18903_layout.fm

REVIEW ARTICLE
Orthopaedic metals and their potential
toxicity in the arthroplasty patient
A REVIEW OF CURRENT KNOWLEDGE AND FUTURE STRATEGIES G. M. Keegan,
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
carcinogenesis.
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
CPTi
(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
chemical properties of wear debris, particularly once the 1. The NJR 2nd Annual Report. National Joint Registry 21st Sept 2005. http://
www.njrcentre.org.uk/documents/reports/2nd_annual_report.html (date last metal has left the effective joint space, the risk posed by orthopaedic metals is difficult to assess. In addition, toxi- 2. No authors listed. Annual Report 2002. The Swedish National Hip Arthroplasty Reg-
cology data obtained from animal studies are limited by ister April 2003. http://www.jru.orthop.gu.se/ (date last accessed 2 October 2006).
protocols which cannot easily be extrapolated to the clini- 3. No authors listed. Annual Report 2004. The Swedish National Hip Arthroplasty Reg-
ister May 2005. http://www.jru.orthop.gu.se/ (date last accessed 3 October 2006).
cal situation. From the limited studies consulted in this 4. No authors listed. Table 12. Number and distribution of total hip replacement hos-
review, several areas have been identified which deserve pitalizations by age group and sex, Canada, Fiscal 2002 compared to Fiscal 1994. Hos- investigation, including immunity, reproduction, the kid- pital Morbidity Database, Canadian Institute for Health Information 2005. http://secure.cihi.ca/cihiweb/en/AR30_2005_tab12_e.html (date last accessed 28 Sep- neys, developmental toxicity, the nervous system and carcinogenesis. The mechanism behind altered peripheral 5. No authors listed. Biological effects of metal wear debris generated from hip implants:
genotoxicity. Medicines and Healthcare Regulatory Agency 21 July 2006. http:// lymphocyte populations needs to be elucidated since this www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDoc- may be indicative of specific prosthesis-derived metal- Name=CON2024535 (date last accessed 21 September 2006).
G. M. KEEGAN, I. D. LEARMONTH, C. P. CASE 6. Wright T, Goodman S. Implant wear in total joint replacement: clinical and biologic
34. Daley B, Doherty AT, Fairman B, Case CP. Wear debris from hip knee replace-
issues, material and design considerations. Rosemount: American Academy of Ortho- ments causes chromosomal damage in human cells in tissue culture. J Bone Joint 7. Jacobs JJ, Gilbert JL, Urban RM. Corrosion of metal orthopaedic implants. J Bone
35. Soloviev A, Schwarz EM, Darowish M, O’Keefe RJ. Sphongomyelinase medi-
Joint Surg [Am] 1998;80-A:268-82.
ates macrophage activation by titanium particles independent of phagocytosis: a rolefor free radicals, NFkappaB and TNF-alpha. J Orthop Res 2005;23:1258-65.
8. Doorn PF, Campbell PA, Worrall J, et al. Metal wear particle characterization
from metal on metal total hip replacements: transmission electron microscopy study 36. Lohmann CH, Schwartz Z, Koster G, et al. Phagocytosis of wear debris by osteo-
of periprosthetic tissues and isolated particles. J Biomed Mater Res 1998;42:103-11.
blasts affects differentiations and local factor production in a manner dependent onparticle composition. Biomaterials 2000;21:551-61.
9. Elfick APD, Green SM, Krikler S, Unsworth A. The nature and dissemination of
UHMWPE wear debris retrieved from periprosthetic tissue of THR. J Biomed Mater 37. Messer RL, Lucas LC. Localization of metallic ions within gingival fibroblast subcel-
lular fractions. J Biomed Mater Res 2002;59:466-72.
10. Kocijan A, Milosev I, Pihlar B. Cobalt-based alloys for orthopaedic applications
38. Harris HH, Levina A, Dillon CT, et al. Time-dependent uptake, distribution and
studied by electrochemical and XPS analysis. J Mater Sci Mater Med 2004;15:643- biotransformation of chromium(VI) in individual and bulk human lung cells: applica- tions of synchrotron radiation techniques. J Biol Inorg Chem 2005;10:105-18.
