Effect-based human biomonitoring of complex chemical mixtures using high-throughput target screening and in vitro bioassays

Abstract

Human biomonitoring is a valuable tool for investigating and understanding the human chemical exposome and its association to human health. Current approaches are mainly focusing on a small subset of already well-studied chemicals and neglect the fact that humans are exposed to a diverse set of complex chemical mixtures. This thesis introduced the concept of effect-based human biomonitoring (EB-HBM), which combines chemical exposure assessment, cell-based in vitro bioassays and in silico models to assess the composition and effects of human-relevant complex chemical mixtures. The developed and optimized models and methods were demonstrated with a case study on neurotoxic mixture effects of chemicals extracted from the blood of 624 pregnant women from a German cohort study. Chemical mixtures were extracted by a holistic two-step extraction method. Over 1,000 chemicals in this large number of samples could be analyzed with a new workflow for automated analysis and quantification. Effect drivers were identified by mixture experiments and modeling. The mixture toxicity concept of concentration addition turned out to valid for predicting the effects of the recreated real-life mixtures. The use of high-throughput target screening combined with cell-based bioassays bears great potential to improve human biomonitoring and provide a novel approach to include mixtures in epidemiological studies.