body wear of a cobalt-chromium (CoCr) femoral head following revision of a fractured ceramic bearing. Removal of the CoCr head was followed by resolution of much of the systemic symptoms. Conclusion: This case supports previous reports of cobalt toxicity secondary to catastrophic third-body wear of a CoCr femoral head following a fractured ceramic bearing. It also demonstrates the potential reversibility of many systemic sequelae associated with cobalt toxicity. To our knowledge, this case represents the highest documented blood cobalt level (45,840 nmol/L). [ABSTRACT FROM AUTHOR]

Cobalt (Co) and its compounds are widely distributed in nature and are part of numerous anthropogenic activities. Although cobalt has a biologically necessary role as metal constituent of vitamin B 12 , excessive exposure has been shown to induce various adverse health effects. This review provides an extended overview of the possible Co sources and related intake routes, the detection and quantification methods for Co intake and the interpretation thereof, and the reported health effects. The Co sources were allocated to four exposure settings: occupational, environmental, dietary and medical exposure. Oral intake of Co supplements and internal exposure through metal-on-metal (MoM) hip implants deliver the highest systemic Co concentrations. The systemic health effects are characterized by a complex clinical syndrome, mainly including neurological (e.g. hearing and visual impairment), cardiovascular and endocrine deficits. Recently, a biokinetic model has been proposed to characterize the dose-response relationship and effects of chronic exposure. According to the model, health effects are unlikely to occur at blood Co concentrations under 300 μg/l (100 μg/l respecting a safety factor of 3) in healthy individuals, hematological and endocrine dysfunctions are the primary health endpoints, and chronic exposure to acceptable doses is not expected to pose considerable health hazards. However, toxic reactions at lower doses have been described in several cases of malfunctioning MoM hip implants, which may be explained by certain underlying pathologies that increase the individual susceptibility for Co-induced systemic toxicity. This may be associated with a decrease in Co bound to serum proteins and an increase in free ionic Co 2+ . As the latter is believed to be the primary toxic form, monitoring of the free fraction of Co 2+ might be advisable for future risk assessment. Furthermore, future research should focus on longitudinal studies in the clinical setting of MoM hip implant patients to further elucidate the dose-response discrepancies. [ABSTRACT FROM AUTHOR]

The influence of cobalt speciation on the toxicity of cobalt to methylotrophic methanogenesis in anaerobic granular sludge was investigated. The cobalt speciation was studied with three different media that contained varying concentrations of complexing ligands [carbonates, phosphates and ethylenediaminetetraacetic acid (EDTA)]. Three fractions (nominal added, dissolved and free) of cobalt were determined in the liquid media and were correlated with data from batch toxicity experiments. The average concentration of cobalt that was required for 50% inhibition of methanogenic activity (IC50) for free Co2+ in the three sets of measurements was 13 μmol/L with a standard deviation of 22% and a similarity of 72% between the data obtained in the three different media for the range of cobalt concentrations investigated. The standard deviation of the IC50 for the other two fractions was much higher, i.e. 85 and 144% for the added cobalt and dissolved cobalt, respectively, and the similarity was almost 0% for both fractions. Complexation (and precipitation) with EDTA, phosphates and carbonates was shown to decrease the toxicity of cobalt on methylotrophic methanogenesis. The free cobalt concentration is proposed to be the key parameter to correlate with cobalt toxicity. Thus, the toxicity of cobalt to granular sludge can be estimated based on the equilibrium-free cobalt concentration. [ABSTRACT FROM AUTHOR]

Safety concerns regarding cobalt-containing metal alloy hip prosthetics (Co-HP) have resulted in product recalls, a medical device alert, and issuance of guidance for clinicians. Recently, cases of suspected prosthetic hip-associated cobalt toxicity (PHACT) from Co-HP have been reported. Although little is known about suspected PHACT, these patients may be referred to medical toxicologists for evaluation and management recommendations. We searched MEDLINE, EMBASE, and unpublished abstracts from toxicology scientific meetings for references relevant to PHACT. Authors independently screened publications for inclusion criteria: publication in English, human study population, subject(s) are symptomatic (except for isolated hip pain), and cobalt values in any matrix (blood, serum, urine, CSF, synovial fluid) available for review. Data from 10 cases are reviewed. Patients with suspected PHACT had findings consistent with cobalt toxicity, including thyroid, cardiac, and neurologic dysfunction. Signs and symptoms appeared between 3 and 72 months after arthroplasty (median 19 months). Neurologic symptoms were most common. Ancillary testing varied considerably. All patients had elevated cobalt levels in one or more matrices. Enhanced elimination was attempted in 27 % of patients. At this time, the information currently available regarding patients with suspected PHACT is inadequate to guide clinical decision making. No consensus has been reached regarding the management of Co-HP patients with systemic symptoms. Indications for chelation have not been established and require further study. Improved case definitions, improved surveillance, and controlled studies are needed to elucidate the scope of this problem and guide future investigations. [ABSTRACT FROM AUTHOR]

Metal toxicity from metal-on-metal hip replacements is now well documented and several large series have reported local reactions. Although less common, there are reports of similar reactions from failed ceramic liners. Systemic effects documented in literature have been grouped into cardiac, neuro-ocular and thyroid signs.~Introduction~Background~We report a case of a patient who had revision for fractured ceramic liner to metal on polyethylene. Third body effect of the ceramic particles led to wear through of the poly liner and the head directly articulating with metal shell. He developed cardiac and neurological features of cobalt toxicity in addition to extensive soft tissue destruction. Revision of the bearing surfaces and synovectomy led to clinical improvement and fall in metal ion levels.~Methods and Results~Results~We recommend 2-stage revision in such situations and close monitoring of all these patients.~Conclusions~Conclusions [ABSTRACT FROM AUTHOR]

Objectives 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. Methods 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. Results 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. Conclusions 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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

