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Prosthetic hip-associated cobalt toxicity (PHACT) is caused by elevated blood cobalt concentrations after hip arthroplasty. The aim of this study is to determine which symptoms are reported most frequently and in what type of bearing. We also try to determine the blood level of cobalt concentrations associated with toxicological symptoms. A systematic review was conducted on the 10th of July according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A methodological quality assessment (risk of bias (RoB)) was performed. Primary outcomes were the reported symptoms of cobalt toxicity and the level of cobalt concentrations in blood. These levels were associated with toxicological symptoms. A total of 7645 references were found of which 67 relevant reports describing 79 patients. The two most used bearings in which PHACT was described were metal-on-metal (MoM) bearings (38 cases) and revised (fractured) ceramic-on-ceramic (CoC) bearings where the former ceramic head was replaced by a metal head (32 cases). Of all reported symptoms, most were seen in the neurological system, of which 24% were in the sensory system and 19.3% were in central/peripheral system, followed by the cardiovascular (22.1%) system. The mean cobalt concentration for MoM-bearings was 123.7 ± 96.8 ppb and 1078.2 ± 1267.5 ppb for the revised fractured CoC-bearings. We recommend not to use a metal-based articulation in the revision of a fractured CoC bearing and suggest close follow-up with yearly blood cobalt concentration controls in patients with a MoM bearing or a revised fractured CoC bearing. Level of Evidence: Level V, systematic review

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.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.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 levels20 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.

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 JohnsonJohnson (JJ)/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.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 JJ/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.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 JJ/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 JJ/DePuy KWA Reporter File records. Physician was the reporter's occupation in 20.48% of reports but seldom reported directly to the FDA.We were not able find in the FDA MAUDE database meaningful warning signs to support the contention that chromium-cobalt-containing Class 3 JJ 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 JJ/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.

Increased accumulation of heavy metal ions such as Cr6+ and Co2+ due to release from prostheses and metallic implants has been reported. These metal ions have been shown to affect both resting and activated lymphocytes. Natural remedies towards mitigating the cytotoxic effects of metal ions are clearly warranted. Polyphenolic compounds which are part of hydrolysable tannins from natural plant sources are considered effective in cheating heavy metal ions in a biological system. We have isolated and characterized a polyphenolic compound (ellagic acid) from Terminalia arjuna fruits that has been tested for its ability to attenuate the metal ion toxicity in primary human lymphocytes in culture. Cr6+ and Co2+ (100 μM) decreased lymphocyte viability and proliferation and increased apoptosis of resting as well as CD3 and/or CD28-stimulated lymphocytes. Metal ions markedly diminished the cytokine (interleukin-2 and interferon-γ) secretion from activated lymphocytes. Pretreatment with ellagic acid at 25, 50, and 100 μM concentrations effectively improved viability and proliferative responses of both resting and activated lymphocytes, while attenuating the apoptotic index. Ellagic acid also tended to normalize the cytokine secretion from the activated lymphocytes even in the presence of metal ions, suggesting broad effects on the adaptive immune system.

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

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.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.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.

Objectives: Based on limited evidence from case reports and small cohort studies of metal-on-metal (MoM) hip implant patients with presumed systemic cobalt (Co) toxicity, and a few animal studies on Co-induced damage to the otovestibular system, it was hypothesised that Co exhibits an ototoxic potential alongside other systemic manifestations. Preliminary investigations from our research group in MoM patients confirmed this assumption for the auditory system, whereas no signs of Co-induced vestibular impairment were detected, and a clear dose-response relationship between the auditory function and the blood Co levels was lacking. Therefore, the current study aimed to extend and validate these findings in a larger sample of MoM patients and control subjects, to explore the potential clinical value of audiovestibular outcome measures in the risk estimation of systemic Co toxicity in this patient population. Design: Fifty patients (32 to 68 years) with a primary unilateral/bilateral MoM hip implant were matched for age, gender, and noise exposure to 50 nonimplanted control subjects. Both groups underwent the same protocol, consisting of an objective auditory [i.e., conventional and high-frequency audiometry, transient-evoked and distortion (TEOAEs and DPOAEs), auditory brainstem responses] and vestibular (i.e., cervical and ocular vestibular evoked myogenic potentials, horizontal and vertical video head impulse tests) test battery, a questionnaire inquiring auditory, balance, and general neurological symptoms, and a blood sample collection to determine the plasma Co concentration. Results: The auditory test battery presented consistently higher audiometric thresholds in the MoM patient group, with group differences ranging from 2.1 to 5.7 dB in the lower frequencies (0.25 to 6.0 kHz) and from 4.6 to 9.3 dB in the high frequencies (8.0 to 14.0 kHz). Group differences at high frequencies were statistically significant (p 0.01). Six patients had elevated Co levels according to our local institutional threshold (>4 or 5 mu g/l for unilateral or bilateral MoM hip implants, resp.), but their audiovestibular outcome measures did not differ significantly from those of the other patients. Conclusions: Corresponding to our preliminary investigations, the results indicate possibly Co-induced (predominantly high-frequency) auditory impairment, probably triggered by toxic damage to the cochlear structures. However, the low mean difference values, the lack of group differences for the patient-reported outcome measures, and the lack of any relationship with the blood Co levels strongly reduce the clinical relevance of these findings. Therefore, the risk of Co-induced ototoxic impairment is considered to be clinically negligible for the majority of MoM hip implant patients, and the use of auditory tests in the risk estimation of systemic Co toxicity should be decided on a case-by-case basis.

