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Abstract

Cobalt exerts well-known and documented toxic effects on the thyroid, heart and the haematopoietic system, in addition to the occupational lung disease, allergic manifestations and a probably carcinogenic action. Cobalt neurotoxicity is reported in isolated cases, and it has never been systematically treated. Bilateral optic atrophy and retinopathy, bilateral nerve deafness and sensory-motor polyneuropathy have been described long ago as a result of chronic occupational exposure to cobal powder or during long-term treatment of anaemia with cobalt chloride. Recently, some patients with high levels of cobalt released from metal prosthesis have been referred as presenting with tinnitus, deafness, vertigo, visual changes, optic atrophy, tremor and peripheral neuropathy. The aim of this work is to group these cases and to identify a possible mechanism of cobalt neurotoxicity, focusing on hypothetic individual susceptibility such as altered metal-binding proteins, altered transport processes in target cells or polymorphic variation of genetic background.

Keywords

cobalt neurotoxicology prosthesis occupational exposure iatrogenic exposure

Introduction

Exposure and effects of cobalt (Co) have been described in many studies, reviews, and toxicology books. Some important reviews^1–6 showed that the main acute and chronic effects concern the respiratory system, heart and thyroid. A genotoxic and carcinogenic action was described in the International Agency for Research on Cancer (IARC) monograph^7,8 in which Co is classified as group 2A (probably carcinogenic to humans).

Isolated case reports of neurological symptoms after exposure to high doses of Co were also described, following professional exposure, therapeutic ingestion of cobalt chloride (CoCl₂) and metallic ion release from cobalt–chromium (Co-Cr) alloy in orthopaedic implants (prosthesis).^9–19

A total of 11 case reports of neurological involvement due to heavy Co intoxication have been published in the last 60 years, 4 of them in the last 2 years, describing the effects of Co released from prostheses in human central nervous system.^16–19 In April 2010 the United Kingdom’s Medical Products and Healthcare Devices Regulatory Agency published a medical device alert that recommended follow-up of metal-on-metal (MoM) hip replacement patients at least annually for 5 years postsurgery in order to reveal its toxicity symptoms.²⁰ However, this document does not take into consideration the effects of Co on the nervous system and the treatment options of Co neurotoxicity. Nevertheless, it seems accepted that there have been about 1 million MoM hips implanted worldwide in the past 15 years, which may be at risk of arthroprosthetic cobaltism.²¹

The aims of this review are to describe the published evidences of Co neurotoxicity, to identify possible mechanisms that influence toxicity and to explain individual susceptibility to it.

Physical and chemical properties of Co

Co is a relatively rare element in the earth’s crust, which is essential to mammals in the form of cobalamin (vitamin B₁₂). Pure Co metal is steel-grey, shiny, hard, ductile, brittle and magnetic with properties similar to those of iron and nickel. It is commonly found with copper, iron, lead, nickel and silver ores in concentrations less than 1%. Co occurs in the (0), (II) and (III) valence states; Co (II) is more stable than Co (III), which is a powerful oxidizing agent that can oxidize water and deliver oxygen. Metallic Co (0) occurs in two allotropic forms, hexagonal and cubic, which are stable at room temperature.³

Sources of Co in the air are both natural (volcanic eruptions, erosion, forest fire, seawater spray) and anthropogenic (burning of fossil fuel, engine emissions, sewage sludge and processing of Co-containing alloys). Typically the mean concentration in air is small (about 1–2 ng/m³) in urban areas and less in remote areas.²²

The use of Co compounds for the manufacture of blue-coloured pottery and glass antedates the Christian era, but the main consumption of Co is now in the production of steel and alloys. Advantages of Co alloys are high melting point, strength and resistance to oxidation. The alloys are made of Co, Cr and other metals (tungsten but also molybdenum, tantalum, niobium, zirconium and hafnium) and are used to produce very hard cutting tools and surfaces subject to heavy wear (e.g. in turbines or space vehicles).^5,6 Less common uses include catalysts in the chemical and oil-refining industry, drying agents in paints, electroplating, radiology and an additive in fertilizer and animal feed.³

For the general population the diet is the main source of exposure to Co; human dietary intake of Co is highly variable, with reported values generally between 5 and 50 μg/day. A diffuse and increasing use of Co alloys in orthopaedic implants that require high resistance, such as knee and hip, has become another important route of exposure. In the occupational setting exposure to Co occurs primarily during Co powder and hard metal production and diamond polishing.^23,24

The main biologically active Co compound is vitamin B₁₂, or cyanocobalamin, in which Co is complexed with four pyrrole nuclei joined in a ring. Vitamin B₁₂ acts as a coenzyme in many enzymatic processes and catalyzes reactions such as the synthesis of methionine, the metabolism of purines and folates and the formation of methylmalonic acid in succinic acid.²⁵ The normal plasmatic concentrations of Co and vitamin B₁₂ are <0.2 ng/ml and 200–900 pg/ml, respectively.⁵

Co neurotoxicity in occupational exposure

Inhalation of Co dust represents the main source of exposure; even in some experimental and clinical conditions the absorption through intact skin has also been demonstrated.^26,27 Co-containing dust may be released into the workplace air during the production of Co compounds mainly during hard metal alloy processing. Characteristic workplace concentrations ranged from 0.01 to 1.7 mg/m³.^24,28,29 In exposure assessment, urinary cobalt (CoU) is the most used biomarker and it enables to quantify the occupational exposure. However, should be considered that CoU rapidly increased in the hours following the cessation of exposure, with a peak of excretion about 3 hours after the end of exposure.²⁴

The American Conference of Governmental Industrial Hygienists (ACGIH) classifies Co as A3 (animal carcinogen) and established a Biological Exposure Index of 15 μg/L of Co in urine and 1 μg/L in blood at the end of workweek and this is equivalent of a TLV-TWA of 0.02 mg/m³.³⁰ For Co-U, the Deutsche Research Foundation (DFG) fixed the exposure equivalents for carcinogenic materials at 6, 15, 30, 60 and 300 μg/L for airborne Co concentrations (Co-air) of 10, 25, 50, 100 and 500 μg/m³.³¹ The representative Co concentrations in serum and urine of occupationally exposed workers are reported in Table 1 .

Table 1.

Levels of cobalt in serum, whole blood and urine in workers exposed to cobalt

Study	Type of exposure	Serum (µg/L)	Whole blood (µg/L)	Urine (µg/L)	Expression of results
Alexanderson and Lidums³²	Producing hard metal		10.5	134	Mean
Morgan³³	Processing cobalt oxide			340	Mean
Angerer et al.³⁴	Producing hard metal		5–48	19–438	Range
Pellet et al.³⁵	Producing cobalt powder			35.1	Mean
Hartung and Schaller³⁶	Grinding of hard metal	2.1		18.0	Median
Ichikawa et al.³⁷	Producing hard metal tools		3.3–18.7	10–235	Range
Posma and Dijstelberger³⁸	Producing hard metal		2.0–18.3	64–64.3^a	Range
Lison et al.³⁹	Producing hard metal			18.2–32.4^a	Range
Scansetti et al.²⁹	Producing hard metal			22.28	Mean
Yokota et al.⁴⁰	Battery plant			28.2 ± 34.0 (1.0–127.8)	Arithmetic mean and standard deviation, range
Broding et al.²³	Hard metal alloy industry			0.81 (0.00–1.46)	Median and interquartile ranges
De Palma et al.⁴¹	Hard metal alloy industry			5.27 ± 2.95	Geometric means and geometric standard deviations

^aμg/g creatinine.

In non-occupationally exposed subjects, the normal concentrations are 0.1–1.5 μg/L in urine, 0.05–1.5 μg/L in blood and 0.05–0.3 μg/L in plasma. Table 2 reports the reference values of Co in urine for the US population from the National Health and Nutrition Survey.⁴²

Table 2.

