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<figure><img src="image_49.png" /></figure>

# Appendix

<table><caption>Table A1. Summary of the *in vitro* assays assessing effects on nuclear and membrane receptors exerted by BPA analogues.</caption><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="14">BPAP</td><td rowspan="14">ERα</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 255 ± 41.0</td><td>Liu X et al. (2019)</td></tr><tr><td>Competitive fluorescence polarization binding assay</td><td></td><td>IC<sub>50</sub> 2.6 µM</td><td>Keminer et al. (2020)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 258 ± 23.6</td><td>Liu X et al. (2021)</td></tr><tr><td>MVLN cells, ERα binding affinity</td><td>1 nM to 100 µM</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>MCF7 - luciferase reporter gene assay</td><td>10 pM to 100 µM</td><td>Agonist; AC<sub>50</sub> 1 µM</td><td>Mesnage et al. (2017)</td></tr><tr><td>HELN-ERα - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Agonist; EC<sub>50</sub> (µM) 0.761 ± 0.151; max efficacy 40%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Agonist: REC<sub>50</sub> 1.9 µM</td><td>Kojima et al. (2019)</td></tr><tr><td>HepG2 - luciferase reporter gene assay</td><td>3 nM to 10 µM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 µM</td><td>Not significant</td><td>van Leeuwen et al. (2019)</td></tr><tr><td>MVLN - luciferase reporter gene assay</td><td></td><td>Antagonist; logRIC<sub>20</sub> -7.61 (M)</td><td>Chen Q et al. (2020)</td></tr><tr><td>HeLa - luciferase reporter gene assay</td><td>10 pM to 10 µM</td><td>Agonist; EC<sub>50</sub> (nM) 351 ± 33</td><td>Liu X et al. (2021)</td></tr><tr><td>OECD TG 455 - STTA assay on hERα-HeLa-9903 cells</td><td>10 nM to 10 µM</td><td>Agonist; EC<sub>50</sub> (µM) 2.00 ± 1.29; max effect 66.63% ± 3.90</td><td>Durcik, Hiti, et al. (2022)</td></tr><tr><td>MCF7 - proliferative potential (E-screen assay)</td><td>10 pM to 100 µM</td><td>Induction; AC<sub>50</sub> 0.39 µM</td><td>Mesnage et al. (2017)</td></tr><tr><td rowspan="14">ERβ</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 62.1 ± 9.27</td><td>Liu X et al. (2019)</td></tr><tr><td>Competitive fluorescence polarization binding assay</td><td></td><td>No effect</td><td>Keminer et al. (2020)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 68.0 ± 9.57</td><td>Liu X et al. (2021)</td></tr><tr><td>HELN-ERβ - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Agonist; EC<sub>50</sub> (µM) 0.61 ± 0.28; max efficacy 40%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Agonist: REC<sub>50</sub> 0.17 µM</td><td>Kojima et al. (2019)</td></tr><tr><td>HepG2 - luciferase reporter gene assay</td><td>3 nM to 10 µM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>HeLa - luciferase reporter gene assay</td><td>10 pM to 10 µM</td><td>Antagonist; IC<sub>50</sub> (nM) 595 ± 56.0</td><td>Liu X et al. (2021)</td></tr><tr><td>ERRγ</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 120 ± 4.20</td><td>Liu X et al. (2019)</td></tr><tr><td>HG5LN-ERRγ - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="14">AR</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> > 10 µM</td><td>Liu X et al. (2019)</td></tr><tr><td>Competitive fluorescence polarization binding assay</td><td></td><td>IC<sub>50</sub> 5.4 µM</td><td>Keminer et al. (2020)</td></tr><tr><td>HELN-AR - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Antagonist; IC<sub>50</sub> (µM) 15.9 ± 3.3</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 - luciferase reporter gene assay</td><td>100 nM to 10 µM</td><td>Antagonist; RIC<sub>50</sub> 8.5 µM</td><td>Kojima et al. (2019)</td></tr><tr><td>HepG2 - luciferase reporter gene assay</td><td>3 nM to 10 µM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 µM</td><td>Antagonist; IC<sub>50</sub> 40 µM</td><td>van Leeuwen et al. (2019)</td></tr><tr><td>MDA-kb2 - luciferase reporter gene assay</td><td>0.1 pM to 10 µM</td><td>Antagonist</td><td>Ma M et al. (2022)</td></tr><tr><td>22Rv1 - protein expression/localization</td><td>10 nM to 50 µM</td><td>Antagonist; IC<sub>50</sub> 16 µM</td><td>Stossi et al. (2016)</td></tr><tr><td>PR</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 330 ± 21.9</td><td>Liu X et al. (2019)</td></tr><tr><td>HELN-PR - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Antagonist; IC<sub>50</sub> (µM) 23.1 ± 9.4</td><td>Grimaldi et al. (2019)</td></tr><tr><td>MCF7 - gene expression</td><td>1 µM</td><td>Induction</td><td>Pelch KE et al. (2019)</td></tr><tr><td rowspan="2">GR</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 30.1 ± 0.923</td><td>Liu X et al. (2019)</td></tr><tr><td>HMLN-GR - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr></tbody></table>

(continued)
<figure><img src="image_50.png" /><figcaption>Table A1. Continued.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">BPE</td><td rowspan="5">PPARγ</td><td>CHO-K1 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>Antagonist; RIC<sub>50</sub> 8.1 μM</td><td>Kojima et al. (2019)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td></td><td>Agonist; logLOEC –6.80 (M)</td><td>Chen Q et al. (2020)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td></td><td>No effect</td><td>Chen Q et al. (2020)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>0.1 pM to 10 μM</td><td>Agonist/antagonist</td><td>Ma M et al. (2022)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> &gt; 10 μM</td><td>Liu X et al. (2019)</td></tr><tr><td rowspan="3">PXR</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 1060 ± 93.2</td><td>Liu X et al. (2019)</td></tr><tr><td>HG5LN-PXR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM) 65.9 ± 15; max efficacy 30%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>COS-7 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>Agonist; REC<sub>20</sub> 9.7 μM</td><td>Kojima et al. (2019)</td></tr><tr><td rowspan="10">ERα</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) = 5300 ± 318</td><td>Liu X et al. (2019)</td></tr><tr><td>BG1Luc4E2 – reporter gene assay (OECD 457)</td><td>100 nM to 100 μM</td><td>Agonist; EC<sub>50</sub> (μM) 0.47 ± 0.08; max efficacy 386 ± 133</td><td>Rosenmai et al. (2014)</td></tr><tr><td>Bioluminescence yeast estrogen screen assay</td><td></td><td>Agonist; EC<sub>50</sub> 7.43 μM</td><td>Ruan et al. (2015)</td></tr><tr><td>Yeast two-hybrid assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> 0.102 μM</td><td>Conroy-Ben et al. (2018)</td></tr><tr><td>HELN-ERα – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM) 0.843 ± 113; max efficacy 72%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist: REC<sub>50</sub> 0.28 μM</td><td>Kojima et al. (2019)</td></tr><tr><td>HepG2 – luciferase reporter gene assay</td><td>3 nM to 10 μM</td><td>Agonist; REC<sub>50</sub> 1.4 μM; max efficacy 88.4%</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 μM</td><td>Agonist; EC<sub>50</sub> 7 μM</td><td>van Leeuwen et al. (2019)</td></tr><tr><td>MVLN – luciferase reporter gene assay</td><td></td><td>Agonist; logREC<sub>20</sub> –6.16 (M)</td><td>Chen Q et al. (2020)</td></tr><tr><td>OECD TG 455 – STTA assay on hERα-HeLa-9903 cells</td><td>10 nM to 25 μM</td><td>Agonist; EC<sub>50</sub> (μM) 2.26 ± 0.87; max effect 127.47% ± 34.68</td><td>Durcik, Hiti, et al. (2022)</td></tr><tr><td rowspan="3">ERβ</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) = 3900 ± 82.7</td><td>Liu X et al. (2019)</td></tr><tr><td>HELN-ERβ – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM) 0.69 ± 0.088; max efficacy 87%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist: REC<sub>50</sub> 94 nM</td><td>Kojima et al. (2019)</td></tr><tr><td rowspan="3">ERRγ</td><td>Competitive receptor binding affinity assay</td><td></td><td>Agonist; REC<sub>50</sub> 4.6 μM; max efficacy 118.7%</td><td>Pelch KE et al. (2019)</td></tr><tr><td>HG5LN-ERRγ – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>IC<sub>50</sub> (nM) = 4.78 ± 0.608</td><td>Liu X et al. (2019)</td></tr><tr><td></td><td></td><td>Agonist; EC<sub>50</sub> (μM) 0.69 ± 0.28; max efficacy 131%</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="5">AR</td><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> &gt; 10 μM</td><td>Liu X et al. (2019)</td></tr><tr><td>CHO – reporter gene assay</td><td>0.4–100 μM</td><td>Antagonist; EC<sub>50</sub> (μM) 1.9 ± 0.9; max efficacy 72% ± 11</td><td>Rosenmai et al. (2014)</td></tr><tr><td>Yeast two-hybrid assay</td><td>1 nM to 10 μM</td><td>Antagonist; IC<sub>50</sub> 6.1 μM</td><td>Conroy-Ben et al. (2018)</td></tr><tr><td>HELN-AR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Antagonist; IC<sub>50</sub> (μM) 1.46 ± 0.68</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>Antagonist; RIC<sub>50</sub> 0.99 μM</td><td>Kojima et al. (2019)</td></tr><tr><td rowspan="5">PR</td><td>MDA-kb2 – luciferase reporter gene assay</td><td>3 nM to 10 μM</td><td>Antagonist; REC<sub>50</sub> 1 μM; max efficacy 89.2%</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 μM</td><td>Antagonist; IC<sub>50</sub> 10 μM</td><td>van Leeuwen et al. (2019)</td></tr><tr><td>AR-CALUX</td><td>10 nM to 10 μM</td><td>Antagonist; IC<sub>50</sub> 1.1 μM</td><td>Šauer et al. (2021)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>0.1 pM to 10 μM</td><td>Antagonist</td><td>Ma M et al. (2022)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>Inert</td><td>Liu X et al. (2019)</td></tr><tr><td>HELN-PR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr></tbody></table>

(continued)
<figure><img src="image_51.png" /><figcaption>Table A1. Continued.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="12">BPP</td><td rowspan="5">GR</td><td>PR-CALUX</td><td>10 nM to 10 µM</td><td>No effect</td><td>Šauer et al. (2021)</td></tr><tr><td>MCF7 - gene expression</td><td>1 µM</td><td>induction</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> &gt; 10 µM</td><td>Liu X et al. (2019)</td></tr><tr><td>HMLN-GR - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 - luciferase reporter gene assay</td><td>100 nM to 10 µM</td><td>No effect</td><td>Kojima et al. (2019)</td></tr><tr><td rowspan="5">PPARγ</td><td>MDA-kb2 - luciferase reporter gene assay</td><td></td><td>No effect</td><td>Chen Q et al. (2020)</td></tr><tr><td>CHO-K1 - luciferase reporter gene assay</td><td></td><td>No effect</td><td>Chen Q et al. (2020)</td></tr><tr><td>MDA-kb2 - luciferase reporter gene assay</td><td>0.1 pM to 10 µM</td><td>Agonist</td><td>Ma M et al. (2022)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>Inert</td><td>Liu X et al. (2019)</td></tr><tr><td>COS-7 - luciferase reporter gene assay</td><td></td><td>IC<sub>50</sub> &gt; 10 µM</td><td>Liu X et al. (2019)</td></tr><tr><td rowspan="5">PXR</td><td>HG5LN-PXR - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td>MDA-kb2 - luciferase reporter gene assay</td><td>100 nM to 10 µM</td><td>No effect</td><td>Kojima et al. (2019)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 152 ± 17.2</td><td>Liu X et al. (2019)</td></tr><tr><td>MVLN cells, ERα binding affinity</td><td>1 nM to 100 µM</td><td>Agonist; EC<sub>50</sub> 0.671 µM; max induction 35.4% (vs. E2)</td><td>Lin et al. (2021)</td></tr><tr><td>HELN-ERα - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Antagonist; IC<sub>50</sub> (µM) 1.91 ± 0.69</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="5">ERβ</td><td>CHO-K1 - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Agonist: REC<sub>20</sub> 0.64 µM</td><td>Kojima et al. (2019)</td></tr><tr><td>HepG2 - luciferase reporter gene assay</td><td>3 nM to 10 µM</td><td>Not significant</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 µM</td><td>Not significant</td><td>van Leeuwen et al. (2019)</td></tr><tr><td>HELN - luciferase reporter gene assay</td><td></td><td>Antagonist; logRIC<sub>20</sub> -8.42 (M)</td><td>Chen Q et al. (2020)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 105 ± 10.8</td><td>Liu X et al. (2019)</td></tr><tr><td rowspan="5">ERRγ</td><td>HELN-ERβ - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Antagonist; IC<sub>50</sub> (µM) 1.81 ± 0.52</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>No effect</td><td>Kojima et al. (2019)</td></tr><tr><td>HepG2 - luciferase reporter gene assay</td><td>3 nM to 10 µM</td><td>Antagonist; REC<sub>50</sub> 0.93 µM; max efficacy 84.1%</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 320 ± 28.5</td><td>Liu X et al. (2019)</td></tr><tr><td>HG5LN-ERRγ - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="5">AR</td><td>HELN-AR - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>IC<sub>50</sub> (nM) 409 ± 38.4</td><td>Liu X et al. (2019)</td></tr><tr><td>CHO-K1 - luciferase reporter gene assay</td><td>100 nM to 10 µM</td><td>Antagonist; IC<sub>50</sub> (µM) 10.8 ± 6.5</td><td>Grimaldi et al. (2019)</td></tr><tr><td>MDA-kb2 - luciferase reporter gene assay</td><td>3 nM to 10 µM</td><td>Antagonist; RIC<sub>50</sub> 7.8 µM</td><td>Kojima et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 µM</td><td>Antagonist; REC<sub>50</sub> 6.5 µM; max efficacy 62.5%</td><td>Pelch KE et al. (2019)</td></tr><tr><td>AR-CALUX</td><td>10 nM to 10 µM</td><td>Antagonist; IC<sub>50</sub> 2 µM</td><td>van Leeuwen et al. (2019)</td></tr><tr><td rowspan="5">PR</td><td>MDA-kb2 - luciferase reporter gene assay</td><td>0.1 pM to 10 µM</td><td>No effect</td><td>Ma M et al. (2022)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>Antagonist</td><td>Ma M et al. (2022)</td></tr><tr><td>HELN-PR - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>IC<sub>50</sub> (nM) 896 ± 68.3</td><td>Liu X et al. (2019)</td></tr><tr><td>PR-CALUX</td><td>10 nM to 10 µM</td><td>Antagonist; IC<sub>50</sub> (µM) 7.18 ± 3.69</td><td>Grimaldi et al. (2019)</td></tr><tr><td>MCF7 - gene expression</td><td>1 µM</td><td>No effect</td><td>Šauer et al. (2021)</td></tr><tr><td rowspan="5">GR</td><td>Competitive receptor binding affinity assay</td><td></td><td>Induction</td><td>Pelch KE et al. (2019)</td></tr><tr><td>HMLN-GR - luciferase reporter gene assay</td><td>1 nM to 10 µM</td><td>Antagonist; IC<sub>50</sub> (µM) 16.1 ± 5.7</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 - luciferase reporter gene assay</td><td>100 nM to 10 µM</td><td>Antagonist; RIC<sub>50</sub> 5.6 µM</td><td>Kojima et al. (2019)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>IC<sub>50</sub> (nM) 213 ± 8.98</td><td>Liu X et al. (2019)</td></tr><tr><td>MDA-kb2 - luciferase reporter gene assay</td><td></td><td>IC<sub>50</sub> (nM) 152 ± 17.2</td><td>Grimaldi et al. (2019)</td></tr></tbody></table>