A 39-year-old female with elevated serum cobalt levels from her bilateral hip prostheses presented with a 3-week history of blurred vision in her left eye. Optical coherence tomography revealed patchy degeneration of the photoreceptor-retinal pigment epithelium (RPE) complex. The lesions were hypofluorescent on indocyanine green angiography. We postulate that this is a case of implant-related chorio-retinal cobalt toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Cobalt (Co) is an essential trace element well known as a constituent of vitamin B12, but different compounds of Co are also described as highly toxic and/or radiotoxic for individuals or the environment. In nuclear power plants, 58Co and 60Co 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 (CoCl2) with or without γ-ray doses to mimic contamination by 60Co, 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 γ-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. [Copyright &y& Elsevier]

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). Environ Toxicol Chem 2014;9999:1-10. © 2014 SETAC [ABSTRACT FROM AUTHOR]

Abstract: 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 14dLC (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 K CoBL=5.13, log K CaBL=3.83, log K MgBL=3.95 and log K HBL=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 14d LC50s 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, LC50s (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. [Copyright &y& Elsevier]

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), sulfur (S), and iron (Fe), chlorophyll a and b, DNA and RNA, reducing and non-reducing sugars, starch, total soluble proteins, protein and non-protein nitrogen, and increased phenol and Co concentrations. In excess Co treated tomato leaves, the activity of catalase decreased and peroxidase, ribonuclease, and acid phosphatase increased. The accumulation of Co was greatest in roots and old leaves and lowest in stem of tomato. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Streptococcus suis is a zoonotic pathogen causing serious infections in swine and humans. Although metals are essential for life, excess amounts of metals are toxic to bacteria. Transcriptome-level data of the mechanisms for resistance to metal toxicity in S. suis are available for no metals other than zinc. Herein, we explored the transcriptome-level changes in S. suis in response to ferrous iron and cobalt toxicity by RNA sequencing. Many genes were differentially expressed in the presence of excess ferrous iron and cobalt. Most genes in response to cobalt toxicity showed the same expression trends as those in response to ferrous iron toxicity. qRT-PCR analysis of the selected genes confirmed the accuracy of RNA sequencing results. Bioinformatic analysis of the differentially expressed genes indicated that ferrous iron and cobalt have similar effects on the cellular processes of S. suis. Ferrous iron treatment resulted in down-regulation of several oxidative stress tolerance-related genes and up-regulation of the genes in an amino acid ABC transporter operon. Expression of several genes in the arginine deiminase system was down-regulated after ferrous iron and cobalt treatment. Collectively, our results suggested that S. suis alters the expression of multiple genes to respond to ferrous iron and cobalt toxicity. [ABSTRACT FROM AUTHOR]

Cobalt is an important metal cofactor of many living cells. However, excessive cobalt is toxic and can cause cell death and even several diseases in humans. Saccharomyces cerevisiae is a useful tool for studying metal homeostasis and many of the genes and pathways are highly conserved in higher eukaryotes including humans. The intracellular cobalt and reactive oxygen species (ROS) levels were measured by an atomic absorption spectrometer and DHE staining method, respectively. The expression of genes involved in scavenging oxidative stress was tested by qPCR method, while the expression of UPRE - lac Z report gene was analyzed via β-galactosidase activity assay. Using a genome-scale genetic screen, 153 cobalt-sensitive and 37 cobalt-tolerant gene deletion mutants were identified from Saccharomyces cerevisiae. We showed that 101 of the cobalt-sensitive mutants accumulated higher intracellular cobalt compared to wild-type. The intracellular ROS levels in 112 of the mutants were induced by cobalt, which might be caused by the decreased expression of genes involved in scavenging oxidative stress in response to cobalt. Moreover, more than one-third of the cobalt-sensitive mutants were also sensitive to tunicamycin, and cobalt stress might induce the unfolded protein response (UPR) through serine/threonine kinase and endoribonuclease Ire1. This study reinforced the fact that cobalt toxicity might be due to the high intracellular cobalt and ROS levels, and the endoplasmic reticulum stress responses induced by cobalt. Elucidating the toxicity mechanisms of cobalt stress response will help reveal new routes for the treatment of the diseases induced by cobalt. Suggested model for the toxicity mechanisms of cobalt stress. Cells uptake the extracellular cobalt via the plasma membrane transporters Smf2, Fet4 and Pho84. Once inside the cell, cobalt generates ROS, causing DNA damage and lipid/protein oxidation, thus inducing the ER stress. The oxidative damage caused by cobalt can be alleviated by inducing the genes involved in oxidative stress scavenging. Unlabelled Image • Cobalt-sensitive and -tolerant mutants were both identified • Cobalt generates ROS by inducing genes involved in scavenging oxidative stress • Cobalt induces UPR through Ire1 • Cobalt toxicity was caused by High intracellular cobalt and ROS levels, ER stress [ABSTRACT FROM AUTHOR]

Prosthetic hip-associated cobalt toxicity (PHACT) is gaining recognition due to the use of metal-on-metal total hip replacements. Identifying true toxicity from merely elevated cobalt levels can be extremely difficult due to the lack of available data. An extensive review of the medical literature was undertaken to characterize cobalt toxicity from prosthetic hips. As an objective approach to making the diagnosis of PHACT, we suggest the following criteria: (1) elevated serum or whole blood cobalt levels due to a prosthetic hip, (2) at least two test-confirmed findings consistent with cobalt toxicity, and (3) exclusion of other etiologies. Adhering to objective diagnostic data for PHACT is a realistic and prudent method by which to eliminate the subjectivity of vague or difficult to identify complaints. These diagnostic criteria are not meant to evaluate prosthetic hardware failure, but as a means to identify systemic cobalt toxicity. Finally, assessment of cobalt toxicity from prosthetic hips should be done in conjunction with a medical toxicologist. [ABSTRACT FROM AUTHOR]

Cobalt is a widely used in the industrial production of hard metals. Cobalt ingestion has been reported to cause widespread systemic toxicity, but its effects on vision have been sparsely reported. The authors report the case of a patient who ingested cattle magnets, which remained in his stomach for an unknown duration of time. These magnets largely consist of cobalt that gradually leached into his blood stream, resulting in protean systemic manifestations, which included optic atrophy. [ABSTRACT FROM AUTHOR]