Geometric mean and selected percentiles of urinary cobalt concentration (µg/L) for the US population from the National Health and Nutrition Survey42

	Geometric means (95% confidence interval)	Selected percentiles (95% confidence interval)
	Geometric means (95% confidence interval)	50th	75th	90th	95th
Total	0.37 (0.36–0.39)	0.39 (0.37–0.41)	0.6 (0.56–0.63)	0.88 (0.84–0.95)	1.33 (1.17–1.47)
Age
20 years and older	0.35 (0.33–0.37)	0.37 (0.35–0.39)	0.55 (0.52–0.60)	0.81 (0.76–0.88)	1.30 (1.05–1.47)
Gender
Male	0.37 (0.35–0.38)	0.38 (0.37–0.40)	0.54 (0.51–0.57)	0.76 (0.69–0.85)	1.06 (0.91–1.27)
Female	0.38 (0.35–0.41)	0.41 (0.37–0.44)	0.66 (0.62–0.70)	1.04 (0.90–1.21)	1.54 (1.30–1.93)
Race/ethnicity
Mexican Americans	0.44 (0.40–0.47)	0.45 (0.42–0.50)	0.68 (0.62–0.72)	1.11 (0.94–1.30)	1.58 (1.33–1.79)
Non-Hispanic blacks	0.41 (0.37–0.45)	0.41 (0.36–0.44)	0.60 (0.56–0.67)	0.93 (0.83–1.11)	1.58 (1.33–1.79)
Non-Hispanic whites	0.36 (0.34–0.38)	0.38 (0.46–0.41)	0.58 (0.53–0.63)	0.86 (0.80–0.94)	1.47 (1.06–1.50)

In exposed workers, in addition to respiratory and cardiovascular diseases and contact dermatitis,⁴³ some effects on the nervous system have also been reported, particularly memory loss, neuropathies and a decreased visual acuity^12,13 (Table 3 ).

Table 3.

Cases of neurotoxicity reported in occupational exposures to cobalt

	Subjects	Exposure before onset of the symptoms	Effects	Cobalt concentration
Jordan et al.¹²	12	Not reported	Difficulties in attention and verbal memory with an apparent sparing of visual-spatial memory	Not reported
Meecham and Humphrey¹³	1	20 months	Progressive bilateral deafness with tinnitus, occasional vertigo and visual failure	234 μg/L CoB

CoB: cobalt in blood.

Jordan and colleagues¹² reported significantly impaired attention (p < 0.05) and verbal memory loss (p < 0.001) in 12 hard metal workers exposed to tungsten carbide and Co (as dust and dissolved in an organic solvent) compared to 26 healthy unexposed controls. Memory deficits were related to difficulties in attention and verbal memory (measured using the Wechsler Memory Scale-Revised), with an apparent sparing of visual-spatial memory. All the exposed workers had pulmonary manifestations of disease and all of them complained of memory difficulties.

A 48-year-old worker exposed to Co dust for 20 months (50 hours a week) developed bilateral optic atrophy and bilateral nerve deafness. On examination his visual acuity was 6/36 in the right eye and 6/60 in the left eye, the temporal margins of the discs were pale and hearing was impaired bilaterally. Co concentration in blood was 234 μg/L and in urine 119 μg/24 h. Fourteen months after discontinuing work, his visual activity improved and hearing returned to normal. The definite improvement in his vision and hearing occurring within 1 month of discontinuing work, strongly suggests that Co toxicity was the cause of the deafness and visual loss.¹³

Iatrogenic Co neurotoxicity

In the past, CoCl₂ has been used in the treatment of refractory anaemia, nephritis and infections. Today this therapy is not used because of the rarity of positive responses and the frequency of adverse effects (mainly goitre, myxoedema and congestive heart failure).¹

Between 1950 and 1970 three cases of neurotoxicity following CoCl₂ consumption were reported (Table 4 )

Table 4.

Neurotoxic effects related to cobalt consumption for anaemia treatment

	Subjects	Exposure before onset of the symptoms	Effects	Cobalt concentration
Gardner⁹	4	16 weeks	Progressive bilateral deafness with tinnitus peripheral neuritis	Not reported
Gardner⁹	1	12 weeks		Not reported
Schirrmacher¹⁰	1	6 months	Limb paraesthesia, unsteady gait, impaired hearing and dizzy spells bilateral nerve deafness, absent ankle reflexes and impaired vibration sense	Not reported
Licht et al.¹¹	1	3 years	Optic atrophy, impaired choroidal perfusion	Not reported

Gardner⁹ studied 17 patients with anaemia and uraemia treated with CoCl₂, 4 patients noted tinnitus after 4–16 weeks of therapy and 1 developed nerve deafness after 12 weeks. Hearing was absent in a frequency range above 1000 cycles/s; within 10 weeks of stopping the drug, the hearing deficit recovered to the pretreatment range; in this patient nerve deafness recurred on re-starting therapy and recovered again when the drug was discontinued. The central nervous system was severely affected; the vestibular and cochlear parts of the eight nerves were damaged, as shown by the abnormal caloric tests and audiometric curves. Paraesthesia in the limbs, absent tendon jerks and calf tenderness indicated that the patient had a peripheral neuritis. The difficulty in walking was probably due to a combination of vestibular damage and peripheral neuropathy. A patient who received 400 mg of CoCl₂ daily for 6 weeks complained of paraesthesias, burning sensation on the soles with numbness of the toes. Symptoms disappeared when the therapy was stopped.

After a 6-month treatment with CoCl₂ (25 mg of CoCl₂ daily), a 35-year-old woman developed limb paraesthesia, unsteady gait, impaired hearing and dizzy spells in addition to nausea, vomiting and weight loss.¹⁰ Clinical examination confirmed bilateral nerve deafness, absent ankle reflexes and impaired vibration sense which all resolved within 4 months of Co withdrawal. Audiometry demonstrated a general decrease in sound perception of all frequencies, and caloric tests were also found to be abnormal. A Diagnosis of chronic renal failure complicated by CoCl₂ poisoning was made; the combination of prolonged exposure to the drug and poor renal clearance probably represents the reason of the severe toxic effects found in this patient.

Licht and co-workers¹¹ reported a case of severe visual disturbances in a man treated with CoCl₂ (200 mg daily) for pancytopenia and hypercellular bone marrow. An ophthalmological examination revealed bilateral reduced visual acuity (right eye 6/60; left eye 6/21). Fundus oculi examination revealed marked pallor of the right optic disk mainly on the temporal side and moderate temporal pallor of the left optic disk, suggesting both optic atrophy and abnormal choroidal perfusion. The peripheral visual field of the right eye showed a concentric constriction, more accentuated on the nasal side, and a central and paramacular scotoma. Both the peripheral and central visual fields of the left eye were normal.

The patient had received a total dose of 73 g of CoCl₂ over a period of 3 years and almost half of this amount had been administered during the 4 months preceding the appearance of the visual disturbances. Following cessation of the drug, there was no further deterioration in vision despite the progression of the underlying disease. The assumption that the visual changes were due to a toxic effect of Co therapy is supported by the fact that there was no further aggravation in visual function following cessation of this therapy.

In these studies, there are no indications of Co body burdens, but the constant intake of CoCl₂ for long periods leads us to consider that Co levels were very high.

Co neurotoxicity and prostheses

Release of Co ions from prosthetic materials occurs by wear, corrosion and mechanisms such as fretting, stress and fatigue.

Several studies have determined Co concentrations following hip replacement and during follow-up after implantation, many of which have compared implanted subjects with a control group. The release of metal ions is a well-documented consequence of total hip arthroplasty implants.^44,45 In some of these studies, Co concentrations in subjects with prosthesis were statistically higher than those in the control groups (Table 5 ).

Table 5.