(continued)
<figure><img src="image_52.png" /><figcaption>Table A1. Continued.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">BPS-MAE</td><td rowspan="3">PPARγ</td><td>MDA-kb2 – luciferase reporter gene assay</td><td rowspan="3">0.1 pM to 10 μM</td><td>Agonist; logLOEC<br/>-9.49 (M)</td><td>Chen Q et al. (2020)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td>Antagonist; logRIC<sub>20</sub><br/>-7.75 (M)</td><td>Chen Q et al. (2020)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>Antagonist</td><td>Ma M et al. (2022)</td></tr><tr><td rowspan="3">PXR</td><td>Competitive receptor binding affinity assay</td><td rowspan="3">1 nM to 10 μM</td><td>Inert</td><td>Liu X et al. (2019)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td>IC<sub>50</sub> (nM) 2450 ± 194</td><td>Liu X et al. (2019)</td></tr><tr><td>HG5LN-PXR – luciferase reporter gene assay</td><td>Agonist; EC<sub>50</sub> (μM)<br/>19 ± 2.3; max<br/>efficacy 44%</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="2">ERα</td><td>COS-7 – luciferase reporter gene assay</td><td rowspan="2">100 nM to 10 μM</td><td>Agonist; REC<sub>20</sub> 6.3 μM</td><td>Kojima et al. (2019)</td></tr><tr><td>Competitive fluorescence polarization binding assay</td><td>No effect</td><td>Keminer et al. (2020)</td></tr><tr><td rowspan="10">BPZ</td><td rowspan="3">ERα</td><td>HepG2 – luciferase reporter gene assay</td><td rowspan="3">3 nM to 10 μM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Competitive fluorescence polarization binding assay</td><td>Inactive</td><td>Keminer et al. (2020)</td></tr><tr><td>HepG2 – luciferase reporter gene assay</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td rowspan="2">ERβ</td><td>Competitive fluorescence polarization binding assay</td><td rowspan="2">3 nM to 10 μM</td><td>No effect</td><td>Keminer et al. (2020)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td rowspan="10">ERα</td><td>Competitive binding affinity assay</td><td rowspan="3">1 nM to 100 μM</td><td>IC<sub>50</sub> (nM) 57.5 ± 5.48</td><td>Liu X et al. (2019)</td></tr><tr><td>Binding (cell-free system)</td><td>Kd (nM) 939 ± 198</td><td>Böckers et al. (2020)</td></tr><tr><td>Competitive fluorescence polarization binding assay</td><td>IC<sub>50</sub> 0.08 μM</td><td>Keminer et al. (2020)</td></tr><tr><td>Competitive binding affinity assay</td><td rowspan="2">1 nM–100 μM</td><td>IC<sub>50</sub> (nM) 61.8 ± 6.66</td><td>Liu X et al. (2019)</td></tr><tr><td>MVLN cells, ERα binding affinity</td><td>Agonist; EC<sub>50</sub> 11 nM; max<br/>induction 58.6% (vs. E2)</td><td>Lin et al. (2021)</td></tr><tr><td>MCF7 – luciferase reporter gene assay</td><td rowspan="2">10 pM to 100 μM</td><td>Agonist; AC<sub>50</sub> 0.4 μM</td><td>Mesnage et al. (2017)</td></tr><tr><td>Yeast two-hybrid assay</td><td>Agonist; EC<sub>50</sub> 8.63 μM</td><td>Conroy-Ben et al. (2018)</td></tr><tr><td>HELN-ERα – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br/>0.124 ± 0.30; max<br/>efficacy 45%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td rowspan="2">1 nM to 10 μM</td><td>Agonist: REC<sub>50</sub> 97 nM</td><td>Kojima et al. (2019)</td></tr><tr><td>HepG2 – luciferase reporter gene assay</td><td>Agonist; REC<sub>50</sub> 0.4 μM; max<br/>efficacy 101.7%</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td rowspan="2">10 pM to 100 μM</td><td>Agonist; EC<sub>50</sub> 6 μM</td><td>van Leeuwen et al. (2019)</td></tr><tr><td>HEK-ESR1 over-expressing cells</td><td>Inactivation: -0.0510 (4 h);<br/>-0.13 (8 h)</td><td>Böckers et al. (2020)</td></tr><tr><td rowspan="10">ERβ</td><td>GeneBLAZer transactivation assay</td><td rowspan="3">10 fM to 10 μM</td><td>Agonist; EC<sub>50</sub> 3.7 pM</td><td>Keminer et al. (2020)</td></tr><tr><td>MVLN – luciferase reporter gene assay</td><td>Agonist; logREC<sub>20</sub><br/>-6.86 (M)</td><td>Chen Q et al. (2020)</td></tr><tr><td>HeLa – luciferase reporter gene assay</td><td>Agonist; EC<sub>50</sub> (nM)<br/>102 ± 7.99</td><td>Liu X et al. (2021)</td></tr><tr><td>MCF7 – proliferative potential (E-screen assay)</td><td rowspan="2">10 pM to 100 μM</td><td>Induction; AC<sub>50</sub> 0.11 μM</td><td>Mesnage et al. (2017)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td>IC<sub>50</sub> (nM) 128 ± 14.1</td><td>Liu X et al. (2019)</td></tr><tr><td>Competitive fluorescence polarization binding assay</td><td rowspan="2">1 nM to 10 μM</td><td>IC<sub>50</sub> 1.1 μM</td><td>Keminer et al. (2020)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td>IC<sub>50</sub> (nM) 132 ± 10.6</td><td>Liu X et al. (2021)</td></tr><tr><td>HELN-ERβ – luciferase reporter gene assay</td><td rowspan="2">1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br/>0.088 ± 0.03; max<br/>efficacy 53%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td>Agonist: REC<sub>50</sub> 18 nM</td><td>Kojima et al. (2019)</td></tr><tr><td>HepG2 – luciferase reporter gene assay</td><td rowspan="2">3 nM to 10 μM</td><td>Agonist; REC<sub>50</sub> 0.5 μM; max<br/>efficacy 61.3%</td><td>Pelch KE et al. (2019)</td></tr><tr><td>GeneBLAZer transactivation assay</td><td>Inactive</td><td>Keminer et al. (2020)</td></tr></tbody></table>

(continued)
<figure><img src="image_53.png" /><figcaption>Table A1. Continued.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="3">ERRγ</td><td rowspan="3">Competitive receptor binding affinity assay</td><td>HeLa – luciferase reporter gene assay</td><td>10 pM to 10 μM</td><td>Antagonist; IC<sub>50</sub> (nM)<br>1160 ± 61.6</td><td>Liu X et al. (2021)</td></tr><tr><td>HG5LN-ERRγ – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>IC<sub>50</sub> (nM) 13.4 ± 1.06</td><td>Liu X et al. (2019)</td></tr><tr><td></td><td></td><td>Agonist; EC<sub>50</sub> (μM)<br>5.24 ± 0.84; max efficacy 115%</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="7">AR</td><td rowspan="7">Competitive receptor binding affinity assay</td><td>MDA-kb2 – luciferase reporter gene assay</td><td>50 μM</td><td>IC<sub>50</sub> (nM) 6680 ± 139</td><td>Liu X et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>1 nM to 10 μM</td><td>IC<sub>50</sub> 1.6 μM</td><td>Keminer et al. (2020)</td></tr><tr><td>HELN-AR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Antagonist</td><td>Kolšek et al. (2015)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>No effect</td><td>Conroy-Ben et al. (2018)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>3 nM to 10 μM</td><td>Antagonist; IC<sub>50</sub> (nM)<br>3.58 ± 1.78</td><td>Grimaldi et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 μM</td><td>Antagonist; RIC<sub>50</sub> 7.3 μM</td><td>Kojima et al. (2019)</td></tr><tr><td>GeneBLAzer transactivation assay</td><td>10 fM to 10 μM</td><td>Antagonist; REC<sub>50</sub> 1.3 μM; max efficacy 80.7%</td><td>Pelch KE et al. (2019)</td></tr><tr><td rowspan="5">PR</td><td rowspan="5">Competitive receptor binding affinity assay</td><td>MDA-kb2 – luciferase reporter gene assay</td><td>0.1 pM to 10 μM</td><td>Antagonist; IC<sub>50</sub> 60 μM<br>inactive</td><td>van Leeuwen et al. (2019)<br>Keminer et al. (2020)</td></tr><tr><td>HELN-PR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Antagonist</td><td>Ma M et al. (2022)</td></tr><tr><td>MCF7 – gene expression</td><td>1 μM</td><td>IC<sub>50</sub> (nM) 1890 ± 158</td><td>Liu X et al. (2019)</td></tr><tr><td>Competitive receptor binding affinity assay</td><td></td><td>Antagonist; IC<sub>50</sub> (μM)<br>7.64 ± 3.22</td><td>Grimaldi et al. (2019)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>50 μM</td><td>Induction</td><td>Pelch KE et al. (2019)</td></tr><tr><td rowspan="7">GR</td><td rowspan="7">Competitive receptor binding affinity assay</td><td>HMLN-GR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>IC<sub>50</sub> (nM) 226 ± 9.89</td><td>Liu X et al. (2019)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>Antagonist; IC<sub>50</sub> 22 μM</td><td>Kolšek et al. (2015)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td></td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td>CHO-K1 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>Antagonist; RIC<sub>50</sub> 8.8 μM</td><td>Kojima et al. (2019)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td></td><td>Agonist; logLOEC –5.70 (M); antagonist; logRIC<sub>20</sub> –8.85 (M)</td><td>Chen Q et al. (2020)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>0.1 pM to 10 μM</td><td>No effect</td><td>Chen Q et al. (2020)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td></td><td>Antagonist</td><td>Ma M et al. (2022)</td></tr><tr><td rowspan="2">PPARγ</td><td rowspan="2">Competitive receptor binding affinity assay</td><td>ERα affinity column</td><td>10 nM to 100 μM</td><td>Inert</td><td>Liu X et al. (2019)</td></tr><tr><td>MCF7 – luciferase reporter gene assay</td><td>100 nM to 1 mM</td><td>IC<sub>50</sub> (nM) 2150 ± 53.3</td><td>Liu X et al. (2019)</td></tr><tr><td rowspan="2">PXR</td><td rowspan="2">Competitive receptor binding affinity assay</td><td>HG5LN-PXR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>10.2 ± 0.98; max efficacy 58%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>COS-7 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>Agonist; REC<sub>50</sub> 8.7 μM</td><td>Kojima et al. (2019)</td></tr><tr><td rowspan="10">TBBPA</td><td rowspan="10">ERα</td><td>MCF7 – competitive binding with 17β-estradiol</td><td>10 nM to 100 μM</td><td>Relative binding affinity (vs. E2) = 0.004%</td><td>Samuelsen et al. (2001)</td></tr><tr><td>MCF7 – competitive binding with 17β-estradiol</td><td>100 nM to 1 mM</td><td>Relative binding affinity (vs. E2) = 0.013%; EC<sub>50</sub> (nM) 250 ± 129</td><td>Olsen et al. (2003)</td></tr><tr><td>ERα affinity column</td><td>1 nM</td><td>No activity</td><td>Riu, Le Maire, et al. (2011)</td></tr><tr><td>MCF7 – luciferase reporter gene assay</td><td></td><td>Antagonist; EC<sub>50</sub> 19 μM</td><td>Kitamura et al. (2005)</td></tr><tr><td>ER-CALUX assay</td><td></td><td>No effect</td><td>Hamers et al. (2006)</td></tr><tr><td>Yeast two-hybrid assay</td><td>1 nM to 100 μM</td><td>No effect</td><td>Li J et al. (2010)</td></tr><tr><td>OECD TG 455 – STTA assay on hERα-HeLa-9903 cells</td><td>10<sup>-5</sup> to 10<sup>-10</sup> M</td><td>No effect</td><td>Lee HK et al. (2012)</td></tr><tr><td>MELN – luciferase reporter gene assay</td><td>0.01–10 μM</td><td>No effect</td><td>Molina-Molina et al. (2013)</td></tr><tr><td>Bioluminescence yeast estrogen screen assay</td><td></td><td>No effect</td><td>Ruan et al. (2015)</td></tr><tr><td>HELN-ERα – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr></tbody></table>

(continued)
<figure><img src="image_54.png" /><figcaption>Table A1. Continued.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">ERβ</td><td rowspan="10">ERβ</td><td>HepG2 – luciferase reporter gene assay</td><td>3 nM to 10 μM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 μM</td><td>Antagonist; IC<sub>50</sub> 0.6 μM</td><td>van Leeuwen et al. (2019)</td></tr><tr><td>OECD TG 455 – STTA assay on hERα-HeLa-9903 cells</td><td>10 nM to 10 μM</td><td>No effect</td><td>Durcik, Hiti, et al. (2022)</td></tr><tr><td>MCF7 – proliferative potential (E-screen assay)</td><td>10 nM to 100 μM</td><td>Relative proliferative potency (vs. E2) &gt; 0.000003</td><td>Samuelsen et al. (2001)</td></tr><tr><td>MCF7 – proliferative potential (E-screen assay)</td><td>100 nM to 1 mM</td><td>No effect</td><td>Olsen et al. (2003)</td></tr><tr><td>MCF7 – proliferative potential (E-screen assay)</td><td>10 nM to 10 μM</td><td>No effect</td><td>Molina-Molina et al. (2013)</td></tr><tr><td>MCF7 – proliferation assay</td><td></td><td>Agonist; EC<sub>20</sub> 124 μM; antagonist; IC<sub>20</sub> 451.2 μM</td><td>Krivoshiev et al. (2016)</td></tr><tr><td>MCF7 – protein expression</td><td>30 μM</td><td>No effect</td><td>Olsen et al. (2003)</td></tr><tr><td>3T3-L1 cells – gene expression</td><td>1 pM to 10 μM</td><td>Induction; 1 pM</td><td>Chappell et al. (2018)</td></tr><tr><td>HELN-ERβ – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="5">ERRγ</td><td rowspan="5">ERRγ</td><td>HepG2 – luciferase reporter gene assay</td><td>3 nM to 10 μM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>3T3-L1 cells – gene expression</td><td>1 pM to 10 μM</td><td>Induction; 100 pM to 10 μM</td><td>Chappell et al. (2018)</td></tr><tr><td>Two-hybrid yeast assay</td><td>1 nM to 1 μM</td><td>No effect</td><td>Li J et al. (2010)</td></tr><tr><td>HG5LN-ERRγ – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td>3T3-L1 cells – gene expression</td><td>1 pM to 10 μM</td><td>Induction; 100 pM</td><td>Chappell et al. (2018)</td></tr><tr><td rowspan="5">GPER</td><td rowspan="5">GPER</td><td>OVCAR-3 proliferation assay</td><td>1, 10, and 50 nM (48 and 72 h)</td><td>Induction; 10 and 50 nM; max efficacy 131% (72 h)</td><td>Hoffmann et al. (2017)</td></tr><tr><td>KGN proliferation assay</td><td>1, 10, and 50 nM (48 and 72 h)</td><td>Induction; 10 and 50 nM; max efficacy 127% (72 h)</td><td>Hoffmann et al. (2017)</td></tr><tr><td>OVCAR-3/KGN gene expression</td><td>1, 10, and 50 nM (48 and 72 h)</td><td>No effect</td><td>Hoffmann et al. (2017)</td></tr><tr><td>3T3-L1 cells – gene expression</td><td>1 pM to 10 μM</td><td>Induction; 1 pM to 10 μM</td><td>Chappell et al. (2018)</td></tr><tr><td>MA-10 protein expression</td><td>10 nM</td><td>Induction</td><td>Gorowska-Wojtowicz et al. (2019)</td></tr><tr><td rowspan="10">AR</td><td rowspan="10">AR</td><td>Competitive binding assay</td><td>1–10 μM</td><td>Antagonist; max effect 62%</td><td>Beck et al. (2016)</td></tr><tr><td>NIH3T3 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>No effect</td><td>Kitamura et al. (2005)</td></tr><tr><td>AR-CALUX assay</td><td></td><td>No effect</td><td>Hamers et al. (2006)</td></tr><tr><td>Two-hybrid yeast assay</td><td>1 nM to 100 μM</td><td>No effect</td><td>Li J et al. (2010)</td></tr><tr><td>PALM – luciferase reporter gene assay</td><td>10 nM to 10 μM</td><td>No effect</td><td>Molina-Molina et al. (2013)</td></tr><tr><td>Yeast receptor bioassay</td><td>10 pM to 100 μM</td><td>Antagonist; IC<sub>50</sub> 982 nM</td><td>Roelofs et al. (2015)</td></tr><tr><td>HEK-293 – luciferase reporter gene assay</td><td>10 μM</td><td>Antagonist; 37% reduction of AR activation</td><td>Beck et al. (2016)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>3 nM to 10 μM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>HELN-AR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td>Yeast two-hybrid assay</td><td>10 pM to 10 μM</td><td>Antagonist; IC<sub>50</sub> 0.4 μM</td><td>van Leeuwen et al. (2019)</td></tr><tr><td>MCF7 AR1 – anti-proliferative potential</td><td>10 nM to 10 μM</td><td>No effect</td><td>Molina-Molina et al. (2013)</td></tr><tr><td rowspan="5">PR</td><td rowspan="5">PR</td><td>PR-CALUX</td><td></td><td>No effect</td><td>Hamers et al. (2006)</td></tr><tr><td>Two-hybrid yeast assay</td><td>1 nM to 100 μM</td><td>Antagonist; RIC<sub>20</sub> 78 nM</td><td>Li J et al. (2010)</td></tr><tr><td>HELN-PR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td>MCF7 – protein expression</td><td>30 μM</td><td>Induction</td><td>Samuelsen et al. (2001)</td></tr><tr><td>MCF7 – protein expression</td><td>30 μM</td><td>Induction</td><td>Olsen et al. (2003)</td></tr><tr><td rowspan="5">GR</td><td rowspan="5">GR</td><td>Competitive binding assay</td><td></td><td>No effect</td><td>Beck et al. (2016)</td></tr><tr><td>Competitive binding assay</td><td>1 nM to 100 μM</td><td>Agonist; EC20 (μM) 0.5 ± 1.1</td><td>Liu QS et al. (2020)</td></tr><tr><td>Yeast receptor bioassay</td><td>10 pM to 100 μM</td><td>Antagonist; IC<sub>50</sub> 22 nM</td><td>Roelofs et al. (2015)</td></tr><tr><td>HEK-293 – luciferase reporter gene assay</td><td></td><td>No effect</td><td>Beck et al. (2016)</td></tr><tr><td>COS7 – luciferase reporter gene assay</td><td>10 nM to 10 μM</td><td>No effect</td><td>Chappell et al. (2018)</td></tr><tr><td rowspan="5">PPARγ</td><td rowspan="5">PPARγ</td><td>HMLN-GR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td>3T3-L1 cells – gene expression</td><td>1 pM to 10 μM</td><td>Induction; 1–100 pM</td><td>Chappell et al. (2018)</td></tr><tr><td>HGELN-PPARγ – competitive binding</td><td>10 nM to 10 μM</td><td>IC<sub>50</sub> 0.7 μM</td><td>Riu, Le Maire, et al. (2011)</td></tr></tbody></table>

