Characteristics of Cobalt-Related Cardiomyopathy in Metal Hip Implant Patients: An Evaluation of 15 Published Reports.

Over 300,000 hip replacements occurred in the USA in 2010, and the frequency is likely increasing annually. Blood Cobalt (Co) concentrations in patients with well-functioning cobalt-chromium (Co-Cr) hip implants are usually elevated above background concentrations relative to the general population. Excessive Co exposure, in rare cases, can result in cardiomyopathy. The purpose of this review was to identify cases of cardiomyopathy in metal-containing hip implant patients and to evaluate the possible cause of each patient's cardiomyopathy. We evaluated 15 cases published between 2009 and 2016, and, based on a review of the preexisting risk factors, blood Co concentrations, and histopathological information published for each patient, they were stratified into one of four categories regarding the association between Co exposure and the development of cardiomyopathy: (1) Co was causal (five cases); (2) Co was contributory (two cases); (3) Co was possibly contributory (six cases); and (4) Co was non-causal (two cases). In all 15 cases, blood Co concentrations (14-6521 µg/L) were elevated beyond levels associated with the majority of metal-containing implant patients (0.1-10 µg/L), and, in many cases, there was evidence of a malfunctioning implant. The data indicate that individuals with well-functioning implants, even those with preexisting risk factors, are at no risk of developing cardiac effects. We conclude that blood Co measurements are informative, but should be interpreted with caution, and in context of other factors evaluated in this analysis. The mere presence of elevated Co is not sufficient to indicate causation for a patient's cardiomyopathy.

Data on the histological and immune cell response in the popliteal lymph node in mice following exposure to metal particles and ions.

Hip implants containing cobalt-chromium (CoCr) have been used for over 80 years. In patients with metal-on-metal (MoM) hip implants, it has been suggested that wear debris particles may contribute to metal sensitization in some individuals, leading to adverse reactions. This article presents data from a study in which the popliteal lymph node assay (PLNA) was used to assess immune responses in mice treated with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3, and NiCl2) or Cr2O3 particles with metal salts ("A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay" (B.E. Tvermoes, K.M. Unice, B. Winans, M. Kovochich, E.S. Fung, W.V. Christian, E. Donovan, B.L. Finley, B.L. Kimber, I. Kimber, D.J. Paustenbach, 2016) [1]). Data are presented on (1) the chemical characterization of TiO2 particles (used as a particle control), (2) clinical observations in mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (3) PLN weight and weight index (WI) in mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (4) histological changes in PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (5) percentages of immune cells in the PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, and (6) percentages of proliferating cells in the PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts.

A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay.

The objective of this preliminary study was to evaluate the threshold for immune stimulation in mice following local exposure to metal particles and ions representative of normal-functioning cobalt-chromium (CoCr) metal-on-metal (MoM) hip implants. The popliteal lymph node assay (PLNA) was used in this study to assess immune responses in BALB/c mice following treatment with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3 and NiCl2), or Cr2O3 particles together with metal salts using single-dose exposures representing approximately 10days (0.000114mg), 19years (0.0800mg), and 40years (0.171mg) of normal implant wear. The immune response elicited following treatment with Cr2O3 particles together with metal salts was also assessed at four additional doses equivalent to approximately 1.5months (0.0005mg), 0.6years (0.0025mg), 2.3years (0.01mg), and 9.3years (0.04mg) of normal implant wear. Mice were injected subcutaneously (50µL) into the right hind foot with the test article, or with the relevant vehicle control. The proliferative response of the draining lymph node cells (LNC) was measured four days after treatment, and stimulation indices (SI) were derived relative to vehicle controls. The PLNA was negative (SI<3) for all Cr2O3 particle doses, and was also negative at the lowest dose of the metal salt mixture, and the lowest four doses of the Cr2O3 particles with metal salt mixture. The PLNA was positive (SI>3) at the highest two doses of the metal salt mixture and the highest three doses of the Cr2O3 particles with the metal salt mixture. The provisional NOAEL and LOAEL values identified in this study for immune activation corresponds to Co and Cr concentrations in the synovial fluid approximately 500 and 2000 times higher than that reported for normal-functioning MoM hip implants, respectively. Overall, these results indicate that normal wear conditions are unlikely to result in immune stimulation in individuals not previously sensitized to metals.

Risks associated with arsenic exposure resulting from the consumption of California wines sold in the United States.