• Growth, water content and osmotic potential decreased under Co stress. • Stress caused a disruption in the photosynthetic capacity in wheat leaves. • Hydrogen peroxide and lipid peroxidation were induced under stress. • SNP/NaHS together with cobalt ameliorated the toxic effect on chloroplast of wheat. • SNP/NaHS maintain of the redox state of ascorbate-glutathione cycle in chloroplast. The role of hydrogen sulfide (H 2 S)/nitric oxide (NO) in mitigating stress-induced damages has gained interest in the past few years. However, the protective mechanism H 2 S and/or NO has towards the chloroplast system through the regulation of redox status and activation of antioxidant capacity in cobalt-treated wheat remain largely unanswered. Triticum aestivum L. cv. Ekiz was treated with alone/in combination of a H 2 S donor (sodium hydrosulfide (NaHS,600μM)), a NO donor (sodium nitroprusside (SNP,100μM)) and a NO scavenger (rutin hydrate (RTN,50μM)) to assess how the donors affect growth, water relations, redox and antioxidant capacity in chloroplasts, under cobalt (Co) concentrations of 150-300 μM. Stress decreased a number of parameters (growth, water content (RWC), osmotic potential (Ψ Π), carbon assimilation rate, stomatal conductance, intercellular CO 2 concentrations, transpiration rate and the transcript levels of rubisco, which subsequently disrupt the photosynthetic capacity). However, SNP/NaHS counteracted the negative effects of stress on these aforementioned parameters and RTN application with stress/non-stress was reversed these effects. Hydrogen peroxide (H 2 O 2) and TBARS were induced under stress in spite of activated ascorbate peroxidase (APX). SNP/NaHS under stress increased activation of superoxide dismutase (SOD), peroxidase (POX), APX, glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), ascorbate (tAsA) and glutathione (GSH). In conclusion, NaHS/SNP are involved in the regulation and modification of growth, water content, rubisco activity and up-regulation of ascorbate-glutathione cycle (AsA-GSH) in chloroplast under stress. [ABSTRACT FROM AUTHOR]

Background: Prosthetic hip-associated cobalt toxicity (PHACT) is an uncommon, but potentially devastating, complication for patients with metal-on-metal hip implants (MoMs). Clinical management of PHACT is poorly defined, with primary intervention being MoM explant followed by chelation therapy. Therapeutic plasma exchange (TPE) in cobalt toxicity has not been previously described. Given that cobalt is predominantly albumin bound, it should theoretically be removed by TPE. Here we report a case of PHACT and our experience using TPE to lower plasma cobalt levels.Case Report: A 61-year-old woman developed deafness, blindness, ambulatory dysfunction, and endocrinopathies after MoM implant. Cobalt levels on admission were greater than 1500 µg/L. In an attempt to rapidly lower cobalt levels before MoM explant, hemodialysis and TPE were performed. Hemodialysis removed negligible amounts of cobalt. One session of TPE temporarily removed approximately two-thirds of measurable cobalt, but levels rebounded to pre-TPE values after 8 hours. It was only after MoM removal that cobalt levels plateaued below 300 µg/L and clinical symptoms improved.Discussion: TPE removed cobalt from a PHACT patient, but a durable decrease in cobalt was only achieved after MoM explant. These findings are comparable to reports where chelation was employed in PHACT patients before MoM explant. The observed rebound phenomenon is likely from rapid equilibration between the immense extravascular tissue source (the MoM) and the intravascular compartment.Conclusion: TPE may serve as adjunctive therapy for PHACT patients whose cobalt levels remain high after explant, especially in patients with renal failure, in whom chelation is contraindicated. [ABSTRACT FROM AUTHOR]

The article presents a case report of an 84-year-old woman with a orthopaedic history who experienced generalized pruritic eczematous rash. She had undergone a metal-on-metal (MoM) right total hip replacement for a fractured femur neck in May 2009. Skin biopsy of the rash revealed urticarial features with no overt histological evidence of a drug eruption. Diagnosis of the patient revealed systemic allergic dermatitis (SAD) caused by cobalt.

Heavy metal stress affects crop growth and yields as wheat (Triticum aestivum L.) growth and development are negatively affected under heavy metal stress. The study examined the effect of cobalt chloride (CoCl2) stress on wheat growth and development. To alleviate this problem, a pot experiment was done to analyze the role of sulfur-rich thiourea (STU) in accelerating the defense system of wheat plants against cobalt toxicity. The experimental treatments were, i) Heavy metal stress (a) control and (b) Cobalt stress (300 µM), ii) STU foliar applications; (a) control and (b) 500 µM single dose was applied after seven days of stress, and iii) Wheat varieties (a) FSD-2008 and (b) Zincol-2016. The results revealed that cobalt stress decreased chlorophyll a by 10%, chlorophyll b by 16%, and carotenoids by 5% while foliar application of STU increased these photosynthetic pigments by 16%, 15%, and 15% respectively under stress conditions as in contrast to control. In addition, cobalt stress enhances hydrogen peroxide production by 11% and malondialdehyde (MDA) by 10%. In comparison, STU applications at 500 µM reduced the production of these reactive oxygen species by 5% and by 20% by up-regulating the activities of antioxidants. Results have revealed that the activities of SOD improved by 29%, POD by 25%, and CAT by 28% under Cobalt stress. Furthermore, the foliar application of STU significantly increased the accumulation of osmoprotectants as TSS was increased by 23% and proline was increased by 24% under cobalt stress. Among wheat varieties, FSD-2008 showed better adaptation under Cobalt stress by showing enhanced photosynthetic pigments and antioxidant activities compared to Zincol-2016. In conclusion, the foliar-applied STU can alleviate the negative impacts of Cobalt stress by improving plant physiological attributes and upregulating the antioxidant defense system in wheat. [ABSTRACT FROM AUTHOR]

