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Nanoparticle-based magnetic hyperthermia is a well-known thermal therapy platform studied to treat solid tumors, but its use for monotherapy is limited due to incomplete tumor eradication at hyperthermia temperature (45 °C). It is often combined with chemotherapy for obtaining a more effective therapeutic outcome. Cubic-shaped cobalt ferrite nanoparticles (Co-Fe NCs) serve as magnetic hyperthermia agents and as a cytotoxic agent due to the known cobalt ion toxicity, allowing the achievement of both heat and cytotoxic effects from a single platform. In addition to this advantage, Co-Fe NCs have the unique ability to form growing chains under an alternating magnetic field (AMF). This unique chain formation, along with the mild hyperthermia and intrinsic cobalt toxicity, leads to complete tumor regression and improved overall survival in an in vivo murine xenograft model, all under clinically approved AMF conditions. Numerical calculations identify magnetic anisotropy as the main Co-Fe NCs' feature to generate such chain formations. This novel combination therapy can improve the effects of magnetic hyperthermia, inaugurating investigation of mechanical behaviors of nanoparticles under AMF, as a new avenue for cancer therapy., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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-lacZ report gene was analyzed via β-galactosidase activity assay., Results: 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., Conclusions: 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., General Significance: Elucidating the toxicity mechanisms of cobalt stress response will help reveal new routes for the treatment of the diseases induced by cobalt., (Copyright © 2020. Published by Elsevier B.V.)

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.

Cobalt (Co) commonly co-exists with copper (Cu) in natural soils, but the information about their combined effects on plants is poorly available. In this study, we hydroponically investigated the combined effects of Co and Cu on two barley genotypes differing in Co toxicity tolerance to reveal the interaction pattern of these two metals. The results showed that single treatment of Co or Cu at the dose of 100 μM led to a significant decrease of growth and photosynthetic rate, and a significant increase of lipid peroxidation, ROS radicals as well as anti-oxidative enzyme (SOD, CAT and GR) activities and glutathione content, with the extent of effect being less in Yan66 than Ea52. The combined treatment of Co and Cu alleviated the toxicity of both metals in comparison with each metal treatment alone, as reflected by improved growth and photosynthesis, and much slight oxidative stress. The alleviation of metal toxicity upon combined treatment is mainly attributed to a drastic reduction of Co uptake and its translocation from roots to shoots. It may be suggested that interaction of Co and Cu on their uptake and movement in plants is antagonistic., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: This study was designed to determine whether systemic cobalt toxicity as an adverse event could be documented using the Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for cobalt-chromium containing hip implant recipients. Class 3 Johnson & Johnson (J&J)/DePuy devices were chosen for analysis because of the large number of adverse event reports related to their Pinnacle and ASR XL Acetabular hip replacement systems. A secondary goal was to characterize the reporters who are populating the information in the MAUDE database and to evaluate the quality of the data and information submitted., Methods: Using FDA MAUDE downloadable data files, 83,528 adverse event medical device narrative reports were identified with the product code of KWA (Prosthesis, Hip, Semiconstrained [Metal Uncemented Acetabular Component]) for J&J/DePuy (KWA Text File). These are class 3 devices and devices with known high failure rates. The ASR XL Acetabular hip replacement Systems and Pinnacle fall into this category. This group of implants was chosen because implant failure is associated with elevated cobalt levels. Two additional subfiles were created from Free Text records in the narrative reports containing key words that indicated a chromium or cobalt (CrCo) device and another for key words indicating elevated levels of cobalt or toxicity. These files were then searched for symptoms of systemic cobalt toxicity with Microsoft Excel using key words pertaining to symptom categories of: cognitive/memory loss, tremor, neuropathy, depression, auditory symptoms, visual symptoms, cardiac, and thyroid disease. Reports are submitted to the FDA at the device component level. It was common for multiple reports to be submitted for a single device., Results: It was not possible to differentiate systemic versus local symptoms for adverse event reports in the neuropathy category. This category was not analyzed. The number of adverse event reports in the other categories ranged from 119 to 16 for the J&J/DePuy KWA Text File and 59 to 4 in the file of records having key words indicating potential elevation of CrCo or toxicity. Cardiac, visual, and auditory conditions were most frequently reported. With the possible exception of cardiomyopathy, the numbers of these reports are far below the prevalence expected in the general population of comparable age. The content of the MAUDE database records often contained little objective data. We found less than 4% of 14,714 records, which indicated cobalt elevation or toxicity contained units for quantitative measurement. There was also frequent use of nondescript, all-encompassing words and phrases such as "mental anguish," found in 321 KWA Text File records. Manufacturers submitted more than 99% of the reports and the most common reporter occupation was attorney, found in 42.24% of the 83,550 J&J/DePuy KWA Reporter File records. Physician was the reporter's occupation in 20.48% of reports but seldom reported directly to the FDA., Conclusions: We were not able find in the FDA MAUDE database meaningful warning signs to support the contention that chromium-cobalt-containing Class 3 J&J and DePuy hip implants caused systemic neurological or thyroid symptoms in patients. The incidence of reported cardiomyopathy was rare but frequent enough to be cause of concern. The redaction of most patient data along with the nonstructured nature of data entry would be expected to hinder the identification of warning signs. Even identification of the type of device could not be consistently carried out. In addition, the FDA needs to implement a methodology to identify and group all reports from a single device implanted into a patient, so duplication of event counting would not occur. Of 83,550 J&J/DePuy KWA Reporter File records, we found only two physician reports sent directly to the FDA. Almost all reports are submitted by manufacturers and are most commonly authored by attorneys. A standard of care needs to be set for physicians to report medical device adverse events to the FDA.