(continued)
<table><caption>Table A1. Continued.</caption><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="15">PPARα/β/δ</td><td rowspan="15">PPARα</td><td>PPARγ affinity column</td><td>1 nM</td><td>Eluted fraction 97.5 ± 0.6%</td><td>Riu, Grimaldi, et al. (2011)</td></tr><tr><td>Competitive binding assay</td><td>1 nM to 50 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>5.7 ± 0.9</td><td>Liu QS et al. (2020)</td></tr><tr><td>HepG2 - luciferase reporter<br>gene assay</td><td>10 nM to 10 μM</td><td>Agonist</td><td>Akiyama et al. (2015)</td></tr><tr><td>COS-7 cells-mPPRE-luciferase<br>reporter gene assay</td><td>0.1 nM to 400 μM</td><td>Agonist; EC<sub>50</sub> 3.9 μM</td><td>Watt and Schlezinger<br>(2015)</td></tr><tr><td>COS7 - luciferase reporter<br>gene assay (mPPARγ)</td><td>10 nM to 10 μM</td><td>Agonist; AC<sub>50</sub> 397 μM</td><td>Chappell et al. (2018)</td></tr><tr><td>COS-7-hPPRE - luciferase<br>reporter gene assay</td><td>10-20 μM</td><td>Agonist</td><td>Andrews et al. (2020)</td></tr><tr><td>HEK293 - luciferase reporter<br>gene assay</td><td></td><td>Agonist; EC<sub>20</sub> (μM)<br>7.7 ± 1.1</td><td>Liu QS et al. (2020)</td></tr><tr><td>HG5LN cell - luciferase<br>reporter gene assay</td><td></td><td>EC<sub>50</sub> (μM) 0.2 ± 0.1</td><td>Garoche et al. (2021)</td></tr><tr><td>Steatotic FaO rat hepatoma<br>cells - gene expression</td><td>1 μM</td><td>Induction</td><td>Grasselli et al. (2014)</td></tr><tr><td>Mouse neocortical neurons -<br>protein expression</td><td>10 μM</td><td>Repression</td><td>Wojtowicz et al. (2014)</td></tr><tr><td>3T3-L1 - gene expression</td><td>10 μM</td><td>Induction</td><td>Akiyama et al. (2015)</td></tr><tr><td>JEG-3 human placental cells -<br>protein expression</td><td>10 nM and 10 μM<br>(24-72 h)</td><td>Induction; 10 nM, 10 μM<br>(24 h), 10 nM (48 h)</td><td>Honkisz and Wójtowicz<br>(2015b)</td></tr><tr><td>Bone marrow cells - gene<br>expression</td><td>10 and 20 μM (7 days)</td><td>Induction; 20 μM</td><td>Watt and Schlezinger 2015</td></tr><tr><td>3T3-L1 - gene expression</td><td>1 pM to 10 μM (8 days)</td><td>Induction, 1 pM to 10 μM</td><td>Chappell et al. (2018)</td></tr><tr><td>hMSCs - gene expression</td><td>10 μM</td><td>Induction</td><td>Kakutani et al. (2018)</td></tr><tr><td>MA-10 protein expression</td><td>10 nM</td><td>Induction</td><td>Gorowska-Wojtowicz et al.<br>(2019)</td></tr><tr><td>Bone marrow cells - gene<br>expression</td><td>20 μM</td><td>No effect</td><td>Andrews et al. (2020)</td></tr><tr><td>3T3-L1 cells - protein<br>expression</td><td>10 and 20 μM (10 days)</td><td>Induction</td><td>Liu QS et al. (2020)</td></tr><tr><td>3T3-L1 - gene expression</td><td>20 μM</td><td>Induction</td><td>Kim S et al. (2021)</td></tr><tr><td>HepG2 transfected with PPARγ<br>- protein expression</td><td>30 μM</td><td>Induction</td><td>Cheng and Volz (2022)</td></tr><tr><td>Fluorescence polarization<br>competitive binding assay</td><td></td><td>Agonist; IC<sub>50</sub> (μM) 68 ± 11</td><td>Li CH et al. (2021)</td></tr><tr><td>HGELN-PPARα/β - luciferase<br>reporter gene assay</td><td></td><td>No effect</td><td>Riu, Grimaldi, et al. (2011)<br>and Riu, Le Maire, et al.<br>(2011)</td></tr><tr><td>HEK293-PPARβ/δ - luciferase<br>reporter gene assay</td><td>0.1-50 μM</td><td>Induction; 25 and 50 μM</td><td>Li CH et al. (2021)</td></tr><tr><td>Steatotic FaO rat hepatoma<br>cells - gene expression (α)</td><td>1 μM</td><td>Repression</td><td>Grasselli et al. (2014)</td></tr><tr><td>Steatotic FaO rat hepatoma<br>cells - gene<br>expression (β/δ)</td><td>1 μM</td><td>Induction</td><td>Grasselli et al. (2014)</td></tr><tr><td>3T3-L1 - gene expression</td><td>20 μM</td><td>Induction</td><td>Kim S et al. (2021)</td></tr><tr><td>HG5LN-hPXR reporter cell line</td><td>10 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>11.97 ± 5.38</td><td>Molina-Molina et al. (2013)</td></tr><tr><td>HG5LN-PXR - luciferase<br>reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>123 ± 49.4; max<br>efficacy 27%</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="10">TCBPA</td><td rowspan="10">ERα</td><td>MCF7 - competitive binding<br>with 17β-estradiol</td><td>100 nM to 1 mM</td><td>Relative binding affinity<br>(vs. E2) = 0.075%; EC<sub>50</sub><br>(2.8 ± 0.82) × 10<sup>-6</sup> M</td><td>Olsen et al. (2003)</td></tr><tr><td>ERα affinity column</td><td>1 nM</td><td>Active; eluted fraction<br>63.1 ± 4.7%</td><td>Riu, Le Maire, et al. (2011)</td></tr><tr><td>MCF7 - luciferase reporter<br>gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> 0.02 μM</td><td>Kitamura et al. (2005)</td></tr><tr><td>Two-hybrid yeast assay</td><td>1 nM to 100 μM</td><td>No effect</td><td>Li J et al. (2010)</td></tr><tr><td>HGELN-ERα stably transfected</td><td>10 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>0.53 ± 0.25</td><td>Riu, Grimaldi, et al. (2011)</td></tr><tr><td>MELN - luciferase reporter<br>gene assay</td><td>10 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>47.60 ± 5.26</td><td>Molina-Molina et al. (2013)</td></tr><tr><td>Bioluminescence yeast<br>estrogen screen assay</td><td></td><td>Agonist; EC<sub>50</sub> 2.53 μM</td><td>Ruan et al. (2015)</td></tr><tr><td>HELN-ERα - luciferase reporter<br>gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>11.7 ± 1.7; max<br>efficacy 70%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>HepG2 - luciferase reporter<br>gene assay</td><td>3 nM to 10 μM</td><td>No significant effect</td><td>Pelch KE et al. (2019)</td></tr></tbody></table>

(continued)
<figure><img src="image_55.png" /><figcaption>Table A1. Continued.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">ERβ</td><td rowspan="10">ERβ</td><td>OECD TG 455 – STTA assay on hERα-HeLa-9903 cells</td><td>10 nM to 50 μM</td><td>Agonist; max effect<br>52.97% ± 2.79</td><td>Durcik, Hiti, et al. (2022)</td></tr><tr><td>MCF7 – proliferative potential (E-screen assay)</td><td>100 nM to 1 mM</td><td>Relative proliferative potential (vs. E2) = 0.00003%</td><td>Olsen et al. (2003)</td></tr><tr><td>MCF7 – proliferative potential (E-screen assay)</td><td>10 nM to 10 μM</td><td>EC<sub>50</sub> 45.8 μM</td><td>Molina-Molina et al. (2013)</td></tr><tr><td>MCF7 – protein expression</td><td>10 μM</td><td>No effect</td><td>Olsen et al. (2003)</td></tr><tr><td>MCF7 – protein expression</td><td>10 nM, 100 nM, and 1 μM (24 h)</td><td>Induction</td><td>Lei, Tang, et al. (2021)</td></tr><tr><td>MCF7 – gene expression</td><td>1, 10, and 25 μM (12 h)</td><td>Induction at 1 and 10 μM; repression at 25 μM</td><td>Lei, Tang, et al. (2021)</td></tr><tr><td>HGELN-ERβ stably transfected</td><td>10 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>1.15 ± 0.51</td><td>Riu, Grimaldi, et al. (2011)</td></tr><tr><td>HELN-ERβ – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>68 ± 17; max efficacy 21%</td><td>Grimaldi et al. (2019)</td></tr><tr><td>HepG2 – luciferase reporter gene assay</td><td>3 nM to 10 μM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td rowspan="2">ERRγ</td><td>Two-hybrid yeast assay</td><td>1 nM to 1 μM</td><td>No effect</td><td>Li J et al. (2010)</td></tr><tr><td>HG5LN-ERRγ – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="5">GPER</td><td>OVCAR-3 proliferation assay</td><td>1, 10, and 50 nM (48 and 72 h)</td><td>No effect</td><td>Hoffmann et al. (2017)</td></tr><tr><td>KGN proliferation assay</td><td>1, 10, and 50 nM (48 and 72 h)</td><td>No effect</td><td>Hoffmann et al. (2017)</td></tr><tr><td>OVCAR-3/KGN gene expression</td><td>1, 10, and 50 nM (48 and 72 h)</td><td>No effect</td><td>Hoffmann et al. (2017)</td></tr><tr><td>MA-10 protein expression</td><td>1 nM</td><td>Repression</td><td>Gorowska-Wojtowicz et al. (2019)</td></tr><tr><td>MCF7/SKBR3/MDA-MB-231 – protein expression</td><td>10 nM, 100 nM, and 1 μM (24 h)</td><td>Induction</td><td>Lei, Tang, et al. (2021)</td></tr><tr><td rowspan="10">AR</td><td>MCF7 – gene expression</td><td>1, 10, and 25 μM (12 h)</td><td>Induction at 1 and 10 μM</td><td>Lei, Tang, et al. (2021)</td></tr><tr><td>SKBR3 gene expression</td><td>10 nM to 10 μM</td><td>Induction</td><td>Yu M et al. (2023)</td></tr><tr><td>NIH3T3 – luciferase reporter gene assay</td><td>100 nM to 10 μM</td><td>Not significant; IC<sub>50</sub><br>870 μM</td><td>Kitamura et al. (2005)</td></tr><tr><td>CV-1 – reporter gene assay</td><td>100 nM to 1010 μM (+1 nM DHT)</td><td>Antagonist; IC<sub>50</sub> 10.45 μM</td><td>Sun et al. (2006)</td></tr><tr><td>CV-1 – reporter gene assay</td><td>100 nM to 1010 μM (+100 nM DHT)</td><td>No effect</td><td>Sun et al. (2006)</td></tr><tr><td>Two-hybrid yeast assay</td><td>1 nM to 100 μM</td><td>Antagonist; RIC<sub>20</sub> 100 nM</td><td>Li J et al. (2010)</td></tr><tr><td>PALM – luciferase reporter gene assay</td><td>10 nM to 10 μM</td><td>No effect</td><td>Molina-Molina et al. (2013)</td></tr><tr><td>MDA-kb2 – luciferase reporter gene assay</td><td>3 nM to 10 μM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>HELN-AR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>Antagonist; IC<sub>50</sub> (μM)<br>13.4 ± 3.7</td><td>Grimaldi et al. (2019)</td></tr><tr><td>MCF7 AR1 – anti-proliferative potential</td><td>10 nM to 10 μM</td><td>No effect</td><td>Molina-Molina et al. (2013)</td></tr><tr><td rowspan="5">PR</td><td>Two-hybrid yeast assay</td><td>1 nM to 100 μM</td><td>Antagonist; RIC<sub>20</sub> 27 nM</td><td>Li J et al. (2010)</td></tr><tr><td>HELN-PR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td>MCF7 – protein expression</td><td>10 μM</td><td>Induction</td><td>Olsen et al. (2003)</td></tr><tr><td>MCF7 – gene expression</td><td>1 μM</td><td>No effect</td><td>Pelch KE et al. (2019)</td></tr><tr><td>MCF7 – gene expression</td><td>1, 10, and 25 μM (12 h)</td><td>Induction at 1, 10, and 25 μM</td><td>Lei, Tang, et al. (2021)</td></tr><tr><td rowspan="2">GR</td><td>SKBR3 gene expression</td><td>10 nM to 10 μM</td><td>Repression</td><td>Yu M et al. (2023)</td></tr><tr><td>HMLN-GR – luciferase reporter gene assay</td><td>1 nM to 10 μM</td><td>No effect</td><td>Grimaldi et al. (2019)</td></tr><tr><td rowspan="5">PPARγ</td><td>HGELN-PPARγ – competitive binding</td><td>10 nM to 10 μM</td><td>IC<sub>50</sub> 6 μM</td><td>Riu, Le Maire, et al. (2011)</td></tr><tr><td>PPARγ affinity column</td><td>1 nM</td><td>Active; eluted fraction<br>84.7 ± 0.5%</td><td>Riu, Grimaldi, et al. (2011)</td></tr><tr><td>HGELN-PPARγ – luciferase reporter gene assay</td><td>10 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>1.28 ± 0.16 μM</td><td>Riu, Grimaldi, et al. (2011)</td></tr><tr><td>HG5LN – luciferase reporter gene assay</td><td>10 pM to 10 μM</td><td>EC<sub>50</sub> (μM) 0.3 ± 0.1</td><td>Garoche et al. (2021)</td></tr><tr><td>MA-10 protein expression</td><td>1 nM</td><td>Repression</td><td>Gorowska-Wojtowicz et al. (2019)</td></tr><tr><td>PPARα/β/δ</td><td>Fluorescence polarization competitive binding assay (PPARβ/δ)</td><td></td><td>Agonist; IC<sub>50</sub> (μM)<br>102 ± 15</td><td>Li CH et al. (2021)</td></tr></tbody></table>

(continued)
<figure><img src="image_56.png" /><figcaption>**Table A1. Continued.**</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Receptor</th><th>Cell/model assay</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="4">PXR</td><td>HGELN-PPARα/β – luciferase reporter assay</td><td></td><td></td><td>No effect</td><td>Riu, Grimaldi, et al. (2011) and Riu, Le Maire, et al. (2011)</td></tr><tr><td>HEK293-PPARβ/δ – luciferase reporter gene assay</td><td></td><td>0.1–50 μM</td><td>Induction; 50 μM</td><td>Li CH et al. (2021)</td></tr><tr><td>HG5LN-hPXR reporter cell line</td><td></td><td>10 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>8.49 ± 0.63 μM</td><td>Molina-Molina et al. (2013)</td></tr><tr><td>HG5LN-PXR – luciferase reporter gene assay</td><td></td><td>1 nM to 10 μM</td><td>Agonist; EC<sub>50</sub> (μM)<br>24.1 ± 1.5; max efficacy 35%</td><td>Grimaldi et al. (2019)</td></tr></tbody></table>

AR: androgen receptor; BPE: bisphenol E; BPAP: bisphenol AP; BPP: bisphenol P; BPS-MAE: bisphenol S 4-allyl ether; BPZ: bisphenol Z; E2: 17β-estradiol; EC: effect-ive concentration; ERα; estrogen receptor α; ERβ; estrogen receptor β; ERR γ: estrogen-related receptor γ; GPER: G protein-coupled estrogen receptor; GR: glucocorticoid receptor; IC: inhibitory concentration; OECD: Organisation for Economic Cooperation and Development; PPAR: peroxisome proliferator-activated receptor; PR: progesterone receptor; PXR: pregnane X receptor; REC: relative effective concentration; RIC: relative inhibitory concentration; TBBPA: tetra-bromo bisphenol A; TCBPA: tetra-chloro bisphenol A; TG: test guideline.

