Comparative in vitro hepatic enzyme assay and species-specific TH modeling

Comparative in vitro hepatic enzyme assay and species-specific thyroid hormones modeling show that cinmethylin has no endocrine disrupting potential

Authors: N. Daguès, S. Melching-Kollmuss, I. Fegert, C. Gomes

BASF SE, Limburgerhof, Germany

Cinmethylin is a new herbicide developed for the selective pre-emergence control of many annual grass weeds. In toxicological studies, cinmethylin induces thyroid histopathological and hormone effects in the rat secondary to liver enzyme induction. To evaluate the human relevance of the thyroid effects, a comparative in vitro hepatic enzyme assay was conducted in rat and human primary hepatocytes, as recommended in the ECHA/EFSA Guidance for the identification of endocrine disruptors (EC 2018/605). Expression of Phase I (CYP) and Phase II (UGT) enzymes were measured after 7 days of exposure to cinmethylin. In addition, a physiologically-based kinetic (PBK) model has been developed to simulate cinmethylin effects on thyroid hormones homeostasis in rats and humans.

Cinmethylin induced CYP2B and CYP3A in rat and human hepatocytes, with a slightly more pronounced effect in male than in female donors for both species. Basal T4-UGT activity in human was 5 to 7 times lower than that in the rat and delta T4-UGT activity showed dose-related increases in cinmethylin-treated rat hepatocytes while no relevant changes were seen in human hepatocytes. The PBK model predicts no effect on the T3 and T4 concentrations and only a minor increase of TSH levels in human, when considering a worst-case exposure scenario unlikely to be achieved in real-life situations.

In conclusion, the interspecies comparative analysis using a combination of in vitro and in silico models allowed 1) to confirm that the thyroid changes observed in vivo in the rat exposed to cinmethylin were secondary to liver enzyme induction and 2) that this mode of action is not relevant to humans. Cinmethylin is therefore devoid of any endocrine disrupting potential.