Orthopaedic metals and their potential
toxicity in the arthroplasty patient

The long-term effects of metal-on-metal arthroplasty are currently under scrutiny because
I. D. Learmonth,
of the potential biological effects of metal wear debris. This review summarises data
C. P. Case
describing the release, dissemination, uptake, biological activity, and potential toxicity of
metal wear debris released from alloys currently used in modern orthopaedics. The

introduction of risk assessment for the evaluation of metal alloys and their use in
arthroplasty patients is discussed and this should include potential harmful effects on
immunity, reproduction, the kidney, developmental toxicity, the nervous system and

Total hip replacement (THR) and resurfacing Prosthesis-derived metal wear debris
arthroplasty have become some of the most Wear debris is generated by mechanical wear, successful elective surgical procedures in surface corrosion or a combination of both, and consists of both particulate and soluble quality of life to hundreds of thousands of forms.6,7 Metal-on-metal articulations gener- patients annually. In 2004, a total of 48 987 ate approximately 6.7 × 1012 to 2.5 × 1014 par- hip procedures were carried out in England ticles every year, which is 13 500 times the number of polyethylene particles produced the number of patients aged 50 years or less from a typical metal-on-polyethylene bearing.8 receiving primary hip replacement in Sweden Despite this, the actual volumetric wear of a increased by 6.0%.2,3 In Canada, the number metal-on-metal articulation is lower because of of hip replacements carried out in patients the nano-scale size of the particles (generally aged less than 45 years during 2002 rose by < 50 nm)8 when compared with polyethylene 11.0% compared with 1994.4 This increasing particles, which are rarely less than 0.1 µm.9 number of younger patients exposed to ortho- Corrosion can occur at all metal surfaces, paedic metal alloys (Table I) has caused con- resulting in either the formation of a protective cern about the long-term biological effects.5 passive layer10-12 or dissolution of the bulk The population is regularly exposed to a vari- metal alloy.13 Cobalt (Co(II)), titanium (Ti(V)), ety of metals through food, water, occupation aluminium (Al(III)), iron (FE(III)), nickel and the environment and the potential risk (Ni(II)) and chromium (Cr(III)) have all been from exposure is assessed and forms the basis detected in solution during the corrosion of of regulatory guidelines imposed to protect metal alloys.13-16 Despite evidence supporting the health of individuals. Risk assessment University of Bristol, Bristol Implant Research Centre, Avon includes a framework for gathering data and (molybdenum) alloy, this remains controver- evaluating their sufficiency and relevance. sial.16,17 Corrosion products predominantly level), Southmead Hospital, Westbury-on-Trym, Bristol This paper aims to describe the exposure, consist of metal oxides (Cr2O3, CoO, TiO2, uptake, dissemination and biological activity of metals released from orthopaedic materi- als. Toxicological data regarding potential ment.18 The deposition of calcium phosphate adverse events after systemic exposure to and the subsequent formation of metal phos- metals have been included. We also introduce phates (CrPO4, Co3(PO4)2, etc) occur in non- synovial environments.19 This may signifi- a framework for the risk assessment of ortho- paedic implants and discuss areas in which cantly alter the biological and chemical proper-ties of free particulate metals outside the G. M. KEEGAN, I. D. LEARMONTH, C. P. CASE Table I. Approximate weight percent of the constituents of different metals used in orthopaedic implants.116 Alloy compositions are standard-
ised by the American Society for Testing and Materials (ASTM vol. 13.01)
Stainless steel
CoCrMo alloys
(ASTM F75)
Ti Alloys
(ASTM F67)
* Ni, nickel; N, nitrogen; Co, cobalt; Cr, chromium; Ti, titanium; Mo, molybdenum; Al, aluminium; Fe, iron; Mn, manganese; Cu, copper; W, tung-sten; C, carbon; Si, silicon; V, vanadium† indicates < 0.05% Prosthesis-derived metal wear products are found those with metal-on-metal articulations, are likely to expe- extensively within the synovial fluid and peri-prosthetic tis- rience elevated metal levels throughout the life of the pros- sues of arthroplasty patients.20 At post-mortem further accumulation has been identified in the regional lymphnodes, liver and spleen.21,22 Because metal particles are very Cellular uptake and biological responses to metal
small (nano scale) the true extent of dissemination is not yet wear debris
