Airborne PM Metal Shares as Predictors of CaEDTA-DMPS-GSH-Provoked Urinary Metal Burden

<b>Context</b>Linking inhaled metal burdens to urinary biomarkers remains an analytical challenge requiring robust exposure–biomarker frameworks.Spontaneous urine measurements often lack sensitivity for low-level metals, motivating provoked-urine approaches.A single-dose provocation combining a hard-coordinating chelator (e.g., EDTA or DTPA, whose carboxylate and amine donors preferentially bind hard Lewis acids such as Al³⁺, Fe³⁺, UO₂²⁺, and Cr³⁺) with a soft-coordinating thiol chelator (e.g., DMPS or DMSA, which target soft metals like Hg²⁺, Cd²⁺, Pb²⁺, Au⁺, and Pt²⁺), all supported by glutathione, not only enhances urinary excretion across the full hardness spectrum but also broadens the dynamic range of provoked metal release.Standardizing provoked‐urine tests (CEMETs) faces reproducibility and validation hurdles due to protocol variability.This analysis evaluates a standardized clinical GSH – Na₂Ca-EDTA – DMPS protocol for its capacity to reflect environmental metal exposure in a large cohort.<br><b>Data Sources</b><br><i>Ambient PM₁₀/PM₂.₅ metal concentrations</i><i> (µg/m³) averaged over five Swiss sites [1].</i>Mean Air Conc. = annual average of PM₁₀ &amp; PM₂.₅ per metal.<i>Provoked CEMET statistics</i><i> (geometric means of n = 1,322 spot-urine tests) [2].</i>Excretion Enhancement Factors (EEFs) measured in a smaller paired cohort [3].Provoked Urine (CEMET) = post-chelation urinary burden (µg/g creatinine).Inferred Baseline Urine = CEMET ÷ EEF (routine unprovoked sampling not performed in the full cohort).<br><b>Rank-Based Correlations (n = 25 metals)</b><br><b>M</b><b>etric Pair </b><b>Spearman ρₛ (p-value)</b><b>Mean Air vs. Provoked (CEMET) </b>0.62 (0.001)<br><b>Mean Air vs. Baseline (inferred) </b>0.39 (0.053)<b>Provoked vs. Baseline </b>0.90 (&lt; 0.001)<br><b>Key Findings</b><br>A <b>ρₛ ≈ 0.62</b> confirms that annual-average PM metal profiles rank-order alongside provoked urinary burdens, supporting a direct link between inhalation and CEMET outcomes.A weaker <b>ρₛ ≈ 0.39</b> with inferred baselines highlights the increased dynamic range afforded by provoked testing.A high <b>ρₛ ≈ 0.90</b> between provoked and inferred baselines—where EEFs were measured in a smaller sub-cohort—demonstrates that chelation amplifies but does not reorder underlying body-burden hierarchies.The pronounced spring 2017 spike in provoked urinary uranium mirrors documented associations between seasonal PM-uranium variability and spontaneous urinary uranium [5], further validating the protocol’s sensitivity and specificity.<b>Caveats</b><i>Hypothesis-generating:</i><i> </i>Correlations alone do not establish causality.<i>EEFs from a sub-cohort:</i> Baseline values for the full dataset are inferred, not directly measured.<b>Conclusion</b><br>These strong correlations indicate that inhaled particulate metals account for significant portions of provoked urinary excretion across the majority of evaluated metals, demonstrating the single-dose GSH–EDTA–DMPS protocol’s effectiveness in capturing inhalation-derived metal burdens. Use this workbook to reproduce analyses, explore metal-specific trends, and inform future environmental and clinical biomarker research.<br><b>References</b>Hüglin C, Grange SK. Chemical characterisation and source identification of PM₁₀ and PM₂.₅ in Switzerland [Internet]. Dübendorf: Empa; 2018. Available from: https://www.bafu.admin.ch/dam/bafu/de/dokumente/luft/externe-studien-berichte/chemical-characterisation-and-source-identification-of-pm-in-switzerland.pdfCarmine TC. Vital CEMET statistics based on 1322 multi-element analyses of 33 metals in spot urine [Dataset]. figshare; 2024. https://doi.org/10.6084/m9.figshare.27198768.v2Carmine TC. Raw Data Spot Urine – multielemental metal analysis pre and post-CEMET [Dataset]. figshare; 2024. https://doi.org/10.6084/m9.figshare.27131976.v1Carmine TC. The Uranium Episode (March–May 2017) in Temporal Context: Associations with CEMET Uranium, Aluminum, and Local PM₁₀ Exposure (2016–2019) [Figure]. figshare; 2024. https://doi.org/10.6084/m9.figshare.27435639.v5Pang Y, Kaufman JD, Correa JC, et al. Association of geography and ambient air pollution with urine metal concentrations in six US cities: The Multi-Ethnic Study of Atherosclerosis. Int J Environ Res Public Health. 2016;13(4):324.<br>