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Next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays

In next generation risk assessment (NGRA), the Dietary Comparator Ratio (DCR) can be used to assess the safety of chemical exposures to humans in a 3R compliant approach. The DCR compares the Exposure Activity Ratio (EAR) for exposure to a compound of interest (EAR(test)) to the EAR for an establish...

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Autores principales: van Tongeren, Tessa C. A., Wang, Si, Carmichael, Paul L., Rietjens, Ivonne M. C. M., Li, Hequn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10182946/
https://www.ncbi.nlm.nih.gov/pubmed/37087486
http://dx.doi.org/10.1007/s00204-023-03480-w
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author van Tongeren, Tessa C. A.
Wang, Si
Carmichael, Paul L.
Rietjens, Ivonne M. C. M.
Li, Hequn
author_facet van Tongeren, Tessa C. A.
Wang, Si
Carmichael, Paul L.
Rietjens, Ivonne M. C. M.
Li, Hequn
author_sort van Tongeren, Tessa C. A.
collection PubMed
description In next generation risk assessment (NGRA), the Dietary Comparator Ratio (DCR) can be used to assess the safety of chemical exposures to humans in a 3R compliant approach. The DCR compares the Exposure Activity Ratio (EAR) for exposure to a compound of interest (EAR(test)) to the EAR for an established safe exposure level to a comparator compound (EAR(comparator)), acting by the same mode of action. It can be concluded that the exposure to a test compound is safe at a corresponding DCR ≤ 1. In this study, genistein (GEN) was selected as a comparator compound by comparison of reported safe internal exposures to GEN to its BMCL(05), as no effect level, the latter determined in the in vitro estrogenic MCF7/Bos proliferation, T47D ER-CALUX, and U2OS ERα-CALUX assay. The EAR(comparator) was defined using the BMCL(05) and EC(50) values from the 3 in vitro assays and subsequently used to calculate the DCRs for exposures to 14 test compounds, predicting the (absence of) estrogenicity. The predictions were evaluated by comparison to reported in vivo estrogenicity in humans for these exposures. The results obtained support in the DCR approach as an important animal-free new approach methodology (NAM) in NGRA and show how in vitro assays can be used to define DCR values. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-023-03480-w.
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spelling pubmed-101829462023-05-15 Next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays van Tongeren, Tessa C. A. Wang, Si Carmichael, Paul L. Rietjens, Ivonne M. C. M. Li, Hequn Arch Toxicol Regulatory Toxicology In next generation risk assessment (NGRA), the Dietary Comparator Ratio (DCR) can be used to assess the safety of chemical exposures to humans in a 3R compliant approach. The DCR compares the Exposure Activity Ratio (EAR) for exposure to a compound of interest (EAR(test)) to the EAR for an established safe exposure level to a comparator compound (EAR(comparator)), acting by the same mode of action. It can be concluded that the exposure to a test compound is safe at a corresponding DCR ≤ 1. In this study, genistein (GEN) was selected as a comparator compound by comparison of reported safe internal exposures to GEN to its BMCL(05), as no effect level, the latter determined in the in vitro estrogenic MCF7/Bos proliferation, T47D ER-CALUX, and U2OS ERα-CALUX assay. The EAR(comparator) was defined using the BMCL(05) and EC(50) values from the 3 in vitro assays and subsequently used to calculate the DCRs for exposures to 14 test compounds, predicting the (absence of) estrogenicity. The predictions were evaluated by comparison to reported in vivo estrogenicity in humans for these exposures. The results obtained support in the DCR approach as an important animal-free new approach methodology (NAM) in NGRA and show how in vitro assays can be used to define DCR values. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-023-03480-w. Springer Berlin Heidelberg 2023-04-22 2023 /pmc/articles/PMC10182946/ /pubmed/37087486 http://dx.doi.org/10.1007/s00204-023-03480-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Regulatory Toxicology
van Tongeren, Tessa C. A.
Wang, Si
Carmichael, Paul L.
Rietjens, Ivonne M. C. M.
Li, Hequn
Next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays
title Next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays
title_full Next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays
title_fullStr Next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays
title_full_unstemmed Next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays
title_short Next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays
title_sort next generation risk assessment of human exposure to estrogens using safe comparator compound values based on in vitro bioactivity assays
topic Regulatory Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10182946/
https://www.ncbi.nlm.nih.gov/pubmed/37087486
http://dx.doi.org/10.1007/s00204-023-03480-w
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