Reflections on internal and external validity in regulatory toxicology of plant protection product active substances

Regulatory toxicology of plant protection product active substances primarily relies on OECD Test Guideline and GLP-compliant animal studies, which may inform regulatory assessments across OECD and other MAD-adhering jurisdictions based on the same underlying study data. While these frameworks ensure harmonized study conduct and technical quality assurance, they do not themselves guarantee internal and external validity. This commentary discusses limited study replication, biological variability in outbred laboratory animal populations, variation in endpoint-specific sensitivity, and the evidentiary value of statistically non-significant and absent findings. Carcinogenicity studies with chlorothalonil illustrate how animal population structure may influence detectability of effects; aclonifen provides an additional example of divergent findings between broadly comparable studies. In such populations, negative findings do not necessarily indicate absence of effects in susceptible subpopulations. Beyond these internal validity aspects, limitations of external validity are discussed in light of pharmaceutical development, where human studies and post-marketing pharmacovigilance provide empirical correction stages. Plant protection product active substance evaluations do not include a mandatory, substance-specific post-authorisation surveillance system comparable to pharmacovigilance for medicinal products. Measures such as improved raw-data accessibility, consideration of outbred population structure, targeted confirmation of pivotal negative findings, and clearer uncertainty communication may strengthen the scientific robustness of regulatory toxicology.