Physiologically Based Toxicokinetic and Toxicodynamic (PBTK-TD) modelling of cis-bifenthrin in Carassius auratus and Xenopus laevis Accounting for Reproductive Toxicity

Pyrethroid insecticides are a class of endocrine disruptors and are believed to exhibit reproductive toxicity to aquatic organisms. Pyrethroids are widely detected in aquatic environments and can accumulate in aquatic organisms, but studies on their accumulation and the associated reproductive toxicity in aquatic organisms are still limited. We utilized Carassius auratus and Xenopus laevis as models for fish and amphibians, respectively, and developed and validated a physiologically based toxicokinetic and toxicodynamic (PBTK-TD) model for adult fish and frogs exposed to typical pyrethroid pesticides cis-bifenthrin (cis-BF). The model includes the brain, kidney, liver, gonads, gills/lungs, well-perfused tissue, and poorly-perfused tissue, which are interconnected by blood circulation in the PBTK process. There are also dynamic relationships between target organ concentrations and reproductive-related endpoints in the TD process. Results showed that the PBTK sub-model accurately described and predicted the uptake, distribution, and disposition kinetics in fish and frogs. In fish, the kidney exhibited the fastest accumulation rate, while in frogs, the skin showed the fastest accumulation rate, followed by the kidney. Sensitivity analysis indicated that parameters such as blood flow and blood distribution coefficients had significant effects on chemical concentrations. A sigmoid Emax model was employed to describe the relationship between the reproductive toxicity effects of cis-BF and its dose-concentration variations. We found that testosterone (T) exhibited the highest correlation coefficient, suggesting that T could serve as an effective biomarker for cis-BF reproductive toxicity. The PBTK-TD model established in this study is beneficial for predicting the toxicological effects of pyrethroids in fish and amphibians.