Development and validation of PBPK models for genistein and daidzein for use in a next-generation risk assessment.

Introduction: All cosmetic ingredients must be evaluated for their safety to consumers. In the absence of data, systemic concentrations of ingredients can be predicted using Physiologically based Pharmacokinetic (PBPK) models. However, more examples are needed to demonstrate how they can be validated and applied in Next-Generation Risk Assessments (NGRA) of cosmetic ingredients. We used a bottom-up approach to develop human PBPK models for genistein and daidzein for a read-across NGRA, whereby genistein was the source chemical for the target chemical, daidzein.

Methods: An oral rat PBPK model for genistein was built using PK-Sim and ADME input data. This formed the basis of the daidzein oral rat PBPK model, for which chemical-specific input parameters were used. Rat PBPK models were then converted to human models using human-specific physiological parameters and human ADME data. skin metabolism and penetration data were used to build the dermal module to represent the major route of exposure to cosmetics.

Results: The initial oral rat model for genistein was qualified since it predicted values within 2-fold of measured PK values. This was used to predict plasma concentrations from the NOAEL for genistein to set test concentrations in bioassays. Intrinsic hepatic clearance and unbound fractions in plasma were identified as sensitive parameters impacting the predicted C values. Sensitivity and uncertainty analyses indicated the developed PBPK models had a moderate level of confidence. An important aspect of the development of the dermal module was the implementation of first-pass metabolism, which was extensive for both chemicals. The final human PBPK model for daidzein was used to convert the PoD of 33 nM (from an estrogen receptor transactivation assay) to an external dose of 0.2% in a body lotion formulation.

Conclusion: PBPK models for genistein and daidzein were developed as a central component of an NGRA read-across case study. This will help to gain regulatory confidence in the use of PBPK models, especially for cosmetic ingredients.