The presented workflow facilitates the rapid and simultaneous exploration of complex environmental exposures and their effect on the human metabolome. Despite issues due to the wide concentration range, the quantification of several endogenous metabolites and exogenous chemicals acquired simultaneously in one short LC-MS/MS run succeeded and preliminary correlations between metabolites and chemicals were revealed. Consequently, the potential effects of specific exposures on the metabolome were directly derived from exposure data in a so far unique way. However, further experiments are required to establish solid causal relationships. Combining two columns and both ionization modes in one single data file drastically decreased measurement time and simplified data evaluation and storage requirements. For deciphering of the exposome, hundreds to thousands of samples will be needed to be analyzed. Therefore the reduced analysis time opens up for so far unseen throughput in exposome-wide association studies for drawing reliable conclusions on the impact of environmental factors on disease development.