11. Milosev I, Metikos-Hukovic M, Strehblow HH. Passive film on orthopaedic
39. Chen H, Davidson T, Singleton S, Garrick MD, Costa M. Nickel decreases cellu-
TiA1V alloy formed in physiological solution investigated by x-ray photoelectron spec- lar iron level and converts cytosolic aconitase to iron-regulatory protein 1 in A549 troscopy. Biomaterials 2002;21:2103-13.
cells. Toxicol Appl Pharmacol 2005;206:275-87.
12. Lorang G, DaCunha Belo M, Simers AMP, Ferreira MGS. Chemical composition
40. Forbes JR, Gros P. Iron, manganese, and cobalt transport by Nramp 1 (S1c11a1) and
Nramp2 (S1c11a2) expressed at the plasma membrane. Blood 2003;102:1884-92.
of passive films on AISI-304 stainless steel. J Electrochem Soc 1994;141:3347-56.
41. Clodfelder BJ, Vincent JB. The time-dependent transport of chromium in adult rats
13. Okazaki Y, Gotoh E. Comparison of metal release from various metallic biomaterials
from the bloodstream to the urine. J Biol Inorg Chem 2005;10:383-93.
in vitro. Biomaterials 2005;26:11-21.
42. Perez G, Garbossa G, DiRisio C, Vittori D, Nesse A. Disturbance of cellular iron
14. Haynes DR, Crotti JN, Haywood MR. Corrosion of and changes in biological
uptake and utilisation by aluminium. J Inorg Biochem 2001;87:21-7.
effects of cobalt chrome alloy and 316L stainless steel prosthetic particles with age.
J Biomed Mater Res 2000;49:167-75.
43. De Cremer K, Van Hulle M, Chery C, et al. Fractionation of vanadium complexes
in serum, packed cells and tissues of Wistar rats by means of gel filtration and anion- 15. Hodgson AWE, Kurz S, Virtanen S, et al. Passive and transpassive behaviour of
exchange chromatography. J Biol Inorg Chem 2002;7:884-90.
CoCrMo in simulated biological solutions. Electrochim Acta 2004;49:2167-78.
44. Hallab NJ, Anderson S, Caicedo M, et al. Effects of soluble metals on human
16. Shettlemore MG, Bundy KJ. Examination of in vivo influences on bioluminescent
peri-implant cells. J Biomed Mater Res A 2005;74-A:124-40.
microbial assessment of corrosion product toxicity. Biomaterials 2001;22:2215-28.
45. Huk O, Catelas I, Mwale F, et al. Induction of apoptosis and necrosis by metal ions
17. Merritt K, Brown SA. Release of hexavalent chromium from corrosion of stainless
in vitro. J Arthroplasty 2004;19(8 Suppl 3):84-7.
steel and cobalt-chromium alloys. J Biomed Mater Res 1995;29:627-33.
46. Hanawa T, Kaga M, Itoh Y, et al. Cytotoxicities of oxides, phosphates and sul-
18. Lewis AC, Heard PJ. The effects of calcium phosphate deposition upon corrosion of
phides of metals. Biomaterials 1992;13:20-4.
CoCr alloys and the potential for implant failure. J Biomed Mater Res 2005;75:365-73.
47. Zhitkovich A, Shrager S, Messer J. Reductive metabolism of Cr(VI) by cysteine
19. Lewis A, Kilburn MR, Heard PJ, et al. The entrapment of corrosion products from
leads to the formation of binary and ternary Cr-DNA adducts in the absence of oxida- CoCr implant alloys in the deposits of calcium phosphate: a comparison of serum, syn- tive DNA damage. Chem Res Toxicol 2000;13:1114-24.
ovial fluid, albumin, EDTA, and water. J Orthop Res 2006;24:1587-96.
