The high-resolution analysis was successful in detecting and quantifying medium to high concentration levels of xenobiotics in the ng/mL range, however, HRMS does capture fewer low-level exposures than targeted QQQ mass spectrometry in the chosen configuration. Nevertheless, the LOQ/LOD of HRMS was low to discover toxicologically relevant contamination levels for many toxicants. The extension of the comparison performed in this work to other vendors/instruments and matrices would allow a more comprehensive investigation of the differences in sensitivity between both techniques, as specific instrumentation impacts the outcome of any comparison. While generalizing our results might not be feasible, certain limitations concerning sensitivity for HRMS were observed for the investigated configuration. Moreover, both instruments were applied in standard acquisition modes used in targeted and non-targeted exposomics. Thus, HRMS was operated in full scan mode and compared to MRM mode for the QQQ. Importantly, the performance of HRMS might improve when using the PRM (Parallel Reaction Monitoring) mode on the HRMS instrument instead of the full scan mode. Individually, xenobiotics at low-levels may not pose a health risk. If mixture effects, longitudinal exposure, and exposure at certain sensitive periods are considered, however, even minor levels may still play a central role in risk assessment and disease development. Therefore, the quantitative information obtained from low-level exposure in QQQ is highly valuable for risk assessments and exposomic investigations. Nevertheless, discovering emerging, unknown, and unexpected contaminants (including biotransformation products) where reference standards are frequently unavailable, is unique to HRMS and makes it essential to elucidate the exposome. However, broad, targeted QQQ methods are a crucial addition to HRMS for quantifying trace level exposures.