A tiered approach to developmental and reproductive toxicology with NAMs
Unilever and Toxys scientists recently published an article in Frontiers in Toxicology entitled “An advancement in developmental and reproductive toxicity (DART) risk assessment: evaluation of a bioactivity and exposure-based NAM toolbox”.
The DART NAM toolbox and NGRA framework
As outlined in Next Generation Risk Assessment (NGRA) frameworks, safety assessments based on NAMs should be exposure driven and be sufficiently protective. A broad outline of endpoints, informative of DART, was previously developed1 and has now been expanded to include additional in vitro and in silico tools to ensure the protectiveness of the framework.
Image 1. Workflow for evaluation of DART framework
Tier 0 of this framework is aimed to generate in silico predictions, relevant to general DART toxicity and estrogen and androgen activity based on chemical structures. For this, Derek Nexus, OECD QSAR Toolbox, VEGA, and OPERA are used and resulting predictions are then compared to previous knowledge. Tier 1 of the framework is aimed to estimate chemical bioactivity and human chemical exposure across selected NAMs. Here, a combination of broad and targeted NAMs, namely high throughput transcriptomics (HTTr), cell stress panel (CSP), in vitro pharmacological profiling (IPP), ReproTracker, DevTOX quickPredict, H295R, and screening CALUX assay are used. Overall, in this NAM toolbox, both molecular initiating events (MIEs) known to be important for DART, and fundamental cellular processes that take place during early embryonic development, such as iPSC metabolism and differentiation are covered.
An evaluation with benchmark compounds
To evaluate this DART NGRA framework, 37 benchmark compounds were selected, including pharmaceuticals, cosmetics, and dietary supplements, across 49 chemical exposure scenarios. 18 out of the 49 scenarios were classified as high-risk chemical exposures from a DART perspective. The DART NAM toolbox approach accurately identified 17 out of these 18 high-risk scenarios. 16 of the 27 low risk exposure scenarios were also accurately classified, highlighting the potential of the framework.
These initial results demonstrate the ability of a tiered NGRA framework that uses a combination of DART-targeted and broad screening tools and that it is protective in the scope of DART safety assessments. It remains essential to expand on chemical exposure tests to build confidence on this approach and to improve understanding in human relevant predictions.
ReproTracker in the context of multitiered approaches for DART
This publication illustrates the potential of the ReproTracker assay and its use in multitiered approaches. With lineage specific information, ReproTracker provides a human relevant biological coverage of endpoints informative of DART as defined within the NGRA framework.
As one of the targeted tools included in the DART NAM toolbox, ReproTracker contributes to the calculation of points of departure (PoDs) to determine bioactivity of the compounds and calculating bioactivity: exposure ratios (BERs). This publication underscores the potential of the ReproTracker assay within multitiered approaches to establish predictive and protective NGRA frameworks.
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