A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay

• Published in: Toxicology and applied pharmacology 2016-10, Vol.308, p.77-90
• Main Authors: Tvermoes, Brooke E., Unice, Kenneth M., Winans, Bethany, Kovochich, Michael, Christian, Whitney V., Donovan, Ellen, Fung, Ernest S., Finley, Brent L., Kimber, Ian, Paustenbach, Dennis J.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; CHROMATES; CHROMIUM CHLORIDES; CHROMIUM OXIDES; COBALT CHLORIDES; DOSES; EVALUATION; FEET; Female; Flow Cytometry; Hypersensitivity; Immune stimulation; IMPLANTS; LYMPH; Lymph node cell activation; LYMPH NODES; Lymph Nodes - drug effects; Lymph Nodes - immunology; Metal-on-metal implants; Metals; Metals - toxicity; MICE; Mice, Inbred BALB C; NICKEL CHLORIDES; PARTICLES; Popliteal Artery; Popliteal lymph node assay; SALTS; STIMULATION
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2016.07.020

The objective of this preliminary study was to evaluate the threshold for immune stimulation in mice following local exposure to metal particles and ions representative of normal-functioning cobalt-chromium (CoCr) metal-on-metal (MoM) hip implants. The popliteal lymph node assay (PLNA) was used in this study to assess immune responses in BALB/c mice following treatment with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3 and NiCl2), or Cr2O3 particles together with metal salts using single-dose exposures representing approximately 10days (0.000114mg), 19years (0.0800mg), and 40years (0.171mg) of normal implant wear. The immune response elicited following treatment with Cr2O3 particles together with metal salts was also assessed at four additional doses equivalent to approximately 1.5months (0.0005mg), 0.6years (0.0025mg), 2.3years (0.01mg), and 9.3years (0.04mg) of normal implant wear. Mice were injected subcutaneously (50μL) into the right hind foot with the test article, or with the relevant vehicle control. The proliferative response of the draining lymph node cells (LNC) was measured four days after treatment, and stimulation indices (SI) were derived relative to vehicle controls. The PLNA was negative (SI3) at the highest two doses of the metal salt mixture and the highest three doses of the Cr2O3 particles with the metal salt mixture. The provisional NOAEL and LOAEL values identified in this study for immune activation corresponds to Co and Cr concentrations in the synovial fluid approximately 500 and 2000 times higher than that reported for normal-functioning MoM hip implants, respectively. Overall, these results indicate that normal wear conditions are unlikely to result in immune stimulation in individuals not previously sensitized to metals. •Immune responses in mice were assessed following treatment with Cr2O3 particles with metal salts.•The PLNA was negative (SI