known. Free or phagocytosed wear particles are trans- The uptake of metal nanoparticles (< 150 nm) by cells ported within the lymphatic system.21,22 Metallic debris occurs by endocytotic processes, particularly non-specific may additionally distribute through the vascular system as receptor-mediated endocytosis and pinocytosis.31 Larger ions or particles.23,24 In occupational biomonitoring, blood particles (> 150 nm) can stimulate phagocytosis in special- and urine metal concentrations are used as biomarkers to ised cells such as macrophages.32 Once internalised, metal particles can induce cytotoxicity,33 chromosomal damage34 In many instances, the mean metal levels identified in and oxidative stress.35 The toxicity of particles is modified exposed workers and joint replacement recipients are com- by passivation14 and particle size.34 These factors both parable. For example, mean whole blood levels of chro- influence the dissolution of metal from the surface, which mium of 5.98 µg L-1 average have been found in chrome- may account for biological activity. Evidence of cell dam- electroplaters25 which is comparable to the mean whole age, such as irregular cell membranes and enlarged mito- blood Cr levels (4.6 µgL-1 or 6.5 µgL-1 depending on the chondria, may be induced by the physical properties of the implant type) in metal-on-metal patients four years post- operatively.26 Biological and atmospheric guidance values The uptake of Cr(VI) occurs readily through anionic have been assigned for Cr and Co by health and safety channels because of the structure of the chromate anion organisations such as the Health and Safety Executive and while Cr(III) accumulates at the plasma membrane.37 the Deutsche Forschungsgemeinschaft. Specifically, expo- Cr(VI) is rapidly reduced to Cr(III), with the transient for- sure equivalents of carcinogenic substances (EKA values) mation of Cr(V) and Cr(IV), and distributed throughout corresponding to the workplace exposure limits,27 in the the cell bound to peptide and/or protein ligands.38 Divalent United Kingdom for Co are 5.0 µgL-1 and 60 µgL-1 in whole metal transporter ((DMT)-1)), expressed in a range of tis- blood and urine, and for Cr are 17 µgL-1 and 20 µgL-1 in sues, and natural resistance-associated macrophage protein erythrocytes and urine respectively.28 Several studies in the (NRAMP)1, located on the phagosomal membrane, may field of orthopaedics have observed patients with biological facilitate the uptake of Co(II) and Ni(II).39,40 Transferrin- metal levels greater than one or more of these values.26,29,30 bound Fe(III), A1(III), Cr(III) or vanadium(V) can be inter- The range of methods used to assess metal levels in ortho- nalised by cell-surface transferrin receptors.41-43 Metal ions paedic studies, such as analytical technique, specimen, and released from orthopaedic implants induce apoptosis and/ time of collection etc, make reliable comparisons difficult or necrosis in a range of cells, with Co(II) and V(III) among between studies and, in general, relatively few studies inves- the most cytotoxic.44,45 Corrosion products, including tigating metal levels are currently available. It is clear, how- CoO, Cr2O3 and CrPO4 also show moderate cytotoxicity.46 ever, that patients with joint replacement, most notably Within the nucleus, Cr(III) can cause mutagenesis by form- ORTHOPAEDIC METALS AND THEIR POTENTIAL TOXICITY IN THE ARTHROPLASTY PATIENT ing adducts with DNA47 and DNA-DNA cross-links.48 Cr, 5 ppb combined Co and Cr was identified, under which no Ni, Co and Ti are redox metals and can generate reactive significant reduction was observed. An inverse correlation oxygen species, such as the superoxide radical (O .
between the concentration of Cr and the numbers of circu- hydroxyl radical (.OH) via a Fenton-driven reaction with lating CD4+ T-cells and CD20+ B-cells has been reported in hydrogen peroxide (H2O2).49 Reactive oxygen specie can patients with metal-on-polyethylene articulations, while induce oxidative damage to DNA,50 proteins,51 and lip- myeloid cells and CD8+ T-cells were consistently decreased ids.52 Inhibition of DNA repair, altered signal transduction regardless of metal levels.64 These effects have not been and gene expression have all been documented in response recreated in experimental animals exposed to metal alloy to a range of orthopaedic metal ions, notably Ni(II), Cr(VI) solutions, although lymphoid populations were signifi- cantly altered.65
The liver. Hepatocellular necrosis often occurs in response
Local tissue reactions
to very high levels of metal in the body, as observed after Aseptic loosening and osteolysis remain the major cause of acute ingestion of Cr(VI) in humans.66 Portal inflammation failure of an implant, despite the re-introduction of metal- and oxidative stress have been observed after exposure to on-metal bearings as an alternative to metal-on-polyethy- A1,61 although pathological changes were not evident in lene articulations.1 In patients with metal-on-polyethylene bearings aseptic loosening is thought to be due to the The kidney. Cr is concentrated in the epithelial cells of the
response of macrophages to particulate wear debris. By proximal renal tubules and can impair renal function, contrast, particles from metal-on-metal bearings have a induce tubular necrosis and cause marked interstitial limited capacity to activate macrophages and may cause changes in experimental animals and humans.68,69 Indica- osteolysis by some immunological reaction involving tors of tubular dysfunction have been identified in human hypersensitivity.55,56 The pattern of inflammation in the subjects exposed to Cr(VI) through occupation.70 Al, Ni peri-prosthetic tissue of loose metal-on-metal articulations and Co are all rapidly excreted by the kidney, hence renal is significantly different to that of metal-on-polyethylene toxicity tends to require significantly larger doses.