Chronic cobalt exposure is characterized by severe cardiac insufficiency. Since the mechanisms of cobalt toxicity are not yet clear, we analysed the effects of chronic cobalt exposure on antioxidant enzyme activities and myocardial mitochondrial ATP production rate in a rat model. One group of rats was fed a conventional diet and another a cobalt supplemented diet for 24 weeks. The manganese-superoxide dismutase activity was markedly reduced in the cobalt rats (18+/-4.7 U/mg protein) compared to the control rats (100+/-22 U/mg protein; p <0.001). Activity in the respiratory chain enzymes succinate-cytochrome c reductase, NADH-cytochrome c reductase and cytochrome c oxidase was also reduced in the cobalt rats (p<0.01). Glutamate dehydrogenase activity, located in the mitochondrial matrix, was unchanged. The mitochondrial ATP production rate in relation to myocardial mass was lower in the cobalt rats for all substrates tested except palmitoyl-l-carnitine + malate. In conclusion, 24 weeks of chronic cobalt exposure induces a marked decrease in manganese-superoxide dismutase activity, a moderate decrease in mitochondrial ATP production rate and a general reduction in the capacity of the respiratory chain. The impairment in mitochondrial ATP production might be secondary to the decreased manganese-superoxide dismutase activity, causing inactivation of mitochondrial factors susceptible to superoxide radicals. [ABSTRACT FROM AUTHOR]

The article discusses the case of a patient with snake eyes sign in the magnetic resonance imaging (MRI) of the cervical spine. Topics discussed include the medical history of the patient, the diagnosis of lower motor neuron (LMN) syndrome of the upper limbs, and cobalt neurotoxicity which resulted from the release of cobalt from the patient's hip prosthesis.

Cobalt-containing alloys are useful for orthopedic applications due to their low volumetric wear rates, corrosion resistance, high mechanical strength, hardness, and fatigue resistance. Unfortunately, these prosthetics release significant levels of cobalt ions, which was only discovered after their widespread implantation into patients requiring hip replacements. These cobalt ions can result in local toxic effects--including peri-implant toxicity, aseptic loosening, and pseudotumor--as well as systemic toxic effects--including neurological, cardiovascular, and endocrine disorders. Failing metal-on-metal (MoM) implants usually necessitate painful, risky, and costly revision surgeries. To treat metallosis arising from failing MoM implants, a synovial fluid-mimicking chelator was designed to remove these metal ions. Hyaluronic acid (HA), the major chemical component of synovial fluid, was functionalized with British anti-Lewisite (BAL) to create a chelator (BAL-HA). BAL-HA effectively binds cobalt and rescues in vitro cell vitality (up to 370% of cells exposed to IC50 levels of cobalt) and enhances the rate of clearance of cobalt in vivo (t1/2 from 48 h to 6 h). A metallosis model was also created to investigate our therapy. Results demonstrate that BAL-HA chelator system is biocompatible and capable of capturing significant amounts of cobalt ions from the hip joint within 30 min, with no risk of kidney failure. This chelation therapy has the potential to mitigate cobalt toxicity from failing MoM implants through noninvasive injections into the joint. [ABSTRACT FROM AUTHOR]

A fifty-two-year-old man underwent heart transplantation at our centre after four years of developing progressive heart failure symptoms due to cobalt toxicity-related cardiomyopathy. Between the ages of forty and forty-two, he underwent bilateral metal-on-metal hip arthroplasties for early onset osteoarthritis. Six years later, he developed increasing fatigue and pericardial effusions. Following a prolonged period of deterioration without a clear cause, the diagnosis of cobalt toxicity-related cardiomyopathy due to cobalt-chromium alloy hip prostheses was eventually made. He underwent bilateral revision hip arthroplasties and was listed for heart transplantation. Metal-on-metal joint replacement is a rare cause of iatrogenic cobalt toxicity. Anaesthetists may encounter patients with unexplained symptoms of heart failure, having a high index of suspicion presenting an opportunity for early diagnosis and intervention before end-stage disease develops. [ABSTRACT FROM AUTHOR]

Heavy metal (e.g. cobalt) pollution causes a serious of environmental and agricultural problems. On the other hand, plant growth-promoting microorganisms enhance plant growth and mitigate heavy metal stress. Herein, we isolated and identified the unclassified species strain NARS9, belong to Haloferax ,. Cobalt (Co, 200 mg/kg soil) stress mitigating impact of the identified on wheat grains yield, primary and secondary metabolism and grain quality was investigated. Co alone significantly induced Co accumulation in wheat grain (260%), and consequently reduced wheat yield (130%) and quality. Haloferax NARS9 alone significantly enhanced grain chemicals composition (i.e., total sugars (89%) and organic acids (e.g., oxalic and isobutyric acids), essential amino acids (e.g., threonine, lysine, and histidine) and unsaturated fatty acids (e.g. eicosenoic, erucic and tetracosenoic acids). Interestingly, Co stress induced wheat grain yield, reduction were significantly mitigated by Haloferax NARS9 treatment by 26% compared to Co stress alone. Under Co stress, Haloferax NARS9 significantly increased sugar metabolism including sucrose and starch levels and their metabolic enzymes (i.e. invertases, sucrose synthase, starch synthase). This in turn increased organic acid (e.g. oxalic (70%) and malic acids (60%)) and amino acids. levels and biosynthetic enzymes, e.g. glutamine synthetase and threonine synthase. Increased sugars levels by Haloferax NARS9 under Co treatment also provided a route for the biosynthesis of saturated fatty acids, particularly palmitic and stearic acids. Furthermore , Haloferax NARS9 treatment supported the wheat nutritive value through increasing minerals (Ca, Fe, Mn, Zn) and antioxidants i.e., polyphenol, flavonoids, ASC and GSH and total polyamines by 50%, 110%, 400%, 30%, and 90% respectively). These in parallel with the increase in the activity of (phenylalanine ammonia-lyase (110%) in phenolic metabolism). Overall, this study demonstrates the potentiality of Haloferax NARS9 in harnessing carbon and nitrogen metabolism differentially in wheat plants to cope with Co toxicity. Our results also suggested that the use of Haloferax NARS9 in agricultural fields can improve growth and nutritional value of wheat grains. [ABSTRACT FROM AUTHOR]