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).

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.

Streptococcus suis is a zoonotic pathogen causing serious infections in both swine and humans. Although metals are essential for life, excess amounts of metals they are toxic to bacteria. when accumulated in excess amounts. Except for zinc, Transcriptome-level data of the mechanisms for resistance to metal-induced toxicity in S. suis are available for no metals other than zinc. have not been investigated from the transcriptome level in S. suis. Herein, we explored the transcriptome-level changes of in S. suis in response to ferrous iron and cobalt toxicity by RNA sequencing. Many A lot of genes were differentially expressed in the presence of excess ferrous iron and cobalt. Most of the genes in response to cobalt toxicity showed the same expression trends as those were expressed in the same trend in response to ferrous iron toxicity. qRT-PCR analysis of the selected genes confirmed the accuracy of RNA sequencing results. Bioinformatics analysis of the differentially expressed genes indicated that ferrous iron and cobalt have similar impacts effects on the cellular processes of S. suis. Treatment with ferrous Ferrous iron treatment resulted in down-regulation of several oxidative stress tolerance-related genes involved in oxidative stress tolerance and up-regulation of the genes in an amino acid ABC transporter operon. Expression of the several genes in the arginine deiminase system was down-regulated in the presence of after ferrous iron and cobalt treatment. Collectively, our results suggested that S. suis alters the expression of a lot of multiple genes to respond to ferrous iron and cobalt toxicity.

Cobalt toxicity is a well-documented complication of total hip arthroplasty (THA) when cobalt-chrome implants are utilized. A recent area of attention is “cobaltism, ” which results from cobalt exposure from cobalt-containing orthopedic implants, chemistry kits, weather indicators, antiquated anemia therapies, cement, fly ash, dyes, mineral wool, asbestos, molds for ceramic tiles, mining, porcelain paint, orthopedic implants, and dental hardware. Like other transition metals, cobalt is a multiorgan toxin. Organ systems affected by acute cobalt poisoning include endocrine, gastrointestinal, central and peripheral nervous system, hematologic, cardiovascular, and metabolic. Chronic inhalational exposures affect the pulmonary system and dermatologic system.

This experiment was undertaken to study the toxic effects of cobalt chloride in rats. Sixty-five rats weighing 207 ± 7 g were used. Cobalt chloride was administrated orally in low and high doses for 90 d. The aim of study was to evaluate the effects of cobalt on blood (RBC, WBC, Hb, PLT and HCT) and to investigate the abilities of deferasirox (DFX) and desferrioxamine (DFO) as chelators in removing cobalt from the blood. Cobalt and iron concentrations were determined by flame atomic absorption spectrometer (FAAS). Results show that both of chelators are able to remove cobalt but DFX was more effective, whereas the combined therapy is more efficient.

Cobalt naturally occurs in air, rocks, soils, and water, and it has diverse industrial and biomedical applications. It is an essential trace metal and cofactor for vitamin B12 (cyanocobalamin) but can be toxic after a minimal increase in concentration. Inhalation and dietary ingestion are the main external sources of cobalt exposure; however, internal exposure from cobalt hip or oral implants and the use of nanoparticles are on the rise. Cobalt is absorbed through the gastrointestinal tract and accumulated in the liver, kidney, pancreas, heart, skeleton, and skeletal muscle. The deficiency in humans with balanced diet has never been reported. It is excreted through kidney, and excretion efficiency decreases with time and elevated dose. Chronic increases of cobalt in serum may result in long-term adverse biological effects such as immune modulation, oxidative DNA damage, and maybe carcinogenesis. Serum cobalt concentrations higher than 300 µg/L are associated with neurological, cardiac, hematological, and endocrine toxicity. The higher level of cobalt in the tissue competes with calcium uptake and influences other signaling involving hypoxic response, oxidative stress, and energy metabolism. Possible abuse of cobalt supplements by athletes as an alternative to Epo doping for enhancing aerobic performance is a deep concern. Food and Drug Administration (FDA) has not established any guidance, however, the European Food Safety Authority (EFSA) has suggested a dose of 600 µg/day.

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. Cite this article: Bone Joint J 2016;98-B:14–20.

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.Cite this article: Bone Joint J 2016;98-B:6–13.

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.

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

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.

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.

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) 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.

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.

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.

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=651.2mug/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.

Heavy metals pollution of soils become the most serious environmental problem resulted in decreased soil fertility and crop yield losses. Cobalt (Co), as a beneficial element, can be a contaminant in soils due to agricultural additives or metal refineries, it causes irreversible damage to several physiological and metabolic constituents at higher concentrations. In this investigation we study the effects of different Co concentrations (0, 50,150, 250, 350 µM as CoCl2) on growth and physiological processes in wheat (Triticum aestivum) plants and discuss the role of spraying with salicylic acid (0.5 mM) for ameliorating effect of cobalt toxicity in wheat leaves. Cobalt causing a significant reduction in fresh and dry biomass, shoot height, water content and total photosynthetic pigments. This was accompanied with accumulation of H2O2 and MDA contents and induction of some antioxidant enzymes activities. There was an increase in SOD activity with increasing Co concentration then decline, a significant increase in APX and PPO activities while CAT was significantly declined. Spraying wheat seedlings with salicylic acid can be recognized to significantly increase in all tested growth parameters and that was attributed to decrease, to some extent, the accumulation of H2O2 and MDA and improve the activity of antioxidant enzymes.

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

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.

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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