Release Is Not Dose: Speciation, Bioavailability and Cellular Signalling of Metal Ions from Orthodontic and Prosthetic Alloys in the Oral Environment

Metal release from orthodontic and prosthetic alloys is measured almost universally as total elemental concentration in artificial or whole saliva and declared safe by comparison with dietary intake, drinking-water limits or toxic thresholds. This critical review argues that the comparison, a legitimate screen for systemic exposure, becomes a category error when used to exclude local mucosal effects. It traces the release literature’s reasoning since 1986 and shows that the extraction medium, not the alloy, determines the quantity and chemical form of what is measured. It then maps oral species onto cellular uptake routes and signalling pathways. Biological effect depends on species (aquo-ion, low-molecular-mass complex, protein adduct, oxyanion or particle); species dictate entry via divalent metal transporter 1, anion transporters, receptor-mediated endocytosis, membrane interaction or phagocytosis, thereby selecting between Toll-like receptor 4, NOD-like receptor family pyrin domain-containing 3, caspase-8, hypoxia-inducible factor 1α and non-apoptotic death programmes; and whole-saliva totals do not describe biofilm, crevicular or intracellular exposure. Oral speciation evidence rests on two nuclear magnetic resonance titrations and one chromium(VI) separation, and most mechanisms are borrowed from other tissues. A speciation-aware exposure model, presented as a hypothesis-generating framework, a minimum reporting set and prioritised experiments are proposed.