Prediction of human prenatal exposure to bisphenol A and bisphenol A glucuronide from an ovine semi-physiological toxicokinetic model

Abstract

Bisphenol A (BPA) risk assessment is hampered by the difficulty of determining the extent of internal exposure in the human fetus and uncertainties regarding BPA toxicokinetics (TK) in the maternal-fetal unit. A feto-maternal TK model describing BPA and BPA glucuronide (BPAG) disposition in sheep was humanized, using human TK data obtained after d6-BPA administration on a cookie, to predict BPA and BPAG kinetics in the human mother-fetus unit. Validation of the model predictions included the assessed dose proportionality of BPA and BPAG disposition and the similarity between the simulated and measured time courses of BPA and BPAG in fetal rhesus monkeys after BPA maternal dosing. The model predicted fluctuations in fetal BPA concentrations associated with typical maternal exposure to BPA through the diet, with similar trough (0.011 ng/L vs 0.014 ng/L) and lower peak BPA concentrations (0.023 ng/L vs 0.14 ng/L) in fetal than in maternal plasma. BPAG concentrations in fetal plasma were predicted to increase over time to reach a steady value (29 ng/L) reflecting the cumulative BPA dose received by the fetus. Model-predicted BPAG concentrations in fetal plasma are consistent with reported levels in human cord blood that may be considered as relevant markers of the BPA dose entering blood throughout fetal life.

Developmental programming: Sex‐specific programming of growth upon prenatal bisphenol A exposure

“…Maternal and umbilical cord concentrations of BPA achieved following the daily subcutaneous administration of an environmentally relevant dose of BPA have not previously been studied in detail. One study investigating the pharmacokinetics of BPA in fetal plasma following single maternal intravenous infusion of 1 mg/kg of BPA in sheep found concentrations approaching ~90 ng/mL 1 hour postinjection (Gauderat et al, ). Maternal concentrations of free BPA achieved in the present study, averaging 12.2 and 26.5 ng/mL respectively at GD65 and GD90, are within the the range reported in a Korean study (range 0.44‐47.1 ng/mL) (Lee et al, ) and our Michigan‐based study during the first trimester (<LOD to 96.43 ng/mL) and at term (<LOD to 89.60 ng/mL) (Veiga‐Lopez, Kannan, et al, ).…”

“…Two simultaneous plasma samples were collected before, 6 and 24 h after the BPA dose using both a routine collection procedure (involving use of plastic instruments) and a plastic-free collection procedure. BPA, bisphenol A (Gauderat et al, 2017).…”

Toward a better understanding of the effects of endocrine disrupting compounds on health: Human-relevant case studies from sheep models

“…A non-linear mixed effect model (NLMEM) was used to simultaneously analyse these toxicokinetic data and build a semi-physiologically-based toxicokinetic model of feto-maternal BPA exchange (Gauderat et al, 2017). The semi-physiologically-based toxicokinetic model of fetomaternal BPA toxicokinetic developed in sheep was then humanised (Gauderat et al, 2016), using toxicokinetic data obtained in adult humans via ingestion of a BPA (d6-BPA) labelled cookie.…”

“…This model enables maternal and fetal compartments to be assessed separately and allows direct fetal administration of EDs, thus by-passing maternal metabolism if required. We use this system to develop a pharmacokinetic-based modelling approach to predict the extent of human fetal tissue exposure to the active form of BPA and by comparison to BPS (Corbel et al, 2013;Gauderat et al, 2017;Grandin et al, 2019Grandin et al, , 2018.…”

Utilization of Data Below the Analytical Limit of Quantitation in Pharmacokinetic Analysis and Modeling: Promoting Interdisciplinary Debate

“…Method numbering system according to Beal, 2001 [12] where appropriate. Keep BLQ observations in the model and estimate the likelihood of those values being between 0 and LLOQ M4 [12,35,116,180,186,187] All BLQ data are substituted with LLOQ/2 M5 [12,24,[30][31][32][33]35,55,62,133,153, BLQ data are substituted with LLOQ/2, however subsequent, consecutive BLQ observations from the same subject are discarded M6 [1,12,34,35,59,63,117,[225][226][227][228][229][230][231][232][233][234][235][236][237][238][239][240][241][242][243] All BLQ data are substituted with 0 M7 [12,31,33,207,244] All BLQ data are substituted with LLOQ …”