Study that have investigated the release of cobalt from metal-on-metal surface arthroplasty. The concentrations of cobalt measured in serum and/or whole blood are expressed in µg/L. In the column ‘Control group’, we reported the statistic results of the comparison between subjects with prostheses and controls

Ref.	Study design	Time after implantation	Number of subjects	Cobalt		Control group	Expression of results	Type of prosthesis
Ref.	Study design	Time after implantation	Number of subjects	Serum	Whole blood	Control group	Expression of results	Type of prosthesis
44	Follow-up		28			No sign	Mean ± SD	Porous coated Co-Cr prostheses
		7–8 (d)		0.08 ± 0.04
		6–120 (w)		0.15 ± 0.04
47	Follow-up		76				Range	MoM THR
		1 (y)			0.1–4	p = 0.007
		2 (y)			0.3–6.5	p = 0.002
48	Case-control	27.5 (m)	20	0.65 (0.29–3.01)		p = 0.01	Median (range)	Oxford Universal Hip (OUH)
49	Follow-up		25				Mean ± 95% CI	Conserve^® plus surface arthoplasty
		3 (m)		1.26 ± 0.37
		6 (m)		1.20 ± 0.77
		12 (m)		1.07 ± 0.26
50	Follow-up	16 (m)		2.24 (0.83–2.59)			Median (range)	MoM THA
51	Case report	7 (m)	1	1.5				Co-Cr inlay and a stainless steel head
52	Follow-up		20				Range	MoM THR
		3 (m)		0.29–2.13
		6 (m)		0.25–1.91
		12 (m)		0.30–1.93
		24 (m)		0.25–0.95
53			10	0.58–7.93			Range	Cementless MoM THA
54			43			P < 0.001	Mean ± SD	MoM THR
54	Case-control	18–58 (m)		0.29 ± 0.17		P < 0.001	Mean ± SD	MoM THR
		62-107 (m)		0.40 ± 0.20
55		15.3 (m)		14.0 ± 10.9		P < 0.001	Mean ± SD	Conserve^® plus surface arthoplasty
15	Case-report	2 y after revision	1	398				Metal head and ceramic inlay
56	Case-control		5	2.01 (1–3.4)		p = 0.003	Mean (range)	Ring CoCr prosthesis
45	Follow-up		64				Mean ± SD	MoM hip resurfacing arthroplasty; Durom resurf. System
		3 (m)			0.90 ± 0.42
		6 (m)			0.80 ± 0.32
		12 (m)			0.67 ± 0.35
		24 (m)			0.59 ± 0.26
46	Follow-up		22				Median (range)	MoM THR
46		10 (y)		0.75 (0.3–50)			Median (range)	MoM THR
57		75 (m)	41	4.28		p < 0.001	Median	Foundation knee system
58	Case report	4 (y)	1	1.45			Mean	MoM hip resurfacing arthoplasty
59			70				Mean	MoM hip resurfacing arthoplasty
59		6 (m)			2.3	p < 0.001	Mean	MoM hip resurfacing arthoplasty
		12 (m)			2.4	p < 0.001
60	Follow-up	8	11			No sign	Mean ± SD	Cr-Co-Mo femoral head and Ti alloy acetabular
60		<5 (y)			0.224 ± 0.013	No sign	Mean ± SD	Cr-Co-Mo femoral head and Ti alloy acetabular
		>5 (y)			0.497 ± 0.145
61		6 (m)	15	2.45			Median	MoM hip resurfacing arthoplasty
62		5–59 (m)	29	1.37	1.16		Mean	Birmingham MoM hip resurfacing arthoplasty
16	Case report	3 m after revision	1		625			Metal femoral head and PE inlay
17	Case report		1	260	549			PE liner with Co-Cr head
63	Follow-up	24 (m)	77		1.49		Median	Unilateral resurfacing prosthesis
18	Case report		1		>400			Co-Cr alloy head and PE liner
19	Case report	36 (m)	2	122				MoM arthroplasty with ASR implants
		12 (m)		23
64	Case report	4 (y)	1		92 (74–110)		Mean (95% CI)	Birmingham MoM hip resurfacing arthoplasty

d: days, m: months, w: weeks, y: years, SD: standard deviation, no sign: nonsignificant, MoM: metal-on-metal, THR: total hip replacement, THA: total hip arthroplasty, ASR: surface replacement implants, PE: polyethylene, Co-Cr: cobalt–chromium, Ti: titanium, Co-Cr-Mo: cobalt–chromium-molybdenum.

High values of Co in biological matrices have been reported in six case reports.^15–19,64 In these subjects, an unusually high amount of metallic debris were evident around the articulating space of the prosthesis (metallosis). However, it is interesting to note that in some studies there were the subjects “outsiders” with high levels of Co in serum or blood not evident in cumulative concentration expressed as geometric/arithmetic mean or median (Table 6 ).

Table 6.

The highest outlier of cobalt concentrations (µg/L) extrapolated from studies of subjects with orthopaedic implants

Study	N	Serum	Whole blood
Schaffer et al.⁴⁷	1		11.50
Rasquinha et al.⁵³	1	7.93
Iavicoli et al.⁵⁵	1	43.20
Grübl et al.⁴⁶	1	50.10
Luetzner et al.⁵⁷	1	47.88
Isaac et al.⁶³	1		88.69
Isaac et al.⁶³	6		>10

Follow-up studies reported a running-in phase during the first 2 years after surgery (0.5–2 million cycles) during which Co ion concentration is significantly elevated.⁶³ After this period, there is a steady state in which the ion concentration is constant until the implant begins to fail and ion concentration begins to rise again.^65,66 A higher degree of running-in wear (15–20 μm/year) was quantified during the first year after surgery and a reduction to 2–5 μm/year after the second and third year.⁶⁷ More detailed investigations about prosthesis corrosion showed no statistically significative differences in Co concentration in the subgroup of different gender, age, body mass index and sports.^54,55

Although Co endogenous exposure has been consistently documented in clinical series and mainly associated with metal ion release from metal prosthesis,^68–70 neurotoxicity has been rarely described.

All the above-mentioned case reports,^15–19 with the exception of Von Schewelov’s study,⁶⁴ reported neurological symptoms (Table 7 ).

Table 7.

Neurotoxic effects in subjects with prostheses and related cobalt levels

	Subjects	Exposure before onset of the symptoms	Effects	Cobalt concentration
Megaterio et al.¹⁴	1	1 year	Sensory-motor polyneuropathy	Not reported
Steen et al.¹⁵	1	2 years	Optic atrophy and retinopathy with malfunction of the macula, bilateral deafness	398 μg/L CoS
Oldenburg et al.¹⁶	1	5 months	Headaches, neuropathy, convulsions and progressive hearing loss	625 CoB
Rizzetti et al.¹⁷	1	4 months	Selective II and VIII bilateral cranial nerve impairment and mild distal sensory-motor disturbances	549 μg/L CoB
Rizzetti et al.¹⁷	1	4 months		260 CoP
Ikeda et al.¹⁸	1	2 years	Progressive sensory disturbance, hearing loss	>400 CoB
Tower¹⁹	2	11–36 months	Tinnitus and hearing loss hand tremor, diminished coordination, poor memory, a non-refractive loss of peripheral visual acuity	122 and 23 CoS

CoB: cobalt in blood, CoS: cobalt in serum, CoP: cobalt in plasma.

Megaterio and colleagues¹⁴ described the case of a 47-year-old man who underwent revision of his right hip arthroplasty; 1 year after surgery, he developed thyreopathy and sensory-motor polyneuropathy. The next year, hip arthroplasty was removed and the Co and Cr concentrations in urine and blood, were higher than the normal values.

Steens and colleagues¹⁵ described a case of severe Co poisoning with neurological involvement after hip arthroplasty revision. A 53-year-old man, treated with a cemented total hip arthroplasty including a ceramic-on-ceramic pairing 6 years previously, underwent revision surgery 3 years later because of hip pain. Two years after surgery, he developed visual loss (he could just recognize outlines and colours but could not read) and deafness, in addition to numbness in his feet. Because of pain in his hip, radiographs performed, which showed prosthesis deterioration and wear. A massive metallosis and more than 500 ml of metallic black synovial fluid were found during revision, and examination of cerebrospinal fluid also showed an elevated Co concentration (3.2 μg/L). An ophthalmological examination revealed toxic atrophy of the optical nerve and retinopathy with malfunction of the macula. After prosthesis removal the hearing loss recovered and the numbness of the feet disappeared while vision recovered only partially.

Three years later, Oldenburg and co-workers¹⁶ reported the case of a 55-year-old man who experienced a massive deterioration of his metal femoral head by overlooked particles of the previously broken ceramic head; Co concentration in biological fluids was severely higher than normal value, and he displayed a severe Co intoxication with multiorganic disorder consisting of hypothyroidism, cardiomyopathy and the involvement of the central nervous system with headaches, neuropathy, convulsions and progressive hearing loss. Moreover, an increased distal sensory latency and a decreased conduction velocity of nervus peroneus were found. The echocardiogram demonstrated a moderate reduced systolic left ventricular function with concentric left ventricular hypertrophy, and the myocardial biopsy showed interstitial fibrosis. The authors described that 6 months after the revision surgery the symptoms subsided completely however in the long-term follow-up the patient’s neurologic symptoms have persisted but without describe it.

