DART Safety

Developmental and reproductive toxicity (DART) refers to potential adverse effects that exposure to an ingredient may have on sexual function and fertility in women and men, as well as pre- and postnatal developmental toxicity in their offspring. Some of these effects may materialise only later in life or even in the next generation.

Aiming to establish a next-generation risk assessment (NGRA) framework for DART, we are developing and evaluating a toolbox consisting of different in silico and in vitro new approach methodologies (NAMs) for exposure predictions and bioactivity measurements that will assure human safety. We are using the knowledge from systemic safety and its exposure prediction tools and bioactivity measurements (high throughput transcriptomics, cell stress panel, and in vitro pharmacological profiling) to account for the specific circumstances in DART.

Exposure

While all our safety assessments are exposure-led, we have developed a strategy using in vitro measured parameters that allow us to predict human-relevant blood concentrations for an ingredient using physiologically-based kinetic (PBK) modelling. During pregnancy, some physiological parameters within the mother change and a foetus, in general, shows different physiology compared to an adult. This can, to a certain extent, be accounted for in PBK modelling software. However, some parameters, including placenta transfer, can be difficult to predict. We are collaborating with experts in the field to build capability for in vitro measurements to complement and evaluate our modelling approaches.

Bioactivity

For bioactivity testing, we have expanded on the in vitro NAMs used in our systemic safety NGRA to achieve the best biological coverage for DART. As a result, we have included additional measurements for DART-specific molecular initiating events in our in vitro pharmacological profiling panel. The DART toolbox has also been improved by adding Toxys ReproTracker® and Steminas devToxquickPredict™ platform, as developmental toxicity-specific in vitro assays. Using benchmark substances and exposure scenarios, we are currently evaluating our approach and in parallel, are working with external partners to address knowledge/data gaps. This includes investigating the use of advanced human cell models for refinement and mechanistic understanding of human-relevant DART endpoints.