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 300μg/l (100μg/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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cobalt (Co) contamination in soils is becoming a severe issue in environment safety and crop production. Calcium (Ca) , as a macro-nutrient element, shows the antagonism with many divalent heavy metals and the capacity of alleviating oxidative stress in plants. In this study, the protective role of Ca in alleviating Co stress was hydroponically investigated using two barley genotypes differing in Co toxicity tolerance. Barley seedlings exposed to 100µM Co showed the significant reduction in growth and photosynthetic rate, and the dramatic increase in the contents of reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH) and oxidized glutathione (GSSG), and the activities of anti-oxidative enzymes, with Ea52 (Co-sensitive) being much more affected than Yan66 (Co-tolerant). Addition of Ca in growth medium alleviated Co toxicity by reducing Co uptake and enhancing the antioxidant capacity. The effect of Ca in alleviating Co toxicity was much greater in Yan66 than in Ea52. The results indicate that the alleviation of Co toxicity in barley plants by Ca is attributed to the reduced Co uptake and enhanced antioxidant capacity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Symptomatic cobalt toxicity from a failed total hip replacement is a rare, but devastating complication. Potential clinical findings include cardiomyopathy, hypothyroidism, skin rash, visual and hearing impairment, polycythaemia, weakness, fatigue, cognitive impairment, and neuropathy. The case is presented of a 74year-old man in whom, after a ceramic-ceramic replacement and two episodes of prosthetic dislocation, it was decided to replace it with a polyethylene-metal total hip arthroplasty (THA). At 6months after the revision he developed symptoms of cobalt toxicity, confirmed by analytical determination (serum cobalt level=651.2μg/L). After removal of the prosthesis, the levels of chromium and cobalt in blood and urine returned to normal, with the patient currently being asymptomatic. It is recommended to use a new ceramic on ceramic bearing at revision, in order to minimise the risk of wear-related cobalt toxicity following breakage of ceramic components., (Copyright © 2016 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

One of the most pressing environmental issues is how to properly dispose of municipal solid waste (MSW), which represents both a substantial source of concern and a challenge. The current study evaluated cobalt (Co) accumulation in MSW, their uptake by different vegetables grown for two years, and related human health risks. Vegetables were grown in four different groups, such as one control (ground soil), and the remaining treatment groups (T1, T2, and T3) received varying concentrations of MSW. The analysis of Co was done through an atomic absorption spectrophotometer (AAS). Results revealed that the concentration of Co was higher in all the vegetables (n = 15) grown in soil supplemented with 75% MSW during 2nd growing year. Among all vegetables, the highest concentration of Co was observed in Solanum tuberosum at T3 during 2nd growing year. The pollution load index (PLI) value for vegetables during both growing years was more than 1 except in control soil. The findings indicated that the highest enrichment factor (EF) and hazard resilience index (HRI) value of 0.09 was present in S. tuberosum. Health index values for cobalt in the study were below 1. The HRI < 1 indicated that consumers do not face any immediate health risks. The investigation of Co concentrations in blood samples obtained from individuals residing in different areas contributes a human health perspective to the research. The findings indicate that the concentration of Co rises with an increasing proportion of MSW. While the metal levels in MSW-treated soil were not high enough to classify the soil as polluted, the results recommend that recycling MSW can substitute mineral fertilizers. Nevertheless, the presence of cobalt in MSW may directly affect soil fertility and could impact crop production and human health., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

