In 1993, Haynes et al. performed experiments using titanium-aluminum-vanadium (Ti-Al-V) and cobalt-chromium (Co-Cr) particles of similar size range and concentration similar to those found in failed hip prostheses. In the abdominal macrophage experiments of rats, Co-Cr yielded a high toxic response while Ti-Al-V increased the release of inflammation-inducing mediators such as prostaglandin E2, interleukin-1, interleukin-6, and tumor necrosis factor. These results implied that debris particles of worn Ti-Al-V could induce the release of inflammatory mediators affecting the tissues surrounding the prosthesis and cause osteolysis. Rogers et al. tested the toxicity of vanadium and niobium in titanium alloys; human monocytes released more inflammatory mediators due to Ti-Al-V compared to titanium-aluminum-niobium (Ti-Al-Nb). The authors thus suggested that metal debris particles might lead to bone loss around the prosthesis.

Studies regarding titanium alloy toxicity were continuously reported in 2000s. Hallab et al. performed experiments using human lymphocytes. Co-Cr-Mo and Ti-6Al-4V were incubated with human serum. This experiment showed that a complex between the protein and metal particles caused a lymphocyte reaction; protein binding with a higher molecular weight caused a larger inflammatory reaction. Dalal et al. experimented with the influence of metal particles in human peri-implant cells, osteoblasts, fibroblasts, and macrophages. Co-Cr-Mo, titanium alloy, zirconium oxide, and zirconium alloy were used. Co-Cr-Mo yielded a toxic reaction that interfered with the viability and proliferation of osteoblasts, fibroblasts, and macrophages. All particles induced inflammatory mediator release to macrophages; Co-Cr-Mo, a titanium alloy, released more inflammatory mediators. These results showed that particles around the metal prosthesis could cause irritation and lead to the failure of orthopedic prostheses.

The behavior of titanium alloy in body environment is affected by complex factors. Yu et al. investigated the synergistic effect of albumin and H₂O₂ on corrosion of Ti6Al4V in physiological saline.