Row colors indicate the different assay types: yellow for competitive binding assays, green for reported gene and yeast assays, blue for proliferation assays, and orange for gene/protein expression assessment.

<table><caption>**Table A2.** Summary of the *in vivo*, *in vitro*, and *in chemico* assays reporting effects on thyroid hormone metabolism exerted by BPA analogues.</caption><thead><tr><th>Evaluated markers</th><th>Experimental model</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td colspan="5"><strong>BPA</strong></td></tr><tr><td rowspan="14">T3</td><td>Rat – adult</td><td>200 mg/kg/d (35 d)</td><td>Inhibition</td><td>Mohammed et al. (2020)</td></tr><tr><td>Rat – adult</td><td>40 mg/kg/d (15 d)</td><td>Induction</td><td>da Silva et al. (2019)</td></tr><tr><td>Rat – adult – female</td><td>40 mg/kg/d (15 d)</td><td>No effect</td><td>da Silva et al. (2018)</td></tr><tr><td>Rat – dams from PND 3 to PND 15 (breastmilk expo). Pups at PND 7 and 21</td><td>0.05 and 5 mg/kg/d</td><td>Dams: no effect.<br>Female pups: no effect.<br>Male pups: no effect</td><td>Santos-Silva et al. (2018)</td></tr><tr><td>Rat – female – during gestation</td><td>0.01 and 0.05 mg/kg/d for gestation and lactation</td><td>No effect</td><td>Silva BS et al. (2019)</td></tr><tr><td>Rat – pregnant and fetus exposed from GD0 to GD20</td><td>20 and 40 mg/kg/d</td><td>Dams and fetus: inhibition</td><td>Ahmed (2016)</td></tr><tr><td>Rat – adult – maternal exposure</td><td>0.01 and 0.05 mg/kg/d for gestation and lactation</td><td>No effect</td><td>Silva BS et al. (2019)</td></tr><tr><td>Ewe adult gestational exposure</td><td>5 mg/kg/d sc</td><td>Inhibition in dams and newborns</td><td>Viguié et al. (2013)</td></tr><tr><td>Mouse CD-1 – pubertally exposed</td><td>0.25 and 25 mg/kg/d (4 w)</td><td>Inhibition</td><td>Jiang et al. (2016)</td></tr><tr><td>Ewe gestational exposure</td><td>0.5–50 and 5000 µg/kg/d sc gestation</td><td>Inhibition in gestating ewes at 50 µg/kg/d no effect on late fetuses</td><td>Guignard et al. (2017)</td></tr><tr><td>C57Bl6 mouse adult</td><td>0.002–0.02–20 mg/kg/d for male<br>0.002–0.02 mg/kg/d for female</td><td>No effect</td><td>Hu C et al. (2023)</td></tr><tr><td>Rat – adult</td><td>200 mg/kg/d (35 d)</td><td>Inhibition</td><td>Mohammed et al. (2020)</td></tr><tr><td>Rat – adult – female</td><td>40 mg/kg/d (15 d)</td><td>No effect</td><td>da Silva et al. (2019)</td></tr><tr><td>Rat – dams and PND 7 and 21 pups, exposed since GD11</td><td>4.4 × 10<sup>-7</sup> and<br>2.2 × 10<sup>-4</sup> M</td><td>Induction<br>Dams: inhibition only at<br>2.2 × 10<sup>-4</sup> M<br>Female pups: no effect<br>Male pups: induction at<br>PND7 and inhibition at<br>PND21</td><td>Xu X et al. (2007)</td></tr><tr><td>Rat – dams from PND 3 to PND 15 (breastmilk expo) pups at PND 7 and 21</td><td>0.05 and 5 mg/kg/d</td><td>Dams: no effect<br>Male pups: inhibition at<br>0.050 mg/kg/d<br>Female pups: no effect</td><td>Santos-Silva et al. (2018)</td></tr><tr><td>Rat – PND 9 pups exposed during gestation</td><td>0, 0.004, 0.04, or 0.4 mg/kg/d</td><td>No effect</td><td>Sadowski et al. (2014)</td></tr><tr><td>Rat – female – during gestation</td><td>0.01 and 0.05 mg/kg/d for gestation and lactation</td><td>No effect</td><td>Silva BS et al. (2019)</td></tr><tr><td>Rat – PND 15 pups, exposed since GD6</td><td>2.5, 25, 250, 2500, or 25,000 mg/kg/d</td><td>No effect</td><td>Bansal and Zoeller (2019)</td></tr><tr><td>Rat – pregnant and fetus exposed from GD0 to GD20</td><td>20 and 40 mg/kg/d</td><td>Dams and fetus: inhibition</td><td>Ahmed (2016)</td></tr><tr><td>Rat – PND 20, exposed since GD6</td><td>4 and 40 mg/kg/d</td><td>No effect</td><td>Kobayashi et al. (2005)</td></tr><tr><td>Rat – pups/maternal exposure</td><td>1, 10, and 50 mg/kg/d</td><td>Induction at P15</td><td>Zoeller et al. (2005)</td></tr></tbody></table>

(continued)
<figure><img src="image_57.png" /><figcaption>**Table A2. Continued.**</figcaption></figure>

<table><thead><tr><th>Evaluated markers</th><th>Experimental model</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">Tsh</td><td>Rat – adult – maternal exposure</td><td>0.01 and 0.05 mg/kg/d for gestation and lactation</td><td>Inhibition: only for 0.01 mg/kg/day</td><td>Silva BS et al. (2019)</td></tr><tr><td>Ewe adult gestational exposure</td><td>5 mg/kg/d sc</td><td>Inhibition in dams and newborns</td><td>Viguié et al. (2013)</td></tr><tr><td>Mouse CD-1 – pubertally exposed</td><td>0.25 and 25 mg/kg/d (4 w)</td><td>Inhibition</td><td>Jiang et al. (2016)</td></tr><tr><td>Ewe gestational exposure</td><td>0.5–50 and 5000 µg/kg/d sc gestation</td><td>Inhibition in gestating ewes at 50 and 5000 µg/kg for free T4 no effect on late fetuses</td><td>Guignard et al. (2017)</td></tr><tr><td>C57Bl6 mouse adult</td><td>0.002–0.02–20 mg/kg/d for male<br>0.002–0.02 mg/kg/d for female</td><td>No effect</td><td>Hu C et al. (2023)</td></tr><tr><td>Rat – adult</td><td>200 mg/kg/d (35 d)</td><td>Induction</td><td>Mohammed et al. (2020)</td></tr><tr><td>Rat – adult – female</td><td>40 mg/kg/d (15 d)</td><td>Inhibition</td><td>da Silva et al. (2018)</td></tr><tr><td>Rat – pups exposed during gestation up to PND9</td><td>0, 0.004, 0.04, or 0.4 mg/kg/d</td><td>No effect</td><td>Sadowski et al. (2014)</td></tr><tr><td>Rat – pregnant and fetus exposed from GD0 to GD20</td><td>20 and 40 mg/kg/d</td><td>Dams and fetus: induction</td><td>Ahmed (2016)</td></tr><tr><td>Rat – pups/maternal exposure</td><td>1, 10, and 50 mg/kg/d</td><td>No effect</td><td>Zoeller et al. (2005)</td></tr><tr><td rowspan="4">Pax8</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0 and 4.4 × 10<sup>-8</sup>,<br>4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>,<br>and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>Tshβ expression: inhibition at 44 µM</td><td>Lee S et al. (2017)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-5</sup>, 3 × 10<sup>-4</sup>, and 10<sup>-4</sup> M (1 d/2 d)</td><td>Induction at 100 µM</td><td>Wu Y et al. (2016)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-9</sup>, 10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup> 10<sup>-5</sup>, and 10<sup>-4</sup> M (1 d/3 d)</td><td>Induction, biphasic</td><td>Gentilcore et al. (2013)</td></tr><tr><td>Human – SKOV-3 cells – ovary</td><td>10<sup>-8</sup>, 10<sup>-7</sup>, and 10<sup>-6</sup> M (1 d)</td><td>Induction, biphasic</td><td>Gentilcore et al. (2013)</td></tr><tr><td rowspan="2">Foxy1</td><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-5</sup>, 3 × 10<sup>-4</sup>, and 10<sup>-4</sup> M (1 d/2 d)</td><td>Induction at 100 µM</td><td>Wu Y et al. (2016)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-9</sup>, 10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup> 10<sup>-5</sup>, and 10<sup>-4</sup> M (1 d/3 d)</td><td>Induction, biphasic</td><td>Gentilcore et al. (2013)</td></tr><tr><td rowspan="4">Nkx2-1</td><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>,<br>4.4 × 10<sup>-6</sup>, and<br>4.4 × 10<sup>-5</sup> M (1 d)</td><td>Induction, non-significant</td><td>Lee S et al. (2017)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-5</sup>, 3 × 10<sup>-4</sup>, and 10<sup>-4</sup> M (1 d/2 d)</td><td>No effect</td><td>Wu Y et al. (2016)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-9</sup>, 10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup> 10<sup>-5</sup>, and 10<sup>-4</sup> M (1 d/3 d)</td><td>Induction, biphasic</td><td>Gentilcore et al. (2013)</td></tr><tr><td>Rat – adult</td><td>200 mg/kg/d (35 d)</td><td>Inhibition of tshr expression</td><td>Mohammed et al. (2020)</td></tr><tr><td rowspan="4">Tshr</td><td>C57Bl6 mouse adult males</td><td>0.02–20 mg/kg/d for male</td><td>Decreased expression at 20 mg/kg no effect at 0.02</td><td>Hu C et al. (2023)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>,<br>4.4 × 10<sup>-6</sup>, and<br>4.4 × 10<sup>-5</sup> M (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-9</sup>, 10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup> 10<sup>-5</sup>, and 10<sup>-4</sup> M (1 d/3 d)</td><td>Induction</td><td>Gentilcore et al. (2013)</td></tr><tr><td>Rat – adult</td><td>200 mg/kg/d (35 d)</td><td>Inhibition of Slc5a5 expression</td><td>Mohammed et al. (2020)</td></tr><tr><td rowspan="7">Nis</td><td>Rat – adult – female</td><td>40 mg/kg/d (15 d)</td><td>Inhibition I<sup>-</sup> uptake</td><td>da Silva et al. (2018)</td></tr><tr><td>C57Bl6 mouse adult male</td><td>0.02–20 mg/kg/d for male</td><td>Decreased expression at both doses</td><td>Hu C et al. (2023)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>,<br>4.4 × 10<sup>-6</sup>, and<br>4.4 × 10<sup>-5</sup> M (1 d)</td><td>Induction: non-significant (2.5×-fold at 100 mg/L)</td><td>Lee S et al. (2017)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup>, 10<sup>-5</sup>, and 10<sup>-4</sup> M (1 h)</td><td>Inhibition I<sup>-</sup> uptake (Ki 1.12 × 10<sup>-4</sup> M)</td><td>Wu Y et al. (2016)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-5</sup>, 3 × 10<sup>-4</sup>, and 10<sup>-4</sup> M (1 d/2 d)</td><td>Inhibition I<sup>-</sup> uptake at 10 and 3 µM for 48 and 24 h exposures, respectively</td><td>Wu Y et al. (2016)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-5</sup>, 3 × 10<sup>-4</sup>, and 10<sup>-4</sup> M (6 h/1 d/2 d)</td><td>Slc5a5 expression: 6 h: no effect<br>24 h and 48 h: inhibition (100 µM)</td><td>Wu Y et al. (2016)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-9</sup>, 10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup> 10<sup>-5</sup>, and 10<sup>-4</sup> M (1 d/3 d)</td><td>Induction</td><td>Gentilcore et al. (2013)</td></tr><tr><td>Duox1</td><td>Rat – PCC13 cells – thyroid</td><td>10<sup>-9</sup> M</td><td>Inhibition</td><td>da Silva et al. (2018)</td></tr><tr><td>Duox2</td><td>Rat – PCC13 cells – thyroid</td><td>10<sup>-9</sup> M</td><td>No effect</td><td>da Silva et al. (2018)</td></tr><tr><td>Tpo</td><td>Rat – PCC13 cells – thyroid</td><td>10<sup>-9</sup> M</td><td>Induction</td><td>da Silva et al. (2018)</td></tr><tr><td></td><td>Rat thyroid microsomes</td><td></td><td>No effect</td><td>Wu Y et al. (2016)</td></tr></tbody></table>

(continued)
<figure><img src="image_58.png" /><figcaption>**Table A2. Continued.**</figcaption></figure>

<table><thead><tr><th>Evaluated markers</th><th>Experimental model</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">Tg</td><td>Rat – adult</td><td>10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup>, 10<sup>-5</sup>, 10<sup>-4</sup>, and 10<sup>-3</sup> M (1 h)</td><td>Inhibition of tpo expression</td><td>Mohammed et al. (2020)</td></tr><tr><td>Rat – adult – female</td><td>200 mg/kg/d (35 d)</td><td>Inhibition</td><td>da Silva et al. (2018)</td></tr><tr><td>C57Bl6 mouse adult male</td><td>40 mg/kg/d (15 d)</td><td>Decreased expression at both doses</td><td>Hu C et al. (2023)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (1 d)</td><td>Induction, non-significant</td><td>Lee S et al. (2017)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-5</sup>, 3 × 10<sup>-4</sup>, and 10<sup>-4</sup> M (6 h/1 d/2 d)</td><td>Tpo expression: 6 h: no effect<br>24 h and 48 h: inhibition (100 µM)</td><td>Wu Y et al. (2016)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-9</sup>, 10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup> 10<sup>-5</sup>, and 10<sup>-4</sup> M (1 d/3 d)</td><td>Induction, biphasic</td><td>Gentilcore et al. (2013)</td></tr><tr><td>Rat – PCC13 cells – thyroid</td><td>10<sup>-9</sup> M</td><td>Inhibition</td><td>da Silva et al. (2018)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (1 d)</td><td>Induction, non-significant</td><td>Lee S et al. (2017)</td></tr><tr><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-5</sup>, 3 × 10<sup>-4</sup>, and 10<sup>-4</sup> M (6 h/1 d/2 d)</td><td>6 h: no effect<br>24 h and 48 h: induction at 100 and 30 µM, respectively</td><td>Wu Y et al. (2016)</td></tr><tr><td rowspan="4">MCT8</td><td>Rat – FRTL-5 cells – thyroid</td><td>10<sup>-9</sup>, 10<sup>-8</sup>, 10<sup>-7</sup>, 10<sup>-6</sup> 10<sup>-5</sup>, and 10<sup>-4</sup> M (1 d/3 d)</td><td>Induction</td><td>Gentilcore et al. (2013)</td></tr><tr><td>MDCK cells – overexpressing human MCT8 gene</td><td>0, 7.8 × 10<sup>-5</sup>, 1.5 × 10<sup>-4</sup>, 3.1 × 10<sup>-4</sup>, 6.3 × 10<sup>-4</sup>, 1.3 × 10<sup>-3</sup>, 2.5 × 10<sup>-3</sup>, and 5 × 10<sup>-3</sup> M</td><td>Inhibition T3 uptake at 125 and 250 µM</td><td>Dong and Wade (2017)</td></tr><tr><td>MDCK cells – overexpressing human MCT8 gene or primary murine astrocytes</td><td>10<sup>-5</sup> M</td><td>No effect on T3 uptake in either cell type</td><td>Johannes et al. (2016)</td></tr><tr><td>TTR</td><td>In chemico</td><td>0–1.5 × 10<sup>-4</sup> M</td><td>Binding affinity constant, 3.10 × 10<sup>5</sup> M</td><td>Cao et al. (2011)</td></tr><tr><td rowspan="5">TBG</td><td>In chemico</td><td>10 concentrations between 10<sup>-11</sup> and 10<sup>-5</sup> M</td><td>IC<sub>50</sub> = 1.67 × 10<sup>-6</sup> M</td><td>Kudo et al. (2006)</td></tr><tr><td>In chemico</td><td>6 concentrations in nM range</td><td>No binding</td><td>Marchesini et al. (2008)</td></tr><tr><td>In chemico</td><td>8 conc. 2 × 10<sup>-9</sup> to 5 × 10<sup>-7</sup> M</td><td>No binding</td><td>Meerts et al. (2000)</td></tr><tr><td>In chemico</td><td>8 conc. 5 × 10<sup>-6</sup> to 5 × 10<sup>-3</sup> M</td><td>IC<sub>50</sub> = 1.42 × 10<sup>-4</sup> M</td><td>Šauer et al. (2021)</td></tr><tr><td>In chemico</td><td>0–1.5 × 10<sup>-4</sup> M</td><td>Affinity constant 5.9 × 10<sup>5</sup> L/M</td><td>Cao et al. (2011)</td></tr><tr><td rowspan="2">HSA</td><td>In chemico</td><td>6 concentrations in nM range</td><td>No binding</td><td>Marchesini et al. (2008)</td></tr><tr><td>In chemico</td><td>0–10<sup>-3</sup> M</td><td>Affinity constants at drug site I and site II are 2.90 × 10<sup>4</sup> and 3.14 × 10<sup>4</sup> L/mol</td><td>Cao et al. (2011)</td></tr><tr><td rowspan="2">Dio1</td><td>Rat liver tissue – DIO1 enzyme</td><td>5 × 10<sup>-6</sup>, 5 × 10<sup>-5</sup>, 4 × 10<sup>-4</sup>, and 5 × 10<sup>-3</sup> M for 1 h</td><td>Inhibition: EC<sub>50</sub> 1.8 × 10<sup>-4</sup> M</td><td>da Silva et al. (2019)</td></tr><tr><td>Rat – GH3 cells – adult – female – pituitary</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td rowspan="2">Dio2</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Rat adipose tissue – DIO2 enzyme</td><td>5 × 10<sup>-6</sup>, 5 × 10<sup>-5</sup>, 4 × 10<sup>-4</sup>, and 5 × 10<sup>-3</sup> M (3 d)</td><td>Inhibition: EC<sub>50</sub> 1.1 × 10<sup>-3</sup> M</td><td>da Silva et al. (2019)</td></tr><tr><td rowspan="5">THRs</td><td>Two-hybrid yeast transactivation assay</td><td></td><td>Modest stimulation, EC<sub>50</sub> = 30.1 µM vs. 0.085 µM for T3</td><td>Lei et al. (2018)</td></tr><tr><td>Human ovarian granulosa cell line</td><td>10<sup>-9</sup> to 10<sup>-7</sup> to 10<sup>-5</sup> M</td><td>No effect on thrα expression</td><td>Mlynarcikova and Scsukova (2020)</td></tr><tr><td>Rat – GH3 cells – adult – female – pituitary</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>Inhibition at 44 µM both thrα and β expression</td><td>Lee S et al. (2017)</td></tr><tr><td>In chemico</td><td>8 conc. 5 × 10<sup>-6</sup> to 5 × 10<sup>-3</sup> M</td><td>No agonistic or antagonistic effects on THRβ</td><td>Šauer et al. (2021)</td></tr><tr><td>Rat – GH3 cells – adult – female – pituitary. Proliferation assay</td><td>From 10<sup>-9</sup> to 10<sup>-6</sup> M</td><td>Weak stimulation of basal and T3-induced GH3 cell proliferation</td><td>Lee J et al. (2018)</td></tr><tr><td></td><td>TSA201 human cells derived from embryonic kidney</td><td></td><td>Weak ligand of THRα and β Antagonist of THRα and β</td><td>Moriyama et al. (2002)</td></tr></tbody></table>

