Developmental and reproductive toxicity (DART) is a critical area of toxicology that is required to assess the impact of new chemicals on adult fertility and embryo development. Industries across the globe rely on DART assessments to safeguard human health, adhering to regulatory standards like those outlined in the ICH S5 (R3) guideline. However, the current regulatory landscape for DART assessments is not without its challenges. Traditional methods rely heavily on animal testing, which comes with significant ethical concerns, high costs, and limited insights into the underlying mechanisms of toxicity.
Our latest research, recently published in Computational Toxicology, details an alternative approach to animal testing, which can be used to screen for DART hazards at the early stages of compound development. This work highlights a step forward in animal-free safety assessments, with the potential to aid regulatory DART-based safety assessments.
Using alternative assays to detect DART hazards
Early identification of developmental toxicants, and the reduction in the need for animal-based methods is desirable. New Approach Methodologies (NAMs), including in silico models, are being developed as innovative alternatives to traditional mammalian testing methods, aiming to align DART assessments with the principles of the 3Rs—reduction, refinement and replacement. These methodologies offer more cost-effective and timely evaluations of DART liabilities.
Due to the implications of a mischaracterised developmental toxicant, both high confidence and understanding of the assessments made using NAMs is required, and multiple NAMs are needed to replace current animal-based assessments. Adverse outcome pathways (AOPs) provide a robust framework for documenting mechanisms of toxicity, NAMs can be associated to key events (KEs) along an AOP.
We have developed and applied a predictive AOP network to effectively identify DART hazards, representing significant progress in enhancing the reliability and confidence in the use of NAMs for DART safety assessments. In future, this innovative research will be beneficial to the wider scientific community, through our in silico tool Kaptis.
A scientifically robust DART AOP network
Available with 50-day open access, the scientific paper by Lhasa experts outlines the development and composition of a vast DART AOP network containing 340 KEs (including 68 molecular initiating events), to provide a formalised approach to documenting the mechanisms of DART. In addition, we evaluate the performance of the network as a DART hazard screening tool; enhancing the development and use of NAMs for hazard identification and aiding in the development of integrated approaches to testing and assessment (IATAs) for regulatory purposes – in turn, helping to progress the 3Rs of animal research.
While other publications have highlighted the limitations of DART (Q)SAR models, which have been developed on traditional toxicity data, our AOP network contextualises a broad range of data. As a result of this, we can make hazard predictions across a much larger chemical space than conventional models. To illustrate the power of our Lhasa DART AOP framework, the publication highlights two key use-cases:
A screening tool for DART hazards:
We assess the effectiveness of this tool against two distinct datasets—a traditional mammalian in vivo toxicity dataset and a zebrafish developmental toxicity study. The results underscore the potential of AOPs to provide early hazard identification, the AOP based approach allows for greatly improved sensitivity when compared to DART models solely based on in vivo data.
Regulatory submission support:
We explore how the AOP framework could support NAM based ICH S5 submissions. This application not only supports the regulatory transition to NAMs but also reinforces the credibility and reliability of these methods in formal assessments. The DART AOP network was able to propose mechanisms of action for 162 of the 197 positive results in the zebrafish assay dataset.
Take advantage of 50 days of open access and see how this innovative approach could impact your work, read the full publication.
We would love to hear from you and discuss how we can support your DART assessments. Contact us to learn more!
