Beyond Blood and Urine: Decoding the Human Chemical Exposome across Matrices and Time

Abstract Environmental chemicals contribute substantially to the global burden of chronic disease, yet for most compounds now detectable in human biological samples, causal links to specific health outcomes remain poorly established. HRMS can profile thousands of chemical features simultaneously in a single sample. What has not kept pace is study design. No investigation has yet combined external environmental source monitoring, multi-matrix internal biomonitoring, and toxicokinetic normalization within a single longitudinal framework. This Perspective argues that closing this design gap is the prerequisite for strengthening causal evidence in environmental health research and proposes an operational framework resting on three contributions: a multi-matrix sampling imperative extending the biological inventory beyond blood and urine to accumulation archives, developmental matrices, and external environmental media; a Unified Exposure Scale translating measurements from heterogeneous matrices onto a common toxicokinetically normalized dosimetric axis; and a two-track hazard prioritization pipeline for the largely uncharacterized molecular dark matter of the exposome. As the Global Human Exposome Project defines its operational infrastructure, these design principles offer a concrete path toward identifying chemical disease drivers before clinical manifestations.