Health risk assessment of cadmium exposure by integration of an in silico physiologically based toxicokinetic model and in vitro tests

Cadmium (Cd) is a common environmental pollutant that can damage multiple organs, including the kidney. To prevent renal effects, international authorities have set health-based guidance values of Cd from epidemiological studies. To explore the health risk of Cd exposure and whether human equivalent doses (HEDs) derived from in vitro tests match the current guidance values, we integrated renal tubular epithelial cell-based assays with a physiologically based toxicokinetic model combined with the Monte Carlo method. For females, the HEDs (μg/kg/week) derived from KE2 (DNA damage), KE3 (cell cycle arrest), and KE4 (apoptosis) were 0.20 (2.5th-97.5th percentiles: 0.09-0.48), 0.52 (0.24-1.26), and 2.73 (1.27-6.57), respectively; for males the respective HEDs were 0.23 (0.10-0.49), 0.60 (0.27-1.30), and 3.11 (1.39-6.78). Among them, HEDKE4 (female) was close to the tolerable weekly intake (2.5 μg/kg/week) set by the European Food Safety Authority. The margin of exposure (MOE) derived from HEDKE4 (female) indicated that risks of renal toxicity for populations living in cadmium-contaminated regions should be of concern. This study provided a new approach methodology (NAM) for environmental chemical risk assessment using in silico and in vitro methods.