title: A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay.
abstract: 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 (SI<3) for all Cr2O3 particle doses, and was also negative at the lowest dose of the metal salt mixture, and the lowest four doses of the Cr2O3 particles with metal salt mixture. The PLNA was positive (SI>3) 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.
authors.affiliation: Cardno ChemRisk, LLC.; 4940 Pearl East Circle Suite 100; Boulder, CO 80301, United States. Electronic address: brooke.tvermoes@cardno.com.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Tvermoes
authors.affiliation: Cardno ChemRisk, LLC.; 20 Stanwix St. Suite 505; Pittsburgh, PA 15222, United States.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Unice
authors.affiliation: Cardno ChemRisk, LLC.; 101 2nd St. Suite 700; San Francisco, CA 94105, United States.
authors.forename: Bethany
authors.initials: B
authors.lastname: Winans
authors.affiliation: Cardno ChemRisk, LLC.; 130 Vantis Suite 170; Aliso Viejo, CA 92656, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Kovochich
authors.affiliation: Cardno ChemRisk, LLC.; 20 Stanwix St. Suite 505; Pittsburgh, PA 15222, United States.
authors.forename: Whitney V
authors.initials: WV
authors.lastname: Christian
authors.affiliation: Cardno ChemRisk, LLC.; 101 2nd St. Suite 700; San Francisco, CA 94105, United States.
authors.forename: Ellen
authors.initials: E
authors.lastname: Donovan
authors.affiliation: Cardno ChemRisk, LLC.; 130 Vantis Suite 170; Aliso Viejo, CA 92656, United States.
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Fung
authors.affiliation: Cardno ChemRisk, LLC.; 101 2nd St. Suite 700; San Francisco, CA 94105, United States.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Finley
authors.affiliation: University of Manchester, Faculty of Life Sciences, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Kimber
authors.affiliation: Cardno ChemRisk, LLC.; 101 2nd St. Suite 700; San Francisco, CA 94105, United States.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Paustenbach
mesh_terms: D000818:Animals; D005260:Female; D005434:Flow Cytometry; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology; D008670:Metals / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D011150:Popliteal Artery
chemical_list: D008670:Metals
keywords: Hypersensitivity; Immune stimulation; Lymph node cell activation; Metal-on-metal implants; Metals; Particles; Popliteal lymph node assay