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We investigated the relationship between the toxic effects of metal wear particles and their ability to stimulate the release of inflammatory mediators implicated in bone resorption. In vitro studies were carried out with use of rat peritoneal macrophages, which were exposed to either cobalt-chromium-alloy or titanium-aluminum-vanadium particles, milled from the metal components of hip prostheses. The particles were in the size-range of, and at concentrations similar to, those found in the tissues surrounding failed prostheses in humans. The titanium-aluminum-vanadium particles showed little toxicity even at high concentrations, while the cobalt-chromium particles were very toxic. The titanium-aluminum-vanadium particles induced significantly more release of prostaglandin E2 than did the cobalt-chromium particles, and this was true for a wide range of concentrations. Exposure to titanium-aluminum-vanadium increased the release of prostaglandin E2, interleukin-1, tumor necrosis factor, and interleukin-6. In contrast, exposure to cobalt-chromium particles was associated with a decreased release of prostaglandin E2 and interleukin-6, and it had little effect on the release of interleukin-1 and tumor necrosis factor.The results of this study demonstrate that there is a difference in the cellular response to different types of metal-alloy wear particles that are of the same size. Cobalt-chromium particles are likely to be more toxic to periprosthetic tissue, but titanium-aluminum-vanadium particles are likely to cause release of more inflammatory mediators implicated in osteolysis. On the basis of these results, we believe that the release of titanium-aluminum-vanadium particles into the periprosthetic tissues may be worse than the release of equivalent numbers of cobalt chromium particles. Therefore, special attention should be given to the design of titanium-aluminum-vanadium implants, particularly modular implants, so that the potential for wear is minimized.