48. Xu J, Bubley GJ, Detrick B, Blankenship LJ, Patierno SR. Chromium (VI) treat-
20. Brien WW, Salvati EA, Betts F, et al. Metal levels in cemented total hip arthro-
ment of normal human lung cells results in guanine-specific DNA polymerase arrest, plasty: a comparison of well-fixed and loose implants. Clin Orthop 1992;276:66-74.
DNA-DNA cross-links and S-phase blockade of cell cycle. Carcinogenesis 21. Case CP, Langkamer VG, James C, et al. Widespread dissemination of metal
debris from implants. J Bone Joint Surg [Br] 1994;76-B:701-12.
49. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and
22. Urban RM, Jacobs JJ, Tomlinson MJ, et al. Dissemination of wear particles to
antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006;160:1-40.
the liver, spleen, and abdominal lymph nodes of patients with hip or knee replace- 50. Lloyd DR, Phillips PH, Carmichael PL. Generation of putative intrastrand cross-
ment. J Bone Joint Surg [Am] 2000;82-A:457-77.
links and strand breaks in DNA by transition metal ion-mediated oxygen radical 23. Olmedo DG, Tasat D, Gugliemotti MB, Cabrini RL. Titanium transport through the
attack. Chem Res Toxicol 1997;10:393-400.
blood stream: an experimental study on rats. J Mater Sci Mater Med 2003;14:1099- 51. Petit A, Mwale F, Tkaczyk C, et al. Induction of protein oxidation by cobalt and
chromium ions in human U937 macrophages. Biomaterials 2005;26:4416-22.
24. Engh CA Jr, Moore KD, Vinh TN, Engh GA. Titanium prosthetic wear debris in
52. Pourahmad J, O’Brien PJ, Jokor F, Daraei B. Carcinogenic metal induces sites of
remote bone marrow: a report of two cases. J Bone Joint Surg [Am] 1997;79-A:1721- reactive oxygen species formation in hepatocytes. Toxicol in Vitro 2003;17:803-10.
53. Witkiewicz-Kucharczyk A, Bal W. Damage of zinc fingers in DNA repair proteins,
25. Gambelungh A, Piccinini R, Ambrogi M, et al. Primary DNA damage in chrome-
a novel molecular mechanism in carcinogenesis. Toxicol Lett 2006;162:29-42.
plating workers. Toxicol 2003;188:187-95.
54. Chen F, Shi X. Intracellular signal transduction of cells in response to carcinogenic
26. Lhotka C, Szekeres T, Steffan I, Zhuber K, Zweymüller K. Four-year study of
metals. Crit Rev Oncol Hematol 2002;42:105-21.
cobalt and chromium blood levels in patients managed with two different metal-on- 55. Willert HG, Buchhorn GH, Fayyazi A, et al. Metal-on-metal bearings and hyper-
metal total hip replacements. J Orthop Res 2003;21:189-95.
sensitivity in patients with artificial hip joints: a clinical and histomorphological study.
27. No authors listed. Table I: List of approved workplace exposure limits.
J Bone Joint Surg [Am] 2005;87-A:28-36.
www.hse.gov.uk/coshh/table1.pdf (date last accessed 2 October 2006).
56. Milosev I, Trebse R, Kovac S, et al. Survivorship and retrieval analysis of Sikomet
28. Morgan MS, Schaller KH. An analysis of criteria for biological limit values devel-
metal-on-metal total hip replacements at a mean of seven years. J Bone Joint Surg oped in Germany and in the United States. Int Arch Occup Environ Health 57. Davies AP, Willert HG, Campbell PA, Learmonth ID, Case CP. An unusual lym-
phocytic perivascular infiltration in tissues around contemporary metal-on-metal joint 29. Schaffer AW, Pilger A, Engelhardt C, Zweymüller K, Ruediger HW. Increased
replacements. J Bone Joint Surg [Am] 2005;87-A:18-27.
blood cobalt and chromium after total hip replacement. Clin Toxicol 1999;37:839-44.
