title: Toxicology-based cancer causation analysis of CoCr-containing hip implants: a quantitative assessment of genotoxicity and tumorigenicity studies.
abstract: In this paper, quantitative methods were used to evaluate the weight of evidence regarding a causative relationship between cobalt-chromium (CoCr)-containing hip implants and increased cancer risk. We reviewed approximately 80 published papers and identified no-observed-adverse-effect level (NOAEL) and/or lowest-observed-adverse-effect level (LOAEL) values for specific endpoints of interest: genotoxic effects from in vitro studies with human cell lines as well as genotoxicity and tumor formation in animal bioassays. Test articles included Co particles and ions, Cr particles and ions, and CoCr alloy particles as well as CoCr alloy implants. The NOAEL/LOAEL values were compared with body burdens of Co/Cr particles and ions we calculated to exist in systemic tissues of hip implant patients under normal and excessive wear conditions. We found that approximately 40 tumor bioassays have been conducted with CoCr alloy implants or Co/Cr particles and ions at levels hundreds to thousands of times higher than those present in hip implant patients, and none reported a statistically significant increased incidence of systemic tumors. Results from in vitro and in vivo genotoxicity assays, which are relatively less informative owing to false positives and other factors, also indicated that DNA effects would be highly unlikely to occur as a result of wear debris from a CoCr implant. Hence, the toxicological weight of evidence suggests that CoCr-containing hip implants are unlikely to be associated with an increased risk of systemic cancers, which is consistent with published and ongoing cancer epidemiology studies involving patients with CoCr hip implants.
authors: Cardno ChemRisk, LLC, 20 Stanwix St., Suite 505, Pittsburgh, PA, 15222, USA.
authors: Whitney V
authors: WV
authors: Christian
authors: Lindsay D
authors: LD
authors: Oliver
authors: Dennis J
authors: DJ
authors: Paustenbach
authors: Marisa L
authors: ML
authors: Kreider
authors: Brent L
authors: BL
authors: Finley
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002858:Chromium Alloys / Q000633:toxicity*; D003035:Cobalt / Q000633:toxicity*; D004249:DNA Damage; D023381:Endpoint Determination; D005069:Evaluation Studies as Topic; D006622:Hip Prosthesis / Q000009:adverse effects*; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced / Q000473:pathology; D019055:No-Observed-Adverse-Effect Level
chemical_list: D002858:Chromium Alloys; D003035:Cobalt
keywords: cancer; chromium; cobalt; genotoxicity; hip implants; risk assessment