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 EU’s 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 is being developed to
prioritize chemicals for mechanism-based toxicity evaluations. This platform focuses on 14 steroidsynthesizing
and -metabolizing enzymes, which have not been considered in systematic toxicity studies so
far. For each target, models are experimentally validated to optimize their predictive power.
Environmental chemical databases are screened for potentially active compounds. Among the virtual
hits, chemicals with direct consumer exposure or high annual production volume are acquired and
tested in vitro. Identified active chemical classes are further investigated by testing structurally related
compounds in the in vitro assays. Based on all experimental results, the pharmacophore models are optimized to correctly separate active from inactive chemicals on the respective targets. For the studied
chemical classes, structure-activity-relationship models are 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.