There is increasing evidence that the imbalance of metals as cobalt (Co) and chromium (Cr) may increase the risk of development and progression of neurodegenerative diseases (NDDs). The human exposure to Co and Cr is derived mostly from industry, orthopedic implants, and polluted environments. Neurological effects of Co and Cr include memory deficit, olfactory dysfunction, spatial disorientation, motor neuron disease, and brain cancer. Mechanisms of Co and Cr neurotoxicity included DNA damage and genomic instability, epigenetic changes, mitochondrial disturbance, lipid peroxidation, oxidative stress, inflammation, and apoptosis. This paper seeks to overview the Co and Cr sources, the mechanisms by which these metals induce NDDs, and their levels in fluids of the general population and patients affected by NDDs. To this end, evidence of Co and Cr unbalance in the human body, mechanistic data, and neurological symptoms were collected using in vivo mammalian studies and human samples., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

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., (© 2016 AABB.)

Introduction: 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., Methods and Results: 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., Conclusions: We recommend 2-stage revision in such situations and close monitoring of all these patients.

Unlabelled: As adverse events related to metal on metal hip arthroplasty have been better understood, there has been increased interest in toxicity related to the high circulating levels of cobalt ions. However, distinguishing true toxicity from benign elevations in cobalt levels can be challenging. The purpose of this review is to examine the use of cobalt alloys in total hip arthroplasty, to review the methods of measuring circulating cobalt levels, to define a level of cobalt which is considered pathological and to review the pathophysiology, risk factors and treatment of cobalt toxicity. To the best of our knowledge, there are 18 published cases where cobalt metal ion toxicity has been attributed to the use of cobalt-chromium alloys in hip arthroplasty. Of these cases, the great majority reported systemic toxic reactions at serum cobalt levels more than 100 μg/L. This review highlights some of the clinical features of cobalt toxicity, with the goal that early awareness may decrease the risk factors for the development of cobalt toxicity and/or reduce its severity., Take Home Message: Severe adverse events can arise from the release of cobalt from metal-on-metal arthroplasties, and as such, orthopaedic surgeons should not only be aware of the presenting problems, but also have the knowledge to treat appropriately., (©2016 The British Editorial Society of Bone & Joint Surgery.)

Unlabelled: Recently, the use of metal-on-metal articulations in total hip arthroplasty (THA) has led to an increase in adverse events owing to local soft-tissue reactions from metal ions and wear debris. While the majority of these implants perform well, it has been increasingly recognised that a small proportion of patients may develop complications secondary to systemic cobalt toxicity when these implants fail. However, distinguishing true toxicity from benign elevations in cobalt ion levels can be challenging. The purpose of this two part series is to review the use of cobalt alloys in THA and to highlight the following related topics of interest: mechanisms of cobalt ion release and their measurement, definitions of pathological cobalt ion levels, and the pathophysiology, risk factors and treatment of cobalt toxicity. Historically, these metal-on-metal arthroplasties are composed of a chromium-cobalt articulation. The release of cobalt is due to the mechanical and oxidative stresses placed on the prosthetic joint. It exerts its pathological effects through direct cellular toxicity. This manuscript will highlight the pathophysiology of cobalt toxicity in patients with metal-on-metal hip arthroplasties., Take Home Message: Patients with new or evolving hip symptoms with a prior history of THA warrant orthopaedic surgical evaluation. Increased awareness of the range of systemic symptoms associated with cobalt toxicity, coupled with prompt orthopaedic intervention, may forestall the development of further complications., (©2016 The British Editorial Society of Bone & Joint Surgery.)

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., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

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)., (© 2014 SETAC.)