Tower¹⁹ reported two cases of Co neurotoxicity in hip replacement. A 49-year-old male reported anxiety, headaches, tinnitus and hearing loss 18 months after the implant; hand tremor, diminished coordination, slow cognition and poor memory after 30 months and a non-refractive loss of peripheral visual acuity after 36 months. Diasystolic dysfunction was found on interval echocardiography. Laboratory findings included a serum Co level of 83 μg/L, a cerebrospinal fluid Co level of 2.2 μg/L and a joint fluid Co level of 3200 μg/L. Eleven months after revision, the patient’s hip pain, affect, cognition, hearing, exercise tolerance, tremor and professional productivity improved, while his tinnitus and visual symptoms were stable.

The second case was about a 49-year-old male who complained of mental fog, memory loss, vertigo, hearing loss and dyspnoea 11 months after the metal on metal hip arthroplasty.

In both cases, the periprosthetic tissues showed necrosis, staining with metal debris and visible wear of the retrieved bearing. All symptoms, except the visual changes in the first case, improved 3 and 6 months post revision.

Recently, Ikeda and colleagues¹⁸ presented the case of a 56-year-old woman with a detailed analysis of polyneuropathy associated with artificial joint-related metallosis. She developed progressive sensory disturbance, hearing loss and hypothyroidism. Neurologically, she had painful dysaesthesia and distal paraesthesia in the elbows and knees, and her joint position sense was impaired in the fingers and feet. She had distal dominant slight muscle weakness, no deep tendon reflexes and bilateral sensorineural hearing loss. Sural nerve biopsy indicated axonopathy; nerve conduction studies showed that no sensory nerve action potentials could be evoked, but the results of motor conduction studies were normal. Pure tone audiometry showed hearing thresholds of 52 and 45 dB in the right and left ear, respectively. In this case, the replacement of ceramic liner fractured with new bearing surface that had a Co-Cr alloy head and a polyethylene liner may be the cause of metallosis observed, the ceramic fragments in the joint space can damage the new metal prosthesis forming metal debris. After revision surgery, blood levels of cobalt decreased, and her symptoms improved.

Two years ago, we reported the case of a 58-year-old woman presenting high concentration of Co released from a hip arthroplasty with hypothyroidism, a selective II and VIII bilateral cranial nerve impairment and mild distal sensory-motor disturbances (numbness and weakness in her lower limbs). Increased concentrations of Co and Cr were found in blood, plasma, urine and cerebrospinal fluid (whole blood: 549, plasma: 260, urine: 1100 and cerebrospinal fluid: 11.4 μg/L). Laboratory investigations ruled out haematologic, infectious, neoplastic, metabolic and immunologic diseases. Concomitantly, the patient underwent various instrumental investigations including brain MRI (revealing hyperintensity of optic nerves and traits), electromyography nerve conduction (EMG/NC; showing mild lower limbs nerve amplitude reduction), acoustic and visual evoked potentials (positive for bilateral absence of brain stem acoustic responses and irregular cortical visual responses). Some months later, she became definitely blind, severely deaf and wheelchair bounded due to severe limb motor weakness. The decreasing Co levels after chelation therapy and removal of the implant gave rise to an improvement in symptoms, especially acoustic deficits. During prosthesis removal a massive infiltration of periprosthetic tissues by metallic debris became evident; subsequent analysis of these fluids displayed elevated concentrations of Co and Cr (404 and 285 mg/L, respectively). In the following 8 months, the patient showed a progressive neurologic improvement leading to the functional recovery of hearing and sensory-motor function with only a partial increase in sight, in spite of the metal levels definitely decreased but still far above the reference values.¹⁷

In all the case reports, except the two cases by Tower,¹⁹ summarized above patients underwent revision surgery, and metal-on-polyethylene components were used after the fracture of a ceramic head. After this kind of revision, extraordinary severe metallosis were observed by several authors and some of them concluded that the use of metal-on-polyethylene articular pairing is contraindicated after ceramic head fracture^65,71; in fact fine ceramic particles can remain in situ and can cause the destruction of all kinds of metals, by acting like a grinding wheel.⁷²

In 2010, the United Kingdom’s Medical Products and Healthcare Devices Regulatory Agency published a medical device alert that recommended following the MoM implantees at least annually for 5 years postsurgery. The alert also recommended to measure Co and Cr in blood and to carry out imaging studies for patients who report painful hip replacements.

In order to identify patients who require closer surveillance, a follow-up determination 3 months after the first test is recommended in patients with Co or Cr >7 μg/L.²⁰ It is interesting to note that the proposed level of 7 μg/L is higher than the Biological Exposure Index of ACGIH for occupationally exposed people (1 μg/L Co in blood). Most patients implanted with MoM bearings have Co levels greater than those allowed in exposed workers and consequently they may develop an increased incidence of subclinical cognitive and cardiac impairments.

All cases, except the second reported by Tower¹⁹ where serum the Co concentration was 23 μl (but Co level in joint fluid was 3300 μg/L), were characterized by high concentrations of Co. In the case reported by Von Schewelov and colleagues,⁶⁴ a woman with metallosis and high levels of Co (92 μg/L) 4 years after a hip resurfacing procedure with a MoM hip implant had no symptoms except mild discomfort and instability in her hip. Only Oldenburg et al.¹⁶ and Tower¹⁹ reported cardiac manifestations similar to the symptoms reported after occupational and iatrogenic exposures.⁶

A determinant factor in the onset of neurological symptoms is certainly the massive amounts of Co for a long period, even though probably there are individual and predisposing factors that explain the low incidence of neurotoxicity among all the subjects with metal prosthesis.

Co toxicokinetics

Co distribution can be influenced, as other metallic elements, by binding to the plasma proteins. It has been reported that albumin and transferrin are the major serum protein carriers for Co in the blood. Co is transported in circulation by albumin,⁷³ and several studies indicated that the metal is bound to the N-terminal peptides of albumin at the sequence Asp-Ala-His-Lys, similar to copper and nickel.^74–76 However, a recent study demonstrated that Co also binds to sites A and B on the albumin molecule.⁷⁷

The Co binding to albumin has been studied because it is the basis of the so-called Albumin Cobalt Binding test (ACB test) approved by the Food and Drug Administration for myocardial ischaemia evaluation. The alteration of the N-terminus of human serum albumin gives rise to the commonly defined ischaemia-modified albumin (IMA).^75,78,79 However, other pathologies such as trauma, scleroderma, diabetes, bacterial or viral infections, end-stage renal disease, liver cirrhosis, brain ischaemia, peripheral arterial disease and cancer are able to influence albumin binding to Co.^80–82 Co binding to human serum albumin is also reduced in the presence of copper; Bar-Or et al.⁷⁶ showed that addition of equimolar concentrations of copper before Co addition in normal plasma resulted in no Co-albumin species formation. In addition, there are also evidences of possible genetic variants of human serum albumin, in particular structural changes at the N-terminus abolish transition metal binding.^83,84

Co ions can also bind to transferrin, a family of large non-haeme iron-binding glycoproteins with a molecular weight of 80 kDa involved in the iron uptake.⁸³ To determine the stability of Co-transferrin complex in the presence of albumin, Smith⁸⁴ incubated a complex with albumin and showed that the absorbance of the complex decreased by about 50%, suggesting that half of the Co from Co-transferrin had been removed. Moshtaghie and co-workers⁸⁵ in a study of Co and iron binding to human serum transferrin showed that iron binding was reduced by 20% when 225 nmol/ml of Co was added to the reaction mixture.

For these reasons, it might be useful to measure the Co in the various blood fractions to assess the distribution of the metal and to quantify the binding with the plasmatic proteins.

