Development of a Physiologically Based Pharmacokinetic (PBPK) Model for F-53B in Pregnant Mice and Its Extrapolation to Humans

Abstract

Chlorinated polyfluorinated ether sulfonic acid (F-53B), a commonly utilized alternative for perfluorooctane sulfonate, was detected in pregnant women and cord blood recently. However, the lack of detailed toxicokinetic information poses a significant challenge in assessing the human risk assessment for F-53B exposure. Our study aimed to develop a physiologically based pharmacokinetic (PBPK) model for pregnant mice, based on toxicokinetic experiments, and extrapolating it to humans. Pregnant mice were administered 80 μg/kg F-53B orally and intravenously on gestational day 13. F-53B concentrations in biological samples were analyzed via ultraperformance liquid chromatography-mass spectrometry. Results showed the highest F-53B accumulation in the brain, followed by the placenta, amniotic fluid, and liver in fetal mice. These toxicokinetic data were applied to F-53B PBPK model development and evaluation, and Monte Carlo simulations were used to characterize the variability and uncertainty in the human population. Most of the predictive values were within a 2-fold range of experimental data (>72%) and had a coefficient of determination (R²) greater than 0.68. The developed mouse model was then extrapolated to the human and evaluated with human biomonitoring data. Our study provides an important step toward improving the understanding of toxicokinetics of F-53B and enhancing the quantitative risk assessments in sensitive populations, particularly in pregnant women and fetuses.

Keywords: F-53B; Monte Carlo (MC) simulation; perfluorooctanesulfonate (PFOS); physiologically based pharmacokinetic (PBPK) modeling.

Figure 1

A schematic of the PBPK model for F-53B in pregnant mice and humans. (A) The maternal model consisted of seven compartments, including the plasma, liver, placenta, fat, mammary glands, kidney, and rest of the body. (B) The fetal model consists of the plasma, brain, liver, rest of the body, and amniotic fluid.

Figure 2

Percentage of F-53B accumulation in pregnant mice and fetal tissues after 96 h of exposure through (A) oral and (B) intravenous (IV) administrations. Different colors represent various tissues/organs and their respective accumulation percentages.

Figure 3

Overall model calibration and evaluation results. (A) Global evaluation of the goodness of model fit between the observed (x-axis) and predicted values (y-axis) and (B) predicted-to-observed ratios versus predicted values plot for F-53B in pregnant mice. In plot B, the histogram represents the distribution of predicted-to-observed ratios. The abbreviation R² represents the adjusted determination coefficients estimated based on calibration data sets. The %2e and %3e indicate the percentage of predicted values was within a 2 and 3-fold error range, respectively.

Figure 4

Comparison of model predictions with in-house experimental data (mean ± SD). (A) Mother (fat and rest of body) and (B) fetus (amniotic fluid and fetal liver) at 96 h postexposure.

Figure 5

Normalized sensitivity coefficients (NSCs) of optimized parameters using the area under curves (AUCs) of F-53B in (A) plasma, liver, and placenta in the pregnant mice, and (B) plasma, brain, and liver in the fetal mice after a single oral dose of 80 μg/kg/day on GD13. Only parameters with NSC ≥ 0.3 are shown in the plots.

Figure 6

Histogram of simulated concentrations compared with measured values of F-53B concentration. The figure compares simulated concentrations with measured values (mean ± SD) in maternal plasma (blue circles) and cord blood (gray diamonds) reported in different studies and various human populations in China. The corresponding numeric data are available in Table S9.