Production of metal debris from implant wear and corrosion processes is now a well understood occurrence following hip arthroplasty. Evidence has shown that metal ions can enter the bloodstream and travel to distant organs including the brain, and in extreme cases, can induce sensorial and neurological diseases. Our objective was tosimultaneously analyze brain anatomy and physiology in patients with long-term and well-functioning implants. Included were subjects who had received total hip or hip resurfacing arthroplastywith an implantation time of a minimum of 7 years (n = 28) and age- and sex-matched controls (n = 32). Blood samples were obtained to measure ion concentrations of cobalt and chromium, and the Montreal Cognitive Assessment was performed. 3T MRI brain scans were completed with an MPRAGE sequence for ROI segmentation and multiecho gradient echo sequences to generate QSM and R2* maps. Mean QSM and R2* values were recorded for five deep brain and four middle and cortical brain structures on both hemispheres: pallidum, putamen, caudate, amygdala, hippocampus, anterior cingulate, inferior temporal, and cerebellum. No differences in QSM or R2* or cognition scores were found between both groups (p > 0.6654). No correlation was found between susceptibility and blood ion levels for cobalt or chromium in any region of the brain. No correlation was found between blood ion levels and cognition scores. Clinical significance: Results suggest that metal ions released by long-term and well-functioning implants do not affect brain integrity., (© 2024 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

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 © 2014 Elsevier B.V. All rights reserved.)

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.

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.

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.

We report two Australian patients with possible cobalt toxicity related to metal-on-metal total hip replacements. Both patients were treated for osteoarthritis with a DePuy ASR (articular surface replacement) XL Acetabular Hip System prosthesis, which contains cobalt and chromium, and which has recently been recalled from the market.

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 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 micromol/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.

Background: 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., Methods: 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., Results: 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, P < 0.001) and the myocardium (16.90 +/- 6.40 vs 0.14 +/- 0.01 mu mol mu g-1 in the control group, P < 0.001). After hydroxocobalamin administration, cobalt concentrations were significantly lower in the diaphragm (25.10 +/- 16.50 mu mol mu g-1, P < 0.001 vs cobalt-treated group) and the myocardium (4.50 +/- 1.20 mu mol mu g, P < 0.001 vs cobalt-treated group)., Conclusion: 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.

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 microM nickel to the growth medium could restore the hydrogenase activity. This restoration resulted in the recovery of anaerobic growth. A further increase of nickel concentration inhibited growth. Thus nickel shows an antagonistic effect on the anaerobic growth of E. coli. To study the mechanism 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.

The present investigation was undertaken to evaluate the toxic effects of CoCl 2 -induced hepatotoxicity and fatty acid changes in juvenile Cyprinus carpio. Fish were divided into six experimental groups in duplicate. The first group served as controls. The second group received the lowest exposure dose at 2.5 µg/L. In the third group, fish were exposed to 25 µg/L of CoCl 2 . The fourth group was exposed to 50 µg/L of CoCl 2 . The last two groups were exposed to the highest doses, 100 and 500 µg/L of CoCl 2 . Total antioxidant activities were estimated using a colorimetric method. Liver fatty acid compositions were analyzed by high-performance gas chromatography (GC). Hepatopathy was identified through microscopic analysis. Exposure of C. carpio to CoCl 2 resulted in hepatotoxicity, indicated by increased levels of malondialdehyde (MDA), hydrogen peroxide (H 2 O 2 ), protein carbonyls (PCO), and alterations in the ferric reducing antioxidant power system (FRAP). Superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GPx), reduced glutathione (GSH), metallothioneins (MTs), and low thiol levels (L-SH) significantly increased, particularly under exposure to the highest CoCl 2 doses (100 and 500 µg/L). Acetylcholinesterase activity decreased significantly in C. carpio exposed to graded CoCl 2 doses. Additionally, there was a decrease in polyunsaturated fatty acids (PUFA), primarily n-3 PUFA, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), while an increase in monounsaturated (MUFA) and saturated fatty acids (SFA), including palmitic (C16:0), stearic (C18:0), palmitoleic (C16:1), and oleic (C18:1) acids, was observed. Histopathological examination of the liver confirmed hepatopathy revealing characteristic tissue changes such as leucocyte infiltration, hepatic cell membrane degradation, vacuolization, and lipid inclusions. The study provided ethnophysiology insights into the responses of C. carpio to CoCl 2 -induced oxidative stress and lipidomic alteration, underscoring its potential as a bioindicator for assessing environmental impacts and metal contamination., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

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]

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.

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]

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.

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

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.