The uptake of Co by the cells represents another important step. Even if it is not known whether Co enters mammalian cells via a specific transporter, it has been shown that P2X7 transporter is involved in the uptake of divalent cations and Co.⁸⁶ In the same way, the divalent metal transporter 1 (DMT1) previously known as DCT1, NRAMP2 or Slc11a2 is a active transporter for iron, zinc, manganese, Co, cadmium, copper, nickel and lead.^87,88

DMT1 is identified as a key protein in the neuron defence mechanism against metal toxicity and it is regulated by a family interacting protein 1 (Ndfip1); in fact the induction of Ndfip1 expression protects neurons from metal toxicity while the absence leads to metal hypersensitivity.⁸⁹ We also mentioned the Zip family protein (ZRT- and IRT-like), a group of proteins with the capacity to transport different divalent cations into the cell.⁹⁰

Mechanism of action

The available data in scientific literature indicate that Co is cytotoxic to many cell types, including neural cells^91–93 and it can induce cell death by apoptosis and necrosis.⁹⁴ Co can cause DNA fragmentation,^95–97 activation of caspases,⁹⁴ increased production of reactive oxygen species (ROS),^92,95,98 augmented phosphorylation of mitogen-activated protein (MAP) kinases^93,94 and transcriptional repression of the human p53 gene.⁹⁸ Studies on the neurotoxic effects of Co in rats have shown behavioural alterations and depletion of neurotransmitters like dopamine, norepinephrine and serotonin.^99,100 Co decreases postsynaptic responses induced by neurotransmitters in vitro and inhibits the synaptic transmission through a presynaptic blockage of calcium channels.¹⁰¹

In an old experimental study, Alagna and D’Acquino¹⁰² found pathological changes in the lens, retina, choroid and optic nerve following subcutaneous administration of CoCl₂ in 16 rabbits (900 mg in 30 days). Fatty degeneration was found in the cells of the outer and inner retinal molecular layers and in the ganglion cells. Marked oedema, pigmentary disturbances and degenerative cellular changes were found in the choroid mainly in the posterior pole. The fibres of the optic nerves were swollen and tortuous with fragmentation in their myelin sheaths.

In 1994, a Polish study¹⁰³ reported atrophy of nerve fibres, injury to the ganglion, lesion in amacrine, bipolar and horizontal cells and alteration in the nucleus of photoreceptors in the retina of rabbits exposed intraperitoneally to CoCl₂ (8 mg/kg/die for 25 days).

The Co action on the retina and optic nerve may have some analogy with the ophthalmic findings found in the toxic optic neuropathy due to other toxicants such as quinine, lead, tobacco and methanol.^104–106

The toxic optic neuropathies are therefore ascribed to mitochondrial oxidative phosphorylation, similar from a clinical point of view to the congenital mitochondrial optic neuropathies, for example, Leber’s hereditary optic neuropathy and Kjer’s optic neuropathy. It is known that many optic neuropathies of both genetic and environmental origins, are determined by mitochondrial dysfunctions.¹⁰⁷

The mitochondria appeared to be a principal target of Co toxicity, as shown by the loss of mitochondrial membrane potential and the apoptogenic factors release from mitochondria.¹⁰⁸ At normoxic conditions, Co is able to stabilize the α-subunit of hypoxia-inducible factor (HIF-1α) by blocking its ubiquitination and proteasomal degradation. Increased levels of HIF-1α result in higher transcription of a set of genes that encode several proteins, for example, glycolytic enzymes, erythropoietin and heat shock proteins, important for the adaptation of cells to hypoxic stress.^109,110 Recent data support an important role of HIF-1α in modulating mitochondrial function. Two studies described HIF-1-dependent induction of pyruvate dehydrogenase kinase-1, which reduces mitochondrial oxygen consumption and ROS production during hypoxia.^111,112 In addition, HIF-1 alters electron transport chain function by mediating switching of a subunit of complex IV.¹¹³

The effects of Co on auditory functions can also be associated with a toxic neuropathy. The ototoxicity of some drugs (antibiotic, anti-malarial and antineoplastic) is caused by the production and action of ROS on basal outer hair cells that appear to be more sensitive.¹¹⁴

It has been shown that basal hair cells of guinea pigs contain lower amounts of the free radical scavenger glutathione and that the addition of this agent, and/or other antioxidants, influences the susceptibility gradient to neomycin.¹¹⁵ Other mechanisms such as aminoglycoside-induced hair cell death are not so clear, even if it is estimated that 17–33% of cases are associated with mutations of the mitochondrial ribosomal RNA (rRNA) gene.¹¹⁶ An analogue Co ototoxicity occurs with cisplatin that generates ROS in explants of cochlear tissues.¹¹⁷ ROS can deplete cochlear tissues of antioxidant protective molecules, for example, glutathione and antioxidant enzymes; this may allow lipid peroxidation, as shown by increased concentrations of malondialdehyde, toxic lipid peroxides and aldehydes (e.g. 4-hydroxynonenal and peroxynitrite).^118,119

It is known that Co ions are able to induce the ROS formation in vivo and in vitro. Co catalyzes the generation of hydroxyl radicals from hydrogen peroxide in a Fenton type reaction. The generation of ROS during hypoxia as well as in the presence of Co has been described.^120,121 Exposure to Co can result in the rise of oxidative stress, decrease of reduced glutathione levels and the gain of oxidized glutathione levels, in addition to activation of the hexose monophosphate shunt and damage to DNA free-radical induced.^121–125

A preferential damage to cochlear hair cells may be explained by heteroplasmic mutations occurring in the mitochondria of specific organs, such as in Leber’s hereditary optic neuropathy. Genetic predisposition to hearing loss induced by cisplatin may be related to mitochondrial mutations. Among 20 patients with ototoxic effect by cisplatin, 5 were found to cluster in a rare European J mitochondrial haplogroup that has been associated with Leber’s hereditary optic atrophy.¹²⁶ Ghelli and colleagues¹²⁷ showed that mitochondrial DNA haplogroups modulated the response of Leber’s optic neuropathy to 2,5-hexanedione, in particular, haplogroup J makes cells more sensitive to its toxic effect.

Furthermore, even the OPA1 gene is involved in autosomal-dominant optic atrophy that affects retinal ganglion cells and the axons forming the optic nerve, leading to progressive visual loss. Specific OPA1 mutations are responsible for other several distinct clinical presentations, such as dominant optic atrophy with deafness and severe multi-systemic syndromes which involve neurological and neuromuscular symptoms similar to those due to mitochondrial oxidative phosphorylation defects or mitochondrial DNA instability.¹²⁸

Finally, the findings brain MRI¹⁷ in one patient with arthroprosthetic cobaltism and sural nerve biopsy in another¹⁸ suggest that neurotoxicity occurs by demyelination and axonal loss. The role of ROS in demyelination is demonstrated and the mechanism of action known.^129,130 Oxidative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria. Oligodendrocytes are sensitive to oxidative stress in vitro, seemingly due to a diminished capacity for antioxidant defence and the presence of raised risk factors. Oxidative stress might therefore result in selective oligodendrocyte death and thereby demyelination in vivo. The reactive species may also damage the myelin sheath, promoting its attack by macrophages. Damage can occur directly by lipid peroxidation and indirectly by the activation of proteases and phospholipase A2.¹²⁹

Conclusion

Bilateral optic atrophy, retinopathy, bilateral nerve deafness and sensory-motor polyneuropathy are sporadically reported in different situations characterized by Co exposures.

At present, the most frequent route of exposure is the release from metallic prosthesis, while in the past occupational or iatrogenic exposures were often signaled. If we consider that in the past 15 years there have been about 1 million of MoM hips implanted worldwide, this argument becomes timely and relevant.

Often, orthopaedic surgeons and the general medical community are unaware that subjects with high Co concentrations are at risk of progressive audio-vestibular, visual and cognitive impairment, and it is not yet known whether these impairments are completely reversible.

It is also possible that a subtle neurotoxicity, like minor alterations in hearing, sight, cognition and memory, in patients with MoM hip implants might be confused with the normal aging.

On the other hand, the small number of cases, with respect to the many people potentially exposed to Co, could be due to different contributory factors such as a random breakage of the prosthesis, an individual predisposition, altered metal-binding proteins, an alteration of transport processes in target cellular or a genetic susceptibility to develop the damage. The possibility of an individual susceptibility may be confirmed by the presence of subjects with high blood concentrations of Co but no clinical symptoms.

In our view, the mechanisms of binding and transport represent the key point for further considerations. The binding proteins besides influencing the proportion of free and active metal can interfere with the prosthesis interface. In fact once the Co is released from the prosthesis, its transport, absorption, excretion and deposition in tissues are strongly dependent on the type of Co biological binders. The association of the released metal to proteins, for instance, might increase the corrosion rate at the implant/biology interface by increasing the dissolution of the surface passive (oxide) film formed on metallic materials. However, an alteration of binding capacity can be easily detected by the determination of Co in different blood fractions.

