Derivation of a Human In Vivo Benchmark Dose for Bisphenol A from ToxCast In Vitro Concentration Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation

Abstract

A computational workflow which integrates physiologically based kinetic (PBK) modelling; global sensitivity analysis (GSA), Approximate Bayesian Computation (ABC), Markov Chain Monte Carlo (MCMC) simulation and the Virtual Cell Based Assay (VCBA) for the estimation of the active, free in vitro concentration of chemical in the reaction medium was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow was designed to estimate parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for bisphenol A (BPA) and high throughput screening (HTS) in vitro concentration-response data, for estrogen and pregnane X receptor activation determined in human liver and kidney cell lines, from the ToxCast/Tox21 database. In vivo benchmark dose 10% lower confidence limits (BMDL10) for oral uptake of BPA (ng/kg BW/day) were calculated from the in vivo dose-responses and compared to the human equivalent dose (HED) BMDL10 for relative kidney weight change in the mouse derived by European Food Safety Authority (EFSA). Three from four in vivo BMDL10 values calculated in this study were similar to the EFSA values whereas the fourth was much smaller. The derivation of an uncertainty factor (UF) to accommodate the uncertainties associated with measurements using human cell lines in vitro, extrapolated to in vivo, could be useful for the derivation of Health Based Guidance Values (HBGV).

Development, testing, parameterisation, and calibration of a human PBPK model for the plasticiser, di-(2-ethylhexyl) terephthalate (DEHTP) using in silico, in vitro and human biomonitoring data

“…TPA measurements would have been useful for the more exacting requirements of a PBPK model and could have yielded considerable reductions in uncertainty associated with absorbed fractions of DEHTP. Given that PBPK models are increasingly important for interpreting data from in vitro experiments (comparison of free, bioactive concentrations in vitro with in vivo tissue dosimetry e.g., in quantitative in vitro to in vivo (QIVIVE) studies ( McNally and Loizou 2015 ; McNally et al, 2018 ; Loizou et al, 2021 ; Loizou et al, 2022 )), a wider view of the potential usage of high-quality data from well conducted BM would be useful when designing controlled human BM studies. The BM studies for Hexamoll ® DINCH ( Koch et al, 2013 ) and Di (2-ethylhexyl) adipate (DEHA) ( Nehring et al, 2019 ; Nehring et al, 2020 ), where important non-specific metabolic products were measured in urine specimens, represent very good examples of study design for the specific requirements of PBPK modelling.…”

The Relationship between Typical Environmental Endocrine Disruptors and Kidney Disease

“…BPA can be detected in virtually 100% of human urine samples [ 121 , 122 , 123 ]. Pharmacokinetic and biomonitoring data indicate that BPA is rapidly and efficiently metabolized after ingestion [ 124 ].…”

A novel method to derive a human safety limit for PFOA by gene expression profiling and modelling

“…These studies, however, did not account for structural uncertainty in the PBK model, nor parameter value uncertainty ( Louisse et al, 2010 ; Louisse et al, 2012 ; Strikwold et al, 2013 ; Louisse et al, 2016 ; Boonpawa et al, 2017a ; Boonpawa et al, 2017b ; Li et al, 2017 ; Punt et al, 2017 ; Strikwold et al, 2017 ; Adam et al, 2019 ; Zhao et al, 2019 ; Shi et al, 2020 ; Zhang et al, 2020 ). It is also well known that the amount of biological mechanistic detail described in a PBK model can have a bearing on model output ( Rowland et al, 2017 ; McNally et al, 2018 ; Loizou et al, 2021 ).…”

“…Here, we calculate a HBGV from the in vitro benchmark concentration modelling of previously published gene expression changes in human primary liver cell spheroids mediated by PFOA ( Rowan-Carroll et al, 2021 ). The in vitro transcriptomics data were translated to in vivo dose-responses with a PBK model for PFOA ( Worley et al, 2017 ; Loizou et al, 2021 ). A TDI (ng/kg BW/day) was calculated from the in vivo dose-responses and compared to the TDI values recommended by the European Food Safety Authority (EFSA) in the Scientific Opinion on the Risk to human health related to the presence of perfluoroalkyl substances in food for effects on the immune system ( Bampidis et al, 2020 ) and previously for increases in serum cholesterol ( Knutsen et al, 2018 ).…”

“…A TDI (ng/kg BW/day) was calculated from the in vivo dose-responses and compared to the TDI values recommended by the European Food Safety Authority (EFSA) in the Scientific Opinion on the Risk to human health related to the presence of perfluoroalkyl substances in food for effects on the immune system ( Bampidis et al, 2020 ) and previously for increases in serum cholesterol ( Knutsen et al, 2018 ). Our work was achieved using a QIVIVE workflow described previously for ethylene glycol monoethyl ether (EGME) ( McNally et al, 2018 ), PFOA ( Loizou et al, 2021 ) and bisphenol A ( Loizou et al, 2022 ) that accounts for PBK model structure uncertainty, parameter value uncertainty, and the calculation of free concentration of chemical in vitro by applying a rigorous statistical (probabilistic) framework to accommodate uncertainties. Overall, the purpose of this study, however, was not to propose an updated animal-free risk assessment for PFOA, since we recognise that much work is still needed to demonstrate in vitro to in vivo concordance for systemic, chronic exposures to environmental xenobiotics.…”