Elsevier

Science of The Total Environment

Volume 432, 15 August 2012, Pages 210-215
Science of The Total Environment

Review
Cobalt metabolism and toxicology—A brief update

https://doi.org/10.1016/j.scitotenv.2012.06.009Get rights and content

Abstract

Cobalt metabolism and toxicology are summarized. The biological functions of cobalt are updated in the light of recent understanding of cobalt interference with the sensing in almost all animal cells of oxygen deficiency (hypoxia). Cobalt (Co2 +) stabilizes the transcriptional activator hypoxia-inducible factor (HIF) and thus mimics hypoxia and stimulates erythropoietin (Epo) production, but probably also by the same mechanism induces a coordinated up-regulation of a number of adaptive responses to hypoxia, many with potential carcinogenic effects. This means on the other hand that cobalt (Co2 +) also may have beneficial effects under conditions of tissue hypoxia, and possibly can represent an alternative to hypoxic preconditioning.

Cobalt is acutely toxic in larger doses, and in mammalian in vitro test systems cobalt ions and cobalt metal are cytotoxic and induce apoptosis and at higher concentrations necrosis with inflammatory response. Cobalt metal and salts are also genotoxic, mainly caused by oxidative DNA damage by reactive oxygen species, perhaps combined with inhibition of DNA repair. Of note, the evidence for carcinogenicity of cobalt metal and cobalt sulfate is considered sufficient in experimental animals, but is as yet considered inadequate in humans. Interestingly, some of the toxic effects of cobalt (Co2 +) have recently been proposed to be due to putative inhibition of Ca2 + entry and Ca2 +-signaling and competition with Ca2 + for intracellular Ca2 +-binding proteins.

The tissue partitioning of cobalt (Co2 +) and its time-dependence after administration of a single dose have been studied in man, but mainly in laboratory animals. Cobalt is accumulated primarily in liver, kidney, pancreas, and heart, with the relative content in skeleton and skeletal muscle increasing with time after cobalt administration. In man the renal excretion is initially rapid but decreasing over the first days, followed by a second, slow phase lasting several weeks, and with a significant long-term retention in tissues for several years. In serum cobalt (Co2 +) binds to albumin, and the concentration of free, ionized Co2 + is estimated at 5–12% of the total cobalt concentration.

In human red cells the membrane transport pathway for cobalt (Co2 +) uptake appears to be shared with calcium (Ca2 +), but with the uptake being essentially irreversible as cobalt is effectively bound in the cytosol and is not itself extruded by the Ca-pump. It is tempting to speculate that this could perhaps also be the case in other animal cells. If this were actually the case, the tissue partitioning and biokinetics of cobalt in cells and tissues would be closely related to the uptake of calcium, with cobalt partitioning primarily into tissues with a high calcium turn-over, and with cobalt accumulation and retention in tissues with a slow turn-over of the cells.

The occupational cobalt exposure, e.g. in cobalt processing plants and hard-metal industry is well known and has probably been somewhat reduced in more recent years due to improved work place hygiene. Of note, however, adverse reactions to heart and lung have recently been demonstrated following cobalt exposure near or slightly under the current occupational exposure limit. Over the last decades the use of cobalt–chromium hard-metal alloys in orthopedic joint replacements, in particular in metal-on-metal bearings in hip joint arthroplasty, has created an entirely new source of internal cobalt exposure. Corrosion and wear produce soluble metal ions and metal debris in the form of huge numbers of wear particles in nanometric size, with systemic dissemination through lymph and systemic vascular system. This may cause adverse local reactions in peri-prosthetic soft-tissues, and in addition systemic toxicity. Of note, the metal nanoparticles have been demonstrated to be clearly more toxic than larger, micrometer-sized particles, and this has made the concept of nanotoxicology a crucial, new discipline. As another new potential source of cobalt exposure, suspicion has been raised that cobalt salts may be misused by athletes as an attractive alternative to Epo doping for enhancing aerobic performance.