The possible mechanisms of action include Co interaction with the mitochondria and the ROS formation with consequent probable mitochondrial neuropathies. It is well known that mitochondrial dysfunction may be caused by specific mutations in the mitochondrial DNA and may enhance the influence of some environmental factors. This predisposition is likely to be genetically determined with a possible role played by polymorphic variation of mitochondrial genetic background.

An interesting starting point for further investigations could be an experimental model of very high Co concentration exposure, that bypassing any subjectivity or individual susceptibility that influences the accumulation, could probably allow the observation of a possible neurotoxic effect.

Footnotes

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Domingo

. Cobalt in the environment and its toxicological implications. Rev Environ Contam Toxicol 1989; 108: 105–132.

Lauwerys

Lison

. Health risks associated with cobalt exposure—an overview. Occup Environ Med 1994; 51: 447–450.

Barceloux

. Cobalt. J Toxicol Clin Toxicol 1999; 37: 201–206.

Angerer

Heinrich

. Cobalt. In: Friberg

Nordberg

Vouk

(eds) Handbook on the toxicology of metals. 2nd ed. New York, NY: Elsevier Science, 1986, pp.251–261.

Lison

. Cobalt. In: Norberg

Fowler

Norberg

Friberg

(eds) Handbook on the toxicology of metals. 3rd ed. Burlington, USA: Elsevier, 2007, pp.511–528.

Smith

HIC

Carson

BL.

Trace metals in the environment. Volume 6: Cobalt. An appraisal of environmental exposure. Ann Arbor, MI: Ann Arbor Science, 1981.

International Agency for Research on Cancer. Chlorinated Drinking-water; Chlorination By-products; Some Other Halogenated Compounds; Cobalt and Cobalt Compounds Monographs on the Evaluation of Carcinogenic Risks to Humans IARC, 1991. Lyon.

International Agency for Research on Cancer. Cobalt in Hard Metals and Cobalt Sulfate, Gallium Arsenide, Indium Phosphide and Vanadium Pentoxide Monographs on the Evaluation of Carcinogenic Risks to Humans IARC, 2006. Lyon.

Gardner

. The use of cobalt chloride in anaemia associated with chronic renal disease. J Lab Clin Med 1953; 49: 56–63.

10.

Schirrmacher

UOE

. Case of cobalt poisoning. Br Med J 1967; 1: 544–545.

11.

Licht

Oliver

Rachmilewitz

. Optic atrophy following treatment with cobalt chloride in a patient with pancytopenia and hypercellular marrow. Isr J Med Sci 1972; 8: 61–66.

12.

Jordan

Whitman

Harbut

. Memory deficits in workers suffering from hard metal disease. Toxicol Lett 1990; 54: 241–243.

13.

Meecham

Humphrey

. Industrial exposure to cobalt causing optic atrophy and nerve deafness: a case report. J Neurol Neurosurg Psychiatry 1991; 54: 374–375.

14.

Megaterio

Galetto

Alossa

Capretto

. Systemic effects of ionic release in wear of prosthetic head: a case report. Giornale Italiano di Ortopedia e Traumatologia 2001; 27: 173–175.

15.

Steens

Von Foerster

Katzer

. Severe cobalt poisoning with loss of sight after ceramic-metal pairing in a hip—a case report. Acta Orthop 2006; 77: 830–832.

16.

Oldenburg

Wegner

Baur

. Severe cobalt intoxication due to prosthesis wear in repeated total hip arthroplasty. J Arthroplasty 2009; 24: 825e15–825e20.

17.

Rizzetti

Liberini

Zarattini

, et al. Loss of sight and sound Could it be the hip? Lancet 2009; 373: 1052.

18.

Ikeda

Takahashi

Kabata

, et al. Polyneuropathy caused by cobalt-chromium metallosis after total hip replacement. Muscle Nerve 2010; 42: 140–143.

19.

Tower

. Arthroprosthetic cobaltism: neurological and cardiac manifestations in two patients with metal-on-metal arthroplasty: a case report. J Bone Joint Surg 2010; 92: 1–5.

20.

Medicines and Healthcare Products Regulatory Agency UK.; MDA/2010/033: All metal-on-metal hip replacements. MDA/2010/033 Issued: 22 April 2010. http://www.mhra.gov.uk/Publications/Safetywarnings/MedicalDeviceAlerts/CON079157 (accessed 10 June 2010).

21.

Tower

. Arthroprosthetic cobaltism: identification of the at-risk patient. Alaska Med 2010; 52: 28–32.

22.

Agency for toxic substances and disease registry. Cobalt. http://www.atsdr.cdc.gov/ToxProfiles/tp33.pdf (2004, accessed 20 March 2010).

23.

Broding

Michalke

Göen

Drexler

. Comparison between exhaled breath condensate analysis as a marker for cobalt and tungsten exposure and biomonitoring in workers of a hard metal alloy processing plant. Int Arch Occup Environ Health 2009; 82: 565–573.

24.

Apostoli

Porru

Alessio

. Urinary cobalt excretion in short time occupational exposure to cobalt powders. Sci Total Environ 1994; 150: 129–132.

25.

Varela-Moreiras

Murphy

Scott

. Cobalamin, folic acid, and homocysteine. Nutr Rev 2009; 67: S69–S72.

26.

Larese Filon

Maina

Adami

. In vitro percutaneous absorption of cobalt. Int Arch Occup Environ Health 2004; 77: 85–89.

27.

Scansetti

Botta

Spinelli

, et al. Absorption and excretion of cobalt in the hard metal industry. Sci Total Environ 1994; 150: 141–144.

28.

Swennen

Buchet

Stánescu

, et al. Epidemiological survey of workers exposed to cobalt oxides, cobalt salts, and cobalt metal. Br J Ind Med 1993; 50: 835–842.

29.

Scansetti

Maina

Botta

, et al. Exposure to cobalt and nickel in the hard-metal production industry. Int Arch Occup Environ Health 1998; 71: 60–63.

30.

ACGIH. TLVs^® BEIs^®: threshold limit values for chemical and physical agents and biological exposure indices. Cincinnati, USA: ACGIH, 2010.

31.

Commission for the Investigation of Health hazards of Chemical Compounds in the Work Area, DFG (ed) List of MAK and BAT values 2006, report no. 42. Weinheim: Wiley-VCH, 2006.

32.

Alexanderson

Lidums

Studies on effects of exposure to cobalt. Concentration of cobalt in blood and urine as indicators of exposure. Arbete Och Halsa 1979; 8: 1–23.

33.

Morgan

. A study into the health and mortality of men exposed to cobalt and oxides. J Soc Occup Med 1983; 33: 181–186.

34.

Angerer

Heinrich

Felixberger

. Verhandlungen der deutschen gesellschaft für Arbeitsmedizin Stuttgart Gentner Verlag, 1984.

35.

Pellet

Perdrix

Vincent

Mallion

. Dosage biologique du cobalt urinarire. Arch Mal Professionnelles 1984; 45: 81–85.

36.

Hartung

Schaller

(eds) Verhandlungen der deutschen gesellschaft für. Arbeitsmedizin: Stuttgart Gentner Verlag, 1984.

37.

Ichikawa

Kusaka

Goto

. Biological monitoring of cobalt exposure, based on cobalt concentrations in blood and urine. Int Arch Occup Environ Health 1985; 55: 269–276.

38.

Posma

Dijstelberger

. Heavy Metals In The Environment TD Lekkas TD Edinburgh CEP consultants LTD; 1985.

39.

Lison

Buchet

Swennen

, et al. Biological monitoring of workers exposed to cobalt metal, salt, oxides, and hard metal dust. Occup Environ Med 1994; 51: 447–450.

40.

Yokota

Johyama

Kunitani

, et al. Urinary elimination of nickel and cobalt in relation to airborne nickel and cobalt exposures in a battery plant. Int Arch Occup Environ Health 2007; 80: 527–531.

41.

De Palma

Manini

Sarnico

, et al. Biological monitoring of tungsten (and cobalt) in workers of a hard metal alloy industry. Int Arch Occup Environ Health 2010; 83: 173–181.