58. Hallab N, Mikecz K, Vermes C, Skipor J, Jacobs JJ. Orthopaedic implant related
30. Pilger A, Schaffer A, Ruediger HW, Osterode W. Urinary 8-hydroxydeoxygua-
metal toxicity in terms of human lymphocyte reactivity to metal-protein complexes nosine and sister chromatid exchanges in patients with total hip replacements. J Tox- produced from cobalt-base an titanium base implant alloy degradation. Mol Cell Bio- icol Environ Health 2002;65:655-64.
31. Shukla R, Bansal V, Chaudhary M, et al. Biocompatability of gold nanoparticles
59. Vittori D, Nesse A, Perez G, Garbossa G. Morphologic and functional alterations
and their endocytotic fate inside the cellular compartment: a microscopic overview.
of erythroid cells induced by long-term ingestion of aluminium. J Inorg Biochem 32. Trindade MC, Lind M, Sun D, et al. In vitro reaction to orthopaedic biomaterials by
60. Ani M, Moshtaghie A. The effect of chromium on parameters related to iron-metab-
macrophages and lymphocytes isolated from patients undergoing revision surgery.
olism. Biol Trace Elem Res 1992;32:57-64.
61. Nayak P. Aluminium: impacts and disease. Environ Res 2002;89:101-15.
33. Podleska L, Weuster M, Dose E, et al. The impact of nanocolloidal wear-particles
on human mononuclear cells. Mat-Wiss u Werkstofftechnik 2006;37:563-9 (in Ger- 62. Tkeshekashvili L, Tsakadze K, Khulusauri O. Effect of some nickel compounds on
red blood cell characteristics. Biol Trace Elem Res 1989;21:337-42.
ORTHOPAEDIC METALS AND THEIR POTENTIAL TOXICITY IN THE ARTHROPLASTY PATIENT 63. Hart A, Hester T, Sinclair K, et al. The association between metal ions from his resurfac-
93. Aruldhas M, Subramaniam S, Sekar P, et al. Chronic chromium exposure-induced
ing and reduced T-cell counts. J Bone Joint Surg [Br] 2006;88-B:449-54.
changes in testicular histoarchitecture are associated with oxidative stress: study in 64. Savarino L, Granchi D, Ciapetti G. Effects of metal ions on white blood cells of patients
a non-human primate (Macaca radiata Geoffroy). Human Reprod 2005;20:2801-13.
with failed total joint arthroplasties. J Biomed Mater Res 1999;47:543-50.
94. Elbetieha A, Al-Hamood MH. Long-term exposure of male and female mice to
65. Ferreira M, de Lourdes Pereira M, Garcia e Costa F, Sousa JP, de Carvalho GS. Com-
trivalent and hexavalent chromium compounds: effect on fertility. Toxicol parative study of metallic biomaterials toxicity: a histochemical and immunohistochemical demonstration in mouse spleen. J Trace Elem Med Biol 2003;17:45-9.
95. Bonde J. The risk of male subfecundity attributable to weldng of metals: studies of
66. Kurosaki K, Nakamura T, Mukai T, Endo T. Unusual findings in a fatal case of poisoning
semen quality, infertility, adverse pregnancy outcome, and childhood malignancy. Int with chromate compounds. Forensic Sci Int 1995;75:57-65.
J Androl 1993;16(Suppl 1):1-29.
67. Kametani K, Nagata T. Quantitative elemental analysis on aluminium accumulation by
96. Kumar S, Sathwara NG, Gautam AK, et al. Semen quality of industrial workers
HVTEM-EDX in liver tissues of mice orally administered with aluminium chloride. Med Mol occupationally exposed to chromium. J Occup Health 2005;47:424-30.
97. Pandey R, Kumar R, Singh SP, Saxena DK, Srivastava SP. Male reproductive
68. Oliveira H, Santos TM, Ramalho-Santos J, de Lourdes Pereira M. Histopathological
effect of nickel sulphate in mice. Biometals 1999;12:339-46.
effects of hexavalent chromium in mouse kidney. Bull Environ Contam Toxicol 2006;76:977- 98. Domingo JL. Vanadium: a review of the reproductive and developmental toxicity.
Reprod Toxicol 1996;10:175-82.
