Trace Element Ionomics of Saliva: A Critical Narrative Review of Analytical Foundations, Physiological Determinants, and Disease Associations

Abstract

Saliva has attracted sustained interest as a non-invasive alternative to blood for characterising the trace element composition, or ionome, of the human body. The application of high-throughput elemental profiling to whole and glandular saliva, commonly described as salivary ionomics, has generated a heterogeneous body of evidence linking essential and non-essential trace elements to periodontal disease, dental caries, oral precancerous and malignant lesions, diabetes mellitus, chronic kidney disease, tobacco exposure, and environmental and occupational contaminant exposure. This review synthesises this literature critically, moving beyond a study-by-study catalogue to evaluate the strength, consistency, and methodological quality of the available evidence. The salivary glands modify trace element concentrations through a two-stage acinar and ductal secretory process that is only partially analogous to the mechanisms governing macro-ion transport, and this physiological complexity, combined with substantial pre-analytical variability in flow rate, stimulation status, collection device, and analytical technique, contributes to marked inconsistency across studies. Sodium and potassium are the most consistently reported discriminants of periodontal status, whereas findings for zinc, copper, manganese, selenium, and toxic elements such as lead, cadmium, and mercury remain conflicting across disease contexts. Reference ranges for most trace elements in saliva are poorly established relative to blood, and few studies adequately control for dental restorative materials, smoking status, age, and sex, all of which independently influence salivary elemental composition. The evidence is strongest for the general feasibility of detecting trace elements in saliva and for associations with recent exposure to environmental contaminants, and weakest for the diagnostic or prognostic utility of any single element or ratio. Future research priorities include harmonised pre-analytical protocols, longitudinal designs capable of distinguishing cause from consequence, and multi-element rather than single-analyte approaches informed by the ionomics paradigm. Salivary trace element ionomics constitutes a promising but still immature field whose translational value depends on methodological standardisation rather than further isolated case-control comparisons.