{"title":"In Vitro Exposure Assessment Improves Hazard Ranking of Bisphenol A Alternatives","authors":"Luise Henneberger, Sophia Bardehly, Arina Kremser, Vanessa Srebny, Beate I. Escher","doi":"10.1021/acs.chemrestox.6c00300","DOIUrl":null,"url":null,"abstract":"<p><em>In vitro</em> toxicity data can be used for\r\ncomparative\r\nhazard assessment of the problematic plastic chemical bisphenol A\r\n(BPA) and its replacement chemicals. Hazard assessment is exclusively\r\nbased on nominal effect concentrations of the BPA alternatives, but\r\ndue to their diversity of physicochemical properties and stability,\r\nthis may lead to inaccurate hazard ranking. In the present study,\r\nchemical stability as well as freely dissolved concentrations (<em>C</em><sub>free</sub>) were determined for BPA and 24 of its\r\nalternatives. BPA and 22 alternatives were found to be stable in bioassay\r\nmedium for up to 48 h. The diglycidyl ether of BPA (BADGE) was completely\r\ndegraded in medium. For BPPH, a loss of up to 37% was observed. A\r\nmass balance model was used to derive <em>C</em><sub>free</sub> of the stable chemicals in the bioassay medium. For model validation, <em>C</em><sub>free</sub> in bioassay medium, as well as binding\r\nto proteins and membrane lipids, was measured for BPA and 15 of the\r\nalternatives. Experimentally determined <em>C</em><sub>free</sub> agreed with model predictions within a factor of 10. Relative effect\r\npotencies (REPs) of the BPA alternatives compared to BPA were calculated\r\nbased on nominal (REP<sub>nom</sub>) and freely dissolved effect concentrations\r\n(REP<sub>free</sub>) for two representative end points (activation\r\nof estrogen receptor α and inhibition of mitochondrial membrane\r\npotential). For hydrophilic and moderately hydrophobic BPA alternatives,\r\nREP<sub>nom</sub> and REP<sub>free</sub> agreed well. REP<sub>free</sub> was up to 147× higher compared to REP<sub>nom</sub> for hydrophobic\r\nand highly protein-bound alternatives like TCBPA or BPAF. BP-MIBK\r\nhad the highest estrogenic potential based on REP<sub>nom</sub>, but\r\nthe highly protein-bound BPAF was identified as most potent based\r\non REP<sub>free</sub>. TCBPA has a lower estrogenic potential than\r\nBPA based on REP<sub>nom</sub> (0.11), but based on REP<sub>free</sub> (12.8), it is more potent than BPA. The results of the present study\r\nhighlight the need to correct for different <em>in vitro</em> exposure conditions to allow accurate hazard ranking.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2099–2108"},"PeriodicalIF":4.1000,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Research in Toxicology","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.chemrestox.6c00300","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/9/30 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
In vitro toxicity data can be used for
comparative
hazard assessment of the problematic plastic chemical bisphenol A
(BPA) and its replacement chemicals. Hazard assessment is exclusively
based on nominal effect concentrations of the BPA alternatives, but
due to their diversity of physicochemical properties and stability,
this may lead to inaccurate hazard ranking. In the present study,
chemical stability as well as freely dissolved concentrations (Cfree) were determined for BPA and 24 of its
alternatives. BPA and 22 alternatives were found to be stable in bioassay
medium for up to 48 h. The diglycidyl ether of BPA (BADGE) was completely
degraded in medium. For BPPH, a loss of up to 37% was observed. A
mass balance model was used to derive Cfree of the stable chemicals in the bioassay medium. For model validation, Cfree in bioassay medium, as well as binding
to proteins and membrane lipids, was measured for BPA and 15 of the
alternatives. Experimentally determined Cfree agreed with model predictions within a factor of 10. Relative effect
potencies (REPs) of the BPA alternatives compared to BPA were calculated
based on nominal (REPnom) and freely dissolved effect concentrations
(REPfree) for two representative end points (activation
of estrogen receptor α and inhibition of mitochondrial membrane
potential). For hydrophilic and moderately hydrophobic BPA alternatives,
REPnom and REPfree agreed well. REPfree was up to 147× higher compared to REPnom for hydrophobic
and highly protein-bound alternatives like TCBPA or BPAF. BP-MIBK
had the highest estrogenic potential based on REPnom, but
the highly protein-bound BPAF was identified as most potent based
on REPfree. TCBPA has a lower estrogenic potential than
BPA based on REPnom (0.11), but based on REPfree (12.8), it is more potent than BPA. The results of the present study
highlight the need to correct for different in vitro exposure conditions to allow accurate hazard ranking.
期刊介绍：
Chemical Research in Toxicology publishes Articles, Rapid Reports, Chemical Profiles, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques.
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