Quantitative in vitro-to-in vivo extrapolation (QIVIVE) of estrogenic and anti-androgenic potencies of BPA and BADGE analogues

Abstract

The goal of the present study was to obtain an in vivo relevant prioritization method for the endocrine potencies of different polycarbonate monomers, by combining in vitro bioassay data with physiologically based kinetic (PBK) modelling. PBK models were developed for a selection of monomers, including bisphenol A (BPA), two bisphenol F (BPF) isomers and four different bisphenol A diglycidyl ethers (BADGEs), using in vitro input data. With these models, the plasma concentrations of the compounds were simulated, providing means to estimate the dose levels at which the in vitro endocrine effect concentrations are reached. The results revealed that, whereas the in vitro relative potencies of different BADGEs (predominantly anti-androgenic effects) can be up to fourfold higher than BPA, the estimated in vivo potencies based on the oral equivalent doses are one to two orders of magnitude lower than BPA because of fast detoxification of the BADGEs. In contrast, the relative potencies of 2,2-BPF and 4,4-BPF increase when accounting for the in vivo availability. 4,4-BPF is estimated to be fivefold more potent than BPA in humans in vivo in inducing estrogenic effects and both 2,2-BPF and 4,4-BPF are estimated to be, respectively, 7 and 11-fold more potent in inducing anti-androgenic effects. These relative potencies were considered to be first-tier estimates, particularly given that the potential influence of intestinal metabolism on the in vivo availability was not accounted for. Overall, it can be concluded that both 2,2-BPF and 4,4-BPF are priority compounds.

Bisphenol A Analogues in Food and Their Hormonal and Obesogenic Effects: A Review

“…Bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB), bisphenol E (BPE), and bisphenol AF (BPAF) are chosen by the industry as a replacement for BPA in the production of polycarbonates and epoxy resins [10,19,20] for the manufacturing of industrial and consumer products [21,22]. There are a limited number of studies on the BPA analogues’ hormonal effects, but most show that they have similar health concerns as BPA [23,24,25,26]. In 2002, we demonstrated the endocrine-disrupting activity of BPA analogues in the expression of estrogen-controlled genes [27].…”

Effects of maternal bisphenol A diglycidyl ether exposure during gestation and lactation on behavior and brain development of the offspring

“…In addition, in the previous toxicological studies, the dose levels range from 50 to 1000 mg/kg/day (EFSA, 2004;Miyazaki et al, Page 19 Hyoung et al, 2007). Moreover, Punt et al (Punt et al, 2019) performed quantitative in vitro-to-in vivo extrapolation and estimated the plasma concentration of BADGE in human. The peak free plasma concentration (C max, free ) of BADGE was 0.00001 µM (= 10 pM).…”

The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds

“…Further, physiologically-based toxicokinetic/pharmacokinetic (PBTK/PBPK) models have been used for prediction of absorption, distribution, metabolism, and excretion (ADME) processes and facilitation of quantitative in vitro-in vivo extrapolation (QIVIVE). Notable examples of MDC specific PBTK models have been suggested for BPA [23], and TPP [24]. (Q)SAR models have been developed for the NRs involved in metabolism disrupting effects, i.e., PPARα, PPARγ, PXR, CAR, LXRα, LXRβ, FXR, for endpoints such as median effective concentration (EC50), and inhibitory affinity constant (K i ) for defined applicability domains (Table S4).…”