Chemical overexposure is a growing environmental risk factor for many medical issues. Cobalt toxicity from environmental, industrial, and medical exposure has previously been linked to neurological impairment. Hence, the current study looked into the neuroprotective potential of curcumin, a natural polyphenol contained in the spice turmeric, against cobalt-induced neurotoxicity. Adult rats were randomly divided into six groups as follows: control, 40 mg/kg cobalt chloride (CoCl2) only, 240 mg/kg curcumin only, 120 mg/kg or 240 mg/kg curcumin, or 100 mg/kg vitamin C co-administered with CoCl2. The administration was via oral route daily for 4 weeks. After that, neurobehavioral tests were undertaken to evaluate short-term spatial memory. Biochemical investigation was performed to determine the hippocampal levels of status via measures of SOD, CAT, GST, and LPO. Furthermore, immunohistochemical assessment of the expression of GFAP and Nrf2 in the hippocampus was carried out. In the CoCl2 group, the results showed altered behavioral responses, a decrease in antioxidant activities, increased expression of GFAP and the number of activated astrocytes, and decreased immunoexpression of Nrf2. These effects were mitigated in the curcumin- and vitamin C–treated groups. These results collectively imply that curcumin enhances memory functions in rats exposed to cobalt possibly by attenuating oxidative responses, mitigating astrocytosis, and modulating Nrf2 signaling. [ABSTRACT FROM AUTHOR]

Objective(s): Cobalt toxicity has become a health concern in recent years, due to overexposure resulting in neurological impairments. With a growing interest in the therapeutic roles of herbs, in toxicity research, it's worth looking into the curative effects of aqueous Prosopis africana seed extract, a plant rich in flavonoids on cobalt-induced neurotoxicity. Materials and Methods: We treated rats with CoCl2 or CoCl2 in combination with aqueous PA seed extract (PAE) orally for 14 days. Control rats received distilled water for the same period. Following treatments, behavioral experiments, analysis for oxidative stress, inflammation, and histological and immunohistochemical analysis were performed. Results: Results revealed that CoCl2 reduced the exploration time, recognition index in the novel object recognition test, percentage spontaneous alternation in the Y-maze tests, and reduced open arm entry and duration in elevated plus-maze. However, treatment with PAE improved these parameters to levels comparable with those of the control group. Furthermore, PAE therapy reduced CoCl2-induced surge in hydrogen peroxide, malondialdehyde, TNF-a and IL-1ß levels in brain homogenate, while also increasing superoxide dismutase and reduced reduced-glutathione activities. CoCl2 exposure resulted in obvious features of neurodegeneration like nuclear disintegration, nuclear shrinkage, and cytoplasmic vacuolations of the cells of the hippocampus and amygdala, with an increased expression of GFAP. The hippocampal and amygdala histology improved after PAE administration, while exacerbated GFAP expressions were attenuated. Conclusion: These findings imply that PAE may be anxiolytic and can help reduce cognitive impairments and hippocampal damage caused by CoCl2 neurotoxicity, via mechanisms that involve attenuation of oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Introduction: There have been concerns about prosthesis failure and the potential for systemic toxicity due to release of cobalt and chromium from metal-on-metal hip joint prostheses (MoM-HP). There is conflicting evidence on whether there is a correlation between higher cobalt and chromium concentrations and systemic toxicity. Methods: We undertook a retrospective review of consecutive patients with MoM-HP referred for outpatient review in toxicology clinics in London, UK, and in the USA recorded in the Toxicology Investigators Consortium (ToxIC) Registry from June 2011 to June 2015. Results: Thirty-one cases were identified; the median (IQR) serum cobalt concentration was 10.0 (3.8-32.8) mcg/L, and the median (IQR) serum chromium concentration was 6.9 (3.7-18.7) mcg/L. Twenty-three (74.2%) had symptoms, most commonly lethargy, hearing loss, and tinnitus. The odds ratios of symptomatic/asymptomatic patients for metal ion concentrations above/below 7 mcg/L were 1.87 (95% CI 0.37-9.57, p = 0.45) and 0.60 (95% CI 0.10-3.50, p = 0.57) for cobalt and chromium, respectively. Two (6.5%) patients with systemic cobalt toxicity had median (IQR) serum cobalt concentrations significantly higher than those without systemic features (630.4 [397.6-863.2] mcg/L versus 9.8 [2.9-16.4] mcg/L; p = 0.017). However, overall, there were no differences between cobalt ( p = 0.38) or chromium ( p = 0.92) concentrations between symptomatic and asymptomatic patients and no clinical features or investigation results correlated with cobalt or chromium concentration. Conclusion: Two (6.5%) of 31 individuals referred for assessment of MoM-HP were diagnosed with systemic cobalt toxicity. However, despite a high prevalence of reported symptoms, neither symptoms nor investigation results correlated with serum cobalt or chromium concentrations. [ABSTRACT FROM AUTHOR]

Patients suffering from chronic mountain sickness (CMS) have excessive erythrocytosis. Low −level cobalt toxicity as a likely contributor has been demonstrated in some subjects. We performed a randomized, placebo controlled clinical trial in Cerro de Pasco, Peru (4380 m), where 84 participants with a hematocrit (HCT) ≥65% and CMS score > 6, were assigned to four treatment groups of placebo, acetazolamide (ACZ, which stimulates respiration), N -acetylcysteine (NAC, an antioxidant that chelates cobalt) and combination of ACZ and NAC for 6 weeks. The primary outcome was change in hematocrit and secondary outcomes were changes in PaO 2 , PaCO 2 , CMS score, and serum and urine cobalt concentrations. The mean (±SD) hematocrit, CMS score and serum cobalt concentrations were 69 ± 4%, 9.8 ± 2.4 and 0.24 ± 0.15 μg/l, respectively for the 66 participants. The ACZ arm had a relative reduction in HCT of 6.6% vs. 2.7% (p = 0.048) and the CMS score fell by 34.9% vs. 14.8% (p = 0.014) compared to placebo, while the reduction in PaCO 2 was 10.5% vs. an increase of 0.6% (p = 0.003), with a relative increase in PaO 2 of 13.6% vs. 3.0%. NAC reduced CMS score compared to placebo (relative reduction of 34.0% vs. 14.8%, p = 0.017), while changes in other parameters failed to reach statistical significance. The combination of ACZ and NAC was no better than ACZ alone. No changes in serum and urine cobalt concentrations were seen within any treatment arms. ACZ reduced polycythemia and CMS score, while NAC improved CMS score without significantly lowering hematocrit. Only a small proportion of subjects had cobalt toxicity, which may relate to the closing of contaminated water sources and several other environmental protection measures. [ABSTRACT FROM AUTHOR]

