Pregnancy-specific physiologically-based toxicokinetic models for bisphenol A and bisphenol S

Abstract

Predictions from physiologically based toxicokinetic (PBTK) models can help inform human health risk assessment for potentially toxic chemicals in the environment. Bisphenol S (BPS) is the second most abundant bisphenol detected in humans in the United States, after bisphenol A (BPA). We have recently demonstrated that BPS, much like BPA, can cross the placental barrier and disrupt placental function. Differences in physicochemical properties, toxicokinetics, and exposure outcomes between BPA and other bisphenols prevent direct extrapolation of existing BPA PBTK models to BPS. The current study aimed to develop pregnancy-specific PBTK (p-PBTK) models for BPA and BPS, using a common p-PBTK model structure. Novel paired maternal and fetal pregnancy data sets for total, unconjugated, and conjugated BPA and BPS plasma concentrations from three independent studies in pregnant sheep were used for model calibration. The nine-compartment (maternal blood, liver, kidney, fat, placenta and rest of body, and fetal liver, blood and rest of body) models simulated maternal and fetal experimental data for both BPA and BPS within one standard deviation for the majority of the experimental data points, highlighting the robustness of both models. Simulations were run to examine fetal exposure following daily maternal exposure to BPA or BPS at their tolerable daily intake dose over a two-week period. These predictive simulations show fetal accumulation of both bisphenols over time. Interestingly, the steady-state approximation following this dosing strategy achieved a fetal concentration of unconjugated BPA to levels observed in cord blood from human biomonitoring studies. These models advance our understanding of bisphenolic compound toxicokinetics during pregnancy and may be used as a quantitative comparison tool in future p-PBTK models for related chemicals.

Keywords: Bisphenol S; Fetal exposure; Pharmacokinetics; Physiologically-based toxicokinetic model; Pregnancy; Toxicokinetics.

Figure 1.. PBTK model scheme.

Nine-compartment PBTK pregnancy model scheme for BPA and BPS. Compartments included are maternal fat (F), liver (L), kidney (K), blood (A), and rest of body (R), placenta (PL), and fetal blood, liver, and rest of body. Model includes subcutaneous first order absorption constant (K_a), placental to fetal (kt₁) and fetal to placental (kt₂) blood diffusion rates, chemical concentration in arterial blood (C_A), maximum rate of enzymatic reaction (V_max) and Michaelis-Menten constant (K_m), renal excretion (KEL_R and KEL_{R_conj}), biliary excretion (KEL_L) – resulting in fecal elimination, and for each of the nine-compartments, the respective blood flow rate (Q-tissue), partition coefficients (P-tissue), tissue concentrations (C-tissue), and venous concentration leaving the tissue (CV-tissue), for unconjugated (left panel) and conjugated (right panel) bisphenols. The addition of _f denotes fetal-specific parameters. BPS molecular structures below represent the difference in unconjugated and conjugated molecular size.

Figure 2.. Simulated toxicokinetic plots of BPA for maternal and fetal circulation.

Experimentally obtained total BPA measurements in sheep maternal plasma over time (gestational age: 114.8 ± 0.8 days; diamonds in panel A) following a single subcutaneous injection of BPA (0.5 mg/kg; dataset #1 (Gingrich et al. 2019)) were used to calibrate simulated total BPA in maternal plasma over time (A; solid blue line). The BPA model was also calibrated against dataset #2 (circles) of unconjugated (B; orange line) and conjugated (C; dotted blue line) BPA from sheep plasma following steady state conditions (continuous intravenous infusion, 2 mg/kg BW/day BPA, gestational age: 108 - 117 days, (Corbel et al. 2013)). This process was repeated for the fetal compartment using fetal plasma concentrations of total (D), unconjugated (E) and conjugated (F) BPA, obtained from the dataset #1 and dataset #2 used for the maternal compartment calibration. All independent dataset values fall within the simulated ranges.

Figure 3.. Simulated toxicokinetic plots of BPS for maternal and fetal circulation.