69. Barceloux DG. Chromium. Clin Toxicol 1999;37:173-94.
99. Llobet JM, Colomina MT, Sirvent JJ, Domingo JL, Corbella J. Reproductive tox-
70. Bonde J, Vittinghus E. Urinary excretion of proteins among metal welders. Human Exp Tox-
icology of aluminium in male mice. Fundam Appl Toxicol 1995;25:45-51.
100. Anderson MB, Pedigo NG, Katz RP, George WJ. Histopathology of testes from
71. Nemery B. Metal toxicity and the respiratory tract. Eur Respir J 1990;3:202-19.
mice chronically treated with cobalt. Reprod Toxicol 1992;6:41-50.
72. Antonini J, Lewis AB, Roberts JR, Whaley DA. Pulmonary effects of welding fumes:
101. Kanojia R, Junaid M, Murthy P. Embryo and fetotoxicity of hexavalent chromium:
review of worker and experimental animal studies. Am J Indust Med 2003;43:350-60.
a long-term study. Toxicol Lett 1998;95:165-72.
73. Yokel R. The toxicology of aluminium in the brain: a review. Neurotoxicology 2000;21:813-
102. Domingo J. Metal-induced developmental toxicity in mammals: a review. J Toxicol
Environ Health 1994;42:123-41.
74. Olivieri G, Novakovic M, Savaskan E, et al. The effects of beta-estradiol on SHSY5Y
103. Yu W, Sipowicz MA, Haines DG, et al. Preconception urethane or chromium (III)
neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and betaamy- treatment of male mice: multiple neoplastic and non-neoplastic changes in offspring.
loid secretion. Neuroscience 2002;113:849-55.
Toxicol Appl Pharmacol 1999;158:161-76.
75. Youdim MB, Ben-Shachar D, Riederer P. Iron in brain functions and dysfunction with
104. Morgan A, El-Tawil O. Effects of ammonium metavandate on fertility and repro-
emphasis on Parkinson’s disease. Eur Neurol 1991;31(Suppl 1):34-40.
ductive performance of adult male and female rats. Pharmacol Res 2003;47:75-85.
76. Travacio M, Polo JM, Llesuy S. Chromium (VI) induces oxidative stress in the mouse brain.
105. Hjollund N, Bonde JP, Jensen JK, et al. Male-mediated spontaneous abortion
among spouses of stainless steel welders. Scand J Work Environ Health 77. Garcia GB, Biancardi M, Quiroga A. Vanadium (V)-induced neurotoxicity in the rat central
nervous system: a histo-immunohistochemical study. Drug Chem Toxicol 2005;28:329-44.
106. O’Leary LM, Hicks AM, Peters JM, London S. Parental occupational exposures
78. Barth A, Schaffer AW, Komaris C, et al. Neurobehavioural effects of vanadium. J Toxicol
and risk of childhood cancer: a review. Am J Int Med 1991;20:17-35.
Environ Health [Am] 2002;65:677-83.
107. Meldrum R, Feinberg JR, Capello WN, Detterline AJ. Clinical outcome and inci-
79. Barceloux D. Cobalt. J Toxicol Clin Toxicol 1999;37:201-16.
dence of pregnancy after bipolar and total hip arthroplasty in young women. J Arthro- 80. Linna A, Oksa P, Groundstroem K, et al. Exposure to cobalt in the production of cobalt and
cobalt compounds and its effects on the heart. Occup Environ Med 2004;61:877-85.
108. Ladon D, Doherty A, Newson R, et al. Changes in metal levels and chromosome
81. Lippmann M, Ito K, Hwang JS, Maciejczyk P, Chen LC. Cardiovascular effects of nickel
aberrations in the peripheral blood of patients after metal-on-metal hip arthroplasty.
in ambient air. Environ Health Perspect 2006;114:1662-9.
J Arthroplasty 2004;19(Suppl 3):78-83.