Abstract: High-resolution 1H NMR spectroscopy demonstrated that addition of Co(II) ions to isolated human salivary supernatants (HSSs) gave rise to its complexation by a variety of biomolecules. The relative efficacies of these complexants/chelators in this context were classifiable by the influence of added Co(II) on their line-widths and chemical shift values, and also the added Co(II) concentration-dependence of these spectral modifications. Those which were most affected by the addition of this metal ion were lactate > formate ≈histidinate > succinate, this order reflecting the ability of these complexants to compete for the available Co(II) in terms of (1) thermodynamic equilibrium constants for the formation of their complexes and (2) their HSS concentrations. Since many of these HSS Co(II) complexants (particularly lactate, formate and histidine) serve as powerful OH scavengers, the results acquired indicate that any of this radical generated from the Co(II) source in such complexes via pseudo-Fenton reactions may be ‘site-specifically’ scavenged. The significance of these observations regarding the in vivo corrosion of cobalt-containing metal alloy dental prostheses (e.g., Co–Cr alloys), the availability of trace levels of this metal ion in human saliva, and cobalt toxicity, is discussed. [Copyright &y& Elsevier]

Purpose: Imaging studies of cobalt toxicity from cobalt-chromium alloy arthroprosthetics have focused on the local intra-articular and peri-articular presentation from failing joint replacements. Most studies investigating neurological findings have been small case series focused on the clinical findings of memory loss, diminished executive function, tremor, hearing and vision loss, depression, and emotional lability. This study utilizes software-based quantitative analysis of brain metabolism to assess the degree of hypometabolism and areas of susceptibility, determine if a pattern of involvement exists, and measure reversibility of findings after prosthetic revision to cobalt-free appliances. Methods: Over 48 months, 247 consecutive patients presenting to an orthopedic clinic with an arthroprosthetic joint containing any cobalt-chromium part were screened with whole blood and urine cobalt levels. A clinically validated inventory of 10 symptoms was obtained. Symptomatic patients with a blood cobalt level above 0.4 mcg/L or urine cobalt greater than 1 mcg/L underwent F-18 FDG PET brain imaging. Analysis was performed with FDA-approved quantitative brain analysis software with the pons as the reference region. Control group was the normal brain atlas within the software. Results: Of the 247 consecutively screened patients, 123 had blood and urine cobalt levels above the threshold. The 69 scanned patients had statistically significant regional hypometabolism and higher symptoms inventory. Fifty-seven patients were retained in the study. Distribution of hypometabolism was in descending order: temporal, frontal, Broca's areas, anterior cingulate, parietal, posterior cingulate, visual, sensorimotor, thalamic, and lastly caudate. Metal-on-metal (MoM) and metal-on-plastic (MoP) joint replacements produced similar patterns of hypometabolism. Of 15 patients with necessary revision surgery, 8 demonstrated improved metabolism when later re-scanned. Conclusion: All scanned patients had regions of significant hypometabolism. Neurological toxicity from elevated systemic cobalt levels following arthroprosthetic joint replacement has a pattern of regional susceptibility similar to heavy metals and solvents, differing from classical dementias and may occur at blood and urine cobalt levels as low as 0.4 mcg/L and 1 mcg/L, respectively. Presently accepted thresholds for cobalt exposure and monitoring may need revision. Quantitative F-18 FDG PET brain imaging may aid in the decision process for treatment options and timing of possible medical versus surgical intervention. [ABSTRACT FROM AUTHOR]

Introduction. One in eight of all total hip replacements requires revision within 10 years, 60% because of wear-related complications. The bearing surfaces may be made of cobalt/chromium, stainless steel, ceramic, or polyethylene. Friction between bearing surfaces and corrosion of non-moving parts can result in increased local and systemic metal concentrations. Objectives. To identify and systematically review published reports of systemic toxicity attributed to metal released from hip implants and to propose criteria for the assessment of these patients. Methods. Medline (from 1950) and Embase (from 1980) were searched to 28 February 2014 using the search terms (text/abstract) chrom* or cobalt* and [toxic* or intox* or poison* or adverse effect or complication] and [prosthes* or 'joint replacement' or hip or arthroplast*] and PubMed (all available years) was searched using the search term (('Chromium/adverse effects'[Mesh] OR 'Chromium/poisoning'[Mesh] OR 'Chromium/toxicity'[Mesh]) OR ('Cobalt/adverse effects'[Mesh] OR 'Cobalt/poisoning'[Mesh] OR 'Cobalt/toxicity'[Mesh])) AND ('Arthroplasty, Replacement, Hip'[Mesh] OR 'Hip Prosthesis'[Mesh]). These searches identified 281 unique references, of which 23 contained original case data. Three further reports were identified from the bibliographies of these papers. As some cases were reported repeatedly the 26 papers described only 18 individual cases. Systemic toxicity. Ten of these eighteen patients had undergone revision from a ceramic-containing bearing to one containing a metal component. The other eight had metal-on-metal prostheses. Systemic toxicity was first manifest months and often several years after placement of the metal-containing joint. The reported systemic features fell into three main categories: neuro-ocular toxicity (14 patients), cardiotoxicity (11 patients) and thyroid toxicity (9 patients). Neurotoxicity was manifest as peripheral neuropathy (8 cases), sensorineural hearing loss (7) and cognitive decline (5); ocular toxicity presented as visual impairment (6). All these neurological features, except cognitive decline, have been associated with cobalt poisoning previously. Type of prosthesis and blood metal concentrations. Where blood or serum metal concentrations were reported ( n = 17 for cobalt and n = 14 for chromium), the median cobalt concentration was 398 (range, 13.6-6521) μg/L and the median chromium concentration was 48 μg/L (in whole blood) (range, 4.1-221 μg/L including serum and blood values). Those patients reported to have systemic features who had received a metal-on-metal prosthesis ( n = 8) had a median peak blood cobalt concentration of 34.5 (range, 13.6-398.6) μg/L; those with a metal-containing revision of a failed ceramic prosthesis ( n = 10) had a median blood cobalt concentration of 506 (range, 353-6521) μg/L. Management. The most common treatment was removal of the metal-containing prosthesis, undertaken in all but 2 patients. This was usually associated with a fall in circulating cobalt concentration and improvement in some or all features. Clinical and toxicological assessment of systemic features. We propose the following criteria for assessing the likelihood that clinical features are related to cobalt toxicity: clinical effects consistent with the known neurological, cardiac, or thyroidal effects of cobalt, and for which any other explanation is less likely; increased blood cobalt concentrations (substantially higher than those in patients with well-functioning prostheses) several months after hip replacement; a fall in the blood cobalt concentration, usually accompanied by signs of improvement in features. When judged by these criteria, the systemic features in 10 of the reported cases are likely to be related to cobalt exposure from a metal-containing hip prosthesis. Conclusions. Rarely, patients exposed to high circulating concentrations of cobalt from failed hip replacements develop neurological damage, hypothyroidism and/or cardiomyopathy, which may not resolve completely even after removal of the prosthesis. The greatest risk of systemic cobalt toxicity seems to result from accelerated wear of a cobalt-containing revision of a failed ceramic prosthesis, rather than from primary failure of a metal-on-metal prosthesis. [ABSTRACT FROM AUTHOR]