Concerns have recently been raised about the presence of arsenic (As) in wine. In this analysis, 101 different California wines were evaluated for organic and inorganic As concentration. The average concentrations of total inorganic As in red, blush and white wines were 6.12µg/L (range: 0.40-20.5µg/L), 21.6µg/L (range: 0.92-41.2µg/L) and 9.5µg/L (0.57-30.4µg/L). The average concentrations of total organic As in red, blush and white wines were 0.64µg/L (0.10-2.74µg/L), 0.99µg/L (0.50-2.28µg/L), and 0.51µg/L (0.10-1.78µg/L). A screening level risk assessment was conducted to assess the potential non-carcinogenic risk resulting from wine consumption. The hazard quotient (HQ) for the inorganic As RfD and the As content of red, blush and white wines was each less than one; indicating that the non-cancer health risk was insignificant. Results indicate that ingestion of California wine does not pose a hazard due to inorganic As content.

Review of cobalt toxicokinetics following oral dosing: Implications for health risk assessments and metal-on-metal hip implant patients.

Cobalt (Co) can stimulate erythropoietin production in individuals at doses exceeding 25 mg CoCl2/day. Co has also been shown to exert effects on the thyroid gland, heart and nervous system at sufficient doses. The biological activity of Co is dictated by the concentration of free (unbound) ionic Co(2+). Blood concentrations, as well as, urinary excretion rates of Co are reliable biomarkers for systemic Co exposure. A recent series of human volunteer Co-supplement studies simultaneously measured Co blood and urine concentrations, as well as, Co speciation in serum, and a number of biochemical and clinical parameters. It was found in these studies that peak Co whole blood concentration as high as 117 µg/L were not associated with changes in hematological parameters such as increased red blood cell (RBC) count, hemoglobin (Hgb) or hematocrit (Hct) levels, nor with changes in cardiac, neurological or, thyroid function. Using a Co biokinetic model, the estimated Co systemic tissue concentrations (e.g., liver, kidney, and heart) following 90-days of Co-dietary supplementation with ∼1 mg Co/day were found to be similar to estimated tissue concentrations in implant patients after 10 years of exposure at continuous steady state Co blood concentration of ∼10 µg/L. This study is the first to present modeled Co tissue concentrations at various doses following sub-chronic and chronic exposure. The modeled steady state tissue Co concentrations in combination with the data on adverse health effects in humans should help in the characterization of potential hazards associated with increased blood Co concentrations due to exposure to dietary supplements or cobalt-chromium (Co-Cr) containing implants.

Screening level health risk assessment of selected metals in apple juice sold in the United States.

Concerns have recently been raised about the presence of metals in apple juices. As such, the concentration of aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), lead (Pb), manganese (Mn), mercury (Hg), and zinc (Zn) were measured in six commercially available brands of apple juice and three organic brands. The concentrations of total As, Cd, Cr, Cu, Hg, and Zn in all nine apple juice brands sampled were below each metal's respective U.S. Food and Drug Administration (FDA) maximum contaminant level for bottled water. However, in some apple juices the levels of Al, Pb, and Mn exceeded FDA maximum contaminant levels for bottled water. Therefore, a screening level risk assessment was carried out to assess the potential non-carcinogenic and carcinogenic risks that may result from metal exposure via apple juice consumption. Changes in blood Pb concentrations were also estimated to characterize potential risk from Pb exposure. Our results suggest that the exposure concentrations of the studied metals do not pose an increased non-carcinogenic risk (Hazard Index<1). Incremental lifetime cancer risk (ILCR) resulting from apple juice consumption was also estimated using both the California Office of Environmental Health Hazard Assessment (OEHHA) and the U.S. EPA cancer slope factor for inorganic As.

Refined biokinetic model for humans exposed to cobalt dietary supplements and other sources of systemic cobalt exposure.

An updated biokinetic model for human exposures to cobalt (Co) was developed based on a comprehensive set of human pharmacokinetics data collected from five male and five female volunteers who ingested ∼1 mg Co/day of a Co supplement for 3 months. Three key experimental observations from the human dosing studies were incorporated into the model: (1) an increase in the measured fraction of large molecular serum protein bound Co from 95% during dosing to 99% after dosing; (2) a linear decrease in Co red blood cell concentration after dosing; and (3) Co renal clearance consistent with estimated glomerular filtration rates and free Co²âº concentration. The model was refined by adding compartments accounting for (1) albumin bound Co in intravascular fluid (serum); (2) albumin bound Co in extravascular fluid with physiologic exchange rates of albumin bound Co between extravascular and intravascular fluid; and (3) a novel sequential cascade of compartments representing red blood cell ages between 1 and 120 days. Reasonable agreement between the modeled and measured urine, serum, and whole blood concentrations were observed (r>0.84, slope=0.79-1.0) with gastrointestinal absorption rates between 9% and 66%. In addition, model predictions agreed well with data from several external studies representing healthy human volunteers, dialysis patients, anephric patients, a Co-poisoning incident and whole body retention studies. Our revised model considerably improves the state of knowledge on human Co kinetics, and should be helpful for evaluating elevated blood Co concentrations in currently exposed populations, such as metal-on-metal (MoM) hip implant patients.