The model was calibrated through experimentally obtained total BPS measurements in sheep maternal plasma over time (gestational age: 114.8 ± 0.8 days; diamonds in panel A) following a single subcutaneous injection of BPS (0.5 mg/kg; dataset #1 (Gingrich et al. 2019)). Simulated total BPS in maternal plasma over time (A; solid blue line) was estimated from this model. The BPS model was also calibrated against dataset #3 (circles) of unconjugated (B; orange line) and conjugated (C; dotted blue line) BPS from sheep plasma following a single bolus intravenous injection (5 mg/kg BPS, gestational age: 109-113, (Grandin et al. 2018)). Insets have been included for these parameters to better demonstrate dataset fit to the simulation. The calibration process was repeated for the fetal compartment using fetal plasma concentrations of total (D), unconjugated (E) and conjugated (F) BPS, obtained from the dataset #1 and dataset #3 used for the maternal compartment calibration (Gingrich et al. 2019; Grandin et al. 2018). All dataset values except conjugated, and to a lesser extent unconjugated fetal BPS, fall within the simulated values.

Figure 4.. Simulation of BPA body burden following two weeks of daily dosing in an ovine model.

Using the BPA-model code, a simulation was run to predict maternal (A) and fetal (B) circulating BPA concentrations over 2 weeks following daily oral BPA administration (arrows) at the EPA reference dose for BPA (50 μg/kg body weight/day, (EPA 2012)). Simulated concentrations include total BPA (solid blue line), conjugated BPA (dotted blue line), and unconjugated BPA (solid orange line). Simulated total and conjugated BPA concentrations appear to nearly overlap and are indistinguishable from each other. To the right of each graph (shaded boxes), a magnified view of unconjugated BPA concentrations is provided. Simulated unconjugated BPA following a single dose is represented by a dotted orange line and exposure average of unconjugated BPA following daily dosing for 2 weeks is represented by the solid black line.

Figure 5.. Simulation of BPS body burden following two weeks of daily dosing in an ovine model.

Using the BPS-model code, a simulation was run to predict maternal (A) and fetal (B) circulating concentrations of BPS following 2 weeks of daily oral BPS administration (arrows) at the EPA reference dose for BPA (50 μg/kg body weight/day, (EPA 2012)). Simulated concentrations include total BPS (solid blue line), conjugated BPS (dotted blue line), and unconjugated BPS (solid orange line). In maternal circulation, simulated total and conjugated BPS concentrations appear to nearly overlap and are indistinguishable from each other. To the right of each graph (shaded boxes), a magnified view of unconjugated BPS concentrations is provided. Simulated unconjugated BPS following a single dose is represented by a dotted orange line and exposure average of unconjugated BPS following daily dosing for 2 weeks is represented by the solid black line.

Figure 6.. Global sensitivity analysis of the fetal compartment for BPA model.

Global sensitivity analysis of fetal compartment parameters for the BPA model run over a 48-h period. Parameters were assessed for unconjugated BPA with (A) and without placental transfer (B) and conjugated BPA with (C) and without placental transfer (D). Sensitivity analysis was depicted as the main effect or percent of output variance for each parameter and was computed every half-hour for 48 h. Parameters evaluated were: K_{d_f} (rate of fetal hepatic deconjugation, solid black line), V_{max_f} (maximum rate of enzymatic reaction, solid red line), K_m (Michaelis-Menten constant, solid blue line), fetal rest-of-body partition coefficient for both unconjugated (PR_{_f}, hashed black line), and conjugated BPA (PR_{_f}^(c), hashed red line), and placental transfer to (kt₁, dotted black line) and from (kt₂, dotted red line) the placenta. The shaded area around the parameter lines depicts a 95% confidence interval.

Figure 7.. Global sensitivity analysis of the fetal compartment for BPS model.

Global sensitivity analysis of fetal compartment parameters for the BPS model run over a 48-h period. Parameters were assessed for unconjugated BPS with (A) and without placental transfer (B) and conjugated BPS with (C) and without placental transfer (D). Sensitivity analysis was depicted as the main effect or percent of output variance, for each parameter and was computed every half-hour for 48 h. Parameters evaluated were: K_{d_f} (rate of fetal hepatic deconjugation, solid black line), V_{max_f} (maximum rate of enzymatic reaction, solid red line), K_{m_f} (Michaelis-Menten constant, solid blue line), fetal rest-of-body partition coefficient for both unconjugated (PR_{_f}, hashed black line) and conjugated BPS (PR_{_f} ^(c), hashed red line), and placental transfer to (kt₁, dotted black line) and from (kt₂, dotted red line) the placenta. The shaded area around the parameter lines depicts a 95 % confidence interval.