In 1966, the "beer drinker's cardiomyopathy" was described in Quebec City, Canada among heavy drinkers following the addition of cobalt by breweries for foam stabilisation. Almost half of those affected died. A similar process has been proposed for cardiovascular periprosthetic metallosis in patients receiving cobalt-containing hip prostheses. This case describes a young man with congenital osteonecrosis treated with cobalt containing prosthetic arthroplasty. Postoperatively, he developed pericardial effusion, dilated cardiomyopathy, polycythemia and lactic acidosis. His serum cobalt level was 156 mcg/L (normal 0.1 - 0.4 mcg/L). Metal-on-metal hip implants have been associated with arthroprosthetic cobaltisim, a presentation indistinguishable from "beer drinker's cardiomyopathy." Up to 35% of hip replacements utilize metal-on-metal bearing surfaces, making this a potentially wide-spread and relatively underappreciated etiology of postoperative idiopathic cardiomyopathy. This clinical vignette emphasizes the importance of considering cobalt cardio-toxicity, or "beer drinker's cardiomyopathy," as a differential diagnosis of idiopathic cardiomyopathy following total hip arthroplasty. [ABSTRACT FROM AUTHOR]

Background: Tungsten carbide (WC) and tungsten carbide cobalt (WC-Co) nanoparticles are of occupational health relevance because of the increasing usage in hard metal industries. Earlier studies showed an enhanced toxic potential for WC-Co compared to WC or cobalt ions alone. Therefore, we investigated the impact of these particles, compared to cobalt ions applied as CoCl2, on the global gene expression level in human keratinocytes (HaCaT) in vitro. Results: WC nanoparticles exerted very little effects on the transcriptomic level after 3 hours and 3 days of exposure. In contrast, WC-Co nanoparticles caused significant transcriptional changes that were similar to those provoked by CoCl2. However, CoCl2 exerted even more pronounced changes in the transcription patterns. Gene set enrichment analyses revealed that the differentially expressed genes were related to hypoxia response, carbohydrate metabolism, endocrine pathways, and targets of several transcription factors. The role of the transcription factor HIF1 (hypoxia inducible factor 1) is particularly highlighted and aspects of downstream events as well as the role of other transcription factors related to cobalt toxicity are considered. Conclusions: This study provides extensive data useful for the understanding of nanoparticle and cobalt toxicity. It shows that WC nanoparticles caused low transcriptional responses while WC-Co nanoparticles are able to exert responses similar to that of free cobalt ions, particularly the induction of hypoxia-like effects via interactions with HIF1α in human keratinocytes. However, the enhanced toxicity of WC-Co particles compared to CoCl2 could not be explained by differences in gene transcription. [ABSTRACT FROM AUTHOR]

Cobalt-containing hip prosthesis may cause systemic toxicity due to the release of cobalt from metal-on-metal (MoM) joint arthroplasty into the bloodstream. High cobalt blood levels can lead to a variety of clinical manifestations, mimicking other disorders, especially autoimmune, hematologic, and infectious diseases. Our purpose is to describe a clinical case of cobalt hip prosthesis intoxication mimicking an autoimmune disease, with systemic inflammation signs, arthro-myalgias unrelated to overt synovitis, and multiple autoantibody positivity. A 69-years-old woman presented with a 1-year history of right coxalgia, recurrent fever, arthro-myalgias, mediastinal and right iliac reactive lymphadenopathy. She underwent hip replacement surgery seven years earlier. The physical examination was unremarkable except for right hip pain. Laboratory tests showed markedly increased inflammatory indices and microbiological tests were all negative. Ultrasound-guided arthrocentesis of right hip yielded limpid fluid with negative cultures. Increased cobalt levels in plasma and urine showed metal intoxication. Magnetic resonance imaging with metal artifact reduction sequence (MARS) confirmed a periprosthetic mass as usually seen in reaction to metal debris. Prosthesis substitution was performed with a resolution of the clinical picture and normalization of cobalt levels. [ABSTRACT FROM AUTHOR]

