Toxicological risk assessment of titanium aluminum vanadium alloys used in implantable orthopedic medical devices and their extractables into the blood circulation according to ISO 10993-17:2002

Diplôme Master d'études avancées Toxicological risk assessment of titanium aluminum vanadium alloys used in implantable orthopedic medical devices and their extractables into the blood circulation according to ISO 10993-17:2002 eng 2022-09-02 2022-07-30 author Laupheimer Charlotte 915975 director FitzGerald Reginald 87 This work covers the toxicological risk assessment of titanium aluminum vanadium alloys (TAV) used in implantable orthopedic medical devices and their allowable limits for extractables into the blood circulation according to ISO 10993-17:2002. To achieve this, existing literature was searched for toxicological data on all relevant endpoints as requested by ISO 10993-17. The parenteral (systemic) tolerable exposure (TE) estimates derived in the toxicological risk assessments for titanium, aluminium and vanadium were 160 μg Ti/day, 250 μg Al/day and 12 μg V/day, respectively. A hypothetical exposure scenario of two intramedullary TAV nails of fictive size was used to correlate the respective TE with the respective worst-case exposure level of each metal. In a cumulative scenario considering the simultaneous implantation of two intramedullary TAV nails in an adult weighing 70 kg, the worst-case levels for patients were assumed to be 10, 150 and 6 μg/day for titanium, aluminium and vanadium, respectively. The margins of safety (MOS) for all three metals were found to be >1 and therefore the worst-case exposure to the two hypothetical devices is considered to be without appreciable harm to health according to ISO 10993-17. However, when further considering upper levels of basal metals in body fluids (blood or serum), the MOS for vanadium equaled 1.0. This equivocal MOS indicates that a more precise assessment of the exposure scenario should be performed when vanadium-containing medical devices are implanted in humans. This also highlights the importance of the appropriate case-specific choice of the implant material, using precise exposure assessment as well as risk-benefit considerations. The search performed in this work revealed that uncertainties remain in the hazard characterization for some endpoints (for example genotoxicity by vanadium) which do not allow to draw a firm conclusion on whether certain toxicities are of concern or at which levels. The present toxicological risk assessment should be updated if new relevant studies are published. Additionally, other uncertainties remain. Most data is based on read-across from related substances and not the elemental metals. Further publicly available studies investigating TAV alloys would be required to establish more accurate and reliable data for each constituent metal of the alloy. Aluminium Titanium Vanadium TAV Titanium alloy Metal toxicity Implants Tolerable exposure Orthopedic implants Medical devices ISO 1099-17 Dewey 610 Dewey 615 Master of Advanced Studies in Toxicology 3 Faculté de médecine 2 31 Section des sciences pharmaceutiques 17 false 1cd76f65-9e60-49e8-b58c-abc9e0978f45 Master thesis Restricted thesis_charlotte_final-2.pdf 954274 application/pdf 43cc359bfc2c965d36c8b2552dad9753368427e373d470f82201d738ce59d64f restrictedAccess Faculté de médecine Faculté des sciences / Section des sciences pharmaceutiques

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Toxicological risk assessment of titanium aluminum vanadium alloys used in implantable orthopedic medical devices and their extractables into the blood circulation according to ISO 10993-17:2002				2022	66	5

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Laupheimer, Charlotte