Effects and blood concentrations of cobalt after ingestion of 1 mg/d by human volunteers for 90 d.

BACKGROUND: Over-the-counter cobalt supplements are available for sale in the United States, but little is known regarding their clinical effects and biokinetic distribution with long-term use. OBJECTIVE: We assessed blood kinetics, biochemical responses, and clinical effects in 5 adult men and 5 adult women who voluntarily ingested ∼ 1.0 mg Co/d (0.080-0.19 mg Co · kg⁻¹ · d⁻¹) of a commercially available cobalt supplement over a 3-mo period. DESIGN: Volunteers were instructed to take the cobalt dietary supplement in the morning according to the manufacturer's label. Blood samples were collected and analyzed for a number of biochemical variables before, during, and after dosing. Hearing, vision, cardiac, and neurologic functions were also assessed in volunteers before, during, and after dosing. RESULTS: After ∼ 90 d of dosing, mean cobalt blood concentrations were lower in men than in women. Mean cobalt whole blood and serum concentrations in men were 20 µg/L (range: 12-33 µg/L) and 25 µg/L (range: 15-46 µg/L), respectively. In women, mean cobalt whole blood and serum concentrations were 53 µg/L (range: 6-117 µg/L) and 71 µg/L (range: 9-149 µg/L), respectively. Estimated red blood cell (RBC) cobalt concentrations suggested that cobalt was sequestered in RBCs during their 120-d life span, which resulted in a slower whole blood clearance compared with serum. The renal clearance of cobalt increased with the serum concentration and was, on average, lower in women (3.5 ± 1.3 mL/min) than in men (5.5 ± 1.9 mL/min). Sex-specific differences were observed in cobalt absorption and excretion. There were no clinically significant changes in biochemical, hematologic, and clinical variables assessed in this study. CONCLUSION: Peak cobalt whole blood concentrations ranging between 9.4 and 117 µg/L were not associated with clinically significant changes in basic hematologic and clinical variables.

31-day study of cobalt(II) chloride ingestion in humans: pharmacokinetics and clinical effects.

The United Kingdom Expert Group on Vitamins and Minerals concluded that ingesting cobalt (Co)-containing supplements up to 1400 µg Co/d is unlikely to produce adverse health effects. However, the associated blood Co concentrations and safety of Co-containing dietary supplements have not been fully characterized. Thus, blood Co kinetics and a toxicological assessment of hematological and biochemical parameters were evaluated following Co dietary supplementation in 5 male and 5 female volunteers who ingested approximately 1000 µg Co/d (10-19 µg Co/kg-d) as cobalt(II) chloride for a period of 31 d. Supplement intake was not associated with significant overt adverse events, alterations in clinical chemistries including blood counts and indicators of thyroid, cardiac, liver, or kidney functions, or metal sensitization. A non-clinically significant (<5%) increase in hemoglobin, hematocrit, and red blood cell (RBC) counts were observed in males but not females 1 wk after dose termination. Mean Co concentrations in whole blood/serum after 31 d of dosing were approximately two-fold higher in females (33/53 µg/L) than in males (16/21 µg/L). In general, steady-state concentrations of Co were achieved in whole blood and/or red blood cells (RBC) within 14-24 d. Temporal patterns of whole blood and serum Co concentrations indicated metal sequestration in RBC accompanied by slower whole blood clearance compared to serum. Data also indicated that peak whole blood Co concentrations up to 91.4 µg/L were not associated with clinically significant changes in clinical chemistries. In addition, Co blood concentrations and systemic uptake via ingestion were generally higher in females.

Analysis of BTEX groundwater concentrations from surface spills associated with hydraulic fracturing operations.

