How safe are environmental chemicals

We are directly exposed to a variety of diverse synthetic chemicals on a daily basis, for example when using cleaning products, cosmetics, drugs, plastics, and food additives. Many of these chemicals, e.g. environmental phenols, phthalates, and herbicides, can be detected in human blood or urine samples. Accordingly, due to the constant exposure to chemicals, it is essential to evaluate potential hazards and health risks. Within the EUs REACH program and the US National Toxicity Program, chemicals are studied for their potential endocrine disrupting effects. At the same time, alternatives to in vivo testing in the form of in silico / in vitro testing are evaluated. In silico predictions are highly useful to prioritize chemicals for in vitro / in vivo testing. Pharmacophore models are excellent in silico screening tools to select potentially active compounds from large chemical databases. However, so far they have hardly been used to suggest chemicals for toxicity evaluations. In the proposed project, a pharmacophore-based in silico screening platform will be developed to prioritize chemicals for mechanism-based toxicity evaluations. This platform will focus on 14 steroid- synthesizing and -metabolizing enzymes, which have not been considered in systematic toxicity studies so far. For each target, models will be experimentally validated to optimize their predictive power. Environmental chemical databases will be screened for potentially active compounds. Among the virtual hits, chemicals with direct consumer exposure or high annual production volume will be acquired and tested in vitro. Identified active chemical classes will be further investigated by testing structurally related compounds in the in vitro assays. Based on all experimental results, the pharmacophore models will be optimized to correctly separate active from inactive chemicals on the respective targets. For the studied chemical classes, structure-activity-relationship models will be built to further optimize the predictions within the respective compound class. The developed model collection and exemplified case studies will lay ground for future, systematic safety evaluations of chemicals. In the future, such in silico platforms combined with in vitro testing are expected to form one basis for toxicity predictions.