Large progress has been made during the past years concerning the development of animal-free test methods that are designed to assess developmental neurotoxicity (DNT) hazard within much shorter time and with lower financial effort than required for animal tests. The concept behind these new approach methods is that brain development requires so-called key neurodevelopment processes, which can be studied one by one with appropriate in vitro systems. It is assumed that a compound interferes with at least one of these processes to trigger DNT. On this basis, test methods have been established to model key neurodevelopment processes, like cell migration, cell differentiation, neurite growth, or formation of electrical networks. Several of these tests have a good documentation and technical robustness status. The next big scientific question is how hits in such screens do translate to DNT toxicants. We explored which procedures need to be implemented to confirm a screen-hit as being robust and toxicologically meaningful. Although such considerations are highly developed in the efficacy area of drug discovery, the field of toxicology has until now hardly developed strategies to ad-dress this scientific problem. Also, this project allowed, for the first time in the DNT field, the evaluation of inter-laboratory variability of the new approach methods used to pre-dict DNT hazard. The latter is generally seen as one of the indispensable conditions for the regulatory use of data. Furthermore, a very initial classification was attempted to characterize otential toxicants as disturbing structural features of nervous system development and/or causing functional deficits.
From (screen) hit to DNT toxicant
Pesticide Research no. 231, June 2025