42.

Fourth National Report on Human Exposure to Environmental Chemicals, Updated Tables, July 2010. Centers for Disease Control and Prevention, Atlanta. http://www.cdc.gov/exposurereport/ (accessed 30 September 2010).

43.

Christensen

Poulsen

. A 1982-1992 surveillance programme on Danish pottery painters Biological levels and health effects following exposure to soluble or insoluble cobalt compounds in cobalt blue dyes. Sci Total Environ 1994; 150: 95–104.

44.

Sunderman

Hopfer

Swift

, et al. Cobalt, chromium and nickel concentrations in body fluids of patients with porous coated knee or hip prostheses. J Orthop Res 1989; 7: 307–315.

45.

Vendittoli

Ganapathi

Lavigne

. Blood and urine metal ion levels in young and active patients after Birmingham hip resurfacing arthroplasty. J Bone Joint Surg Br 2007; 89: 989–990.

46.

Grübl

Marker

Brodner

, et al. Long-term follow-up of metal-on-metal total hip replacement. J Orthop Res 2007; 25: 841–848.

47.

Schaffer

Pilger

Engelhardt

, et al. Increased blood cobalt and chromium after total hip replacement. J Toxicol Clin Toxicol 1999; 37: 839–844.

48.

Harding

Bonomo

Crawford

, et al. Serum levels of cobalt and chromium in a complex modular total hip arthroplasty system. J Arthroplasty 2002; 17: 893–895.

49.

Skipor

Campbell

Patterson

, et al. Serum and urine metal levels in patients with metal-on-metal surface arthroplasty. J Mater Sci Mater Med 2002; 13: 1227–1234.

50.

Clarke

Lee

Arora

Villar

. Levels of metal ions after small- and large-diameter metal-on-metal hip arthroplasty. J Bone Joint Surg Br 2003; 85: 913–917.

51.

Keel

Kuster

. Massive wear of an incompatible metal-on-metal articulation in total hip arthroplasty. J Arthroplasty 2004; 19: 638–642.

52.

Back

Young

Shimmin

. How do serum cobalt and chromium levels change after metal-on-metal hip resurfacing? Clin Orthop Relat Res 2005; 438: 177–181.

53.

Rasquinha

Ranawat

Weiskopf

, et al. Serum metal levels and bearing surfaces in total hip arthroplasty. J Arthroplasty 2006; 21: 47–52.

54.

Milosev

Pisot

Campbell

. Serum levels of cobalt and chromium in patients with Sikomet metal-metal total hip replacements. J Orthop Res 2005; 23: 526–535.

55.

Iavicoli

Falcone

Alessandrelli

, et al. The release of metals from metal-on-metal surface arthroplasty of the hip. J Trace Elem Med Biol 2006; 20: 25–31.

56.

Sauvé

Mountney

Khan

, et al. Metal ion levels after metal-on-metal Ring total hip replacement: a 30-year follow-up study. J Bone Joint Surg Br 2007; 89: 586–590.

57.

Luetzner

Krummenauer

Lengel

, et al. Serum metal ion exposure after total knee arthroplasty. Clin Orthop Relat Res 2007; 461: 136–142.

58.

De Haan

Campbell

Reid

, et al. Metal ion levels in atriathlete with a metal-on-metal resurfacing arthroplasty of the hip. J Bone Joint Surg Br 2007; 89: 538–541.

59.

Antoniou

Zukor

Mwale

, et al. Metal ion levels in the blood of patients after hip resurfacing: a comparison between twenty-height and thirty-six millimeter-head metal-on-metal prostheses. J Bone Joint Surg 2008; 90: 142–148.

60.

Sarmiento-González

Marchante-Gayón

Tejerina-Lobo

. High-resolution ICP-MS determination of Ti, V, Cr, Co, Ni, and Mo in human blood and urine of patients implanted with a hip or knee prosthesis. Anal Bioanal Chem 2008; 391: 2583–2589.

61.

Heisel

Streich

Krachler

, et al. Characterization of the running-in period in total hip resurfacing arthroplasty: an in vivo and in vitro metal ion analysis. J Bone Joint Surg 2008; 90: 125–133.

62.

Walter

Marel

Harbury

Wearne

. Distribution of chromium and cobalt ions in various blood fractions after resurfacing hip arthroplasty. J Arthroplasty 2008; 23: 814–821.

63.

Isaac

Siebel

Oakeshott

, et al. Changes in whole blood metal ion levels following resurfacing: serial measurements in a multi-centre study. Hip Int 2009; 19: 330–337.

64.

Von Schewelov

Sanzén

. Catastrophic failure due to aggressive metallosis 4 years after hip resurfacing in a woman in her forties—a case report. Acta Orthop 2010; 81: 402–404.

65.

Lhotka

Szekeres

Steffan

, et al. Four-year study of cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip replacements. J Orthop Res 2003; 21: 189–195.

66.

Maezawa

Nozawa

Hirose

, et al. Cobalt and chromium concentrations in patients with metal-on-metal and other cementless total hip arthroplasty. Arch Orthop Trauma Surg 2002; 122: 283–287.

67.

Schmidt

Bak

Hambrecht

, et al. Feasibility of a visual prosthesis for the blind based on intracortical microstimulation of the visual cortex. Brain 1996; 119: 507–522.

68.

Amstutz

Beaule

Dorey

, et al. Metal-on-metal hybrid surface arthroplasty: two to six-year follow-up study. J Bone Joint Surg 2004; 86: 28–39.

69.

Basle

Bertrand

Guyetant

, et al. Migration of metal and polyethylene particles from articular prostheses may generate lymphadenopathy with histiocytosis. J Biomed Mater Res 1996; 30: 157–163.

70.

Szuszczewicz

Schmalzried

Petersen

. Progressive bilateral pelvic osteolysis in a patient with McKee-Farrar metal–metal total hip prostheses. J Arthroplasty 1997; 12: 819–824.

71.

Matziolis

Perka

Disch

. Massive metallosis after revision of a fractured ceramic head onto a metal head. Arch Orthop Trauma Surg 2003; 123: 48–50.

72.

Gallinaro

Piolatto

. Blind and deaf after total hip replacement? author reply of Rizzetti MC, Liberini P, Zarattini G, Catalani S, Pazzaglia U, Apostoli P, Padovani. Lancet 2009; 373: 1944; author reply 1944-5.

73.

Sadler

Tucker

Viles

. Involvement of a lysine residue in the N-terminal Ni²⁺ and Cu²⁺ binding site of serum albumins. Comparison with Co²⁺, Cd²⁺ and Al³⁺. Eur J Biochem 1994; 220: 193–200.

74.

Bar-Or

Lau

Winkler

. A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. Am J Emerg Med 2000; 19: 311–315.

75.

Bar-Or

Rael

Bar-Or

, et al. The cobalt-albumin binding assay: insights into its mode of action. Clin Chim Acta 2008; 387: 120–127.

76.

Bar-Or

Rael

Lau

, et al. An analog of the human albumin N-terminus (Asp-Ala-His-Lys) prevents formation of copper-induced reactive oxygen species. Biochem Biophys Res Commun 2001; 284: 856–862.

77.

Mothes

Faller

. Evidence that the principal CoII-binding site in human serum albumin is not at the N-terminus: implication on the albumin cobalt binding test for detecting myocardial ischemia. Biochemistry 2007; 46: 2267–2274.

78.

Lippi

Brocco

Salvagno

, et al. High-workload endurance training may increase serum ischemia-modified albumin concentrations. Clin Chem Lab Med 2005; 43: 741–744.

79.

Lippi

Montagnana

Salvagno

Guidi

. Potential value for new diagnostic markers in the early recognition of acute coronary syndromes. Can J Emerg Med 2006; 8: 27–31.

80.

Govender

De Greef

Delport

, et al. Biological variation of ischaemia-modified albumin in healthy subjects. Cardiovasc J Afr 2008; 19: 141–144.

81.

Bhagavan

Lai

Rios

, et al. Evaluation of human serum albumin cobalt binding assay for the assessment of myocardial ischemia and myocardial infarction. Clin Chem 2003; 49: 581–585.

82.

Sheat

Peach

George

. Rapid detection and initial characterization albumin. Clin Chem 1991; 37: 1221–1224.

