Comprehensive liquid chromatography high-resolution mass spectrometry (LC-HRMS)-based approaches promise to more comprehensively elucidate the exposome in future exposome-wide association studies (ExWAS). A broad spectrum of small molecules with diverse chemical properties ranging from endogenous metabolites to environmental xenobiotics can be determined with this technique. External stressors, including xenobiotics and environmental changes, are measured simultaneously as phenotypical changes in response to these exposures. Thus, LC-HRMS is an ideal platform for developing more holistic methods to study the exposome . Its applicability to investigating the impact of environmental toxicants on the endogenous metabolome has previously been showcased . Metabolomics has been applied in large metabolome-wide association studies (MWAS) to investigate the biological mechanisms of diseases, their diagnosis and treatment. Several studies succeeded in deriving biological effects from their data, although data interpretation remains a challenge . The approach also plays an essential role in biomarker discovery and personalized medicine . However, the study of external stressors and complex environmental exposures is clearly less explored and constitutes the next frontier in the current era of omic-scale exposure measurement and systems toxicology.