(continued)
<figure><img src="image_59.png" /><figcaption>Table A2. Continued.</figcaption></figure>

<table><thead><tr><th>Evaluated markers</th><th>Experimental model</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td></td><td>cells transfected with <i>thrs</i> and HEPG2 (endogenous TRs)</td><td>1 nM to 100 µM for TtSA cells<br>1 nM to 10 µM for HepG2</td><td>From 1 µM in transfected TSA201 cells for THRα1 and from 100 nM for THRβ1<br>Antagonist at 10 µM for endogenous THRs in HEPG2</td><td></td></tr><tr><td colspan="5"><strong>BPAP</strong></td></tr><tr><td>Tshβ</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0.034, 0.34, 3.4, and 34 µM (2 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Pax8</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.34, 3.4, and 34 µM (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Nkx2.1</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.34, 3.4, and 34 µM (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tshr</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.34, 3.4, and 34 µM (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Slc5a5</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.34, 3.4, and 34 µM (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tpo</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.34, 3.4, and 34 µM (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tg</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.34, 3.4, and 34 µM (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Dio1</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0.034, 0.34, 3.4, and 34 µM (2 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Dio2</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0.034, 0.34, 3.4, and 34 µM (2 d)</td><td>Inhibition at 34 µM</td><td>Lee S et al. (2017)</td></tr><tr><td>Thrα</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0.034, 0.34, 3.4, and 34 µM (2 d)</td><td>Inhibition at 34 µM</td><td>Lee S et al. (2017)</td></tr><tr><td>Thrβ</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0.034, 0.34, 3.4, and 34 µM (2 d)</td><td>Inhibition at 34 µM</td><td>Lee S et al. (2017)</td></tr><tr><td>THRs</td><td>Rat – GH3 cells – adult – female – pituitary. proliferation assay</td><td>From 10<sup>-9</sup> to 10<sup>-6</sup> M</td><td>Weak stimulation of basal and T3-induced GH3 cell proliferation at 10<sup>-6</sup> M after 96 h exposure</td><td>Lee S et al. (2017)</td></tr><tr><td colspan="5"><strong>BPE</strong></td></tr><tr><td>TTR</td><td>In chemico TTR THRβ callux assay</td><td>8 conc. 5 × 10<sup>-6</sup> to 5 × 10<sup>-3</sup> M</td><td>Weak potency for T3 binding inhibition: IC<sub>50</sub> = 1.3 × 10<sup>-4</sup> M</td><td>Šauer et al. (2021)</td></tr><tr><td>THRs</td><td>In chemico TTR THRβ callux assay<br>In chemico hybrid yeast assay THRα</td><td>8 conc. 5 × 10<sup>-6</sup> to 5 × 10<sup>-3</sup> M</td><td>No agonistic or antagonistic activity on THRβ<br>Stimulation with low potency = 69.9 µM (vs. 0.085 µM for T3)</td><td>Šauer et al. (2021)<br>Lei et al. (2017)</td></tr><tr><td colspan="5"><strong>BPP</strong></td></tr><tr><td>Thrβ</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>30–30 µM</td><td>Inhibition of <i>thrβ</i> expression from 3 µM</td><td>Lee S et al. (2017)</td></tr><tr><td>Tshβ</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>Inhibition, non-significant</td><td>Lee S et al. (2017)</td></tr><tr><td>Pax8</td><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Nkx2.1</td><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tshr</td><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Slc5a5</td><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tpo</td><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tg</td><td>Rat – FRTL-5 cells – thyroid</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (1 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Dio1</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>Inhibition at 10 mg/L</td><td>Lee S et al. (2017)</td></tr><tr><td>Dio2</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>Inhibition at 10 mg/L</td><td>Lee S et al. (2017)</td></tr><tr><td>Thrα</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Thrβ</td><td>Rat – GH3 cells – adult – female – pituitary</td><td>0, 4.4 × 10<sup>-8</sup>, 4.4 × 10<sup>-7</sup>, 4.4 × 10<sup>-6</sup>, and 4.4 × 10<sup>-5</sup> M (2 d)</td><td>Inhibition</td><td>Lee S et al. (2017)</td></tr></tbody></table>

(continued)
<figure><img src="image_60.png" /><figcaption>Table A2. Continued.</figcaption></figure>

<table><thead><tr><th>Evaluated markers</th><th>Experimental model</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td>THRs</td><td>Rat – GH3 cells – adult –<br>female – pituitary.<br>proliferation assay</td><td>From 10<sup>-9</sup> to 10<sup>-6</sup> M</td><td>Weak stimulation of basal<br>and T3-induced GH3 cell<br>proliferation at 10<sup>-6</sup>M after<br>96 h exposure</td><td>Lee J et al. (2018)</td></tr><tr><td>BPZ</td><td></td><td></td><td></td><td></td></tr><tr><td>Tshβ</td><td>Rat – GH3 cells – adult –<br>female – pituitary.<br>proliferation assay</td><td>From 10<sup>-9</sup> to 10<sup>-6</sup> M</td><td>Weak stimulation of basal<br>and T3-induced GH3 cell<br>proliferation at 10<sup>-6</sup> M<br>after 96 h exposure</td><td>Lee J et al. (2018)</td></tr><tr><td>Pax8</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.46, 4.6, and 46 μM</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Nkx2.1</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.46, 4.6, and 46 μM</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tshr</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.46, 4.6, and 46 μM</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Slc5a5</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.46, 4.6, and 46 μM</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tpo</td><td>Rat – FRTL-5 cells – thyroid</td><td>0.46, 4.6, and 46 μM</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Tg</td><td>0.46, 4.6, and 46 μM</td><td>0.46, 4.6, and 46 μM</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Dio1</td><td>Rat – GH3 cells – adult –<br>female – pituitary</td><td>0.046, 0.46, 4.6, and 46 μM</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>Dio2</td><td>Rat – GH3 cells – adult –<br>female – pituitary</td><td>0.046, 0.46, 4.6, and 46 μM</td><td>Inhibition at 46 μM</td><td>Lee S et al. (2017)</td></tr><tr><td>Thrα</td><td>Rat – GH3 cells – adult –<br>female – pituitary</td><td>0.046, 0.46, 4.6, and 46 μM</td><td>Inhibition at 0.46 μM</td><td>Lee S et al. (2017)</td></tr><tr><td>Thrβ</td><td>Rat – GH3 cells – adult –<br>female – pituitary</td><td>0.046, 0.46, 4.6, and 46 μM</td><td>Inhibition at 4.6 μM</td><td>Lee S et al. (2017)</td></tr><tr><td>Tshβ</td><td>Rat – GH3 cells – adult –<br>female – pituitary</td><td>0.046, 0.46, 4.6, and 46 μM</td><td>No effect</td><td>Lee S et al. (2017)</td></tr><tr><td>TBBPA</td><td></td><td></td><td></td><td></td></tr><tr><td>T3</td><td>Rat – adult</td><td>0, 30, 100, or 300 mg/kg/<br>d (28d)</td><td>Males: induction BMDL<sub>10</sub><br>124 mg/kg/d<br>Females: no effect</td><td>EFSA (2011)</td></tr><tr><td></td><td>Rat – adult</td><td>0, 30, 100, and 300 mg/kg/<br>d (28d)</td><td>Males: induction<br>Females: no effect<br>BMDL of 123.8 mg/kg/d</td><td>Van der Ven et al. (2008)</td></tr><tr><td></td><td>Rat – adult</td><td>0, 100, 300, and 1000 mg/kg/<br>d (13 w)</td><td>No effect</td><td>Osimitz et al. (2016)</td></tr><tr><td></td><td>Rat – adult</td><td>100, 300, and 1000 mg/kg/<br>d (13 w)</td><td>No effect</td><td>EFSA 2011</td></tr><tr><td></td><td>Rat – adult</td><td>250 mg/kg/d (5 d)</td><td>No effect</td><td>Sanders et al. (2016)</td></tr><tr><td></td><td>Rat – adults – female and<br>male – pups</td><td>10, 100, and 1000 mg/kg/<br>d (12 w)</td><td>Inhibition only for adult<br>males at highest conc.</td><td>EFSA (2011)</td></tr><tr><td></td><td>Rat – pups from adults<br>exposed 70 (m) and 14 (f)<br>days prior to mating and<br>through lactation</td><td>0, 3, 10, 30, 100, 300, 1000,<br>or 3000 mg/kg/d</td><td>Female pups: Induction<br>BMDL<sub>10</sub> 2.3 mg/kg/d</td><td>EFSA (2011)</td></tr><tr><td></td><td>Rat – pups from GD10 to<br>PND 20</td><td>0–100–1000–10,000 ppm in<br>diet</td><td>Male pups: inhibition at PND<br>for 100 and 1000 ppm<br>No effect at PNW11</td><td>Saegusa et al. (2009)</td></tr><tr><td></td><td>Rat – pups exposed in utero<br>until PND21</td><td>3, 10, 30, 100, 300, 1000, and<br>3000 mg/kg/d</td><td>Female pups: induction,<br>BMDL 2.3 mg/kg/d<br>Male pups: no effect</td><td>Van der Ven et al. (2008)</td></tr><tr><td></td><td>Rat adult and GSD21exposed<br>during pregnancy and<br>lactation</td><td>10–100–1000 mg/kg/d</td><td>Adult male: decreased at<br>highest concentration<br>Adult female: no effect<br>Pups: no effect</td><td>Cope et al. (2015)</td></tr><tr><td>T4</td><td>Rat – adult</td><td>0, 30, 100, or 300 mg/kg/<br>d (28 d)</td><td>Males: inhibition BMDL<sub>10</sub><br>48 mg/kg/d<br>Females: no effect</td><td>EFSA (2011)</td></tr><tr><td></td><td>Rat – adult</td><td>0, 30, 100, and 300 mg/kg/<br>d (28 d)</td><td>Males: inhibition<br>Females: no effect<br>BMDL of 48 mg/kg/d</td><td>Van der Ven et al. (2008)</td></tr><tr><td></td><td>Rat – adult</td><td>0, 100, 300, and 1000 mg/kg/<br>d (13 w)</td><td>Males: inhibition at 33 and<br>90 d. Not dose dep.<br>Females: inhibition at 33 d.<br>Not dose dep.</td><td>Osimitz et al. (2016)</td></tr><tr><td></td><td>Rat – adult</td><td>100, 300, and 1000 mg/kg/<br>d (13 w)</td><td>Inhibition at all conc</td><td>EFSA (2011)</td></tr><tr><td></td><td>Rat – adult</td><td>250 mg/kg/d (5 d)</td><td>Inhibition</td><td>Sanders et al. (2016)</td></tr><tr><td></td><td>Rat – adult – female and<br>male</td><td>10, 100, and 1000 mg/kg/<br>d (12 w)</td><td>Adult males: inhibition at 100<br>and 1000 mg/kg/day<br>Pups both sexes: inhibition<br>at 100 and 1000 mg/kg/<br>day.</td><td>EFSA (2011)</td></tr><tr><td></td><td>Rat – pups</td><td></td><td>Adult females: inhibition at<br>1000 mg/kg/day</td><td></td></tr></tbody></table>

(continued)
<figure><img src="image_61.png" /><figcaption>Table A2. Continued.</figcaption></figure>