articulations, and is characterised by perivascular infiltra- The respiratory system. The effects of exposure to Co, Ni
tion of lymphocytes and the accumulation of plasma cells.57 and Cr on the respiratory system are well documented71 Experimental data suggest that orthopaedic metals induce because of the frequency of occupational exposure and immunological effects which support a cell-mediated include an increased incidence of asthma and inflammatory conditions. These effects are often observed in stainless-steel welders, who are repeatedly exposed to metal fumes Systemic toxicology
containing Cr and Ni.72 Toxic responses of the respiratory Information regarding metal-induced toxicity is based on a system are largely related to inhalation exposure and are limited amount of epidemiological and experimental stud- therefore difficult to extrapolate to a vascular route.
ies involving in vitro and in vivo models. Unfortunately, The nervous system. Several neurological manifestations
there are few data available on the systemic effects of metal have been attributed to A1 intoxication in humans, includ- in arthroplasty patients. At present, the following toxic ing include memory loss, jerking, ataxia and neurofibrillary degeneration.61 The development of some neuropatho- The blood. Both A1 and Cr(VI) can induce changes in
logical conditions, including amyotrophic lateral sclerosis, haemoglobin and haematocrit values which are linked to Parkinsonian dementia, dialysis encephalopathy and senile their ability to disrupt cellular iron utilisation.59,60 In renal plaques of Alzheimer’s disease, may be related to the patients, the effect of impaired A1 clearance is associated accumulation of A1 in the brain.61 A1 is generally associ- with the development of microcytic anaemia.61 No signific- ated with changes which may reduce nerve conductivity, ant effect of Ni(II) has been identified in vivo, although in promote neuronal degeneration and increase Fe-induced vitro oxidative effects, predominantly lipid peroxidation, at oxidative damage.73 In relation to Alzheimer’s disease, A1 high concentrations have been reported.62 has significant effects on the formation and aggregation of The immune system. Metals modulate the activities of
associated proteins such as β-amyloid, the secretion of immunocompetent cells by a variety of immunostimulatory which is increased in vitro by Co(II).74 Oxidative stress may or immunosuppressive mechanisms. With regard to ortho- be significant in the development and/or progression of paedic metal ions, the effects generally include altered func- neurodegenerative disorders, particularly in response to tion of T-cells, B-cells and macrophages, modified cytokine Fe.75 Markers of oxidative damage have been identified in release, the formation of immunogenic compounds and the brains of experimental animals exposed to Cr(VI) and direct immunotoxicity. A significant reduction in circula- V(V).76,77 Significant alterations in visuospatial ability and ting lymphocytes, in particular CD8+ T-cells has been attention span have been observed in male workers with a observed in patients with metal-on-metal articulations, mean serum level of 14.4 ppb of V resulting from occupa- although this did not form a linear correlation with serum metal concentrations.63 However, a threshold value of G. M. KEEGAN, I. D. LEARMONTH, C. P. CASE The heart and vascular systems. The accumulation of Co
workers in chromium sulphate manufacturing had a in the myocardium can induce cardiomyopathy, which was significant positive correlation between the incidence of particularly evident after the 1966 episode of ‘beer-drinkers’ morphologically abnormal sperm and blood Cr levels.96 cardiomyopathy’, during which Co was used as a foam-sta- Exposure to Ni(II), V, A1 and Co(II) has been shown to bilising agent in beer.79 Altered left ventricular function induce some limited reproductive toxic effects in male relaxation was evident in a small series of cobalt produc- experimental animals, such as abnormal histopathology tion workers exposed to an average of 0.40 mg Co year-1, and spermatogenesis.97-100 However, there seems to be a although clinically significant cardiac dysfunction was distinct lack of data relating to the effects of these metals in absent.80 Ni and V were thought to have contributed to changes in cardiac function in experimental animals after the Developmental toxicology. An increase of Co and Cr has
inhalation of fine ambient particulate matter was shown to recently been described in the cord blood in a study of ten significantly increase the mortality to cardiovascular disease.81 women with metal-on-metal resurfacing, who became The musculoskeletal system. Deposition of A1 in the bone