83.

Sun

Sadler

. Transferrin as a metal ion mediator. Chem Rev 1999; 99: 2817–2842.

84.

Smith

TAD

. Human serum transferrin cobalt complex: stability and cellular uptake of cobalt. Bioorg Med Chem 2005; 13: 4576–4579.

85.

Moshtaghie

Badii

Mohammadian

. The comparative study of binding characteristics of cobalt and iron to human serum transferrin. J Res Med Sci 2004; 6: 250–254.

86.

Virginio

Church

North

Surprenant

. Effects of divalent cations, protons and calmidazolium at the rat P2X7 receptor. Neuropharmacology 1997; 36: 1285–1294.

87.

Picard

Govoni

Jabado

Gros

. Nramp2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool. J Biol Chem 2000; 275: 35738–35745.

88.

Forbes

Gros

. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 2003; 102: 1884–1892.

89.

Howitt

Putz

Lackovic

, et al. Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc Natl Acad Sci U S A 2009; 106: 15489–15494.

90.

Himeno

Yanagiya

Fujishiro

. The role of zinc transporters in cadmium and manganese transport in mammalian cells. Biochimie 2009; 91: 1218–1222.

91.

Wang

Hazra

Mitra

, et al. Mitochondrial DNA damage and a hypoxic response are induced by CoCl(2) in rat neuronal PC12 cells. Nucleic Acids Res 2000; 28: 2135–2140.

92.

Olivieri

Hess

Savaskan

, et al. Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion. J Pineal Res 2001; 31: 320–325.

93.

Yang

Pyen

Lee

, et al. Cobalt chloride induced apoptosis and extracellular signal-regulated protein kinase 1/2 activation in rat C6 glioma cells. J Biochem Mol Biol 2004; 37: 480–486.

94.

Zou

Zeng

Zhuo

, et al. Involvement of caspase-3 and p38 mitogen-activated protein kinase in cobalt chloride-induced apoptosis in PC12 cells. J Neurosci Res 2002; 67: 837–843.

95.

Zou

Yan

, et al. Cobalt chloride induces PC12 cells apoptosis through reactive oxygen species and accompanied by AP-1 activation. J Neurosci Res 2001; 64: 646–653.

96.

Araya

Maruyama

Inoue

, et al. Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 2002; 283: L849–L858.

97.

Graham

Frazier

Thompson

, et al. A unique pathway of cardiac myocyte death caused by hypoxia-acidosis. J Exp Biol 2004; 207: 3189–3200.

98.

Lee

Rho

. Transcriptional repression of the human p53 gene by cobalt chloride mimicking hypoxia. FEBS Lett 2001; 507: 259–263.

99.

Czarnota

Whitman

Berman

. Activity and passive-avoidance learning in cobalt-injected rats. Int J Neurosci 1998; 93: 29–33.

100.

Hasan

Ali

Anwar

. Cobalt-induced depletion of dopamine, norepinephrine & 5-hydroxytryptamine concentration in different regions of the rat brain. Indian J Exp Biol 1980; 18: 1051–1053.

101.

Gerber

Gähwiler

. Cobalt blocks postsynaptic responses induced by neurotransmitters in the hippocampus in vitro. Neurosci Lett 1991; 134: 53–56.

102.

Alagna

D’Acquino

. Alterazioni oculari da cloruro di cobalto. Archivio di Ottalmologia 1956; 60: 5–29.

103.

Monies

Prost

. Experimental studies on lesions of eye tissues in cobalt intoxication. Klinika Oczna 1994; 96: 135–139.

104.

Prasad

Kodali

Khuraijam

, et al. Acute confusion and blindness from quinine toxicity. Eur J Emerg Med 2003; 10: 353–356.

105.

Fox

Rubinstein

Hsu

Developmental lead exposure inhibits adult rat retinal, but not kidney, Na+,K(+)-ATPase. Toxicol Appl Pharmacol 1991; 109: 482–493.

106.

Tsao

Aitken

Johns

. Smoking as an aetiological factor in a pedigree with Leber’s hereditary optic neuropathy. Br J Ophthalmol 1999; 83: 577–581.

107.

Carelli

Ross-Cisneros

Sadun

. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retinal Eye Res 2004; 23: 53–89.

108.

Karovic

Tonazzini

Rebola

, et al. Toxic effects of cobalt in primary cultures of mouse astrocytes: similarities with hypoxia and role of HIF-1alpha. Biochem Pharmacol 2007; 73: 694–708.

109.

Sharp

Ran

, et al. Hypoxic preconditioning protects against ischemic brain injury. NeuroRx 2004; 1: 26–35.

110.

Wiesener

Maxwell

. HIF and oxygen sensing; as important to life as the air we breathe? Ann Med 2003; 35: 183–190.

111.

Kim

Tchernyshyov

Semenza

Dang

. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3: 177–185.

112.

Papandreou

Cairns

Fontana

, et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006; 3: 187–197.

113.

Fukuda

Zhang

Kim

, et al. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 2007; 129: 111–122.

114.

Hirose

Hockenberry

Rubel

. Reactive oxygen species in chick hair cells after gentamicin exposure in vitro. Hear Res 1997; 104: 1–14.

115.

Sha

Taylor

Forge

. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res 2001; 155: 1–8.

116.

Hirose

Westrum

Cunningham

Rubel

. Electron microscopy of degenerative changes in the chick basilar papilla after gentamicin exposure. J Comp Neurol 2004; 470: 164–180.

117.

Clerici

DiMartino

Prasad

. Direct effect of reactive oxygen species on cochlear outer hair cells. Hear Res 1995; 84: 30–40.

118.

Rybak

Whitworth

Mukherjea

Ramkumar

. Mechanisms of cisplatin induced ototoxicity and prevention. Hear Res 2007; 226: 157–167.

119.

Lee

Nakagawa

Kita

. Role of reactive radicals in degeneration of the auditory system of mice following cisplatin treatment. Acta Otolaryngol 2004; 124: 1131–1135.

120.

Semenza

. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999; 15: 551–578.

121.

Valko

Rhodes

Moncol

, et al. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006; 160: 1–40.

122.

Lewis

CPL

Demedts

Nemery

Indices of oxidative stress in hamster lung following exposure to cobalt(II) ions: In vivo and in vitro studies. Am J Respir Cell Mol Biol 1991; 5: 163–169.

123.

Kasprzak

Zastawny

North

, et al. Oxidative DNA base damage in renal, hepatic, and pulmonary chromatin of rats after intraperitoneal injection of cobalt(II) acetate. Chem Res Toxicol 1994; 7: 329–335.

124.

Hoet

PMH

Roesems

Demedts

Nemery

. Activation of the hexose monophosphate shunt in rat type II pneumocytes as an early marker of oxidative stress caused by cobalt particles. Arch Toxicol 2002; 76: 1–7.

125.

Ivancsits

Diem

Pilger

Rüdiger

. Induction of 8-hydroxy-2'-deoxyguanosine by cobalt(II) and hydrogen peroxide in vitro. J Toxicol Environ Health A 2002; 65: 665–676.

126.

Peters

Preisler-Adams

Lanvers-Kaminsky

. Sequence variations of mitochondrial DNA and individual sensitivity to the ototoxic effect of cisplatin. Anticancer Res 2003; 23: 1249–1255.

127.

Ghelli

Porcelli

Zanna

, et al. The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber's hereditary optic neuropathy cells to 2,5-hexanedione toxicity. PLoS One 2009; 4: e7922.

128.

Amati-Bonneau

Milea

Bonneau

, et al. OPA1-associated disorders: phenotypes and pathophysiology. Int J Biochem Cell Biol 2009; 41: 1855–1865.

129.

Smith

Kapoor

Felts

. Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol 1999; 9: 69–92.

130.

Hartung

Jung

Stoll

, et al. Inflammatory mediators in demyelinating disorders of the CNS and PNS. J Neuroimmunol 1992; 40: 197–210.

Neurotoxicity of cobalt

Abstract

Keywords

Introduction

Physical and chemical properties of Co

Co neurotoxicity in occupational exposure

Iatrogenic Co neurotoxicity

Co neurotoxicity and prostheses

Co toxicokinetics

Mechanism of action

Conclusion

Footnotes

References