<table><thead><tr><th>Evaluated markers</th><th>Experimental model</th><th>Dose range (time)</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">Tsh/TSH</td><td>Rat – adult and GSD21 pups exposed during pregnancy and lactation</td><td>10, 100, or 1000 mg/kg/d</td><td>Adult males and females: inhibition, dose dep. NOEL: 10 mg/kg/d Pups: inhibition</td><td>Cope et al. (2015)</td></tr><tr><td>Rat – pups from adults exposed 70 (m) and 14 (f) days prior to mating and through lactation</td><td>0, 3, 10, 30, 100, 300, 1000, or 3000 mg/kg/d</td><td>Male pups: inhibition Female pups: inhibition BMDL10 16 mg/kg/d BMDL10 31 mg/kg/d</td><td>EFSA (2011)</td></tr><tr><td>Rat – pups from GD10 to PND 20</td><td>0–100–1000–10,000 ppm in diet</td><td>No effect</td><td>Saegusa et al. (2009)</td></tr><tr><td>Rat – pups exposed in utero until PND21</td><td>3, 10, 30, 100, 300, 1000, and 3000 mg/kg/d</td><td>Inhibition. BMDL 30.8 mg/kg/ d (m) and 16.1 mg/kg/d (f)</td><td>Van der Ven et al. (2008)</td></tr><tr><td>Rat – pregnant and fetuses</td><td>5 mg/kg/d from GD10 to 16</td><td>No effect in dams or fetuses</td><td>Meerts et al. (1999)</td></tr><tr><td>Rat – adult</td><td>0, 100, 300, and 1000 mg/kg/ d (13 w)</td><td>No effect</td><td>Osimitz et al. (2016)</td></tr><tr><td>Rat – adult</td><td>100, 300, and 1000 mg/kg/ d (13 w)</td><td>No effect</td><td>EFSA (2011)</td></tr><tr><td>Rat – adult</td><td>250 mg/kg/d (5 d)</td><td>Induction non-significant</td><td>Sanders et al. (2016)</td></tr><tr><td>Rat – adults and pups</td><td>10, 100, and 1000 mg/kg/ d (12 w)</td><td>No effect</td><td>EFSA (2011)</td></tr><tr><td>Rat – adult and GSD21 pups exposed during pregnancy and lactation</td><td>10, 100, or 1000 mg/kg/d</td><td>No effects</td><td>Cope et al. (2015)</td></tr><tr><td>Rat – pups from GD10 to PND 20</td><td>0–100–1000–10,000 ppm in diet</td><td>No effect</td><td>Saegusa et al. (2009)</td></tr><tr><td>Rat – pregnant and fetuses</td><td>5 mg/kg/d</td><td>Increased TSH concentration in fetuses</td><td>Meerts et al. (1999)</td></tr><tr><td rowspan="4">TTR</td><td>In chemico</td><td>10 concentrations between 10<sup>-11</sup> and 10<sup>-5</sup> M</td><td>Binding affinity: IC<sub>50</sub> = 3.1 × 10<sup>-9</sup> M</td><td>Kudo et al. (2006)</td></tr><tr><td>In chemico</td><td>6 concentrations in nM range</td><td>Strong binding affinity: IC<sub>50</sub> = 1.9 × 10<sup>-8</sup> M</td><td>Marchesini et al. (2008)</td></tr><tr><td>In chemico</td><td>8 conc. 2 × 10<sup>-9</sup> to 5 × 10<sup>-7</sup> nM</td><td>Strong binding affinity: IC<sub>50</sub> = 7.7 × 10<sup>-9</sup> M</td><td>Meerts et al. (2000)</td></tr><tr><td>In chemico</td><td>8 conc. 10<sup>-10</sup> to 10<sup>-5</sup> M</td><td>Binding affinity: IC<sub>50</sub> = 3 × 10<sup>-8</sup> M</td><td>Šauer et al. (2021)</td></tr><tr><td>TBG</td><td>In chemico</td><td>6 concentrations in nM range</td><td>No binding affinity</td><td>Marchesini et al. (2008)</td></tr><tr><td rowspan="2">THRs</td><td>In chemico</td><td>Seven different concentrations from 50 µM and twofold dilutions between two consecutive concentrations</td><td>Relative binding potency/T3 15 and 100-fold lower for THRα and β, respectively</td><td>Ren et al. (2020)</td></tr><tr><td>GH3 cells, competitive inhibition of 125I-T3 binding to nuclear fractions Basal and T3-induced cell growth and GH production</td><td>10<sup>-7</sup> to 10<sup>-4</sup> M</td><td>Weak binding to THR: concentration-dependent inhibition of 125I-T3-binding from 10<sup>-6</sup> to 10<sup>-4</sup> M (10<sup>-10</sup> for T3) Agonistic effect from 10<sup>-6</sup> M Not antagonistic effect</td><td>Kitamura et al. (2002)</td></tr><tr><td colspan="5" style="background-color: #6A6A6A; color: white; text-align: left; font-weight: bold;">TCBPA</td></tr><tr><td>THRs</td><td>In chemico</td><td>0–10<sup>-4</sup> M</td><td>Induction IC<sub>50</sub> = 2.2 × 10<sup>-9</sup> M</td><td>Jugan et al. (2007)</td></tr><tr><td rowspan="3">TTR</td><td>In chemico Competitive binding assay</td><td>10 concentrations between 10<sup>-11</sup> and 10<sup>-5</sup> M</td><td>IC<sub>50</sub> = 3.2 × 10<sup>-8</sup> M</td><td>Kudo et al. (2006)</td></tr><tr><td>In chemico Competitive binding assay</td><td>6 concentrations in nM range</td><td>Weak binding capacity: IC<sub>50</sub> = 1.1 × 10<sup>-7</sup> M</td><td>Marchesini et al. (2008)</td></tr><tr><td>In chemico competitive binding assay</td><td>8 conc. 2 × 10<sup>-9</sup> to 5 × 10<sup>-7</sup> nM</td><td>No binding capacity</td><td>Meerts et al. (2000)</td></tr><tr><td>TBG</td><td>In chemico</td><td>6 concentrations in nM range</td><td>Weak binding to THR: concentration-dependent inhibition of 125I-T3-binding from 10<sup>-6</sup> to 10<sup>-4</sup> M (10<sup>-10</sup> for T3) Agonistic effect from 10<sup>-5</sup> to 10<sup>-4</sup> M No antagonistic effect</td><td>Marchesini et al. (2008)</td></tr><tr><td>THRs</td><td>GH3 cells, competitive inhibition of 125I-T3 binding to nuclear fractions Basal and T3-induced cell growth and GH production</td><td>10<sup>-7</sup> to 10<sup>-4</sup> M</td><td>Weak binding to THR: concentration-dependent inhibition of 125I-T3-binding from 10<sup>-6</sup> to 10<sup>-4</sup> M (10<sup>-10</sup> for T3) Agonistic effect from 10<sup>-5</sup> to 10<sup>-4</sup> M No antagonistic effect</td><td>Kitamura et al. (2002)</td></tr></tbody></table>

BMDL: benchmark dose lower bound; BPA: bisphenol A; BPAP: bisphenol AP; BPE: bisphenol E; BPP: bisphenol P; BPZ: bisphenol Z; Dio: iodothyronine deiodinase; Duox: dual oxidase; EC: effective concentration; Foxe1: forkhead box protein E1; GD: gestational day; HSA: human serum albumin; IC: inhibitory concentration; MCT8: monocarboxylate transporter 8; Nkx2-1: NK homeobox protein 1; Nis: sodium/iodide symporter; Pax8: paired box 8; PND: post-natal day; Slc5a5: solute carrier family 5 member 5; T3: triiodothyronine; T4: thyroxine; TBBPA: tetra-bromo bisphenol A; TBG: thyroxine-binding globulin; TCBPA: tetra-chloro bisphenol A; Tg: thyroglobulin; THR: thyroid hormone receptor; Tpo: thyroperoxidase; Tsh: thyroid-stimulating hormone; Tshr: thyroid-stimulating hormone receptor; TTR: transthyretin.

Row colors indicate the different assay types: yellow for *in vivo* assays; blue for *in vitro* assays, and orange for enzyme/*in chemico* assays.
<figure><img src="image_62.png" /><figcaption>**Table A3.** Summary of the *in vitro* assays reporting effects on steroid hormone secretion and gene expression of steroidogenic enzymes.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Hormone/enzyme</th><th>Cell model/assay</th><th>Dose range/time</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="7">BPAP</td><td>17β-estradiol</td><td>H295R adrenal cells</td><td>1.56, 6.25, and 25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>Testosterone</td><td>H295R adrenal cells</td><td>1.56, 6.25, and 25 nM (48 h)</td><td>Decrease: 6.25 and 25 nM</td><td>Lin et al. (2021)</td></tr><tr><td>CYP11A</td><td>H295R adrenal cells – gene expression</td><td>1.56, 6.25, and 25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>StAR</td><td>H295R adrenal cells – gene expression</td><td>1.56, 6.25, and 25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>CYP17</td><td>H295R adrenal cells – gene expression</td><td>1.56, 6.25, and 25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>CYP19</td><td>H295R adrenal cells – gene expression</td><td>1.56, 6.25, and 25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>3βHSD2</td><td>H295R adrenal cells – gene expression</td><td>1.56, 6.25, and 25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td rowspan="10">BPE</td><td>Progesterone</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>Increase: EC<sub>50</sub> 18.2 μM (8.8–37.9, 95% CI); max efficacy 689%</td><td>Rosenmai et al. (2014)</td></tr><tr><td>17α-OH progesterone</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>Increase: EC<sub>50</sub> 23.0 μM (14.9–35.7, 95% CI); max efficacy 198%</td><td>Rosenmai et al. (2014)</td></tr><tr><td>DHEA</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>Decrease: EC<sub>50</sub> 0.5 μM (0.2–1.6, 95% CI); max efficacy 68%</td><td>Rosenmai et al. (2014)</td></tr><tr><td>Androstenedione</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>Decrease: EC<sub>50</sub> 0.3 μM (0.1–0.9, 95% CI); max efficacy 73%</td><td>Rosenmai et al. (2014)</td></tr><tr><td>Estrone</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>Increase: EC<sub>50</sub> 13.6 μM (6.2–29.7, 95% CI); max efficacy 226%</td><td>Rosenmai et al. (2014)</td></tr><tr><td>17β-estradiol</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>Increase: EC<sub>50</sub> 22.2 μM ±0.7; max efficacy 212 ± 29%</td><td>Rosenmai et al. (2014)</td></tr><tr><td>Testosterone</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>Decrease: EC<sub>50</sub> 5.0 μM (3.4–7.3, 95% CI); max efficacy 58%</td><td>Rosenmai et al. (2014)</td></tr><tr><td>Cortisol</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>No effect</td><td>Rosenmai et al. (2014)</td></tr><tr><td>Corticosterone</td><td>H295R steroidogenesis assay</td><td>0.8–50 μM</td><td>Increase: EC<sub>50</sub> 16.1 μM (10.6–24.6, 95% CI); max efficacy 292%</td><td>Rosenmai et al. (2014)</td></tr><tr><td rowspan="2">BPP</td><td>17β-estradiol</td><td>H295R adrenal cells</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>Testosterone</td><td>H295R adrenal cells</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td rowspan="7">BPZ</td><td>17β-estradiol</td><td>H295R adrenal cells</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>Testosterone</td><td>H295R adrenal cells</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>Decrease: 0.39 and 6.25 nM</td><td>Lin et al. (2021)</td></tr><tr><td>CYP11A</td><td>H295R adrenal cells – gene expression</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>Decrease: 6.25 nM</td><td>Lin et al. (2021)</td></tr><tr><td>StAR</td><td>H295R adrenal cells – gene expression</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>CYP17</td><td>H295R adrenal cells – gene expression</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>CYP19</td><td>H295R adrenal cells – gene expression</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td>3βHSD2</td><td>H295R adrenal cells – gene expression</td><td>0.39, 1.56, and 6.25 nM (48 h)</td><td>No effect</td><td>Lin et al. (2021)</td></tr><tr><td rowspan="3">TBBPA</td><td>Progesterone</td><td>MA-10 mouse Leydig cells</td><td>10 μM (48 h)</td><td>Increase</td><td>Roelofs et al. (2015)</td></tr><tr><td></td><td>JEG-3 human placental cells</td><td>1 nM to 50 μM (24–72 h)</td><td>Increase: 1–50 nM (48 h), 100 nM 1 μM (48–72 h), 10–50 μM (24–72 h); max efficacy threefold at 50 μM (72 h)</td><td>Honkisz and Wójtowicz (2015b)</td></tr><tr><td>17α-OH progesterone</td><td>MA-10 mouse Leydig cells</td><td>10 μM (48 h)</td><td>Increase</td><td>Roelofs et al. (2015)</td></tr></tbody></table>

(continued)
<figure><img src="image_63.png" /><figcaption>Table A3. Continued.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Hormone/enzyme</th><th>Cell model/assay</th><th>Dose range/time</th><th>Response; EC<sub>50</sub>/effect size</th><th>Reference</th></tr></thead><tbody><tr><td></td><td>Androstenedione</td><td>MA-10 mouse Leydig cells</td><td>10 µM (48 h)</td><td>Increase</td><td>Roelofs et al. (2015)</td></tr><tr><td rowspan="2">17β-estradiol</td><td></td><td>MA-10 mouse Leydig cells</td><td>10 nM</td><td>Decrease</td><td>Gorowska-Wojtowicz et al. (2019)</td></tr><tr><td></td><td>JEG-3 human placental cells</td><td>1 nM to 50 µM (24–72 h)</td><td>Increase: 1 nM and 50 µM (72 h), 10 nM to 1 µM (24–72 h), 10 µM (48–72 h); max efficacy 26–41% at 72 h</td><td>Honkisz and Wójtowicz (2015a)</td></tr><tr><td></td><td></td><td>Human placental explants</td><td>5 nM to 50 µM (16 h)</td><td>Decrease (0.7-fold at 5 µM)</td><td>Arita et al. (2018)</td></tr><tr><td rowspan="3">Testosterone</td><td></td><td>MA-10 mouse Leydig cells</td><td>0–30 µM</td><td>Increase (46-fold at 30 µM)</td><td>Dankers et al. (2013)</td></tr><tr><td></td><td>MA-10 mouse Leydig cells</td><td>10, 30, and 100 µM (48 h)</td><td>Increase (56-fold at 100 µM)</td><td>Roelofs et al. (2015)</td></tr><tr><td></td><td>Human placental explants</td><td>5 nM to 50 µM (16 h)</td><td>Increase (6.09-fold at 500 nM)</td><td>Arita et al. (2018)</td></tr><tr><td>11-Deoxycorticosterone</td><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM (48 h)</td><td>Increase</td><td>Roelofs et al. (2015)</td></tr><tr><td>β-hCG</td><td></td><td>JEG-3 human placental cells</td><td>1 nM to 50 µM (24–72 h)</td><td>Decrease: 1 nM (72 h), 10 nM, 100 nM to 10 µM (24–72 h), 50 nM, 50 µM (24 and 72 h); max efficacy 37% 50 µM (72 h)</td><td>Honkisz and Wójtowicz (2015b)</td></tr><tr><td>CYP11A</td><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>Induction</td><td>Dankers et al. (2013)</td></tr><tr><td></td><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>No effect</td><td>Roelofs et al. (2015)</td></tr><tr><td rowspan="2">StAR</td><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>Induction</td><td>Dankers et al. (2013)</td></tr><tr><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>No effect</td><td>Roelofs et al. (2015)</td></tr><tr><td rowspan="2">CYP17</td><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>Induction</td><td>Dankers et al. (2013)</td></tr><tr><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>No effect</td><td>Roelofs et al. (2015)</td></tr><tr><td rowspan="2">3β-HSD</td><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>No effect</td><td>Dankers et al. (2013)</td></tr><tr><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>No effect</td><td>Roelofs et al. (2015)</td></tr><tr><td rowspan="2">17β-Hsd</td><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>No effect</td><td>Dankers et al. (2013)</td></tr><tr><td></td><td>MA-10 mouse Leydig cells</td><td>10 µM</td><td>No effect</td><td>Roelofs et al. (2015)</td></tr><tr><td rowspan="3">CYP19 (aromatase)</td><td></td><td>H295R adrenal cells</td><td>2.5 and 7.5 µM</td><td>No effect</td><td>Cantón et al. (2005)</td></tr><tr><td></td><td>JEG-3 human placental cells – protein expression</td><td>10 nM, 100 nM, and 10 µM (24 h)</td><td>Increase: 100 nM and 10 µM</td><td>Honkisz and Wójtowicz (2015a)</td></tr><tr><td></td><td>JEG-3 human placental cells – enzyme activity</td><td>10 nM, 100 nM, and 10 µM (24–72 h)</td><td>Increase: 10 nM (48–72 h), 100 nM, 10 µM (24–72 h); max efficacy 41% for 10 µM at 72 h</td><td>Honkisz and Wójtowicz (2015a)</td></tr><tr><td>TCBPA</td><td>CYP21</td><td>H295R adrenal cells – gene expression</td><td></td><td>Induction</td><td>Song et al. (2008)</td></tr><tr><td></td><td>17β-estradiol</td><td>MA-10 mouse Leydig cells</td><td>1 nM</td><td>Decrease</td><td>Gorowska-Wojtowicz et al. (2019)</td></tr></tbody></table>