pregnant following surgery, suggesting that orthopaedic occurs as a consequence of chronic exposure and has been metals may translocate from the maternal to the fetal linked to osteomalacia, bone pain, pathological fractures, circulation.101 Experimental animal studies suggest that proximal myopathy and the failure to respond to vitamin D3 several metals, including Cr, Co, Ni, V and Al, may induce therapy.82 Orthopaedic metal particles and soluble metal developmental toxicity.102 For example, Cr(VI) exposure in compounds adversely affect osteoblast function, which male and/or female mice either before or during gestation may in turn influence bone remodelling.83 can affect the number of implantations and viable fetuses The endocrine system. A1, Cr(II), Co, Ni and V can all
resulting from conception.94 Many metals can also induce bind to cellular oestrogen receptors, which may contribute teratogenic malformations, including Cr, Ni, and V.102 to aberrant oestrogen signalling.84 Ni(II), Cr(VI), A1 and Transgenerational carcinogenesis, which refers to the trans- Co(II) have the capacity to alter the production or circula- mission of the risk of cancer to the untreated progeny of tion of sex hormones in experimental models, which is parents exposed to carcinogens before mating, has been normally due to a direct effect on the reproductive cells, as observed in response to some metals, such as Cr(III).103 In in the case of Cr(VI).85 Co(II) prevents the uptake of iodine addition to the transplacental route, the passage of metals into the hormone thyroxine by its inhibition of the enzyme from the mother to the developing offspring may occur dur- tyrosine iodinase, which can induce hypothyroidism.86 ing lactation, as has been suggested in a study with V.104 In Occupational exposure in a small series of Danish pottery one large study, the incidence of congenital malformations painters showed no effect on normal thyroid function and cancer in the children of male stainless-steel workers despite evidence indicating an altered thyroid metabo- was not significantly increased,95 but follow-up investiga- lism.87 A1 is known to disrupt parathyroid hormone levels, tion revealed a significantly increased risk of spontaneous which may account for A1-induced bone disorders in dial- abortion among the partners of these male workers.105 Epi- demiological studies have also found a relationship The visual and auditory systems. A1, Co, and Ni can cause
between parental occupational exposure and an increased severe retinal degeneration at high concentrations in exper- risk of childhood cancer, but the exact aetiological agent imental animals.88,89 Recently, a case was reported of a man remains unknown.106 In a very limited study of 13 female who had extreme wear of a CoCrMo femoral head and arthroplasty patients, the incidence of pregnancy-related com- increased concentrations of Co in the serum (398 µg l-1) plications did not differ from that in the general population.107 and cerebrospinal fluid (3.2 µg l-1).90 He suffered loss of Carcinogenesis. An increased incidence of chromosomal
vision, hearing impairment, numbness of the feet and aberrations has been found in the peripheral lymphocytes of both arthroplasty patients, and welders.108,109 The sig- The skin. Metal-induced skin reactions can include contact
nificance of this finding and its relationship to an increased dermatitis, urticaria and/or vasculitis.91 The incidence of risk of cancer remains unknown, but there is a growing dermal reactions and positive skin-patch testing to Co, Ni consensus that metal-induced DNA damage may lead to and Cr in patients with total joint replacement, with stable carcinogenesis. Occupational metal exposure such as to Cr, and loose prostheses increases by 15% and 50% respec- has been linked to an increased risk of cancer.110 Studies in tively, above those of the general population.92 Norway on patients with THR have identified a small but The reproductive system. Chronic exposure to Cr(VI)
significant excess in the incidence of haematopoietic, pros- induces numerous effects detrimental to fertility in experi- tate and endometrial cancer and malignant mela- mental animal models.93,94 These include decreased sperm noma.111,112 The International Agency for Research on count, epithelial degradation, abnormalities of the sperm, a Cancer, which publishes information on the risks posed by reduced number of follicles and ova, and an increased num- chemicals on the development of human cancers,113 has ber of atretic follicles. A large epidemiological study in classified Cr(VI) and Ni(II) as carcinogenic, metallic Ni and stainless-steel workers found no significant causal link soluble Co as possibly carcinogenic, and metallic Cr, Cr(III) between exposure to Cr and reduced sperm quality,95 but ORTHOPAEDIC METALS AND THEIR POTENTIAL TOXICITY IN THE ARTHROPLASTY PATIENT compounds and implanted orthopaedic alloys as unclassifi- induced toxicity. The incidence of metal-induced toxicity in the kidney can be clarified by renal monitoring of arthro-plasty patients. In the light of current International Agency Conclusions