The cobalt toxicity in vitro seems to reside mainly with ionized cobalt. It is tempting to speculate that ionized cobalt is also the primary toxic form for systemic toxicity in vivo. Under this assumption, the relevant parameter for risk assessment would be the time-averaged value for systemic cobalt ion exposure that from a theoretical point of view might be obtained by measuring the cobalt content in red cells, since their cobalt uptake reflects uptake only of free ionized cobalt (Co2 +), and since the uptake during their 120 days life span is practically irreversible. This clearly calls for future clinical studies in exposed individuals with a systematic comparison of concurrent measurements of cobalt concentration in red cells and in serum.

Introduction

The toxic effects of cobalt are well known, and its absorption, distribution, metabolism and excretion have been thoroughly reviewed by e.g. Lauwerys and Lison (1994), Barceloux (1999) and Leggett (2008). For extensive and authoritative reviews see also ATSDR (2004) review and WHO (2006) summary. Recent studies have provided insight into the interference of cobalt (Co2 +) with the oxygen sensors in the hypoxia response pathway present in almost all animal cells, contributing to the understanding of the possible carcinogenic effects of cobalt. Moreover, insight has been provided into the membrane transport and accumulation of cobalt in human red blood cells. The results suggest that the transport pathway for cobalt (Co2 +) uptake is shared with calcium, with implications for cobalt biokinetics, and finally suggest that for biomonitoring long-term systemic cobalt exposure, occupationally or in patients e.g. following cobalt–chromium alloy metal-on-metal hip replacement, one should measure the cobalt content in red blood cells rather than the cobalt concentration in whole-blood or serum, to give an average value for the exposure over time. This would also apply to monitoring cases of potential misuse of cobalt salts to enhance aerobic performance. Moreover, the red cell cobalt content would reflect their exposure to ionized cobalt (Co2 +) that seems likely to be the primary toxic form. The present paper is a brief update of the biological functions of cobalt with special reference to its toxicity. Of note, the effects of cobalt are not only harmful, but may also be beneficial. Cobalt stimulates erythropoietin production and increases erythropoiesis, leading to increased oxygen-carrying capacity of the blood which is helpful under conditions of ischemia and tissue hypoxia. Moreover, preconditioning with cobalt salts akin to hypoxic preconditioning promotes tissue adaptation to hypoxia, improves hypoxic/ischemic tolerance and enhances physical endurance performance. It has even been proposed that cobalt preconditioning could possibly prevent high altitude-induced oxidative stress and ameliorate mountain sickness.

Section snippets

Cobalt toxicology. Adverse and putative beneficial effects of cobalt

The transition group metal cobalt is present in trace amounts in the human diet, primarily in vegetables and fish, and in drinking water. Cobalt is an essential micronutrient in the form of vitamin B12 (hydroxocobalamin), but inorganic cobalt as such is not required in human diets, and cobalt deficiency has never been described in humans (Taylor and Marks, 1978). A number of bacterial metalloenzymes (or metal-activated enzymes) have been identified that are dependent on cobalt in a form other

Metabolism of cobalt

For optimizing biomonitoring of systemic human exposure to toxic metals, and for valid interpretation of the results, it is essential to consider their metabolism and toxicokinetics (see, e.g. Christensen, 1995). The metabolism of cobalt (and its radioisotopes) has been studied both in man and in laboratory animals. Water-soluble cobalt salts are rapidly absorbed from the small intestine, though the bioavailability is incomplete and quite variable (see Leggett, 2008, and references therein).

Cobalt exposure. Biomonitoring of long-term systemic cobalt exposure

The occupational cobalt exposure in cobalt processing plants, hard-metal industry, diamond polishing and ceramic industry (e.g. the use of cobalt blue dyes) is well known and has been reviewed (see, e.g. Christensen, 1995). The occupational exposure has probably been somewhat reduced in more recent years due to improved work place hygiene. Of note, however, adverse reactions to heart and lung have recently been demonstrated following cobalt exposure near or slightly under the current

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