The EuroMix human biomonitoring study: Source-to-dose modeling of cumulative and aggregate exposure for the bisphenols BPA, BPS, and BPF and comparison with measured urinary levels.

BACKGROUND: Bisphenol A (BPA) and, with increasing occurrence, its analogs bisphenol S (BPS) and bisphenol F (BPF) are applied in many consumer products, leading to humans being exposed from a vast number of sources and via several routes. Estrogenic and anti-androgenic effects are exerted by the chemical BPA, and also by its analogs. Therefore, realistic exposure assessments are needed for assessing risks related to cumulative exposure. OBJECTIVES: Biomonitoring for BPA, BPS, and BPF was conducted in a human study embedded in the EU project EuroMix and the measured urinary concentrations were compared to source-to-dose calculations for source allocation and plausibility test of the model. METHODS: For two 24-hour study periods separated by 2-3 weeks, 144 adult volunteers in Norway kept detailed diaries on food consumption, personal care product (PCP) use, and thermal paper (TP) handling. Concurrently, 24 h urine was collected and urinary levels of BPA, BPS, and BPF were analyzed using ultra-high performance liquid chromatography and tandem mass spectrometry (UPLC-MS-MS). In line with the information obtained from the first study day, bisphenol exposure from food, PCPs, TP, and dust was modeled primarily individual-based with probabilistic models. Estimates for BP excretion over 24 h were obtained with the models and compared to measured amounts. RESULTS: Modeled aggregate internal exposures covered the full range of measured urinary amounts for all BP analogs. In general, individual-based medians of modeled BPA exposures were in good agreement with the measurements, but individual-specific correlation was lacking. Modeled exposures mostly underestimated BPS and BPF levels in participants with positive measurements (53% and 8%), except for the P95 values of modeled BPS exposure that were higher than measured amounts if TP was handled. Most likely, diet and TP were the sources contributing the most to BP exposure in this study. Urinary measurements did not reveal a significant correlation between the amounts of canned food consumed, the number of PCPs used, or the number of TP handling events and levels of BPA, BPS, or BPF. CONCLUSIONS: The good agreement between the ranges of modeled BPA exposure and measured BPA amounts indicates that available concentrations, especially from the main exposure source food, mirror the exposure situation realistically, and suggests that the exposure model considers the relevant exposure sources. The lack of individual-specific correlations means that the individual measured amounts and modeled exposures did not vary in parallel, e.g. due to mismatch of BP concentrations in food, TP, and other sources, or delayed internal exposure. The underestimation of modeled BPS and BPF exposure suggests that not all relevant sources were included in the respective exposure models. This could be due to a lack of input data, e.g. for food items, or due to an increased replacement of BPA with structural analogs compared to the used concentration and occurrence data.

Linking Probabilistic Exposure and Pharmacokinetic Modeling To Assess the Cumulative Risk from the Bisphenols BPA, BPS, BPF, and BPAF for Europeans.

The bisphenols S, F, and AF (BPS, BPF, and BPAF) are used to replace the endocrine disrupting chemical bisphenol A (BPA) while exerting estrogenic effects of comparable potency. We assessed the cumulative risk for the aforementioned BPs in Europe and compared the risk before and after the year 2011, which was when the first BPA restrictions became effective. For this, we probabilistically modeled external exposures from food, personal care products (PCPs), thermal paper, and dust (using the tools MCRA and PACEM for exposures from food and PCPs, respectively). We calculated internal concentrations of unconjugated BPs with substance-specific PBPK models and cumulated these concentrations normalized by estrogenic potency. The resulting mean internal cumulative exposures to unconjugated BPs were 3.8 and 2.1 ng/kg bw/day before and after restrictions, respectively. This decline was mainly caused by the replacement of BPA by BPS in thermal paper and the lower dermal uptake of BPS compared to BPA. However, the decline was not significant: the selected uncertainty intervals overlapped (P2.5-P97.5 uncertainty intervals of 2.7-4.9 and 1.3-6.3 ng/kg bw/day before and after restrictions, respectively). The upper uncertainty bounds for cumulative exposure were higher after restrictions, which reflects the larger uncertainty around exposures to substitutes compared to BPA.

Physiologically Based Pharmacokinetic (PBPK) Modeling of the Bisphenols BPA, BPS, BPF, and BPAF with New Experimental Metabolic Parameters: Comparing the Pharmacokinetic Behavior of BPA with Its Substitutes.

BACKGROUND: The endocrine disrupting chemical bisphenol A (BPA) has been facing stricter regulations in recent years. BPA analogs, such as the bisphenols S, F, and AF (BPS, BPF, and BPAF) are increasingly used as replacement chemicals, although they were found to exert estrogenic effects similar to those of BPA. Research has shown that only the parent compounds have affinity to the estrogen receptors, suggesting that the pharmacokinetic behavior of bisphenols (BPs) can influence their potency. OBJECTIVES: Our goal was to compare the pharmacokinetic behaviors of BPA, BPS, BPF, and BPAF for different age groups after environmentally relevant external exposures by taking into account substance-specific metabolism kinetics and partitioning behavior. This comparison allowed us to investigate the consequences of replacing BPA with other BPs. METHODS: We readjusted a physiologically based pharmacokinetic (PBPK) model for peroral exposure to BPA and extended it to include dermal exposure. We experimentally assessed hepatic and intestinal glucuronidation kinetics of BPS, BPF, and BPAF to parametrize the model for these BPs and calibrated the BPS model with a biomonitoring study. We used the PBPK models to compare resulting internal exposures and focused on females of childbearing age in a two-dimensional Monte Carlo uncertainty analysis. RESULTS: Within environmentally relevant concentration ranges, BPAF and BPS were glucuronized at highest and lowest rates, respectively, in the intestine and the liver. The predominant routes of BPS and BPAF exposure were peroral and dermal exposure, respectively. The calibration of the BPS model with measured concentrations showed that enterohepatic recirculation may be important. Assuming equal external exposures, BPS exposure led to the highest internal concentrations of unconjugated BPs. CONCLUSIONS: Our data suggest that the replacement of BPA with structural analogs may not lower the risk for endocrine disruption. Exposure to both BPS and BPAF might be more critical than BPA exposure, if their respective estrogenic potencies are taken into account. https://doi.org/10.1289/EHP2739.

Structural Transformation of 8-5-Coupled Dehydrodiferulates by Human Intestinal Microbiota.

Ingested dehydrodiferulates (DFAs) are partially released from cereal dietary fiber by human colonic microbiota, but little research has explored the further microbial metabolism of 8-5-coupled DFAs. This study investigated the in vitro microbial metabolism and elucidated major metabolites of free 8-5-DFAs (benzofuran and open forms) and an esterified analogue, 8-5-DFA diethyl ester (benzofuran). Synthesized standard compounds were incubated with fresh human fecal suspensions. Metabolites were isolated and structurally elucidated using high-resolution-LC-time-of-flight-(ToF)-MS, GC-MS, and NMR. Nine metabolite structures were unambiguously characterized with NMR, and four additional metabolites were tentatively identified to reveal structural conversion motifs: propenyl side chain hydrogenation (all substrates), O-demethylation and reductive ring-opening (8-5-DFA diethyl ester and free 8-5-DFA [benzofuran]), and de-esterification (8-5-DFA diethyl ester). A pathway of microbial 8-5-DFA metabolism was proposed based on metabolite formation kinetics. Importantly, de-esterification of the 8-5-DFA diethyl ester occurred primarily after and/or concurrently with other metabolism steps. Cleavage to monomers was not observed.