for Research on Cancer classification of metals, in particu- The European Food Safety Authority and the World Health lar Co and Cr, monitoring of the incidence of cancer in Organisation have recently discussed the use of risk assess- patients must remain a high priority. This should include ment in the evaluation of genotoxic and carcinogenic sub- evaluation of the possible relationship between metal- stances in food.114 Data obtained from approved in vitro induced chromosomal aberrations, genotoxicity and and in vivo models and human epidemiological studies carcinogenesis. Relatively few studies have addressed the form the basis of standard risk assessment. Dose-response potential effects of prosthesis-derived metals on the repro- analysis allows quantification of the no adverse effect level ductive system. This is particularly important in males and and the low adverse effect level calculated against the should begin with analysis of sperm to determine whether experimental uncertainty. This allows potential human risk prosthesis-derived metal has an effect on fertility. It is to be classified according to exposure and for informed improbable that female fertility would be affected by decisions regarding risk management to be made in con- circulating metal although this should not be dismissed.
junction with other considerations including socio- Epidemiological monitoring of arthroplasty patients, female partners and offspring would indicate any increases Risk assessment of orthopaedic metals in THR must in stillbirth, spontaneous abortion, birth defects and child- comprise a structured risk/benefit analysis, assessing the hood cancer. Cognitive testing may help to uncover poten- direct benefits of THR to the patient and the risks related to tial neurotoxic effects occurring from prosthesis-derived outcomes, failure of the implant and prosthesis-derived metal. Liver-function tests and cardiac monitoring would metals. THR has revolutionised the treatment of osteo- clarify any possible toxicity within patients and may be arthritis and other crippling conditions, with most patients worthwhile, but should not take priority. At present, eluci- noticing a signifcant improvement in their quality of life.115 dation of the exact mechanism behind aseptic loosening has Most available survivorship and mortality data have been been the main focus in orthopaedic research and continues obtained from select series and misrepresent current clinical to provide information regarding tissue and cellular trends. Over the coming years however, as longer follow- responses to metal debris, although the role of oxidative ups become available, initiatives such as the Swedish Hip stress and chronic immune-driven damage should perhaps Register and the National Joint Registry (NJR) for England and Wales will become an invaluable data source relating to Finally, it is imperative that we continue to support initi- joint replacement outcomes. Risk assessment of prosthesis- atives such as the Swedish National Hip Arthroplasty Reg- derived metal requires estimation of exposure to the ister and the National Joint Register in England and Wales patient, which should be based on numerous factors includ- since they will give a sophisticated, patient-based risk ing the type of prosthesis, patient activity, the potential assessment and provide the scope for continuous improve- length of exposure and the likelihood of increased metal ments in the field of orthopaedics. The benefits of ortho- release through implant loosening. The last is a complex paedic surgery are proven, but the risks are theoretical or situation since the relationship between elevated steady- uncertain. Therefore any decision on the use of orthopaedic state metal levels and loosening is unknown, as is the ideal metal alloys, particularly in articulations, should not be interval between patient discomfort and clinical interven- taken lightly and must be the product of further research tion. Associated risk also depends on the type of articula- and careful consideration of risk versus benefit.
tion and the alloy used in the components.
We would like to thank the Frances and Augustus Newman Foundation for their This review has outlined the ‘potential hazards’ of circu- lating metals based on the available information. However,without detailed characterisation of both the physical and References
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Smarxt disposal - common questions

W h a t i s S M A R x T D I S P O S A L ? SMARXT DISPOSAL is a public awareness campaign that targets medication consumers to providing guidance on proper disposal of unused and or expired prescription and over-the-counter medications. SMARXT DISPOSAL raises awareness about the potential environmental impacts from improperly disposed medications. This national campa

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Original must be mailed. Please keep a copy for your records. Completed Medical Forms must be mailed for STC by May 19 and BV by June 30, for Camp Medical Staff to review. Pages 1- 4 are to be completed by parent/guardian and reviewed by the health care provider at the time of examination. This form is used to help camp medical staff in determining appropriate care. This information will b

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