Differential endocrine and reproductive responses across generations: highlighting the need for holistic assessment in regulatory toxicology.

In 2024, Bichlmaier published a retrospective statistical analysis of 112 Extended One-Generation Reproductive Toxicity Studies (EOGRTS), concluding that reproductive and endocrine effects rarely demonstrate cross-generational continuity. He contended that findings limited to a single generation should be interpreted independently and need not exhibit generational consistency to be toxicologically relevant. We question the underlying premise that there is no biological plausibility for continuity as this conflicts with prevailing scientific and regulatory approaches that emphasise biological coherence and mechanistic relationship. The current review presents a re-analysis of the data used by Bichlmaier and critically examines the analytical framework used, considers established toxicological principles and regulatory standards and draws on the critiques presented by Arts et al. (Arch Toxicol 99:3047-3305, 2025). Through a comprehensive weight-of-evidence critique, we demonstrate that the analytical assumptions underpinning Bichlmaier's study fail to account for core principles such as adversity, dose-response relationships, effect magnitude, and mechanistic coherence, thereby undermining the utility of the findings for regulatory toxicology.