82. Jeffery E, Ebero K, Burgess E, Cannata J, Greger JL. Systemic aluminium toxicity:
109. Iarmarcovai G, Sari-Minodier I, Chagpoul F, et al. Risk assessment of welders
effects on bone, hematopoietic tissue, and kidney. J Toxicol Environ Health 1996;48:649-65.
using analysis of eight metals by ICP-MS in blood and urine and DNA damage evalu-ation by the comet and micronucleus assays: influence of XRCC1 and XRCC2 polymor- 83. Vermes C, Glant TT, Hallab NJ, et al. The potential role of the osteoblast in the develop-
phisms. Mutagenesis 2005;20:425-32.
ment of periprosthetic osteolysis: review of in vitro osteoblast responses to wear debris, cor-rosion products, and cytokines and growth factors. J Arthroplasty 2001;16(Suppl 1):95-100.
110. Cole P, Rodu B. Epidemiologic studies of chrome and cancer mortality: a series of
meta-analyses. Reg Toxicol Pharmacol 2005;43:225-31.
84. Darbre PD. Metalloestrogens: an emerging class of inorganic xenoestrogens with potential
to add to the oestrogenic burden of the human breast. J Appl Toxicol 2006;26:191-7.
111.Visuri T, Pukkala E, Pulkinen P, Paavolainen P. Decreased cancer risk in patients
who have been operated on with total hip and knee arthroplasty for primary osteoar- 85. Murthy RC, Junaid M, Saxena D. Ovarian dysfunction in mice following chromium (VI)
thritis: a meta-analysis of 6 Nordic cohorts with 73,000 patients. Acta Orthop Scand exposure. Toxicol Lett 1996;89:147-54.
86. Brock T, Stopford W. Bioaccessibility of metals in human health risk assessment: evaluat-
ing risk from exposure to cobalt compounds. J Environ Monit 2003;5;71-7.
112. Visuri T, Pukkala E, Polkkinen P, Paavolainen P. Cancer incidence and causes of
death among total hip replacement patients: a review based on Nordic cohorts with 87. Prescott E, Netterstrom B, Faber J, et al. Effect of occupational exposure to cobalt blue
a special emphasis on metal-on-metal bearings. Proc Instn Mech Engrs dyes on the thyroid volume and function of female plate painters. Scand J Work Environ 113. No authors listed. IARC monographs on the evaluation of carcinogenic risk to
88. Lu Z-Y, Gong H, Ameniya J. Aluminum chloride induces retinal changes in the rat. Toxicol
humans. 2004. http://monographs.iarc.fr/ (date last accessed 5 October 2006).
114. Barlow S, Renwick AG, Kleiner J, et al. Risk assessment of substances that are
89. Khosla PK, Murthy KS, Tewari H. Retinal toxicity of trace elements. Indian J Ophthalmol
both genotoxic and carcinogenic: report of an International Conference organised by EFSA and WHO with support of ILSI Europe. Food Chem Toxicol 2006;44:1636-50.
90. Steens W, von Foerster G, Katzer A. Severe cobtalt poisoning with loss of sight after
115. Rissanen P, Aro S, Slatis P, et al. Health and quality of life before and after hip or
ceramic-metal pairing in a hip: a case report. Acta Orthop 2006;77:830-2.
knee arthroplasty. J Arthroplasty 1995;10:169-75.
91. Hallab N, Jacobs J, Black J. Hypersensitivity to metallic biomaterials: a review of
leukocyte migration inhibition assays. Biomaterials 2000;21:1301-14.
116. Jacobs J, Skipor AK, Patterson LM, et al. Metal release in patients who have
had primary total hip arthroplasty: a prospective, controlled longitudinal study. J 92. Hallab N, Mikecz K, Jacobs J. Metal sensitivity in patients with orthopaedic
Bone Joint Surg [Am] 1998;80-A:1447-58.
implants. J Bone Joint Surg [Am] 2001;83-A:428-36.

Source: http://www.plusmed.si/uploads/datoteke/C7-Keegan%20et%20al%20-%20Orthopaedic%20Metals%20and%20their%20potential%20toxicity%20-%202007%20JBJS.pdf