The model of this application is a deployment of the model published by Thépaut et al. (2023) in the paper titled "PBPK modeling to support risk assessment of pyrethroid exposure in French pregnant women".

The p-PBPK model includes a maternal and a fetal sub-model (Fig. 1). The maternal sub-model includes 23 tissue compartments for the parent compounds. The fetal sub-model is connected to the maternal sub-model through the placenta and has 19 fetal compartments. This p-PBPK model was based on the lifetime model developed by Beaudouin et al. (2010) which was applied to pyrethroids by Quindroit et al. (2019) for adults only. In their model, Quindroit et al. (2019) modified the initial model to account for the pyrethroids’ kinetics and to include the kinetics of the metabolites. In our study, only the oral route was considered.

In this model, the organ growth for maternal and fetal parts of the model were described as in the lifetime model of Beaudouin et al. (2010). Since the volume of distribution increase during pregnancy, a hemodilution is observed in pregnant women. Hence, the equation describing hematocrit (HCT) was modified as proposed by Dallmann et al. (2017). Maternal cardiac output was corrected with HCT and increased during pregnancy. This increase in cardiac output leads to an increase in blood flow to all organs during pregnancy. Uterine blood flow was described using an equation developed by Dallmann et al. (2017). Concerning fetal blood flows, equations from Abduljalil et al. (2021) were applied in the model.

Compound specific parameters for parent compounds were set using in vivo animal data, due to the lack of in vivo or in vitro human data. For permethrin, the tissue:blood partition coefficients in mother and fetus were obtained from a study in which a p-PBPK model was calibrated with toxicokinetic data in pregnant rats (Personne et al., 2021). In mothers, isomer specific values were determined whereas experimental data in fetuses did not allow to estimate isomers values. Because cypermethrin data was lacking, the values of permethrin were used for cypermethrin due to their structural similarities. For deltamethrin, the partition coefficients determined by Mirfazaelian et al. (2006) for adult rats were applied to the mothers (Table B in supplementary material). Placental partition coefficients for both cypermethrin and permethrin were set to the ones proposed by Personne et al. (2021) for permethrin. Deltamethrin placenta:blood partition coefficient was set to the placental partition coefficient of trans-permethrin determined by Personne et al. (2021) due to more similar kinetics compared to cis-permethrin. Placental transfers for the 3 pyrethroids were set as the one calibrated for permethrin (Personne et al., 2021). Data on deltamethrin kinetics in the pregnant population are scarce. However, few in vivo studies suggest that DLT accumulates more in juvenile rat brains compared to adults (Sheets et al., 1994; Tornero-Velez et al., 2010). Thus, the fetal partition coefficients for deltamethrin were also set as to those determined for permethrin in Personne et al. (2021) because they describe a higher pyrethroid accumulation in the brain compared to deltamethrin partition coefficient in adults. For maternal compartments such as the adipose tissue, brain and muscles, the compound's distribution accounts for permeability coefficients to describe the ability of the compound to reach the organ tissue from the blood circulation. These coefficients have been scaled from rat data (Godin et al., 2010; Willemin et al., 2016) to humans. Regarding metabolites excretion, the model considers the excretion of 4 metabolites: 3-PBA, cis-DCCA, trans-DCCA and DBCA. Since 3-PBA is a common metabolite to various PYR, a parameter (Rate_Input_PBA) was taken into account to consider the part of 3-PBA coming from other exposure to PYR, therefore an additional source of 3-PBA was considered into the model.

Figure 1. Schematic representation of the p-PBPK model (from Thépaut et al. (2023)).

References:

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Dallmann, A., Ince, I., Meyer, M., Willmann, S., Eissing, T., Hempel, G., 2017. Gestation-specific changes in the anatomy and physiology of healthy pregnant women: an extended repository of model parameters for physiologically based pharmacokineticmodeling in pregnancy. Clin. Pharmacokinet. 56, 1303–1330.

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