UNLABELLED: Concerns have arisen among the public regarding the potentialfor drinking-water contamination from the migration of methane gas and hazardous chemicals associated with hydraulic fracturing and horizontal drilling. However, little attention has been paid to the potentialfor groundwater contamination resulting from surface spills from storage and production facilities at active well sites. We performed a search for publically available data regarding groundwater contamination from spills at ULS. drilling sites. The Colorado Oil and Gas Conservation Commission (COGCC) database was selected for further analysis because it was the most detailed. The majority ofspills were in Weld County, Colorado, which has the highest density of wells that used hydraulic fracturing for completion, many producing both methane gas and crude oil. We analyzed publically available data reported by operators to the COGCC regarding surface spills that impacted groundwater From July 2010 to July 2011, we noted 77 reported surface spills impacting the groundwater in Weld County, which resulted in surface spills associated with less than 0.5% of the active wells. The reported data included groundwater samples that were analyzed for benzene, toluene, ethylbenzene, andxylene (BTEX) components of crude oil. For groundwater samples taken both within the spill excavation area and on the first reported date of sampling, the BTEX measurements exceeded National Drinking Water maximum contaminant levels (MCLs) in 90, 30, 12, and 8% of the samples, respectively. However, actions taken to remediate the spills were effective at reducing BJTEX levels, with at least 84% of the spills reportedly achieving remediation as of May 2012. Our analysis demonstrates that surface spills are an important route of potential groundwater contamination from hydraulic fracturing activities and should be a focus of programs to protect groundwater IMPLICATIONS: While benzene can occur naturally in groundwater sources, spills and migration of chemicals used for hydraulic fracturing activities have recently been thought to be a main source of benzene contamination in groundwater. However, there is little scientific literature to support that claim. Therefore, we accessed a publically available database and tracked the number of reported surface spills with potential groundwater impact over a 1-year period. Although the number of surface spills was minimal, our analysis provides scientific evidence that benzene can contaminate groundwater sources following surface spills at active well sites.

A review of the health hazards posed by cobalt.

Cobalt (Co) is an essential element with ubiquitous dietary exposure and possible incremental exposure due to dietary supplements, occupation and medical devices. Adverse health effects, such as cardiomyopathy and vision or hearing impairment, were reported at peak blood Co concentrations typically over 700 µg/L (8-40 weeks), while reversible hypothyroidism and polycythemia were reported in humans at ~300 µg/L and higher (≥2 weeks). Lung cancer risks associated with certain inhalation exposures have not been observed following Co ingestion and Co alloy implants. The mode of action for systemic toxicity relates directly to free Co(II) ion interactions with various receptors, ion channels and biomolecules resulting in generally reversible effects. Certain dose-response anomalies for Co toxicity likely relate to rare disease states known to reduce systemic Co(II)-ion binding to blood proteins. Based on the available information, most people with clearly elevated serum Co, like supplement users and hip implant patients, have >90% of Co as albumin-bound, with considerable excess binding capacity to sequester Co(II) ions. This paper reviews the scientific literature regarding the chemistry, pharmacokinetics and systemic toxicology of Co, and the likely role of free Co(II) ions to explain dose-response relationships. Based on currently available data, it might be useful to monitor implant patients for signs of hypothyroidism and polycythemia starting at blood or serum Co concentrations above 100 µg/L. This concentration is derived by applying an uncertainty factor of 3 to the 300 µg/L point of departure and this should adequately account for the fact that persons in the various studies were exposed for less than one year. A higher uncertainty factor could be warranted but Co has a relatively fast elimination, and many of the populations studied were of children and those with kidney problems. Closer follow-up of patients who also exhibit chronic disease states leading to clinically important hypoalbuminemia and/or severe ischemia modified albumin (IMA) elevations should be considered.

Cobalt whole blood concentrations in healthy adult male volunteers following two-weeks of ingesting a cobalt supplement.

Recently, there has been an increase in the marketing and sales of dietary supplements, energy drinks, and other consumer products that may contain relatively high concentrations of essential elements. Cobalt-containing supplements are readily available in the U.S. and have been marketed to consumers as energy enhancers. However, little information is available regarding cobalt (Co) body burden and steady-state blood concentrations following the intake of Co dietary supplements. We assessed Co whole blood concentrations in four healthy adult male volunteers who ingested a commercially available Co supplement (0.4 mg Co/day) for 15 or 16 days. Pre-supplementation blood Co concentrations were less than the reporting limit of 0.5 µg/L, consistent with background concentrations reported to range between 0.1 and 0.4 µg/L. The mean whole blood Co concentration in the volunteers after 15 or 16 days of dosing was 3.6 µg Co/L and ranged from 1.8 to 5.1 µg Co/L. The mean observed concentration in the study group was approximately 9-36 times greater than background concentrations. Further studies of Co whole blood concentrations following supplementation over longer time periods with additional monitoring of physiological parameters may provide useful information for evaluating the health of persons who take various doses of Co.

