Predicting the developmental toxicity of 8-methyl-benzo[a]pyrene (BaP) by physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry and read-across from BaP

The present study predicts an in vivo dose-response curve for developmental toxicity of 8-methyl-benzo[a]pyrene (8-MBaP) in rats using PBK model-facilitated reverse dosimetry and read-across from a previously developed model for BaP. As for BaP, in vitro developmental toxicity of 8-MBaP in the mouse embryonic stem cell test (mEST) was shown to require bioactivation to its 3-hydroxy metabolite (3-OH-8-MBaP). To facilitate extrapolation of the in vitro observed developmental toxicity of 3-OH-8-MBaP to an in vivo dose–response curve for 8-MBaP, a PBK model for 8-MBaP was built based on the previously developed PBK model for BaP. The PBK models for BaP and 8-MBaP were validated based on (i) comparison of predicted blood concentrations of BaP or 8-MaP to blood concentrations in rats dosed with BaP or 8-MBaP in the present study and (ii) literature-reported blood concentrations of BaP and its metabolite 3-OH-BaP in rats upon dosing with BaP. The predicted half maximal effect dose (ED₅₀) for developmental toxicity of 8-MBaP that was derived from the predicted in vivo dose–response curve was 1.3-fold lower than that of BaP for which the predicted value was in line with the reported in vivo ED₅₀. The present study illustrates how a new approach methodology (NAM) can be applied to predict developmental toxicity of a methyl substituted PAH, by PBK modeling facilitated read-across from a non-substituted PAH with available in vivo data. The method also elucidates how a methyl substituent could affect the kinetics and subsequent developmental toxicity of a non-substituted PAH.