BPAP: bisphenol AP; BPE: bisphenol E; BPP: bisphenol P; BPZ: bisphenol Z; CI: confidence interval; CYP: cytochrome P450; DHEA: dehydroepiandrosterone; EC: effective concentration; HSD: hydroxysteroid dehydrogenase; StAR: steroidogenic acute regulatory protein; TBBPA: tetra-bromo bisphenol A; TCBPA: tetra-chloro bisphenol A.
<table><caption>Table A4. *In vivo* studies describing the neural effects of developmental exposure to BPA alternatives.</caption><thead><tr><th>Exposure period</th><th>Species/sex</th><th>Exposure duration</th><th>Exposure route</th><th>Substances/ doses</th><th>Age at analyses</th><th>Behavioral analyses</th><th>Neuroanatomical, endocrine, and molecular analyses</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">Prenatal/ postnatal</td><td rowspan="10">C57BL/6 mice<br/>Males and<br/>females</td><td rowspan="10">From 7 days<br/>premating<br/>to the end<br/>of lactation</td><td rowspan="10">Drinking water</td><td rowspan="10">BPAP: 0.4 mg/<br/>kg bw/d</td><td rowspan="10">Postnatal<br/>weeks 6<br/>to 7</td><td rowspan="10">Open-field test: Reduced number of entries, speed, and distance traveled in the center in BPAP-exposed males and females.<br/><br/>Elevated plus maze: Reduced time spent in the open arms for BPAP-exposed females.<br/><br/>Marble burying test: Increased repetitive behaviors in BPAP-exposed males and females.<br/><br/>Novel object recognition: Reduced time spent in exploration of the novel object in BPAP-exposed males and females.<br/><br/>Three chamber test: Reduced sociability and social novelty for BPAP-exposed males and females.</td><td rowspan="10">Hematoxylin/eosin and Nissl staining<br/>The number of surviving cells was reduced in the dentate gyrus (DG) and CA1 area of BPAP-exposed males and females.<br/><br/>Omic analyses<br/>RNAseq analysis in BPAP-exposed males: 501 differentially expressed genes (168 downregulated and 333 up-regulated), with an enrichment in pathways related to behavior, synaptic signaling, neuronal development, and migration.<br/><br/>Single nucleus RNA-seq of the hippocampus<br/>Among the cell types identified (neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells), the proportion of differentially expressed genes was as follows:<br/>astrocyte &gt; microglia &gt; neurons and OPC &gt; oligodendrocytes. In gene set enrichment analysis, the identified pathways were related to Parkinson and neurodegeneration pathways in all cell clusters. The expression of microglial (C1qc, Ctss, and Iba1) and inflammatory (Tnfa, Cxcl10, Cxcl11, Il10, etc.) markers was up-regulated, while gene expression of development associated genes (Il1rapl1, Sgk3, Ncam2, Kirrel, and Fkbp5) was down-regulated in BPAP-exposed animals.<br/><br/>Immunohistochemistry<br/>Increased Iba1-immunoreactivity in the hippocampus of BPAP-exposed animals.<br/><br/>General and reproductive parameters<br/>Unchanged maternal, pregnancy duration, litter size, and sex ratio.<br/><br/>Reduced body weight of dams and male and female offspring exposed to the highest TBBPA dose.<br/><br/>Increased T4 levels in offspring of both sexes and reduced T3 levels in females.</td><td rowspan="10">Wu X et al. (2023)</td></tr><tr><td rowspan="9">Wistar rats<br/>Males and<br/>females</td><td rowspan="9">Premating<br/>exposure 10<br/>wks for<br/>fathers, 2<br/>wks for<br/>mothers.<br/>Then<br/>throughout<br/>gestation/<br/>lactation.<br/>Weaning at<br/>PND21</td><td rowspan="9">Oral</td><td rowspan="9">TBBPA: 37.5,<br/>125, 375,<br/>1250, 3750,<br/>12,500, or<br/>37,500 mg/<br/>kg diet,<br/>equivalent<br/>to 3, 10, 30,<br/>100, 300,<br/>1000, and<br/>3000 mg/<br/>kg bw</td><td rowspan="9">Analyses at PND50-110:<br/>Auditory response: Evaluation of brainstem auditory evoked potentials (BAEPs).<br/>In TBBPA-exposed females, BAEP thresholds and wave IV latency were increased in the low frequency range. In male rats, thresholds were unaffected, but absolute latency of wave IV and interpeak latencies II-IV showed exposure-related increases at low frequencies.<br/>Context and cue conditioned fear: No statistically significant effects were found.<br/><br/>Analyses at PND90-140:<br/>Sweet preference: No statistically significant effects were observed on saccharin intake.</td><td rowspan="9">Lilienthal et al. (2008)</td></tr><tr><td rowspan="8">Analyses at PND50-110:<br/>Auditory response: Evaluation of brainstem auditory evoked potentials (BAEPs).<br/>In TBBPA-exposed females, BAEP thresholds and wave IV latency were increased in the low frequency range. In male rats, thresholds were unaffected, but absolute latency of wave IV and interpeak latencies II-IV showed exposure-related increases at low frequencies.<br/>Context and cue conditioned fear: No statistically significant effects were found.</td></tr><tr><td rowspan="7">Analyses at PND90-140:<br/>Sweet preference: No statistically significant effects were observed on saccharin intake.</td></tr><tr><td rowspan="6">Analyses at PND50</td></tr><tr><td rowspan="5">Analyses at PND21</td></tr><tr><td rowspan="4">Analyses at PND90-140:</td></tr><tr><td rowspan="3">Analyses at PND90-140:</td></tr><tr><td rowspan="2">Analyses at PND90-140:</td></tr><tr><td rowspan="1">Analyses at PND90-140:</td></tr></tbody></table>

(continued)

<figure><img src="image_64.png" /></figure>
<figure><img src="image_65.png" /><figcaption>Table A4. Continued.</figcaption></figure>

<table><thead><tr><th>Exposure period</th><th>Species/sex</th><th>Exposure duration</th><th>Exposure route</th><th>Substances/ doses</th><th>Age at analyses</th><th>Behavioral analyses</th><th>Neuroanatomical, endocrine, and molecular analyses</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="2">Sprague- Dawley rats</td><td rowspan="2">GD0 to GD19</td><td rowspan="2">GD10 to PND20 (weaning at PND21)</td><td rowspan="2">Oral (diet)</td><td rowspan="2">TBBPA: 100, 1000, or 10,000 ppm</td><td rowspan="2">PND20<br>PND77</td><td rowspan="2">P and F1: TH levels<br>F2:</td><td rowspan="2">neurobehavior and brain histology</td><td>Increased cell count for Reelin-expressing interneurons in the hilus at the two highest doses at PND20.<br>Increased cell count for NeuN-expressing interneurons in the hilus at the two highest doses at PND77.<br>Unchanged GAD-67 immunoreactivity at PND20 or PND77, immunoreactivity of EphA5 (tyrosine kinase receptor involved in neurogenesis, neuronal migration, and plasticity) and Tac3 (role in survival and function of dopaminergic neurons) at PND20.<br>No effect on brain weight and thyroid hormone levels.<br>No detectable effects were found for the following assessment.<br><i>Neurofunctional or neurobehavioral deficits.</i><br>F1 generation: Neurological evaluation (lacrimation, salivation, urination and defecation frequencies, piloerection, pupillary light and reflexes, presence or absence of convulsions, abnormal movement and stereotypes, abnormal secretions, posture, muscle tone, forelimb and hind limb grip strength, etc.<br>F2 generation: Functional observation battery</td><td>Saegusa et al. (2012)</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td>Thinning of the brain parietal cortex in F2 animals at PND 11 at the maternal oral dose of 1000 mg/kg/ d.<br>Increased T3/T4 ratio in females of P generation at 1000 mg/kg, and males and females of F1 generation at 100 and 1000 mg/ kg. No effects on plasmatic TSH.<br>No effects on body weight or pubertal timing.</td></tr><tr><td rowspan="2">Wistar rat<br>Males and females</td><td rowspan="2">Exp1: GD9 to PND21<br>Exp2: GD6 to PND21 then offspring dosed until PND90</td><td rowspan="2">Oral</td><td rowspan="2">TBBPA: 0.1 mg/ kg bw/d<br>Exp2: 0.1, 25, and 250 mg/ kg bw/d</td><td rowspan="2">Adulthood</td><td rowspan="2">TBBPA: 0.2 mg/ kg bw/d</td><td rowspan="2">PND21 to week 20</td><td rowspan="2">Experiment 1:<br>No effect in the dark light box or elevated plus maze for both sexes. Increased wheel activity of females exposed to TBBPA at 0.1 mg/kg/d.<br>Experiment 2:<br>Reduced time spent and number of entries and increased latency to enter in the central zone of the OFT for PND90 males exposed to 25 mg/kg/d.<br>Reduced number of entries in the open arms of the EPM for PND145 males exposed to 25 and 250 mg/kg/d.<br><i>Open field test (OFT) at PND21:</i> No effect on activity.<br><i>Sociability and social hierarchy at weeks 10-20:</i><br>The mean velocity was increased in the chamber of the stranger mouse.<br>Less time with the familiar and novel mice.<br>Reduced interest in social novelty.<br>Effects on body weight by other endocrine disruptors (BDE-47 and BPS) affected social rank of exposed animals.</td><td>Rock et al. (2019)</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>Kim B et al. (2015)</td></tr><tr><td>CD-1 male mice</td><td>GD8 to PND21</td><td>Oral</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="9">Intranasal</td><td>Liu QS et al. (2018)</td></tr></tbody></table>

(continued)
<table><caption>Table A4. Continued.</caption><thead><tr><th>Exposure period</th><th>Species/sex</th><th>Exposure duration</th><th>Exposure route</th><th>Substances/ doses</th><th>Age at analyses</th><th>Behavioral analyses</th><th>Neuroanatomical, endocrine, and molecular analyses</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="2">Sprague Dawley male rats</td><td>PND2 to PND23</td><td></td><td>TBBPA-bis(2-hydroxyethyl ether)</td><td>0.086 mg/kg</td><td>Just after exposure</td><td rowspan="2">Rotarod: Reduced latency to fall for the two doses at constant and acceleration speed modes.<br>Open field test: Lower total traveled distance, traveled distance in the center, moving velocity, number of entries in the central zone at both doses.</td><td rowspan="2">Microarray analysis of the cerebrum: Affected gene expression measured for the higher dose: 911 upregulated and 433 downregulated genes<br>Hematoxylin/eosin staining: lighter staining of the area under the cortex, demyelinated white matter, reduced neural cell number, pyknotic nuclei in TBBPA-086.</td><td rowspan="2">Viberg and Eriksson (2011)</td></tr><tr><td></td><td></td><td>0.86 mg/kg</td><td></td><td></td></tr><tr><td>NMRI male mice</td><td>A single oral dose at PND10</td><td>Oral (gavage)</td><td>TBBPA: 11.5 mg/kg bw</td><td>PND11 PND17</td><td></td><td></td><td>PND11: no effects of TBBPA on calcium/calmodulin-dependent protein kinase II (CamKII), synaptophysin and Tau protein levels in the hippocampus and cortex.<br>PND17: decreased binding sites of the nicotinic ligand cytisine in the frontal cortex.<br>TBBPA levels determined using LC/ESI-MS/MS system: High amounts of TBBPA, were detected in the striatum after treatment with 0.1 mg/kg or 5 mg/kg body weight TBBPA; nonspecific accumulation of TBBPA after treatment with 250 mg/kg bw.</td><td>Nakajima et al. (2009)</td></tr><tr><td rowspan="2">ddY male mice</td><td>PND21 Acute: 3 h before the behavioral tests</td><td>Oral</td><td>TBBPA: 0.1 mg/kg, 5 mg/kg, or 250 mg/kg bw</td><td>PND22 to PND28: MWM</td><td></td><td>Open-field test: increased horizontal movement activities at 5 mg/kg.<br>Contextual fear conditioning paradigm: more freezing behavior for mice treated with TBBPA (0.1 mg/kg or 5 mg/kg bw) than controls.<br>Y-maze test: TBBPA (0.1 mg/kg bw) increased the spontaneous alternation behavior.<br>Morris water maze: Trajectories shown but no quantification of the time spent in the target quadrant.<br>Novel object recognition: No effect.</td><td rowspan="2">Analyses in the hippocampus<br>Increased reactive oxygen species at the higher dose and reduced glutathione at both doses.<br>Increased Bax and reduced Bcl2 at the higher dose.<br>Reduced BDNF levels at both doses, reduced PSD-95 levels at the higher dose.<br>Increased acetylcholine esterase levels at the higher dose, reduced acetylcholine transferase levels at both doses.<br>Neurogenesis in the DG: TBBPA at 100 and 500 mg/kg reduced hippocampal neurogenesis by decreasing the survival and neuronal differentiation of newly generated cells without affecting proliferation of NPCs.<br>Increased GFAP and Iba-1 fluorescence at the two highest doses without neuronal death; reduced BDNF levels and p-CREB immune-density at 500 mg/kg.</td><td rowspan="2">Wang J and Dai (2022)</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td rowspan="2">Prepubertal/ pubertal</td><td>Kunming male mice</td><td>28 days: PND21 to PND49</td><td>Oral</td><td>TBBPA: 50 and 100 mg/kg bw/d</td><td>PND22 to PND28: MWM</td><td></td><td>Passive avoidance test: TBBPA at 100 and 500 mg/kg reduced memory retention.</td><td>Kim AH et al. (2017)</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>C57BL/6 male mice</td><td>2 weeks from PND42 to PND56</td><td>Oral</td><td>TBBPA: 20, 100, or 500 mg/kg</td><td>PND56: behavioral tests<br>PND65: sacrifice</td><td></td><td></td><td></td><td></td></tr></tbody></table>

Bax: Bcl-2-associated X; Bcl2: B-cell lymphoma 2; BDNF: brain-derived neurotrophic factor; bw: body weight; C1qc: complement C1q C chain; CREB: c-AMP response element-binding protein; Ctss: cathepsin S; Cxcl10: C-X-C motif chemokine ligand 10; Cxcl11: C-X-C motif chemokine ligand 11; FKbp5: FK506 binding protein 5; GFAP: glial fibrillary acidic protein; Iba1: ionized calcium-binding adapter molecule 1; Il10: interleukin 10; Il1rap1: interleukin 1 receptor accessory protein like 1; Kirrel: Kirre like nephrin family adhesion molecule 1; LC/ESI-MS/MS: liquid chromatography electrospray ionization tandem mass spectrometry; Ncam2: neural cell adhesion molecule 2; NeuN: neuronal nuclear protein; p-CREB: phospho-CREB; PND: postnatal day; RNA-seq: RNA sequencing; Sgk3: serum/glucocorticoid regulated kinase; T3: triiodothyronine; Tnfa: tumor necrosis factor α; wks: weeks.
<table><caption>**Table A5.** *In vitro* studies reporting the neural effects of BPA alternatives.</caption><thead><tr><th>Substances and doses</th><th>Cell types</th><th>Analyses</th><th>Reference</th></tr></thead><tbody><tr><td>BPA, BPS, BPF, BPE, BPB, BPZ, and BPAF<br>All substances at 1, 10, and 100 nM in 0.01% DMSO</td><td>(i) Human embryonic stem cells (hESCs)<br>(ii) hESC differentiated into neural epithelium<br>(iii) neuron-like cells differentiated from adherent Neuronal Stem Cells</td><td>Cytotoxicity severity was assessed for all targeted compounds based on the IC<sub>50</sub> calculation or estimation; BPAF was defined as the most cytotoxic chemical tested whereas BPF and BPS the less cytotoxic.<br>The results pointed out that BPA and its analogues did induce neurogenesis impairment (neural epithelium generation) at early stages of neurogenesis but did not exclude that the latter could interfere with a later stage of neurodevelopment.<br>Gene expression related to axon guidance process was not modified by the exposure of BPA and its analogues; normalized values of the total and maximum- neurite length were down-regulated by BPA in a dose dependent manner.<br>A significant reduction of total neurite length was noted for 4 out of the 6 BPA analogues tested (BPS, BPF, BPA, or BPAF) at 1 nM; while only 100 nM of BPB, BPZ, or BPE triggered a noticeable decrease in the total length of neurite.<br><i>Treatment for 24 h:</i><br>All bisphenols except BPPH increased ROS levels, since 1 nM (BPA, BPE) or 100 nM (BPC) or at 10 µM (BPG, BPAP, and BPP).<br>The protein levels of Bax, Bak1, and caspase-3 were increased by 100 nM except for BPP and BPPH. The apoptosis rate was also increased since 100 nM (BPA and BPC) or at 10 µM (BPE, BPG, BPP, and BPBP).<br>BPA, BPE, BPC, BPG, and BPAP at 10 µM and BPAP at 100 nM also significantly increased Ca<sup>2+</sup> levels at IMR-32 cells.<br><i>Treatment for 3 h:</i><br>BPA, BPE, BPC, BPAP, and BPP at 10 µM increased intracellular Ca<sup>2+</sup> levels in IMR-32 cells, suggesting an activation of GPER. This effect was attenuated by GPER antagonist (G15) treatment (except for BPP). The ROS levels induced by BPC and BPAP were also reduced by G15.<br>Molecular dynamics simulation suggests that BPA, BPE, BPC, and BPAP may activate GPER.<br>Toxicity induced in HE-OC1 auditory cell line.<br>Increased percentage of apoptotic cells at 18 h and 24 h in corto organ explants from postnatal day 2 rats.<br>A significant increase of LDH was observed in TBBPA-treated cells (10 and 20 µM) compared to the control cells; LC50 values were estimated at 7 µM.<br>The concentration levels of BPA of 5 and 15 µM did not induce CGC death. These results highlight that the cytotoxic effects observed in vitro seem to be related to the bromination of chemical tested.<br>At the dose of 5 µM, TBBPA triggered nuclear morphology alteration in CGC, chromatin condensation yielding and 63% of apoptotic cells.<br>TBBPA altered gene expression entailed in programmed neuronal death.<br>The authors observed an absence of programmed necrosis induction, an early suppression of autophagy and anti-apoptotic genes, followed by a late activation of apoptosis-associated genes.<br>TBBPA exposure induced, during the follow-up periods (3, 6, and 24 h), a gradual reduction in the % of living cells. The integrity of the plasma membrane was maintained, and a higher number of neurons with irregular shapes and shrinking nuclei was observed.<br>Levels of expression of SNAP-25 gene were reduced by 48 and 64% for VPA and Nag, respectively, and enhanced by 49% and 66% for TBBPA and THAL in comparison to controls.<br>The SNAP-25 protein levels in CGCs were reduced by 73% for VPA and</td><td>Liang X et al. (2020)<br><br>Wang L et al. (2023)<br><br>Park C et al. (2016)<br><br>Reistad et al. (2007)<br><br>Lenart et al. (2017)<br><br>Zieminska et al. (2016)</td></tr><tr><td>BPA, BPE, BPAP, BPP, BPC, BPG, BPBP, and BPPH<br>All substances at 1 nM, 100 nM, and 10 µM for 3 h or 24 h.</td><td>IMR-32 neuroblastoma cell line</td><td>-HEI-OC1 auditory cell line<br>Corti organ explants from postnatal day 2 rats<br>Primary cerebellar granule cells (CGC)<br>- Wistar rats</td><td></td></tr><tr><td>TBBPA<br>HEI-OC1 cells: 125 µg/mL of TBBPA for 6, 12,18, and 24 h<br>TBBPA<br>Doses: 2, 5, and 10 µM<br>BPA 10 and 15 µM 0.1% DMSO<br>24 h incubation</td><td>Primary cerebellar granule cells (CGC)<br>- Wistar rats</td><td>Primary cerebellar granule cells (CGC)<br>- Wistar rats</td><td></td></tr><tr><td>TBBPA<br>Doses: 10 and 25 µM for 30 min<br>Time points 3-, 6-, and 24-hour</td><td>Primary cerebellar granule cells (CGC)<br>- Wistar rats</td><td>Primary cerebellar granule cells (CGC)<br>- Wistar rats</td><td></td></tr><tr><td>TBBPA<br>Thimerosal (TH), silver nanoparticles (NaAg), valproic acid (VPA), and thalidomide (THAL)</td><td></td><td></td><td></td></tr></tbody></table>