Inorganic cobalt supplementation: prediction of cobalt levels in whole blood and urine using a biokinetic model.

Soluble cobalt (Co) supplements with recommended daily doses up to 1000 µg Co/day are increasingly being marketed to consumers interested in healthy living practices. For example, some athletes may consider using Co supplements as blood doping agents, as Co is known to stimulate erythropoesis. However, the distribution and excretion kinetics of ingested Co are understood in a limited fashion. We used a Co-specific biokinetic model to estimate whole blood and urine Co levels resulting from oral exposure or ingestion of Co in amounts exceeding typical dietary intake rates. Following 10 days of Co supplementation at a rate of 400 to 1000 µg/day, predicted adult Co concentrations range from 1.7 to 10 µg/L in whole blood, and from 20 to 120 µg/L in urine. Chronic supplementation (≥ 1 year) at a rate of 1000 µg Co/day is predicted to result in blood levels of 5.7 to 13 µg/L, and in urine levels from 65 to 150 µg/L. The model predictions are within those measured in humans following ingestion of known doses. The methodology presented in this paper can be used to predict urinary or blood Co levels following acute or chronic occupational incidental ingestion, medicinal therapy, supplemental intake, or other non-occupational exposures.

Cadmium induces transcription independently of intracellular calcium mobilization.

BACKGROUND: Exposure to cadmium is associated with human pathologies and altered gene expression. The molecular mechanisms by which cadmium affects transcription remain unclear. It has been proposed that cadmium activates transcription by altering intracellular calcium concentration ([Ca(2+)](i)) and disrupting calcium-mediated intracellular signaling processes. This hypothesis is based on several studies that may be technically problematic; including the use of BAPTA chelators, BAPTA-based fluorescent sensors, and cytotoxic concentrations of metal. METHODOLOGY/PRINCIPAL FINDING: In the present report, the effects of cadmium on [Ca(2+)](i) under non-cytotoxic and cytotoxic conditions was monitored using the protein-based calcium sensor yellow cameleon (YC3.60), which was stably expressed in HEK293 cells. In HEK293 constitutively expressing YC3.60, this calcium sensor was found to be insensitive to cadmium. Exposing HEK293::YC3.60 cells to non-cytotoxic cadmium concentrations was sufficient to induce transcription of cadmium-responsive genes but did not affect [Ca(2+)](i) mobilization or increase steady-state mRNA levels of calcium-responsive genes. In contrast, exposure to cytotoxic concentrations of cadmium significantly reduced intracellular calcium stores and altered calcium-responsive gene expression. CONCLUSIONS/SIGNIFICANCE: These data indicate that at low levels, cadmium induces transcription independently of intracellular calcium mobilization. The results also support a model whereby cytotoxic levels of cadmium activate calcium-responsive transcription as a general response to metal-induced intracellular damage and not via a specific mechanism. Thus, the modulation of intracellular calcium may not be a primary mechanism by which cadmium regulates transcription.

Molecular characterization of numr-1 and numr-2: genes that increase both resistance to metal-induced stress and lifespan in Caenorhabditis elegans.

To define the mechanisms involved in the molecular response to the carcinogenic metal cadmium, two novel metal-inducible genes from C. elegans were characterized: numr-1 and numr-2 (nuclear localized metal responsive). numr-1 and numr-2 sequences and cellular patterns of expression are identical, indicating that these are functionally equivalent genes. Constitutive transcription of numr-1 and numr-2 is developmentally regulated and occurs in the intestine, in head and tail neurons, and vulva muscles. Exposure to metals induces numr-1 and numr-2 transcription in pharyngeal and intestinal cells. Other environmental stressors do not affect transcription, indicating that these are metal-specific, stress-responsive genes. NUMR-1 and NUMR-2 target to nuclei and colocalize with HSF-1, suggesting that they may be components of nuclear stress granules. Nematodes overexpressing NUMR-1 and NUMR-2 are resistant to stress and live longer than control animals; likewise reducing expression increases sensitivity to metals and decreases neuromuscular functions. Upstream regulatory regions of both genes contain potential binding sites for DAF-16 and SKN-1, which are components of the insulin-IGF-like signaling pathway. This pathway regulates longevity and stress responses in C. elegans. NUMR-1 and NUMR-2 may function to promote resistance to environmental stressors and longevity, which is mediated by the insulin-IGF-like signaling pathway.