Regulatory experience with the comparative in vitro metabolism study based on an analysis of 70 studies with...

The use of pesticides is an inseparable and undeniable part of modern agriculture to ensure sufficient food supply for a still-growing population but, due to their intrinsic toxic nature, rigorous testing is needed before making them available on the market. In the European Union, in vitro metabolism studies with the active ingredients became mandatory in 2013. Unfortunately, in contrast to most other toxicological endpoints, a harmonised test guideline for their conduct is not yet available. More than 10 years after its introduction, we aimed to analyse the practical experience with that data requirement. For this purpose, 70 comparative in vitro metabolism studies were reviewed. Significant methodological differences were noticed among the studies, including species selection, test systems, tested concentrations, and incubation times. These differences and the deviations from existing but not legally binding recommendations limit the use that could be made of these studies, in particular beyond a simple comparison of human and rat metabolism. There is an urgent need for a harmonised guidance how to perform the in vitro biotransformation studies. Its implementation would not only increase the likelihood to identify unique or disproportionate human metabolites but might also support next-generation risk assessment.