(continued)

<figure><img src="image_66.png" /></figure>
<figure><img src="image_67.png" /><figcaption>Table A5. Continued.</figcaption></figure>

<table><thead><tr><th>Substances and doses</th><th>Cell types</th><th>Analyses</th><th>Reference</th></tr></thead><tbody><tr><td>Doses: TBBPA from 1 up to 100 µM, THAL and VPA from 0.01 up to 5 mM</td><td></td><td>69% for TH, and enhanced by 21% for Nag, 25% for THAL and by 79% for TBBPA in comparison to controls.</td><td></td></tr><tr><td>24 h exposure<br>TBBPA<br>Doses: 10 and 25 µM</td><td>Primary cerebellar granule cells (CGC)<br>– Wistar rats</td><td>Increase in intracellular concentration of zinc ions in primary CGC exposed to TBBPA. This increase was linked with an increase in its levels in the extracellular compartment and a decrease in the total cellular pool of zinc.<br>Alterations of in the mitochondrial membrane potential (ΔΨm) in CGC after TBBPA exposure. Decreased catalase activity after 30 min of incubation of CGC cultures with TBBPA.</td><td>Zieminska et al. (2017)</td></tr><tr><td>TBBPA<br>Doses: from 7.5 to 25 µM</td><td>Primary cerebellar granule cells (CGC)<br>– Wistar rats</td><td>CGC were depolarized by TBBPA exposure in primary culture and rat cerebellar slices.<br>TBBPA did not modify NMDA receptor radio-ligand binding to rat cortical membranes.<br>TBBPA induced glutamate release and depolarization mediated by AMPAR and NMDAR.</td><td>Diamandakis et al. (2019)</td></tr><tr><td>TBBPA, DBPE, and HBCDD<br>All substances: 0–30 µM for up to 12 h</td><td>SH-SYSY human neuroblastoma cells</td><td>The tested chemicals were found to be cytotoxic at low concentrations (2.7–28 µM depending on the compound). Intracellular levels of [Ca<sup>2+</sup>] and ROS were in these neuronal cells. The 3-targeted compounds induce cell death, at least in part by apoptosis via activation of caspases.<br>Rapid depolarization of mitochondria and cytochrome c release in these neuronal cells were induced by exposure to these BFRs. Cells exposed to HBCDD and TBBPA (1–5 µM), showed elevated levels of caspase 3/7 activity compared to control cells. Exposure to DBPE at 10 µM also showed an increase in caspase 3/7 activity.<br>HBCDD induces mitochondrial depolarization of cells within a few seconds of exposure. This was observed by a fast decrease in rhodamine123 fluorescence in the cells. The study showed that HBCDD triggered an increase in Aβ-42 levels in the extracellular compartment in a time- and dose-dependent manner. Significant levels of Aβ-42 peptide were therefore measured in cells exposed to HBCDD for only 4 h in comparison to controls.<br>Exposure to TBBPA and DBPE at levels of 3–10 µM for 12 h also showed a significant increase in Aβ-42 concentrations in treated cells versus the control cells.</td><td>Al-Mousa and Michelangeli (2012)</td></tr><tr><td>TCBPA, TBBPA, TBBPS, BDE-47, and BDE-209<br>BDE-209 doses: 10, 100, and 1000 nM<br>TBBPA, TCBPA, TBBPS, BDE-47, as well as mix of 5 compounds: 0.01, 0.1, 1, and 5 µM</td><td>Human embryonic stem cell (HESC)</td><td>Deregulation of transcription factors determinant for neuronal development like ZIC1, ZIC3, HES3, IGFBP3 as well as DLX5 by the five targeted chemicals.<br>All the 5 chemicals targeted dysregulated genes (e.g. CNTN2, SLIT1, LRRC4C, RELN, CBLN1, CHRN84, and GDF7) involved in axon growth/ guidance and neuron transmission-related processes.<br>AhR and WNT signaling pathways were impacted by all compounds. All five flame retardants significantly up-regulated CYP1A1 gene expression, suggesting that all of them could behave as agonists for the AhR signaling pathway.</td><td>Liang S et al. (2019)</td></tr><tr><td>TBBPA<br>Doses: 1 nM to 100 µM at 30 min, 3, 6, and 24 h</td><td>Primary hippocampal neuron – Swiss mouse embryos (day 17–18 of gestation).</td><td>Caspase-3 activation and apoptotic body formation were observed at concentration levels from 100 nM to 100 µM of TBBPA. TBBPA cytotoxic effects were highlighted at concentration levels between 50 nM and 100 µM.<br>TBBPA did not trigger changes in cellular ROS levels. Nevertheless, an enhancement of fluorescence signal was noted in a cell-free model following TBBPA exposure (10–100 µM).</td><td>Szychowski and Wojtowicz (2016)</td></tr></tbody></table>

(continued)
<figure><img src="image_68.png" /><figcaption>**Table A5. Continued.**</figcaption></figure>

<table><thead><tr><th>Substances and doses</th><th>Cell types</th><th>Analyses</th><th>Reference</th></tr></thead><tbody><tr><td>TBBPA, pentabromophenol (PBP), triphenyl phosphate (TPP)<br>All substances at 10 and 40 µM in 0.0004% DMSO</td><td>BV-2 cells</td><td>Pro-inflammatory responses were impacted in a limited way.<br>Mitochondrial respiration: (i) basal respiration was altered by PBP, (ii) ATP-related respiration was impacted by PBP and TBBPA, and (iii) maximal respiration by all 3 flame retardants.<br>Basal glycolytic rate was impaired by PBP and TBBPA and compensatory glycolysis was altered by all three compounds.<br>Phagocytosis was diminished by PBP and TBBPA.<br>Direct and secondary activation of the NLRP3 inflammasome by PBP, aggregate formation.</td><td>Bowen et al. (2020)</td></tr></tbody></table>

Ach: acetylcholine; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AhR: anyl hydrocarbon receptor; Bak1: BCL2 antagonist/killer 1; Bax: Bcl-2-associated X; BFR: brominated flame retardant; CGC: cerebellar granule cells; GPER: G protein-coupled estrogen receptor; HFR: halogenated flame retardant; hESCs: human embryonic stem cells; LOEC: the lowest observed effect concentration; NMDAR: N-methyl-D-aspartate receptor; ROS: reactive oxygen species.
<table><caption>**Table A6.** Summary of studies addressing the genotoxicity of the most commonly employed and data-rich BPA alternatives.</caption><thead><tr><th>Substance</th><th>Cell model</th><th>Assay</th><th>Exposure conditions</th><th>Effect</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="12">BPF</td><td rowspan="12">HepG2 cells</td><td>Comet assay</td><td>0.1, 1, and 10 µM, for 4 and 24 h</td><td>Positive at ≥1 µM, for 4 h treatment</td><td>Fic et al. (2013)</td></tr><tr><td>Micronucleus assay</td><td>0.625-10 µM, for 48, 72, and 96 h</td><td>No cytotoxicity at 12.5, 25, 50, and 100 µM, for 24 h</td><td></td></tr><tr><td>γH2AX</td><td>0.625-10 µM, for 48 h<br>2.5, 5, 10, 15, and 20 µg/mL for 24 and 72 h</td><td>Positive, for 72 and 96 h exposures<br>Positive - mixture of BPA/BPF/BPS/BPAF, for 48 h exposure<br>Positive<br>Negative</td><td>Yu M et al. (2023)<br>Yu M et al. (2023)<br>Hercog et al. (2019)</td></tr><tr><td>Hu-PBMC model</td><td>Comet assay<br>Comet assay<br>Comet assay<br>Fpg-modified comet assay</td><td>0.01-10 µg/mL<br>0.0001-1 µg/mL</td><td>Cytotoxicity at 20 µg/mL, for 72 h<br>Positive, after 1 h and 4 h exposure<br>Positive, after 4 h and 48 h exposure<br>Positive<br>Positive (oxidative DNA damage) versus standard Comet</td><td>Mokra et al. (2017)<br>Kose et al. (2020)</td></tr><tr><td>RWPE-1 cells</td><td></td><td></td><td></td><td></td></tr><tr><td>RAD54<sup>-/-</sup> mutant chicken<br>DT40 cells</td><td>γH2AX</td><td>125 µM, for 1 h</td><td>IC<sub>50</sub> = 65 µM<br>Negative</td><td>Lee S et al. (2013)</td></tr><tr><td>S. Typhimurium strains<br>TA98, TA100</td><td>Chromosomal aberration<br>Ames test</td><td>31.3, 62.5, and 125 µM, for 48 h<br>4, 20, 100, and 500 µg/plate ± S9</td><td>Positive at 62.5 µM<br>Negative</td><td>Fic et al. (2013)</td></tr><tr><td rowspan="12">BPAF</td><td rowspan="12">HepG2 cells</td><td>Comet assay</td><td>0.1, 1, and 10 µM, for 4 and 24 h</td><td>Positive at ≥1 µM, for 4 h<br>No cytotoxicity at 12.5, 25, 50, and 100 µM, for 24 h</td><td>Fic et al. (2013)</td></tr><tr><td>γH2AX</td><td>2.5, 5, 10, and 20 µg/mL, for 24 and 72 h</td><td>Negative<br>No cytotoxicity at 2.5, 5, 10, and 20 µg/mL, for 24 cytotoxicity at 20 µg/mL, for 72 h</td><td>Hercog et al. (2019)</td></tr><tr><td>HepG2 3D spheroids</td><td>Comet assay</td><td>0.01, 0.1, 1, 10, and 40 µM, for 24 h<br>0.01, 0.1, 1, and 10 µM, for 96 h</td><td>Positive<br>Positive</td><td>Sendra et al. (2023)</td></tr><tr><td>Hu-PBMC model</td><td>Comet assay</td><td>0.01, 0.1, 1, 10, and 40 µM, for 24 h<br>0.01, 0.1, 1, and 10 µM for 96 h</td><td>Negative<br>Positive</td><td>Mokra et al. (2017)<br>Positive<br>Negative</td></tr><tr><td>Hu-PBMC model</td><td>Comet assay</td><td>0.01-10 µg/mL, for 1 h and 4 h<br>1 and 10 µg/mL, for 1 h 0.1 and 1 µg/mL, for 4 h</td><td>Positive<br>Positive</td><td>Mokra et al. (2018)<br>Lee S et al. (2013)</td></tr><tr><td>RAD54<sup>-/-</sup> mutant chicken<br>DT40 cells</td><td>γH2AX</td><td>0.001-1 µg/mL, for 4 h and 48 h<br>50 µM, for 1 h</td><td>Negative<br>Negative</td><td>Fic et al. (2013)</td></tr><tr><td>S. Typhimurium strains<br>TA98, TA100</td><td>Chromosomal aberration<br>Ames test</td><td>12.5, 25, and 50 µM, for 48 h<br>4, 20, 100, and 500 µg/plate ± S9</td><td>Negative<br>Negative</td><td>Abdallah et al. (2023)<br>Increased reciprocal chromosomal exchanges, aneuploid oocytes and oxidative DNA damage in NMRI and OGG1KO mice (higher than WT).</td></tr><tr><td>Germ cells of NMRI mice<br>(wild-type) and OGG1-deficient C57/BI6 mice</td><td>Chromosomal exchanges and aneuploidy, 8-Oxoguanine level (IF)</td><td>10 µM in drinking water from 10.5 to 18.5 days postconception (dpc) (500 µg/kg/day)</td><td></td><td></td></tr><tr><td rowspan="3">BPS</td><td rowspan="3">HepG2 cells</td><td>Comet assay</td><td>0.1, 1, and 10 µM for 4 and 24 h</td><td>Positive at 1 µM and above/4 h treatment</td><td>Fic et al. (2013)</td></tr><tr><td>γH2AX</td><td>2.5, 5, 10, and 20 µg/mL, for 24 and 72 h</td><td>No cytotoxicity at 12.5, 25, 50, and 100 µM for 24 h<br>Negative<br>No cytotoxicity at 2.5, 5, 10, and 20 µg/mL, for 24 and 72 h</td><td>Hercog et al. (2019)</td></tr><tr><td></td><td></td><td></td><td></td></tr></tbody></table>

(continued)

<figure><img src="image_69.png" /></figure>
<table><caption>Table A6. Continued.</caption><thead><tr><th>Substance</th><th>Cell model</th><th>Assay</th><th>Exposure conditions</th><th>Effect</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="4">HepG2 3D spheroids</td><td rowspan="4">Comet assay</td><td>γH2AX<br>Micronucleus assay</td><td>Positive<br>Positive for 72 and 96 h exposure<br>Positive – mixture of BPA/BPF/BPS/BPAF, for 48 h exposure</td><td></td><td>Yu M et al. (2023)</td></tr><tr><td>Comet assay</td><td>Positive<br>Positive<br>Positive</td><td></td><td>Sendra et al. (2023)</td></tr><tr><td>γH2AX</td><td>Negative<br>Positive</td><td></td><td></td></tr><tr><td>Comet assay<br>γH2AX<br>DNA damage response (DDR)<br>activation (ATM, ATR, p53, Chk1, γH2AX)</td><td>Positive (but no quantitative data reported)<br>Positive (less than 4 foci/nucleus, not biologically relevant)<br>No DDR activation<br>Cytotoxicity – positive; dose-response relationship at 12.5, 25, 50, 100, and 200 μM for 24 h</td><td></td><td></td></tr><tr><td>BEAS-2B cells</td><td>Comet assay<br>γH2AX<br>DNA damage response (DDR)<br>activation (ATM, ATR, p53, Chk1, γH2AX)</td><td>200 μM, for 24 h<br>200 μM for 24 h<br>200 μM, for 24 h</td><td>Increased level of intracellular ROS (DCF assay), at 200 μM for 24 h<br>Positive after 1 h and 4 h exposure<br>Positive, after 4 h exposure</td><td></td><td>George and Rupasinghe (2018)</td></tr><tr><td>Hu-PBMC model</td><td>Comet assay – neutral version</td><td>0.01–10 μg/mL<br>10 μg/mL</td><td>Positive after 1 h and 4 h exposure</td><td></td><td>Mokra et al. (2017)</td></tr><tr><td>Hu-PBMC model<br>RWPE-1 cells</td><td>Comet assay<br>Comet assay<br>Fpg-modified comet assay</td><td>0.0001–1 μg/mL<br>0.50, 100, 200, 300, and 600 μM, for 24 h</td><td>Positive after 4 h and 48 h exposure<br>Positive (oxidative DNA damage)<br>IC<sub>50</sub> = 108 μM<br>Positive</td><td></td><td>Mokra et al. (2018)<br>Kose et al. (2020)</td></tr><tr><td>RAD54<sup>γ</sup>-mutant chicken<br>DT40 cells</td><td>γH2AX</td><td>125 μM for 1 h</td><td>Positive at 125 μM</td><td></td><td>Lee S et al. (2013)</td></tr><tr><td>S. Typhimurium strains<br>TA98, TA100</td><td>Ames test</td><td>Chromosomal aberration</td><td>62.5, 125, and 250 μM<br>for 48 h<br>4, 20, 100, and 500 μg/ plate ± S9</td><td>Negative</td><td>Fic et al. (2013)</td></tr></tbody></table>

BEAS-2B cells: human lung-derived epithelial cell line; BPAF: bisphenol AF; BPAR: bisphenol AP; BPF: bisphenol F; BPS: bisphenol S; Fpg: formamidopyrimidine DNA-glycosylase; γH2AX: histone family member X; HepG2 cells: human hepatoma-derived cell line; Hu-PBMC: humanized peripheral blood mononuclear cell model; IC: inhibitory concentration; OGG1: 8-oxoguanine glycosylase; RAD54<sup>γ</sup>-mutant: defective in RAD54 gene; RPWE-1 cells: human prostate-derived epithelial cell line; S. typhimurium: *Salmonella typhimurium*.

<figure><img src="image_70.png" /></figure>