High levels of circulating cobalt ions in blood have been reported to induce systemic reactions in patients with metal-on-metal (MoM) hip implants. We still lack information regarding these adverse effects, which may specifically impact on patients showing adverse neurological symptoms. To investigate this, we used a battery of in vitro viability and proliferation assays to identify toxic cobalt chloride (CoCl 2) concentrations in two different brain cell types: SH-SY5Y neuroblastoma and U-373 astrocytoma cells. Cobalt cytotoxicity was characterised by MTT and Neutral Red (NR) assays at concentrations ranging from 0 to 500 μM after 24, 48, and 72 h exposure. MTT and NR showed a dose- and time-dependent toxicity with cobalt decreasing cell viability at high concentrations. IC50s for MTT at 72 h (astrocytes: 333.15 ± 22.88; neurons: 100.01 ± 5.91 μM) and for BrdU proliferation assays (astrocytes: 212.89 ± 9.84; neurons: 88.86 ± 19.03 μM) demonstrate that SH-SY5Y neurons are significantly more vulnerable to cobalt than astrocytes. Increased BrdU and MTT assay sensitivity suggested that DNA synthesis and metabolism disruption were involved in Co toxicity. Intracellular cobalt level measured by ICP-MS was significant after 100 μM treatment. Astrocytes displayed improved resistance to cobalt toxicity and higher uptake, which may reflect their neuroprotective nature. In summary, exposure to high concentrations of extracellular cobalt has deleterious effects in neurons and astrocytes, with neurons showing particular sensitivity. • We investigated the effects of cobalt on viability and uptake in CNS cell lines. • MTT and NR assays show that cobalt ions are toxic at high concentrations in vitro. • MTT and BrdU sensitivity suggests that Co jeopardises metabolism and DNA synthesis. • Cobalt metal uptake is dose-dependent in neuroblastoma and astrocytoma cells. • Astrocytoma exhibit greater resistance to cobalt toxicity despite a higher uptake. [ABSTRACT FROM AUTHOR]

Although cobalt is a required nutrient, it is toxic due to its ability to generate reactive oxygen species (ROS) and damage DNA. ROS generation by Co2+ often has been compared to that of Fe2+ or Cu+, disregarding the reduction potential differences among these metal ions. In plasmid DNA damage studies, a maximum of 15% DNA damage is observed with Co2+/H 2 O 2 treatment (up to 50 μM and 400 μM, respectively) significantly lower than the 90% damage observed for Fe2+/H 2 O 2 or Cu+/H 2 O 2 treatment. However, when ascorbate is added to the Co2+/H 2 O 2 system, a synergistic effect results in 90% DNA damage. DNA damage by Fe2+/H 2 O 2 can be prevented by polyphenol antioxidants, but polyphenols both prevent and promote DNA damage by Cu+/H 2 O 2. When tested for cobalt-mediated DNA damage affects, eight of ten polyphenols (epicatechin gallate, epigallocatechin gallate, propyl gallate, gallic acid, methyl-3,4,5-trihydroxybenzoate, methyl-4,5-dihydroxybenzoate, protocatechuic acid, and epicatechin) prevent cobalt-mediated DNA damage with IC 50 values of 1.3 to 27 μM and two (epigallocatechin and vanillic acid) prevent little to no DNA damage. EPR studies demonstrate cobalt-mediated formation of •OH, O 2 •ˉ, and •OOH, but not 1O 2 in the presence of H 2 O 2 and ascorbate. Epigallocatechin gallate and methyl-4,5-dihydroxybenzoate significantly reduce ROS generated by Co2+/H 2 O 2 /ascorbate, consistent with their prevention of cobalt-mediated DNA damage. Thus, while cobalt, iron, and copper are all d -block metal ions, cobalt ROS generation and its prevention is significantly different from that of iron and copper. In contrast to Fe(II), Co(II) does not damage DNA in the presence of hydrogen peroxide alone. Instead, it generates reactive oxygen species (ROS) and damages DNA in the presence of both hydrogen peroxide and ascorbate. Some polyphenols can bind Co(II) and scavenge these ROS to prevent cobalt-mediated DNA damage. [Display omitted] • Unlike Fe(II), Co(II) does not damage DNA in the presence of only hydrogen peroxide. • With H 2 O 2 and ascorbate, Co(II) generates hydroxyl and ascorbyl radicals to damage DNA. • Some polyphenols prevent Co-mediated DNA damage and compete with ascorbate to bind Co(II). • Antioxidant-metal binding may be one way to prevent cobalt toxicity. [ABSTRACT FROM AUTHOR]

The effect of two concentrations of cobalt (Co 2+ ) on photosynthetic activity and antioxidative response in Lemna minor L. were assessed 24, 48 and 72 h after the start of the exposure. Higher concentration of cobalt (1 mM) induced growth inhibition while lower concentration (0.01 mM) 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 Q A − 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. [ABSTRACT FROM AUTHOR]

Recent, unexpected high failure rates of metal-on-metal hip implants have reintroduced the issue of cobalt toxicity. An adverse reaction to cobalt ions and cobalt-induced lung injury occurs during environmental exposure and is now strictly controlled. Currently adverse reaction occurs to cobalt nanoparticles during wear and tear of metal-on-metal hip implants of which the underlying mechanism is not fully understood. The putative role of the hypoxia-inducible factor (HIF) pathway in the mechanism of cobalt nanoparticle (Co-NPs) toxicity was examined using the U937 cell line, human alveolar macrophages and monocyte-derived macrophages. Co-NPs (5–20 μg/ml)-induced cytotoxicity (viability ranged from 75% to <20% of control, respectively) and reactive oxygen species (ROS), whereas a comparable concentration of cobalt ions (Co(II); up to 350 μM) did not. Co-NPs induced HIF-1α stabilization. Addition of ascorbic acid (100 µM) and glutathione (1 mM) both prevented the increased ROS. However, only treatment with ascorbic acid reduced HIF-1α levels and prevented cell death, indicating that a ROS-independent pathway is involved in Co-NPs-induced cytotoxicity. Replenishing intracellular ascorbate, which is crucial in preventing HIF pathway activation, modified Co-induced HIF target gene expression and the inflammatory response, by decreasing interleukin-1 beta (IL-1β) mRNA and protein expression. Addition of glutathione had no effect on Co-NPs-induced HIF target gene expression or inflammatory response. Thus, Co-NPs induce the HIF pathway by depleting intracellular ascorbate, leading to HIF stabilization and pathway activation. This suggests a strong, ROS-independent role for HIF activation in Co-NPs-induced cytotoxicity and a possible role for HIF in metal-on-metal hip implant pathology. [ABSTRACT FROM PUBLISHER]